Dept of Anatomy

DEPT OF ANATOMY

Researcher : Cai Z

List of Research Outputs

Zhou Y., Bhatia I., Cai Z., He Q., Cheung P.T. and Chiu J., Proteomic analysis of neonatal mouse brain: evidence for hypoxia- and ischemia-induced dephosphorylation of collapsin response mediator proteins, J Proteome Research. 2008, 7: 2507.

Researcher : Chan HHL

List of Research Outputs

Li S.Y., Yau S.Y., Chen B., Tay D.K.C., Lee V.W.H., Pu M., Chan H.H.L. and So K.F., Enhanced Survival of Melanopsin-expressing Retinal Ganglion Cells After Injury is Associated with the PI3 K/Akt Pathway, Cellular and Molecular Neurobiology. 2008, 28: 1095-1107.

Researcher : Chan KC

List of Research Outputs

Ellis-Behnke R.G., Liang Y., Chan K.C., Tay D.K.C., So K.F. and Wu E.X., Assessing the progression of functional regeneration of the visual system, 6th Picower-RIKEN Symposium, M.I.T., Cambridge USA. 2007.

Researcher : Chan PK

List of Research Outputs

Chan P.K., Wai A., Philipsen S. and Tan-Un K.C., 5' HS₅ of the Human b-globin Locus Control Region is Dispensable for the Formation of the b-globin Active Chromatin Hub, PLoS One. 2008, 3 (5): e2134.

Researcher : Chan YF

List of Research Outputs

Chan Y.F., Tang F. and O W.S., Adrenomedullin in the Rat Testis. II: Its Production, Actions on Inhibin Secretion, Regulation by Follicle-Stimulating Hormone, and Its Interaction with Endothelin 1 in the, Sertoli Cell Biol Reprod . 2008, 78: 780-5.

Chan Y.F., O W.S. and Tang F., Adrenomedullin in the rat testis. I: Its production, actions on testosterone secretion, regulation by human chorionic conadotropin, and its interaction with endothelin 1 in the Leydig cell, Biology of Reproduction. 2008, 78: 773-779.

Chan Y.F., Tang F. and O W.S., Adrenomedullin in the rat testis. II: Its production, actions on inhibin secretion, regulation by follicle-stimulating hormone, and its interaction with endothelin 1 in the sertoli cell, Biology of Reproduction. 2008, 78: 780-785.

Chan Y.F., O W.S. and Tang F., Adrenomedullin in the rat testis. I: its production, actions on testosterone secretion, regulation by human chorionic gonadotropin, and its interaction with endothelin 1 in the, Leydig cell.Biol Reprod. 2008, 78: 773-9.

Researcher : Chan YF

List of Research Outputs

Researcher : Chang RCC

Project Title:	Microglai/macrophages and neuroprotection in glaucoma
Investigator(s):	Chang RCC
Department:	Anatomy
Source(s) of Funding:	American Health Assistance Foundation - National Glaucoma Research
Start Date:	04/2005

Abstract:

To prove or disapprove our hypothesis in a chronic neurodegenerative disease like glaucoma, we have set the following three specific aims for our study: (1) To investigate differential effects of conventional- or restricted-stimulation of microglia/ macrophages on RGC death in a chronic hypertension model of glaucoma induced by laser-photocoagulation. (2) To examine the expression of neurotrophic factors or pro-inflammatory factors from microglia/macrophages undergone conventional or restricted stimulation. (3) To study whether neuroprotective effects exhibited by Chinese herbal medicine Lycium barbarum (wolfberry) are mediated via restricted stimulation on microglia/ macrophages.

Project Title:	Elucidation of the functional roles of PKR in death receptor adaptors-mediated β-amyloid peptide neurotoxicity and in Alzheimer's disease
Investigator(s):	Chang RCC, So KF
Department:	Anatomy
Source(s) of Funding:	Competitive Earmarked Research Grants (CERG)
Start Date:	11/2005

Abstract:

To investigate how DR adaptor signaling modulates PKR in vitro so that inhibition of both pathways can maximize neuroprotection; to study the relationship of these two pathways and neuroprotection by inhibiting them in vivo; to examine the co-localization of accumulated phosphor-PKR and -DR adaptors in postmortem human AD brain tissues; to investigate whether activation of these two pathways can be found in plasma lymphocytes of AD patients.

Project Title:	Significant of double-stranded RNA-dependent protein kinase in neuronal death of Alzheimer's disease
Investigator(s):	Chang RCC
Department:	Anatomy
Source(s) of Funding:	France/Hong Kong Joint Research Scheme - Travel Grants
Start Date:	01/2006

Abstract:

To investigate how death receptor adaptor signaling modulates PKR in vitro so that inhibition of both pathways can maximize neuroprotection; to examine the co-localization of accumlated phosphor-PKR and -DR adaptors in postmortem human AD brain tissues; to investigate whether activation of these two pathways can be found in plasma lymphocytes of AD patients.

Project Title:	Molecular signaling of synaptic degeneration in Alzheimer's disease
Investigator(s):	Chang RCC
Department:	Anatomy
Source(s) of Funding:	Seed Funding Programme for Basic Research
Start Date:	02/2006

Abstract:

Key issues and problems being addressed: The current treatment for Alzheimer’s disease (AD) is to preserve the cellular levels of neurotransmitter for memory. However, this strategy cannot prevent the loss of neurons or even be implemented in patients at early state of disease such as mild cognitive impairment (MCI). Alternative strategy to safeguard neurons such as prevention of neuronal loss or even loss of neuronal communications should be further explored. Increasing lines of evidence have shown that failure of inter-neuronal communication via synapses may contribute to early memory loss and precede neuronal degeneration. Accumulation of cerebral β-amyloid (Aβ) peptide attenuates induction of long-term potentiation (LTP) which is essential in leaning and memory. Loss of synapses (synaptic degeneration) is a structural change observed in the failure of inter-neuronal communication and memory. Therefore, synaptic degeneration is a key issue in studying dementia and cognitive decline in AD. Although amyloid plaque is a pathological feature of AD, many reports have demonstrated that plaques may not be the primary causes of synaptic degeneration and cognitive decline. In an experimental model of transgenic mice over-expressing human amyloid precursor protein (hAPP) to increase cerebral Aβ levels, synaptic deficits can be detected well before plaque formation. All these results support our hypothesis that synaptic degeneration is an early event leading to the obstruction of axonal transport and in turn neuronal apotposis. Increasing lines of evidence have demonstrated that oligomeric form of Aβ peptide can bind to α7 nicotinic receptor (α7nAchR) resulting in synaptic degeneration in cholinergic and glutamatergic neurons. Instead of fibrillary form of Aβ peptide found in the plaques, oligomeric form of Aβ peptide primarily binds to synapses. While evidence of synaptic degeneration has been documented, little is known about the signaling mechanisms of synaptic degeneration leading to other modes of degeneration such as blockage of axonal transport, formation of autophagic vesicles and neuronal apoptosis. It should be noted that blockage of axonal transport and neuronal apoptosis have long been demonstrated by Aβ peptide neurotoxicity. Therefore, the problem being addressed in this proposal is to investigate the molecular mechanisms from synaptic degeneration leading to blockage of axonal transport and neuronal apoptosis. Goal and specific aims: The goal of this proposed study is to elucidate molecular signaling events linking synaptic degeneration, blockage of axonal transport, formation of autophagic vesicles, and neuronal apoptosis. We will focus our study in the degeneration of synaptic terminals because concrete evidence has been made from our preliminary study about the loss of synaptic density proteins. To achieve this goal, we have three specific aims in this proposed study. (1) To trace the temporal profile of synaptic degeneration, axonal blockage, formation of autophagic vesicles and neuronal apoptosis in live cultured hippocampal neurons exposed to oligomeric Aβ peptide by using molecular biology and 2-photon confocal imaging techniques. (2) To investigate signaling events associated with the loss of glutamate receptors such as NMDA and AMPA receptors, mGluR5 and their scaffold proteins leading to formation of autophagic vesicles and neuronal apoptosis by using immunoprecipitation and western-blot analysis. (3) To elucidate the signaling events of translational control in synaptic degeneration and neuronal apoptosis because translational control has been implicated to play significant roles in synaptic plasticity, autophagic neuronal death and neuronal apoptosis. All these three specific aims can be worked out independently, but the implication of the results are highly connected. The results of this study can shed light of how different modes of neurodegeneration orchestrate together attributing to progressive neurodegeneration in AD.

Project Title:	Elucidating the biological mechanisms of autophagy in Alzheimer's disease
Investigator(s):	Chang RCC, Chu LW
Department:	Anatomy
Source(s) of Funding:	Competitive Earmarked Research Grants (CERG)
Start Date:	01/2007

Abstract:

To investigate how DR adaptor signaling modulates PKR in vitro so that inhibition of both pathways can maximize neuroprotection; to study the relationship of these two pathways and neuroprotection by inhibiting them in vivo; to examine the co-localization of accumulated phospho-PKR and -DR adaptors in postmortem human AD brain tissues; to investigate whether activation these two pathways can be found in plasma lymphocytes of AD patients.

Project Title:	Investigating the molecular events leading to the collapse of endoplasmic reticulum in neurodegeneration of Alzheimer's disease
Investigator(s):	Chang RCC
Department:	Anatomy
Source(s) of Funding:	Seed Funding Programme for Basic Research
Start Date:	03/2007

Abstract:

The objective of this proposed study is to elucidate the biological mechanisms and molecular events leading to collapse of the endoplasmic reticulum (ER) by β-amyloid (Aβ) peptide neurotoxicity in Alzheimer's disease (AD). To address our objective, I have set the following three specific aims in this study:1. To investigate how and to what extent these three factors: (a) distortion of intracellular cytoskeleton; (b) activation of calpain; and (c) activation of protease leads to collapse of ER in Aβ-peptide neurotoxicity.2. To examine whether Rho-associated coiled-coil-containing protein kinase (ROCK) modulate cytoskeleton resulting in ER collapse in Aβ-peptide neurotoxicity.3. To test whether tau protein-phosphorylation kinases (glycogen synthase kinase 3β, GSK3β; cyclin-dependent protein kinase 5, CDK5) modulate cytoskeleton resulting in ER collapse in Aβ-peptide neurotoxicity. Degeneration of neurons is a long-term key issue in AD. Neurons can undergo neuronal apoptosis, autophagic death, synaptic degeneration and dysfunction of axonal transport in the pathological processes of AD. While these four modes of degenerative processes have long been studied, my laboratory has recently discovered a new mode of death process, namely collapse of ER (Lai et al., In preparation). Using live-cell imaging technology, cultured neurons exposed to Aβ peptide (the toxin in AD) displays collapse of ER shortly right after exposure. The collapsed ER gradually aggregates in the cell body and are digested by lysosomes. In addition, aggregated ER fragment triggers the formation of autophagosomes, initiating the processes of autophagy. In view of all these new findings, the urgent key issue is to investigate the molecular events and even signaling pathways leading to the collapse of ER in Aβ-peptide neurotoxicity. Collapse of ER may explain why extracellular Aβ peptide could not trigger ER-stress responses signaling. The ER-stress responses are potentially beneficial to neurons as they can stop the accumulation of mis-folded proteins in the ER. While Aβ peptide induces ER collapse and does not trigger ER-stress responses, similar responses cannot be observed in parkinsonism mimetics such as 6-hydroxydopamine and MPP+. Therefore, ER collapse may represent a new mode of death process uniquely found in Aβ peptide neurotoxicity of AD. The scientific merit of this proposed study is to elucidate the biological mechanisms of this novel mode of neurodegeneration. Since all the new discoveries are originated from this laboratory, the study has very high originality.

List of Research Outputs

Chang M.P., Chang R.C.C., Wang M. and So K.F., A review on the laboratory investigations and epidemiological studies of black tea, In: Chi-Tang Ho, James E. Simon, Fereidoon Shahidi and Yu Shao, ACS Symposium Series 987, Dietary Supplements. Washington, DC, American Chemical Society, 2008.

Chang R.C.C., Chairman for organizing International Workshop, International Workshop Hong Kong, Dementias: From Public Health to Therapeutics. 2008.

Chang R.C.C., Yik S.Y., Ho Y.S., Lai S.W. and So K.F., Direct neurotoxic effects of dsRNA: Implication of virus-induced neurodegeneration , Society for Neuroscience 2007. Program No. 605.23.

Chang R.C.C., Exploring Direct and Indirect Neuroprotective Targets for Neurodegenerative Diseases, Neurodegenerative Disease Group, R & D China, GlaxoSmithKline. 2008.

Chang R.C.C., International Society to Advance Alzheimer Research and Treatment Travel Fellowship, International Society to Advance Alzheimer Research and Treatment. 2008.

Chang R.C.C., Polysaccharides from medicinal herbs as potential drug lead in Alzheimer's disease, 10th International Hong Kong/Springfield Symposium on Advances Alzheimer Therapy. 2008.

Chang R.C.C., Yu M.S., Ho Y.S., Lai S.W., Chiu K. and So K.F., Polysaccharides from medicinal herbs as potential drug lead in Alzheimer's disease, Neurobiology of Aging . 2008, 29S: S4-S5.

Chang R.C.C., The Open Enzyme Inhibition Journal. 2008, 1.

Chang R.C.C. and So K.F., Use of anti-aging herbal medicine, Lycium barbarum, against aging-associated diseases. What do we know so far?, Cellular Molecular Neurobiology. 2008, 28: 643-652.

Chao J., Yu M.S., Ho Y.S., Wang M. and Chang R.C.C., Dietary oxyresveratrol attenuates neurotoxicity induced by 6-hydroxydopamine in SH-SY5Y cells, Federation of European Neurosciences Societies Abstracts. 2007, 4: Poster 184.15.

Chao J., Yu M.S., Ho Y.S., Wang M. and Chang R.C.C., Dietary oxyresveratrol prevents 6-hydroxydopamine-induced neurotoxicity in SH-SY5Y cells, Third International Symposium on Healthy Aging: Improving the Health of an Aging Population, March 1-2, 2008, Hong Kong. 2008, 51 P11.

Cheung Y.T., Yu M.S., Lai S.W., So K.F. and Chang R.C.C., Global protein translation control in beta-amyloid peptide induced neurotoxicity, Third International Symposium on Healthy Aging: Improving the Health of an Aging Population, March 1-2, 2008 Hong Kong. 2008, 49 P2.

Cheung Y.T., Yu M.S., Lai S.W., So K.F. and Chang R.C.C., Global protein translation control in beta-amyloid peptide neurotoxicity, Federation of European Neurosciences Societies Abstracts. 2007, 4: Poster 014.3.

Chiu K., Yeung S.C., Ho Y.S., Chan W., So K.F. and Chang R.C.C., Best Poster Award, Hong Kong Society of Immunology. 2008.

Chiu K., Chang R.C.C. and So K.F., Intravitreous injection for establishing ocular disease model , Journal of Visualized Experiments. 2007, 8.

Chiu K., Chang R.C.C. and So K.F., Laser induced chronic ocular hypertension model on SD rats, Journal of Visualized Experiments. 2007, 10.

Chiu K., Lau W.M., Lau H.T., So K.F. and Chang R.C.C., Micro-dissection of rat brain for RNA and protein extraction from specific brain region, Journal of Visualized Experiments. 2007, 7.

Chiu K., Yeung S.C., Ho Y.S., Chan W., So K.F. and Chang R.C.C., Neuroprotective effect of IL-10 on retinal ganglion cell survival in experimental glaucoma model, Hong Kong Society for Immunology 2008 Annual General Meeting and Scientific Meeting, April 19, 2008, Hong Kong.. 2008, 26.

Chiu K., Lau W.M., Yeung S.C., Chang R.C.C. and So K.F., Retrograde labeling of reinal ganglion cells by application of Fluoro-Gold on the surafce of superior colliculus, Journal of Visualized Experiments. 2008.

Ho Y.S., Yu M.S., Lai S.W., So K.F., Yuen W.H. and Chang R.C.C., Characterizing the neuroprotective effects of alkaline extract of Lycium barbarum on b-amyloid peptide neurotoxicity, Brain Research. 2007, 1158: 123-134.

Ho Y.S., Yu M.S., Lai S.W., So K.F., Yuen W.H. and Chang R.C.C., Lycium barbarum as a potential drug to attenuate neurodegeneration in Alzheimer's disease, 2007 TWGHs Eddie Wang Symposium on Integrated Chinese and Western Medicine. 2007, 197.

Ho Y.S., Yu M.S., Yik S.Y., Lai S.W., So K.F., Yuen W.H. and Chang R.C.C., Lycium barbarum protects neurons against neurodegeneration in Alzheimer's disease through multiple approaches, Third International Symposium on Healthy Aging: Improving the Health of an Aging Population, March 1-2, 2008, Hong Kong. 2008, 44 OP10.

Lai S.W., So K.F. and Chang R.C.C., Aggregation/collapse of endoplasmic reticulum prior activaton of programmed cell death, Society for Neuroscience 2007. Program No. 688.18.

Lai S.W., So K.F., Yuen W.H., So K.F., Zee S.S.Y. and Chang R.C.C., Antagonizing Beta-amyloid Peptide Neurotoxicity of the Anti-aging Fungus Ganoderma Lucidum, Brain Research . 2008, 1190: 215-224.

Lai S.W., Preisler J., Yu M.S., Lee D.H.S. and Chang R.C.C., Mechanism of b-amyloid-dependent neurotoxicity in primary hippocampal neurons: evidence for induction of endoplasmic reticulum aggregation, Alzheimer's Disease Keystone Symposia, March 24-29, Colorado, U. S. A.. 2008, 55 Poster 117.

So K.F. and Chang R.C.C., Molecular mechanism of neuroprotection in glaucoma and Alzheimer's disease using Gouqizi, HKU TCM Workshop, December 14, 2007. 24.

Suen K.C., Chan W.K. and Chang R.C.C., Research-based learning associated with an authentic topic can rpomote active learning in high school neuroscience lessons, Society for Neuroscience 2007.

Sze C.W., Song J., Chang R.C.C., Wong R.N.S., Tong Y. and Zhang Y., Research Advances on the Anti-aging Profile of Fructus lycii: an Ancient Chinese Herbal Medicine, Journal of Complementary and Integrative Medicine. 2008, Vol. 5: Iss. 1, Art. 8.

Yik S.Y., Yu M.S., Ho Y.S., Lai S.W., Cheung Y.T., So K.F. and Chang R.C.C., Significance of dsRNA-elicited neurotoxicity, neuroprotection of minocycline on viral induced neurodegeneration, Third International Symposium on Healthy Aging: Improving the Health of an Aging Population, March 1-2,2008, Hong Kong.. 2008, 52 P14.

Yu M.S., Lai S.W., Ho Y.S., Zee S.S.Y., So K.F., Yuen W.H. and Chang R.C.C., Characterization of the Effects of Anti-aging Medicine Fructus Lycii on b-amyloid Peptide Neurotoxicity , International Journal of Molecular Medicine . 2007, 20: 261-268.

Yu M.S., Lai S.W., Suen K.C., So K.F., Hugon J. and Chang R.C.C., Neuronal apoptosis induced by extracellular accumulation of beta-amyloid peptides is independent of unfolded protein responses, 7th IBRO World Congress of Neuroscience. 2007.

Yu M.S., So K.F., Fang J.N., Yuen W.H. and Chang R.C.C., Neuroprotective polysaccharides from Nerium indicum rescue cultured neurons from beta-amyloid peptides-induced apoptosis via different mechanisms, Society for Neuroscience 2007. Program No. 169.8.

Researcher : Chen B

List of Research Outputs

Li S.Y., Yau S.Y., Chen B., Tay D.K.C., Lee V.W.H., Pu M., Chan H.H.L. and So K.F., Enhanced Survival of Melanopsin-expressing Retinal Ganglion Cells After Injury is Associated with the PI3 K/Akt Pathway, Cellular and Molecular Neurobiology. 2008, 28: 1095-1107.

Researcher : Cheng ACO

List of Research Outputs

Cheng A.C.O., Lucas P.W., Yuen H.K.L., Lam D.S.C. and So K.F., Surgical anatomy of the Chinese orbit, Ophthalmic Plastic and Reconstructive Surgery. 2008, 24(2): 136-141.

Researcher : Cheung A

Project Title:	Telomere erosion and initiation of chromosomal instability in human cells undergoing immortalization
Investigator(s):	Cheung A, Tsao GSW, Guan XY
Department:	Anatomy
Source(s) of Funding:	Competitive Earmarked Research Grants (CERG)
Start Date:	09/2003

Abstract:

To obtain telomere length profiles for indivdual chromosomes and to characterize dynamic telomere shortening in pre-crisis cells; to determine if the chromosomes with shorter telomeres or faster telomere shortening are more frequently involved in the formation of chromosome aberrations during immortalization.

Project Title:	Centromeric instability in human cells undergoing immortalization
Investigator(s):	Cheung A, Tsao GSW
Department:	Anatomy
Source(s) of Funding:	Seed Funding Programme for Basic Research
Start Date:	03/2005

Abstract:

The main objectives of this project are to: 1) investigate whether centromeric instability (characterized by dynamic formation of centromeric rearrangements, breaks, deletions or iso-chromosomes) is a general phenomenon in human cells undergoing immortalization; 2) examine whether DNA damage signals are colocalized with centromeres, and whether centromeric instability is associated with up-regulation of proteins promoting G2-M-phase transition, which is the checkpoint asking whether all DNA has been replicated and errors corrected.

Project Title:	Role of Id-1 in esophageal carcinogenesis
Investigator(s):	Cheung A, Tsao GSW, Wong YC, Wang X
Department:	Anatomy
Source(s) of Funding:	Seed Funding Programme for Basic Research
Start Date:	01/2006

Abstract:

Gain and amplification of chromosome 20q is frequently observed in a wide variety of cancers, including esophageal cancer. This chromosomal region contains a number of candidiate oncogenes including AIB1, Id-1, MDM2, AURKA and ZNF217. The function and significance of these genes in esophageal carcinogenesis remains elusive. Our recent investigations on prostate and nasopharyngeal carcinomas have provided strong evidence to support an oncogenic role of Id-1gene in epithelial cancers. We hypothesize that Id-1 also functions as an oncogene in esophageal cancer and that its oncogenic effect may be regulated through different pathways. This project aims to investigate the role and mechanisms of action of Id-1 in esophageal carcinogenesis through ectopic expression and silencing of the gene in esophageal cancer cell lines, as well as normal esophageal cells. The objectives of this proposal are:1. To study the direct effects of Id-1 on esophageal cancer cell proliferation and survival.Overexpression of Id-1 in primary esophageal squamous cell carcinoma (ESCC) tumors and in two ESCC cell lines was previously reported [Hu et al. 2001], but its significance and functional roles in ESCC remain unclear. Growth promotion and suppression of apoptosis are possible functions of Id-1 in esophageal cancer. Through ectopic expression of Id-1 in ESCC cell lines with low/undetectable Id-1 expression under serum free conditions, the direct effects of Id-1 on tumor cell growth, cell cycle progression, and cell viability can be studied. 2. To dissect the signaling pathways that mediate the function of Id-1 in ESCC cell proliferation and survival.The Id (inhibition of differentiation and inhibition of DNA binding) family of proteins are helix-loop-helix (HLH) proteins that form non-functional heterodimers with basic HLH transcription factors and prevent them from binding to DNA, thus inhibiting the transcription of genes associated with cell differentiation [Benezra et al. 1990]. Recent studies indicate that Id-1 protein also affects multiple pathways associated with cell proliferation and apoptosis. In prostate cancer, for example, Id-1 induced cell proliferation is associated with down-regulation of p16INK4A expression and increased phosphorylation of RB, as well as activation of MAPK pathway. Id-1 expression also protects prostate cancer cells against apoptosis through activation of NF-κB (nuclear factor-kappa B) signaling pathway [reviewed in Wong et al. 2004]. Although both esophageal and prostate carcinomas are of epithelial origin, they differ in etiology and in mechanisms of carcinogenesis. Genetic alterations such as cyclin D1 amplification, p53 mutation and loss of p16INK4A which are very common in ESCC are rarely detected in primary prostate tumors. It is possible that the downstream pathways of Id-1 in ESCC may differ from that of prostate cancer. Our preliminary data suggested that Id-1 increased cell proliferation in ESCC cells through up-regulation of MDM2 and/or down-regulation of p21WAF1. This objective aims to confirm this observation, and to explore other mechanisms and signaling pathways that may be associated with Id-1 function in ESCC.3. To investigate the role of Id-1 in lifespan extension and immortalization of human esophageal epithelial cells.Overcoming replicative senescence and achieving cellular mmortalization are prerequisite steps in malignant transformation. Although ectopic overexpression of Id-1 alone does not seem able to achieve immortalization in human cells, it had been shown to delay senesence and even immortalize human keratinocytes through activation of telomerase [Alani et al. 1999; Nickoloff et al. 2000]. We hypothesize that expression of Id-1 may be upregulated during immortalization of esophageal epithelial cells, and that forced expression of Id-1 in primary esophageal epithelial cells may help promote immortalization. This objective therefore helps determine if Id-1 may play a role in initiating esophageal tumorigenesis. References:Alani RM, Hasskarl J, Grace M, Hernandez MC, Israel MA, Munger K (1999) Proc Natl Acad Sci USA 96:9637-9641.Benezra R, Davis RL, Lockshon D, Turner DL, Weintraub H (1990). Cell 61:49-59.Nickoloff BJ, Chaturvedi V, Bacon P, Qin JZ, Denning MF, et al. (2000). J Biol Chem 275:27501-27504.Hu YC, Lam KY, Law S, Wong J, Srivastava G (2001). Clin Cancer Res 7:2213-2221.Wong YC, Wang X, Ling MT (2004). Apoptosis 9:279-289.

Project Title:	Id-1 protects esophageal cancer cells from apoptosis through activation of PI3K-Akt and NFκB signaling pathways
Investigator(s):	Cheung A
Department:	Anatomy
Source(s) of Funding:	Small Project Funding
Start Date:	11/2006

Abstract:

Id-1 (inhibitor of differentiation or inhibition of DNA binding) is a helix-loop-helix (HLH) protein which lacks the basic domain for DNA binding and thus functions as a dominant inhibitor of the basic HLH transcription factors by forming heterodimers, thus inhibiting gene expression [Benezra et al. 1990]. Up-regulation of Id-1 has been found in many types of human cancer including esophageal squamous cell carcinoma (ESCC) [Hu et al. 2001]. In our recent paper, we reported that ectopic expression of Id-1 stimulates esophageal cancer cell proliferation by activation of MDM2 and suppression of p21 [Hui et al. 2006], rather than activation of p16/Rb pathway as in prostate and hepatocellular cancer cells. Our findings suggest that the oncogenic function of Id-1 in esophageal cancer may preferentially involve signaling pathways different from that in other cancers. In addition to increasing cell proliferation, Id-1 is also known to protect cancer cells against apoptosis [Hui et al. 2006; Ling et al. 2003] but the detailed mechanisms are still unclear. In this study, we aim to study the anti-apoptotic mechanisms of Id-1 in esophageal cancer. We hypothesize that the Id-1 protects esophageal cancer cells from apoptosis through activation of NFκB activity, and that this effect may be mediated via the PI3K-Akt signaling pathway.The objectives are:1. To determine if Id-1 protects esophageal cancer cells from apoptosis through activation of NFκB signaling pathway. Rationale: TNF-α is a cytokine that induces apoptosis in a host of cells. We previously reported that Id-1 protects esophageal cancer cells from TNF-α induced apoptosis but had not investigated the detailed mechanisms underlying this phenomenon [Hui et al. 2006]. In prostate cancer cells, one of the downstream mechanisms implicated is the nuclear factor kappa B (NFκB) pathway [Ling et al. 2003], but whether the same holds for esophageal cancer and exactly how Id-1 activates the NFκB signaling remain to be elucidated. We have generated stable Id-1 expressing clones, as well as empty vector control clones, from an esophageal squamous cell carcinoma cell line (HKESC-3) that expresses very low level of Id-1 protein under serum-free condition. By treating these clones with TNF-α and comparing the expression levels of apoptosis marker proteins (caspase-2 and PARP) between Id-1 expressing clones and vector control, we can determine the direct effects of Id-1 on TNF-α induced apoptosis in esophageal cancer cells. At the same time, the NFκB-DNA binding activity and nuclear expression of NFκB subunits p65 and p50 in the transfectant clones can also be determined. This objective therefore serves to establish a correlation between apoptosis and NFκB activation in esophageal cancer cells.2. To examine if the effect of Id-1 on NFκB activity and apoptosis is associated with the PI3K-Akt signaling pathway.Rationale: The phosphatidylinositol-3-kinase (PI3K) and Akt (Protein Kinase B) signaling pathway regulates a wide spectrum of cellular functions. PI3 kinases are ubiquitously expressed and respond to activation of a large number of plasma membrane receptors. Once activated, PI3K triggers a cascade of events including activation of its main effector Akt, which serves as a key regulator of cellular functions such as proliferation and survival [Paez & Seller 2002]. Although the PI3K-Akt pathway is known to be a key cytoprotective response upstream of NFκB [Kane et al. 1999], its relationship with Id-1 has not been reported. This objective aims to determine whether ectopic Id-1 expression can activate Akt, and whether inhibition of PI3 kinase can abolish the effects of Id-1 on Akt and NFκB. Together with the results obtained in Objective 1, we shall be able to test our hypothesis that Id-1 protects esophageal cancer cells from apoptosis through activation of NFκB activity, and that this effect may be mediated via the PI3 kinase/Akt signaling pathway. References: Benezra R, Davis RL, Lockshon D, Turner DL, Weintraub H (1990). Cell 61:49-59.Hu YC, Lam KY, Law S, Wong J, Srivastava G. (2001). Clin Cancer Res 7:2213-2221.Hui CM, Cheung PY, Ling MT, Tsao SW, Wang X, Wong YC, Cheung ALM (2006). Int J Cancer 119:508-514.Kane LP, Shapiro VS, Stokoe D, Weiss A (1999). Curr Biol 9:601-604.Ling MT, Wang X, Ouyang XS, Xu K, Tsao SW, Wong YC (2003). Oncogene 22:4498-4508.Paez JG and Sellers WR (2002). PI3/PTEN/ALT Pathway- A Critical Mediator of Ongoing Signaling. Ed. David Frank, 'Signal Transduction in Cancer' Kluwer Academic Publishers, Boston. pp 1-6.

Project Title:	Centromeric instability in human cells undergoing immortalization: implication for progression of chromosomal instability in carcinogenesis
Investigator(s):	Cheung A, Tsao GSW, Guan XY, Deng W
Department:	Anatomy
Source(s) of Funding:	Competitive Earmarked Research Grants (CERG)
Start Date:	01/2007

Abstract:

To investigate whether centromeric instability is a general phenomenon in human cells undergoing immortalization; to study the mechanisms underlying centromeric instability in human cells undergoing immortalization.

List of Research Outputs

Cheung A., Applied Immunohistochemistry & Molecular Morphology, Editorial Board. Lippincott Williams & Wilkins, 2008.

Cheung A., Deng W., Tsao G.S.W. and Guan X.Y., Centromeric instability in human cells undergoing immortalization., Proceedings of American Association for Cancer Research Annual Meeting; 2008 Apr 12-16; San Diego, CA. Abstract nr 4318. 2008, 4318.

Cheung A., Editorial Board, In: Clive R Taylor, Jiang Gu, Applied Immunohistochemistry & Molecular Morphology. Lippincott Williams & Wilkins, 2007.

Cheung A., Editorial Board, Applied Immunohistochemistry & Molecular Morphology. Lippincott Williams & Wilkins, 2008.

Cheung A., Journal Editor, The Open Pathology Journal. Bentham Open, 2008.

Cheung A. and Deng W., Telomere dysfunction, genome instability and cancer, Frontiers in Bioscience. 2008, 13: 2075-2090.

Cheung P.Y., Deng W., Tsao G.S.W. and Cheung A., Role of cyclin D1 in conferring malignant phenotypes on immortalized esophageal epithelial cells., Proceedings of the American Association for Cancer Research Annual Meeting, San Diego, U. S. A., April 12-16, 2008. Abstract 5581.. 2008, 5581.

Deng W., Tsao G.S.W., Guan X.Y. and Cheung A., Microtubule breakage is not a major mechanism for resolving end-to-end chromosome fusions generated by telomere dysfunction during the early process of immortalization, Chromosoma. 2007, 116: 557-568.

Fung K.L., Wong Y.C., Cheung A. and Wang X., MAD2 expression and its significance in mitotic checkpoint control in testicular germ cell tumour, AACR Centennial conference, LA, USA, April 14-18 2007. 2008, 1233.

Li B., Cheung P.Y., Wang X., Tsao G.S.W., Ling M.T., Wong Y.C. and Cheung A., Id-1 activation of PI3K/Akt/NFkB signaling pathway and its significance in promoting survival of esophageal cancer cells, Carcinogenesis. 2007, 28(11): 2313-2320.

Man C.W.Y., Rosa J., Yip Y.L., Cheung A., Kwong Y.L., Doxsey S.J. and Tsao G.S.W., Id1 overexpression induces tetraploidization and multiple abnormal mitotic phenotypes by modulating Aurora A , Molecular Biology Of The Cell. USA, The American Society for Cell Biology, 2008, 19: 2389-2401.

Tse W.W., Deng W., Tsao G.S.W. and Cheung A., Methylation status of tumor related genes during immortalization of human cervical epithelial cell lines. , Proceedings of American Association for Cancer Research Annual Meeting; 2008 Apr 12-16; San Diego, CA. Abstract nr 48.. 2008, 48.

Zhang X., Ling M.T., Wang Q., Lau C.K., Leung C.L., Lee T.K., Cheung A., Wong Y.C. and Wang X., Identification of a novel inhibitor of differentiation-1 (ID-1) binding partner, caveolin-1, and its role in epithelial-mesenchymal transition and resistance to apoptosis in prostate cancer cells, The Journal of Biological Chemistry. 2007, 282(46): 33284-33294.

Researcher : Cheung AKH

List of Research Outputs

Cheung A.K.H., Lo A.C.Y., So K.F., Chung S.S.M. and Chung S.K., Gene deletion and pharmacological inhibition of aldose reductase protect against retinal ischemic injury, Experimental Eye Research. 2007, 85: 608-616.

Researcher : Cheung ALM

Project Title:	Telomere erosion and initiation of chromosomal instability in human cells undergoing immortalization
Investigator(s):	Cheung A, Tsao GSW, Guan XY
Department:	Anatomy
Source(s) of Funding:	Competitive Earmarked Research Grants (CERG)
Start Date:	09/2003

Abstract:

Project Title:	Centromeric instability in human cells undergoing immortalization
Investigator(s):	Cheung A, Tsao GSW
Department:	Anatomy
Source(s) of Funding:	Seed Funding Programme for Basic Research
Start Date:	03/2005

Abstract:

Project Title:	Role of Id-1 in esophageal carcinogenesis
Investigator(s):	Cheung A, Tsao GSW, Wong YC, Wang X
Department:	Anatomy
Source(s) of Funding:	Seed Funding Programme for Basic Research
Start Date:	01/2006

Abstract:

Project Title:	Id-1 protects esophageal cancer cells from apoptosis through activation of PI3K-Akt and NFκB signaling pathways
Investigator(s):	Cheung A
Department:	Anatomy
Source(s) of Funding:	Small Project Funding
Start Date:	11/2006

Abstract:

Project Title:	Centromeric instability in human cells undergoing immortalization: implication for progression of chromosomal instability in carcinogenesis
Investigator(s):	Cheung A, Tsao GSW, Guan XY, Deng W
Department:	Anatomy
Source(s) of Funding:	Competitive Earmarked Research Grants (CERG)
Start Date:	01/2007

Abstract:

Researcher : Cheung HW

List of Research Outputs

To K.W., Cheung H.W., Ling M.T., Wong Y.C. and Wang X., MAD2ΔC induces aneuploidy and promotes anchorage-independent growth in human prostate epithelial cells. , Oncogene. 2008, 27: 347-357.

Wang X., Cheung H.W., Chun C.S., Jin D. and Wong Y.C., Mitotic checkpoint defects in human cancers and their implications to chemotherapy, Frontiers in Bioscience. 2008, 13: 2103-2114.

Researcher : Cheung HW

List of Research Outputs

To K.W., Cheung H.W., Ling M.T., Wong Y.C. and Wang X., MAD2ΔC induces aneuploidy and promotes anchorage-independent growth in human prostate epithelial cells. , Oncogene. 2008, 27: 347-357.

Wang X., Cheung H.W., Chun C.S., Jin D. and Wong Y.C., Mitotic checkpoint defects in human cancers and their implications to chemotherapy, Frontiers in Bioscience. 2008, 13: 2103-2114.

Researcher : Cheung KHA

List of Research Outputs

Cheung K.H.A., Genetic and pharmacological approaches to study the role of the polyol pathway enzymes in diabetic and ischemic retinopathy. 2007, 140 pages.

Researcher : Cheung PY

List of Research Outputs

Cheung P.Y., Deng W., Tsao G.S.W. and Cheung A., Role of cyclin D1 in conferring malignant phenotypes on immortalized esophageal epithelial cells., Proceedings of the American Association for Cancer Research Annual Meeting, San Diego, U. S. A., April 12-16, 2008. Abstract 5581.. 2008, 5581.

Li B., Cheung P.Y., Wang X., Tsao G.S.W., Ling M.T., Wong Y.C. and Cheung A., Id-1 activation of PI3K/Akt/NFkB signaling pathway and its significance in promoting survival of esophageal cancer cells, Carcinogenesis. 2007, 28(11): 2313-2320.

Researcher : Cheung SF

List of Research Outputs

Ellis-Behnke R.G., Liang Y., Cheung S.F., Tay D.K.C. and So K.F., Nano contrast enhancement agents used in the eye for tracing axons: Trauma or illlumination?, ARVO 2008 Annual Meeting, April 27-May 1, 2008, Florida, U. S. A.. 2008, No. 4014.

Researcher : Cheung YT

List of Research Outputs

Cheung Y.T., Yu M.S., Lai S.W., So K.F. and Chang R.C.C., Global protein translation control in beta-amyloid peptide induced neurotoxicity, Third International Symposium on Healthy Aging: Improving the Health of an Aging Population, March 1-2, 2008 Hong Kong. 2008, 49 P2.

Cheung Y.T., Yu M.S., Lai S.W., So K.F. and Chang R.C.C., Global protein translation control in beta-amyloid peptide neurotoxicity, Federation of European Neurosciences Societies Abstracts. 2007, 4: Poster 014.3.

Yik S.Y., Yu M.S., Ho Y.S., Lai S.W., Cheung Y.T., So K.F. and Chang R.C.C., Significance of dsRNA-elicited neurotoxicity, neuroprotection of minocycline on viral induced neurodegeneration, Third International Symposium on Healthy Aging: Improving the Health of an Aging Population, March 1-2,2008, Hong Kong.. 2008, 52 P14.

Researcher : Ching YP

Project Title:	Roles and regulation of group II p21-activated protein kinases:-implications in cancer metastasis
Investigator(s):	Ching YP, Jin D, Ng IOL
Department:	Pathology
Source(s) of Funding:	Competitive Earmarked Research Grants (CERG)
Start Date:	01/2005

Abstract:

To study: (1) Characterisation of the interaction between Pak5 and NM23 i) co-immunoprecipitation of Pak5 adn NM23 ii) defining the binding domain between Pak 5 and NM23 iii) xploring the interaction between Pak4 adn NM23. (2) Impact of Pak5-NM23 interaction in the biochemical properties of Pak5 and NM23 i) nucleotide diphosphate kinase activity ii) GTPase activating activity iii) in vitro kinase activity iv) subcellular localisation. 3) Roles of PakII in cancer metastasis using HCC as a model i) expression profile of Pak4 in HCC ii) clinicopathological analysis iii) cell invasion assay.

Project Title:	Roles of p21-activated protein kinase (Pak) 1 in the pathogenesis of liver cancer
Investigator(s):	Ching YP
Department:	Pathology
Source(s) of Funding:	Seed Funding Programme for Basic Research
Start Date:	07/2005

Abstract:

To characterize the overexpression of Pak1 protein and its activities in human HCC; to delineate the signaling pathways mediated by Pak1 in HCC; to investigate the roles of Pak1 in the metastasis of HCC.

Project Title:	Roles of p21-activated protein kinase (Pak) 1 in the pathogenesis of liver cancer
Investigator(s):	Ching YP, Ng IOL, Jin D, Yau TO
Department:	Pathology
Source(s) of Funding:	Competitive Earmarked Research Grants (CERG)
Start Date:	01/2006

Abstract:

(1) To characterize the mechanisms leading to Pak1 overexpression in human HCC; (2) to delineate the roles of Pak1 in hepatocarcinogenesis: (i) Phosphorylation of possible downstream targets of Pak1 in human HCCs. (ii) characterization of the tumorigenic activity of Pak1 in HCC cells. (iii) characterization of the anti-apoptotic activity of Pak1 in HCC cells. (3) to investigate the role of Pak1 in cancer metastasis: >(i) regulation of cell motility and cell adhesion by Pak1 in HCC cells. (ii) HGF/Rac1/Cdc42/Pak1 signaling in HCC metastasis. (iii) HGF/Pak1 mediated angiogenic activity. (iii) HGF/Pak1 mediated angiogenic activity.</I

Project Title:	Functional characterization of a putative tumour suppressor, AMP-activated protein kinase, in liver cancer
Investigator(s):	Ching YP
Department:	Pathology
Source(s) of Funding:	Seed Funding Programme for Basic Research
Start Date:	02/2006

Abstract:

Purpose of study Liver cancer (hepatocellular carcinoma, HCC) is one of the most common cancers in the world, especially in Asia and Africa, and is the third most common fatal cancer in Hong Kong. While the risk factors are well defined, the underlying molecular mechanisms of HCC are still far from clear. Since the development of HCC is a multistep process, our long-standing interest is to identify tumour suppressor genes that play important roles in hepatocarcinogenesis. In our search, we have found that a hepatic kinase called AMP-activated protein kinase (AMPK), a key regulator for lipid and glucose metabolism in response to energy stress, is frequently downregulated in HCC cell lines and clinical samples (42%). Interestingly, recent discoveries have shown that tumour suppressors LKB1 and TSC2 lie upstream and downstream of AMPK, respectively, indicating that AMPK may be important in the regulation of cell growth, proliferation and apoptosis. Our pilot studies have also demonstrated that ectopic expression of the AMPK catalytic subunit in HepG2 cells significantly suppresses cell growth in colony formation assay. Conversely, HCC cell line with stable knockdown of AMPK catalystic subunit expression displays a much higher proliferation rate than that of the parental cell line (see research plan). These results suggest that AMPK possesses an activity to inhibit HCC cell growth. Here we propose to fully document the expression of AMPK and its effectors in HCC. We will explore the molecular basis of the underexpression of AMPK catalytic subunit in human HCC. We will also confirm the tumour suppressor activity of AMPK and delineate the molecular mechanisms by which loss of AMPK contributes to the formation of HCC. Findings derived from our work should shed important light on the pathogenesis of HCC and may provide novel targets for therapeutic intervention. Key issue and problem being address So far, the overall prognosis of HCC is unsatisfactory due to high incidence of recurrence and metastasis. It is therefore a high priority to unravel the molecular mechanisms underlying the pathogenesis of HCC so that better treatment modalities can be designed. In previous reports and our preliminary study, activation of AMPK has been demonstrated to play a role in suppressing the growth of cancer cells. These results prompt us to further address the pathogenic role of AMPK in HCC and to determine how dysregulation of AMPK leads to hepatocarcinogenesis. In this study, we will define the tumour suppressive function of AMPK in HCC and the regulatory roles of AMPK in cell signalling. Since AMPK is an important physiological regulator of cellular metabolism in response to nutrient stress and energy supply, our proposed study should advance our understanding on whether perturbation of energy metabolism can possibly linked to carcinogenesis. Results obtained in this study will derive novel insight on how the loss of AMPK function leads to the formation of cancer, aiming to provide opportunity for new molecular drug targets.

Project Title:	Molecular neurobiology: Regulation of p21-activated protein kinase 5 in neurodegenerative disease
Investigator(s):	Ching YP
Department:	Anatomy
Source(s) of Funding:	Matching Fund for NSFC Young Researcher Award
Start Date:	01/2007
Completion Date:	12/2009

Abstract:

To study molecular neurobiology: regulation of p21-activated protein kinase 5 in neurodegenerative disease.

Project Title:	Functional characterisation of a putative tumor suppressor gene, TAX1BP2, in liver cancer
Investigator(s):	Ching YP
Department:	Pathology
Source(s) of Funding:	Seed Funding Programme for Basic Research
Start Date:	04/2007

Abstract:

1. Key issues and problem being addressed: Liver cancer (hepatocellular carcinoma, HCC) is one of the most common cancers worldwide. The prognosis of HCC patients is often poor because of the delay in diagnosis and its high recurrence rate after surgery. Although the risk factors of HCC, such as hepatitis B and C virus infection, cirrhosis, and dietary aflatoxin are well established, the genetic mechanisms in the pathogenesis and tumour progression are poorly defined. Chromosome instability that leads to clonal expansion of genetically altered cells is a hallmark of cancer and is highly relevant to hepatocarcinogenesis. Thus characterization of tumor suppressor genes and elucidation of the mechanisms of chromosome instability are both major challenges in liver cancer research. 2. Purpose of proposed project: Recently, we have identified and characterized a novel cellular centrosomal protein, which we have named TAX1BP2 (Ching et al., 2006, Nature cell Biology 8: 717-24). We have demonstrated that TAX1BP2 plays an important role in the regulation of centrosome duplication, and dysregulation of TAX1BP2 may lead to aneuplody of cells. In our preliminary study, we observed that TAX1BP2 is frequently underexpressed in human HCC (40%) and the underexpression of TAX1BP2 transcript is significantly associated with a poorer prognosis in terms of shorter overall survival rates. In addition, TAX1BP2 is localized at the chromosome locus 1p36, which is also a frequently deleted region in HCC. As HBV infection is a major risk factor of HCC, particularly in this region and locally, we have found that the HBV viral oncoprotein HBx interacts with TAX1BP2 in co-immunofluorescence staining and co-immunoprecipitation. Taken together, these data have laid a solid foundation for TAX1BP2 to be a putative tumor suppressor gene in HCC and regulated by HBx. In this proposal, we will (1) further confirm the underexpression of TAX1BP2 in HCC with Western blotting and immunohistochemical staining and (2) also elucidate the molecular basis for the loss of TAX1BP2 expression. In addition, we will (3) determine how TAX1BP2 can suppress HCC formation and (4) the importance of its interaction with HBx. Thus findings from this study will significantly advance our understanding of TAX1BP2 in the pathogenesis of HCC and may eventually lead to the development of new drug targets and better therapeutic treatments.

List of Research Outputs

Ching Y.P., Chan S.F., Jeang K.T. and Jin D., 2007 Faculty Research Output Prize, In: "Retroviral oncoprotein Tax targets coiled-coil centrosomal protein TAX1BP2 to induce centrosome overduplication" , The University of Hong Kong . Nature Cell Biology, 2007, 8: 717-724.

Ching Y.P., How does Basic Medical Research help in Drug Discovery? , In: Celebrating 120 Years of Medical Education , "Explore the World of Medicine" Public Lecture Series. 2007.

Kok K.H., Ching Y.P. and Jin D., Human TRBP and PACT directly interact with each other and form a complex with Dicer to promote the production of small interfering RNA., American Society for Virlogy 26th Annual Meeting, Oregon State University, Corvallis, Oregon, USA. 2007.

Ma C., Ying C., Yuan Z., Song B., Li D., Liu Y., Lai B., Li W., Chen R., Ching Y.P. and Li M., Dp5 is a c-Jun target gene and required for apoptosis induced by potassium deprivation in cerebellar granule neurons, Journal of Biological Chemistry. 2007, 282: 30901-9.

Mak G.W.Y., Leong V.Y.L., Yau T.O., Ng I.O.L. and Ching Y.P., Functional characterization of C53 and its possible roles in tumorigenesis, Oncogenes and Human Cancer- The next 25 years / Nature-Centro Nacional de Investigaciones Oncologicas (CNIO) Conference . 2007.

Mei Y., Yuan Z., Song B., Li D., Ma C., Hu C., Ching Y.P. and Li M., Activating transcription factor 3 up-regulated by c-Jun NH(2)-terminal kinase/c-Jun contributes to apoptosis induced by potassium deprivation in cerebellar granule neurons. , Neuroscience. 2008, 151: 771-9.

Ng M.H., Ching Y.P. and Jin D., Identification and Characterization of a Novel Interaction Partner of Centrosomal Coiled-coil Protein TAX1BP2, 12th Research Postgraduate Symposium, December 12 & 14, 2007 . 2007.

Researcher : Chiu J

Project Title:	Biochemical and proteomic analyses of arsenic carcinogenesis
Investigator(s):	Chiu J, Leung SY, He Q
Department:	Institute of Molecular Biology
Source(s) of Funding:	Competitive Earmarked Research Grants (CERG)
Start Date:	09/2003

Abstract:

To establish and examine the processes of in vitro carcinogenesis induced by arsenic; to identify key elements of oxidative stress that involve in arsenic-induced cell transformation by biochemical and proteomic approaches; to determine which signaling pathway that mediates arsenic-induced cell transformation by proteomic approach.

List of Research Outputs

Chiu J., Lok C.N., Ho C.M., Chen R., He Q., Yu W.Y., Sun H., Tam P.K.H. and Che C.M., Proteomic analysis of the mode of antibacterial action of silver nanoparticles, NanoBiotechnology World Conference, Nov. 13-14, 2007, Boston, MA, U. S. A.. 2007.

He Q., Zhu R., Lei T., Ng M.Y.M., Luk J.M.C., Sham P.C., Lau G. and Chiu J., Toward the proteomic identification of biomarkers for the prediction of HBV related hepatocellular carcinoma, Journal of Cellular Biochemistry. 2008, 103: 740-752.

Lau T.Y., Wang Y. and Chiu J., Reactive oxygen species: Current knowledge and applications in cancer research and therapeutic, Journal of Cellular Biochemistry. 2008, 104: 657-667.

Lei T., He Q.Y., Wang Y.L., Si L.S. and Chiu J., Heparin chromatography to deplete high-abundance proteins for serum proteomics, Clinica Chimica Acta. 2008, 388: 173-178.

Lo A.C.Y., Cheung A.K.H., Yeung C.M., He Q., Chiu J., Chung S.S.M. and Chung S.K., Deletion of aldose reductase leads to protection against cerebral ischemic injury., Journal of Cerebral Blood Flow and Metabolism. 2007, 27: 1496-1509.

Lok C.N., Ehrlich H.P., White S.L., Buttolph T.R., Cultroneo K.R. and Chiu J., Oligodeoxynucleotide decoy therapy blocks type 1 procollagen transcription and the prolyl hydroxylase b subunit translation, Journal of Cellular Biochemistry. 2008, 103: 1066-1075.

Sun X., Chiu J. and He Q.Y., Fractionation of proteins by immobilized metal affinity chromatography, In: A. Posch, Methods in Molecular Biology. U. S. A., Human Press, 2008, 424: 205-212.

Sun X., Ge R., Chiu J., Sun H. and He Q.Y., Identification of proteins related to nickel homeostasis in Helicobater pylori by immobilized metal affinity chromatography and two-dimensional gel electrophoresis, Metal-Based Drugs. 2008, 2008 Article ID 289490: 6 pages.

Sun X., Ge R., Chiu J., Sun H. and He Q., Identification of proteins related to nickel homeostasis in Helicobater pylori by immobilized metal affinity chromatography and two-dimensional gel electrophoresis, Metal-based Drug. 2007, 289890-1 to 289890-6.

Sun X., Ge R., Chiu J., Sun H. and He Q.Y., Lipoprotein MtsA of MtsABC in Streptococcus pyogenes primarily binds ferrous ion with bicarbonate as a synergistic anion, FEBS Letters. 2008, 582: 1351-1354.

Wang Y., Che C.M., Chiu J. and He Q.Y., Dioscin (Saponin)-induced generation of reactive oxygen species through mitochondria dysfunction: A proteomic-based study, Journal of Proteome Research. 2007, 6: 4703-4710.

Wang Y., Chiu J. and He Q.Y., Isolation of cytoplasmatic proteins from cultured cells for two-dimensional gel electrophoresis, In: A. Posch, Methods in Molecular Biology. U. S. A., Human Press, 2008, 425: 101-112.

Wang Y., He Q.Y., Che C.M., Tsao G.S.W., Sun R.W.Y. and Chiu J., Modulation of gold(III) porphyrin 1a-induced apoptosis by mitogen-activated protein kinase signaling pathways, Biochemical Pharmacology. 2008, 75: 1282-1291.

Wong C.C., Wang Y., Cheng K.W., Chiu J., He Q. and Chen S.F., Comparative proteomic analysis of indioside D-triggered cell death in HeLa cells, Journal of Proteome Research. 2008, 7: 2050-2058.

Zhou Y., Bhatia I., Cai Z., He Q., Cheung P.T. and Chiu J., Proteomic analysis of neonatal mouse brain: evidence for hypoxia- and ischemia-induced dephosphorylation of collapsin response mediator proteins, J Proteome Research. 2008, 7: 2507.

Researcher : Chiu K

List of Research Outputs

Chang R.C.C., Yu M.S., Ho Y.S., Lai S.W., Chiu K. and So K.F., Polysaccharides from medicinal herbs as potential drug lead in Alzheimer's disease, Neurobiology of Aging . 2008, 29S: S4-S5.

Chiu K., Yeung S.C., Ho Y.S., Chan W., So K.F. and Chang R.C.C., Best Poster Award, Hong Kong Society of Immunology. 2008.

Chiu K., Chang R.C.C. and So K.F., Intravitreous injection for establishing ocular disease model , Journal of Visualized Experiments. 2007, 8.

Chiu K., Chang R.C.C. and So K.F., Laser induced chronic ocular hypertension model on SD rats, Journal of Visualized Experiments. 2007, 10.

Chiu K., Lau W.M., Lau H.T., So K.F. and Chang R.C.C., Micro-dissection of rat brain for RNA and protein extraction from specific brain region, Journal of Visualized Experiments. 2007, 7.

Chiu K., Yeung S.C., Ho Y.S., Chan W., So K.F. and Chang R.C.C., Neuroprotective effect of IL-10 on retinal ganglion cell survival in experimental glaucoma model, Hong Kong Society for Immunology 2008 Annual General Meeting and Scientific Meeting, April 19, 2008, Hong Kong.. 2008, 26.

Chiu K., Lau W.M., Yeung S.C., Chang R.C.C. and So K.F., Retrograde labeling of reinal ganglion cells by application of Fluoro-Gold on the surafce of superior colliculus, Journal of Visualized Experiments. 2008.

Researcher : Chiu YT

List of Research Outputs

Chiu Y.T., Wong Y.C. and Ling M.T., Identification of a novel androgen receptor corepressor, CDC25A, in prostate cancer cells., 12th Research Postgraduate Symposium, HKU Medical Faculty, Dec 12 and 14 2007. . 2007, 95.

Howard E.W., Lee D.T.W., Chiu Y.T., Chua C.W., Wang X. and Wong Y.C., Evidence of a novel docetaxel sensitizer, garlic-derived S-allylmercaptocysteine, as a treatment option for hormone refractory prostate cancer, International Journal of Cancer. 2008, 122: 1941-1948.

Researcher : Chu Q

List of Research Outputs

Wong Y.C., Howard E.W., Chu Q. and Wang X., Garlic derived compounds, S-allylcysteine (SAC) and S-allylmercaptocysteine (SAMC), synergise with Docetaxel to suppress growth of androgen refractory prostate cancer., BIT life Science’s 1st World Cancer Congress, June 12-17 2008, Shanghai, China.. 2008, 85.

Wong Y.C., Howard E.W., Chu Q. and Wang X., Garlic derived compounds, SAC and SAMC, synergise with docetaxel to inhibit the growth of hormone refractory prostate cancer, Proceeding of 5th APICA International Congress of Anatomists and the 8th Iranian congress of Anatomical Sciences, May 16-19, 2008. Tehran, Iran.. 2008, 79-80.

Wong Y.C., Howard E.W., Chu Q., Lee D.T.W. and Wang X., Garlic extract synergizes with docetaxel in suppressing the hormone refractory prostate cancer growth, Proceeding of 12th World Congress on Advances in Oncology and 10th International Symposium on Molecular Medicine held in Hersonissos, Crete, Greece from October 11-13, 2007.Int J Mol Medicine . 2007, 20, Suppl 1: S7.

Researcher : Chu TH

List of Research Outputs

Mi S., Hu B., Hahm K., Luo Y., Hui S.K., Yuan Q.J., Wong W.M., Wang L., Su H., Chu T.H., Guo J., Zhang W., So K.F., Pepinsky B., Shao Z., Graff C., Garber E., Jung V., Wu E.X. and Wu W., LINGO-1 antagonist promotes spinal cord remyelination and axonal integrity in MOG-induced experimental autoimmune encephalomyelitis, Nature Medicine. 2007, 13(10): 1228-1233.

Su H., Chu T.H. and Wu W., Lithium enhances proliferation and neuronal differentiation of neural progenitor cells in vitro and after transplantation into the adult rat spinal cord, The 37 Annual Meeting Society for Neuroscience, U.S.A., Nov. 2007.

Researcher : Chua CW

List of Research Outputs

Howard E.W., Leung C.L., Yuen H.F., Chua C.W., Lee D.T.W., Chan K.W., Wang X. and Wong Y.C., Decreased adhesiveness, resistance to anoikis and suppression of GRP94 are integral to the survival of circulating tumor cells in prostate cancer, Clinical and Experimental Metastasis. 2008, 25: 497-508.

Howard E.W., Lee D.T.W., Chiu Y.T., Chua C.W., Wang X. and Wong Y.C., Evidence of a novel docetaxel sensitizer, garlic-derived S-allylmercaptocysteine, as a treatment option for hormone refractory prostate cancer, International Journal of Cancer. 2008, 122: 1941-1948.

Researcher : Chua CW

List of Research Outputs

Researcher : Chung SK

Project Title:	Molecular mechanisms of dementia associated with aging-related diseases, alzheimer's and multi-infarct
Investigator(s):	Chung SK
Department:	Institute of Molecular Biology
Source(s) of Funding:	Competitive Earmarked Research Grants (CERG)
Start Date:	12/2003

Abstract:

To characterize of GET, TET or ETKO mice with human Swedish mutation in APP gene; to determine amyloidogenesis and neuropathological features in ET-1/mutant APPYAC brain; to determine memory deficit and brain activity in ET-1/mutant APPYAC mice; to determine the role of infarct and mutant APP on oxidative stress and neuropathogical features; to determine efficacy of ECE inhibitor and ETA and ETB receptors antagonists for neurotoxicity.

Project Title:	Genetic approaches to understand the pathogenesis of diabetic neuropathy: common, debilitating disease
Investigator(s):	Chung SK
Department:	Institute of Molecular Biology
Source(s) of Funding:	Competitive Earmarked Research Grants (CERG)
Start Date:	01/2005

Abstract:

To determine contributions of AR and SD to the increased oxidative stress in diabetic nervous tissues; to determine the relationship between AR activity and the activation of NF-[kappa]B and PKC; to determine the contributions of vascular and nervous tissues to the diabetes-induced MNCV deficit; to determine the role of AR in the pathogenesis of chronic neuropathy by using the Thy1-YFP transgenic mice.

Project Title:	Conditional knockout of osmotic responsive element binding protein, OREBP/NFAT5/TonEBP, to study its role in brain edema and infarct after ischemic stroke: a leading cause of mortality and morbidity
Investigator(s):	Chung SK
Department:	Anatomy
Source(s) of Funding:	Competitive Earmarked Research Grants (CERG)
Start Date:	01/2007

Abstract:

To determine the role of OREBP in brain water content, edema and infarct after ischemic stroke using two lines of heterozygous OREBP knockout mice derived from 2-independent ES cells; to determine the molecular signals downstream to OREBP in contributing to astrocyte and neruronal cell death during ischemic and hypertonic stress using primary astrocyte and neuronal cultures from embryos of homozygous OREBP-deficient mice; to investigate the effects of conditional deletion of OREBP in astrocytes or neurons on brain edema and infarct after ischemic stroke.

List of Research Outputs

Cheung A.K.H., Lo A.C.Y., So K.F., Chung S.S.M. and Chung S.K., Gene deletion and pharmacological inhibition of aldose reductase protect against retinal ischemic injury, Experimental Eye Research. 2007, 85: 608-616.

Lo A.C.Y., Cheung A.K.H., Yeung C.M., He Q., Chiu J., Chung S.S.M. and Chung S.K., Deletion of aldose reductase leads to protection against cerebral ischemic injury., Journal of Cerebral Blood Flow and Metabolism. 2007, 27: 1496-1509.

Qiu L., Wu X., Chau J.F.L., Szeto Y.Y., Tam W.Y., Guo Z., Chung S.K., Oates P.J., Chung S.S.M. and Yang J.Y., Aldose Reductase Regulates Hepatic Peroxisome Proliferator-activated Receptor {alpha} Phosphorylation and Activity to Impact Lipid Homeostasis., Journal of Biological Chemistry. 2008, 283: 17175-17183.

Tang W.H., Wu S., Wong T.M., Chung S.K. and Chung S.S.M., Polyol Pathway Mediates Iron-induced Oxidative Injury In Ischemic-reperfused Rat Heart, Free Radical Biology Medicine. 2008, 45: 602-10.

Researcher : Deng W

List of Research Outputs

Cheung A., Deng W., Tsao G.S.W. and Guan X.Y., Centromeric instability in human cells undergoing immortalization., Proceedings of American Association for Cancer Research Annual Meeting; 2008 Apr 12-16; San Diego, CA. Abstract nr 4318. 2008, 4318.

Cheung A. and Deng W., Telomere dysfunction, genome instability and cancer, Frontiers in Bioscience. 2008, 13: 2075-2090.

Cheung P.Y., Deng W., Tsao G.S.W. and Cheung A., Role of cyclin D1 in conferring malignant phenotypes on immortalized esophageal epithelial cells., Proceedings of the American Association for Cancer Research Annual Meeting, San Diego, U. S. A., April 12-16, 2008. Abstract 5581.. 2008, 5581.

Deng W., Tsao G.S.W., Guan X.Y. and Cheung A., Microtubule breakage is not a major mechanism for resolving end-to-end chromosome fusions generated by telomere dysfunction during the early process of immortalization, Chromosoma. 2007, 116: 557-568.

Tse W.W., Deng W., Tsao G.S.W. and Cheung A., Methylation status of tumor related genes during immortalization of human cervical epithelial cell lines. , Proceedings of American Association for Cancer Research Annual Meeting; 2008 Apr 12-16; San Diego, CA. Abstract nr 48.. 2008, 48.

Wang X.Y., Lai Z.S., Yeung C.M., Wang J.D., Deng W., Hang Y.J., Kung H.F., Jiang B. and Lin M.C., Establishment and Characterization of a New Cell Line Derived from Human Colorectal Laterally Spreading Tumor , World Journal of Gastroenterology. 2008, 14(8): 1204-1211.

Researcher : Deng W

Project Title:	Dynamics of numerical chromosome instability in human cells undergoing immortalization
Investigator(s):	Deng W, Cheung A
Department:	Anatomy
Source(s) of Funding:	Small Project Funding
Start Date:	10/2005

Abstract:

Chromosome instability is a major form of genomic instability that helps drive development of human cancer [1]. Numerical chromosome instability is manifested by dynamic changes of chromosome numbers, i.e., losses or gains of whole-chromosomes, which are almost ubiquitous in human cancer. Since thousands of genes can be affected by whole-chromosome losses or gains, this type of instability is more efficient in inducing genetic alterations than mere gene mutations. However, to date, the mechanisms underlying numerical chromosome instability still remain unclear. The objectives of this study are: (1) To test whether telomere dysfunction induces numerical chromosome instability It has been a long-standing mystery why pre-immortal, immortalized and cancer cells universally have nonrandom numerical chromosome abnormalities. Recent studies on telomeres, the terminal structure crucial for protecting chromosomes against end-fusions, provide some hints. Since telomere lengths on individual chromosomes are recently found to be highly heterogeneous, we hypothesize that the chromosomes with the shortest telomeres are most susceptible to fusion-bridge formation; and the bridge could be broken in microtubule due to the pulling forces of the fused chromosomes during subsequent cell division. This would result in preferential losses or gains of specific chromosomes with dysfunctional telomeres. (2) To test whether aneuploidy promotes numerical chromosome instability It is hypothesized that the initial whole-chromosome losses or gains (generally termed aneuploidy) may trigger asymmetrical production of mitotic elements, which then destabilizes the karyotype and generates greater aneuploidy, causing a chain-reaction or autocatalysis of numerical chromosome instability [2]. The hypothesis predicts that numerical chromosome instability would increase with the degree of aneuploidy and cell population doublings. This would drive the continued progression of numerical chromosome instability. (3) To test whether centrosome abnormality contributes to numerical chromosome instability During mitosis, two duplicated centrosomes normally serve as organizing centers of the two poles of the mitotic spindle to provide the machinery for the correct separation of two groups of chromosomes. We hypothesize that multiple centrosomes may cause multi-polar mitosis and thus failed segregation of a whole set of chromosomes. We therefore propose to investigate the dynamics of centrosome abnormality and the subsequent dynamic generation of nearly whole sets of chromosome number abnormalities in the process of immortalization to better define their causal relationship. Reference: 1.Lengauer,C., Kinzler,K.W. and Vogelstein,B. (1998). Genetic instabilities in human cancers. Nature, 396:643-649. 2.Li, R., Sonik,A., Stindl,R., Rasnick,D., and Duesberg,P. (2000). Aneuploidy vs. gene mutation hypothesis of cancer: recent study claims mutation but is found to support aneuploidy. Proc. Natl. Acad. Sci. U. S. A., 97:3236-3241.

List of Research Outputs

Cheung A. and Deng W., Telomere dysfunction, genome instability and cancer, Frontiers in Bioscience. 2008, 13: 2075-2090.

Researcher : Di K

List of Research Outputs

Di K., Wong Y.C. and Wang X., Id-1 promotes TGF-b1-induced cell motility through HSP27 activation and disassembly of adherens junction in prostate epithelial cells, Experimental Cell Research. 2007, 313: 3983-3999.

Di K., The role of Id-1 on proliferation, motility and mitotic regulation of prostate epithelial cells. 2007, 174 pages.

Researcher : Ellis-Behnke RG

List of Research Outputs

Ellis-Behnke R.G., Assessing functional regeneration of the visual system, 14th Annual Optic Nerve Rescue and Restoration Think Tank, New York USA. 2007.

Ellis-Behnke R.G., Liang Y., Chan K.C., Tay D.K.C., So K.F. and Wu E.X., Assessing the progression of functional regeneration of the visual system, 6th Picower-RIKEN Symposium, M.I.T., Cambridge USA. 2007.

Ellis-Behnke R.G., Liang Y., You S., Tay D.K.C., So K.F. and Schneider G.E., Beyond nano neuro knitting: creating a more permissive environment using SAPNS with Chondroitinase ABC for brain lesion repair and functional return of vision, International Brain Research Organization (IBRO), Melbourne, Australia. 2007.

Ellis-Behnke R.G., Liang Y., Tay D.K.C., You S.W., Schneider G.E. and So K.F., Beyond nano neuro knitting: creating of a more permissive environment using SAPNS with chondroitinase ABC for brain lesion repair and functional return of vision, 7th IBRO World Congress of Neuroscience , July 12-17, 2007, Melbourne, Australia. 2007, 272 POS-SUN-045.

Ellis-Behnke R.G., From Nano Neuro Knitting to Crystal Clear Surgery, Annual Conference of the World Future Society-Symposium "Nanotechnology: Innovations and Opportunities," Minneapolis USA. 2007.

Ellis-Behnke R.G., Innovative Medical Teaching Methods, Dept of Anatomy & Cell Biology, Wayne State University School of Medicine, Detroit USA. 2007.

Ellis-Behnke R.G., Keynote speaker - Serendipity in Product Development, 2007 System Design and Management Conference, Cambridge USA. 2007.

Ellis-Behnke R.G., Keynote speaker: Nanomachines that help repair the brain, 1st IEEE International Conference on Nano/Molecular Medicine and Engineering, Macau SAR China. 2007.

Ellis-Behnke R.G., Licensing agreement with Clear Nano Solutions, Hemostasis. 2008.

Ellis-Behnke R.G., Nano Hemostat Solution, Asia-Oceanic Society for Glaucoma/Pfizer Japan Symposium, Bangkok, Thailand. 2007.

Ellis-Behnke R.G., Nano Knitting: Peptide Nanofiber Scaffold for Brain Repair, National Neurotrauma Society 25th Annual Symposium, Kansas City USA. 2007.

Ellis-Behnke R.G., Liang Y., Cheung S.F., Tay D.K.C. and So K.F., Nano contrast enhancement agents used in the eye for tracing axons: Trauma or illlumination?, ARVO 2008 Annual Meeting, April 27-May 1, 2008, Florida, U. S. A.. 2008, No. 4014.

Ellis-Behnke R.G., Nano neurology and the 4 P's of CNS regeneration: Preserve, Permit, Promote, Plasticity, In: Wei, Nanomedicine, an Issue of Medical Clinics. Philadelphia USA, Elsevier, 2007, 91-5: 937–962.

Ellis-Behnke R.G., Nanobiotechnology Symposium - The Intersection of Nanotechnology and Medicine, 5th ISOPE HPM Symposium: Nanomaterials for Structural Application, Lisbon, Portugal. 2007.

Ellis-Behnke R.G., Nanohealing In Hamster Vision, Nanomedicine For Functional Recovery Of Central Nervous System, 4th Meeting of the American Academy of Nanomedicine, Washington DC. 2008.

Ellis-Behnke R.G., Liang Y., Tay D.K.C. and So K.F., Nanomachines that help repair the brain, 1st IEEE International Conference on Nano/Molecular Medicine and Engineering, Macau SAR China. 2007.

Ellis-Behnke R.G., Nanomedicine and the transfer and commercialization of intellectual property from academia to business, In: Harvard Alumni Health Conference, 2007.

Ellis-Behnke R.G., Nanomedicine and the transfer and commercialization of intellectual property from academia to business, Roundtable leader, Harvard Alumni Health Conference, Boston USA. 2007.

Ellis-Behnke R.G., Nanomedicine: Nanotechnology, Biology, and Medicine, Neurology Editor . Elsevier, 2008.

Ellis-Behnke R.G., Nanotechnology: From CNS Regeneration to Crystal Clear Surgery, National Institutes of Health - Nanomedicine/Nanotechnology Special Interest Group, Bethesda USA. 2007.

Ellis-Behnke R.G., Neural Tissue Regeneration, Visiting Programme on Biomedical Engineering, Hong Kong. 2007.

Ellis-Behnke R.G., Patenting challenges in nanomedicine, Executive committee meeting, American Intellectual Property Association, Washington DC USA. 2007.

Ellis-Behnke R.G., Progress towards the paperless classroom, Frontiers of Education in Medicine, Hong Kong. 2007.

Ellis-Behnke R.G., Recent successes of tissue bioengineering in ophthalmology, American Academy Ophthalmology Symposium on Regenerative Ophthalmology, New Orleans USA. 2007.

Ellis-Behnke R.G., Summary Of Nanobiomedical Research Over The Past Year, Association of Research in Vision and Ophthalmology, Ft Lauderdale USA. 2008.

Ellis-Behnke R.G., Symposium Chair - Nanomaterials: Synthesis and Processing, 5th ISOPE HPM Symposium: Nanomaterials for Structural Application, Lisbon, Portugal. 2007.

Ellis-Behnke R.G., The 4 P's of CNS regeneration, Dept of Anatomy & Cell Biology Research Seminar Series, Wayne State University Medical School, Detroit USA. 2007.

Ellis-Behnke R.G., The impact of nanotechnology on eye treatments, 7th International Symposium on Ocular Pharmacology and Therapeutics, Budapest, Hungary. 2008.

Ellis-Behnke R.G., Liang Y., Tay D.K.C., Schneider G.E. and So K.F., The impact of nanotechnology on eye treatments, 7th International Symposium on Ocular Pharmacology and Therapeutics, Budapest, Hungary . 2008.

Ellis-Behnke R.G., The use of nanotechnology to repair the body, In: 3rd Strategies for Engineered Negligible Senescence (SENS), Cambridge UK, 2007.

Ellis-Behnke R.G., Using A 7 Tesla Fmri And A Nano Contrast Agent To Visualize Regenerating Axons In Vivo In Hamster Optic Tract Transection, 18th International Congress of Eye Research, Beijing China. 2008.

Ellis-Behnke R.G., Liang Y., Tay D.K.C., Schneider G.E. and So K.F., Using Nanotechnology For Tissue Bioengineering In Ophthalmology, 31st World Ophthalmology Congress, Symposium on Nanotechnology. 2008.

Ellis-Behnke R.G., Teather L.A., Schneider G.E. and So K.F., Using Nanotechnology To Design Potential Therapies For CNS Regeneration, Current Pharmaceutical Design. 2007, 13(24): 2519-2538.

Ellis-Behnke R.G., Using Nanotechnology To Repair The Body, Office of Naval Research, Washington DC, USA. 2007.

Ellis-Behnke R.G., Using Nanotechnology To Repair The Brain, 3rd Annual Conference of SENS (Strategies for Engineered Negligible Senescence): "Combating Neurodegeneration," Cambridge UK. 2007.

Ellis-Behnke R.G., Using Nanotechnology To Repair The CNS: From The 4 Ps Of Regeneration To Crystal Clear Surgery To In Vivo Non-invasive Imaging Of Regenerating Axons , 1st Unither Nanomedical & Telemedical Technology Conference, Quebec, Canada. 2008.

Ellis-Behnke R.G., Liang Y., Tay D.K.C., Schneider G.E. and So K.F., Using Nanotechnology To Repair The CNS: From The 4 Ps Of Regeneration To Crystal Clear Surgery To In Vivo Non-invasive Imaging Of Regenerating Axons , 1st Unither Nanomedical and Telemedical Technology conference. 2008.

Ellis-Behnke R.G., Liang Y., Tay D.K.C., So K.F. and Wu E.X., Using a 7 Tesla fMRI and Nano Contrast Agent to Visualize Regeneration of Axons in vivo after Chronic Injury in the Hamster Optic Tract , Society for Neuroscience, San Diego USA . 2007.

Ellis-Behnke R.G., Using nanotechnology for surgical interventions, 1st IEEE International Conference on Nano/Molecular Medicine and Engineering - Cardiovascular Symposium, Macau SAR China. 2007.

Ellis-Behnke R.G., Using nanotechnology for tissue bioengineering in ophthalmology, 31st World Ophthalmology Congress, Symposium on Nanotechnology, Hong Kong SAR China. 2008.

Ellis-Behnke R.G., Using nanotechnology to repair the CNS: from the 4 Ps of regeneration to crystal clear surgery to in vivo noninvasive imaging of regenerating axons, Brain & Cognitive Sciences Fall Colloquium Series, Masssachusetts Institute of Technology, Cambridge USA. 2007.

Ellis-Behnke R.G., Using nanotechnology to repair the visual system, New England School of Optometry Research Seminar, Boston USA. 2008.

Ellis-Behnke R.G., Using self-assembling nanofiber peptides to repair the body, Dept of Materials Science and Metallurgy, Trinity College, Cambridge University, UK. 2007.

Ellis-Behnke R.G., Visualizing axon regeneration in vivo after chronic injury using a 7 Tesla fMRI and nano contrast agent , Dept. of Radiology, Memorial Sloan-Kettering Cancer Center, New York USA . 2007.

Guo J., Su H., Zeng Y., Liang Y., Wong W.M., Ellis-Behnke R.G., So K.F. and Wu W., Reknitting The Injured Spinal Cord By Self Assembling Peptide Nanofiber Scaffold, Nanomedicine: Nanotechnology, Biology and Medicine. 2007, 3(4): 311-321.

Guo J., Liang Y., Zeng Y., Ellis-Behnke R.G., So K.F. and Wu W., Reknitting the spinal cord using a self-assembling peptide nanofiber scaffold to promote functional recovery, Society for Neuroscience, San Diego USA. 2007.

Schneider G.E., Ellis-Behnke R.G. and So K.F., Nano neuro knitting of the severed optic tract with return of function, ARVO 2008 Annual Meeting, April 27-May 1, 2008, Florida, U. S. A.. 2008, 371.

So K.F. and Ellis-Behnke R.G., Nanomedicine for CNS regeneration and instant hemostasis, 2nd congress of International Society of Reconstructive Neurosurgery and 5th Scientific Meeting of the WFNS Neurorehabilitation Committee, September 13-16, 2007, Taipei, Taiwan. 2007, 79 S15-3.

So K.F. and Ellis-Behnke R.G., Nanomedicine for CNS regeneration and instant hemostasis, The 5th Asian-Pacific International Congress of Anatomists & The 8th Iranian Congress of Anatomical Sciences, May 16-19, 2008, Iran. 2008, 126-127.

So K.F., Liang Y., Tay D.K.C. and Ellis-Behnke R.G., Regenerative Medicine in Vision, 1st Pan Pacific Symposium on Stem Cells Research 2008, May 31-June 2, 2008. 98.

Ye Z., Zhang H., Luo H., Wang S., Zhou Q., Du X., Tang C., Chen L., Liu J., Shi Y.K., Zhang Y., Ellis-Behnke R.G. and Zhao X., Temperature and pH Effects on Biophysical and Morphological Properties of Self-assembling Peptide, Journal of Peptide Science. 2008, 14: 152-162.

Researcher : Feng H

List of Research Outputs

Feng H., Tsao G.S.W., Ngan H.Y.S., Xue W., Kwan H.S., Siu K.Y., Liao X., Wong E.S.Y. and Cheung A.N.Y., Over-expression of Prostatic Stem Cell Antigen (PSCA) is associated with Gestational Trophoblastic neoplasia. , Histopathology. 2007, 52: 167-174.

Feng H., Tsao G.S.W., Ngan H.Y.S., Xue W., Kwan H.S., Siu K.Y., Liao X., Wong E.S.Y. and Cheung A.N.Y., Overexpression of prostate stem cell antigen is associated with gestational trophoblastic neoplasia, Histopathology. 2008, 52(2): 167-174.

Researcher : Feng H

List of Research Outputs

Researcher : Fu Q

List of Research Outputs

Fu Q., Hu B., Wu W., Pepinsky R.B., Mi S. and So K.F., Blocking LINGO-1 function promotes retinal ganglion cell survival following ocular hypertension and optic nerve transection, Investigative Ophthalmology & Visual Science. 2008, 49(3): 975-985.

Fu Q., Characterization of novel neuroprotectants for rescuing retinal ganglion cell loss in an ocular hypertensive model of glaucoma. 2007, 186 pages.

Fu Q., Wu W., Wang H., Li X., Lee V.W.H. and So K.F., Up-regulated endogenous erythropoietin/erythropoietin receptor system and exogenous erythropoietin rescue retinal ganglion cells after chronic ocular hypertension, Cellular and Molecular Neurobiology. 2008, 28: 317-329.

Researcher : Fung KL

List of Research Outputs

Fung K.L., Wong Y.C., Cheung A. and Wang X., MAD2 expression and its significance in mitotic checkpoint control in testicular germ cell tumour, AACR Centennial conference, LA, USA, April 14-18 2007. 2008, 1233.

Fung K.L., Significance of MAD2 in mitotic checkpoint control and cisplatin sensitivity of testicular germ cell tumour cells. 2007, 228 pages.

Researcher : Guo J

List of Research Outputs

Guo J., Su H., Zeng Y., Liang Y., Wong W.M., Ellis-Behnke R.G., So K.F. and Wu W., Reknitting The Injured Spinal Cord By Self Assembling Peptide Nanofiber Scaffold, Nanomedicine: Nanotechnology, Biology and Medicine. 2007, 3(4): 311-321.

Guo J., Liang Y., Zeng Y., Ellis-Behnke R.G., So K.F. and Wu W., Reknitting the spinal cord using a self-assembling peptide nanofiber scaffold to promote functional recovery, Society for Neuroscience, San Diego USA. 2007.

Mi S., Hu B., Hahm K., Luo Y., Hui S.K., Yuan Q.J., Wong W.M., Wang L., Su H., Chu T.H., Guo J., Zhang W., So K.F., Pepinsky B., Shao Z., Graff C., Garber E., Jung V., Wu E.X. and Wu W., LINGO-1 antagonist promotes spinal cord remyelination and axonal integrity in MOG-induced experimental autoimmune encephalomyelitis, Nature Medicine. 2007, 13(10): 1228-1233.

Researcher : Ho CT

List of Research Outputs

Ho C.T., Tipoe G.L., Liong E.C., Leung T.M., Lau T.Y.H., Fung M.L. and Nanji A.A., Decreased adiponectin and antioxidant enzymes are associated with necroinflammatory changes and fibrosis in a rat model for non-alcoholic fatty liver disease (NAFLD), Hepatology International. 2008, 2: S151-S152.

Researcher : Ho YS

List of Research Outputs

Chang R.C.C., Yik S.Y., Ho Y.S., Lai S.W. and So K.F., Direct neurotoxic effects of dsRNA: Implication of virus-induced neurodegeneration , Society for Neuroscience 2007. Program No. 605.23.

Chang R.C.C., Yu M.S., Ho Y.S., Lai S.W., Chiu K. and So K.F., Polysaccharides from medicinal herbs as potential drug lead in Alzheimer's disease, Neurobiology of Aging . 2008, 29S: S4-S5.

Chao J., Yu M.S., Ho Y.S., Wang M. and Chang R.C.C., Dietary oxyresveratrol attenuates neurotoxicity induced by 6-hydroxydopamine in SH-SY5Y cells, Federation of European Neurosciences Societies Abstracts. 2007, 4: Poster 184.15.

Chao J., Yu M.S., Ho Y.S., Wang M. and Chang R.C.C., Dietary oxyresveratrol prevents 6-hydroxydopamine-induced neurotoxicity in SH-SY5Y cells, Third International Symposium on Healthy Aging: Improving the Health of an Aging Population, March 1-2, 2008, Hong Kong. 2008, 51 P11.

Chiu K., Yeung S.C., Ho Y.S., Chan W., So K.F. and Chang R.C.C., Best Poster Award, Hong Kong Society of Immunology. 2008.

Chiu K., Yeung S.C., Ho Y.S., Chan W., So K.F. and Chang R.C.C., Neuroprotective effect of IL-10 on retinal ganglion cell survival in experimental glaucoma model, Hong Kong Society for Immunology 2008 Annual General Meeting and Scientific Meeting, April 19, 2008, Hong Kong.. 2008, 26.

Ho Y.S., Yu M.S., Lai S.W., So K.F., Yuen W.H. and Chang R.C.C., Characterizing the neuroprotective effects of alkaline extract of Lycium barbarum on b-amyloid peptide neurotoxicity, Brain Research. 2007, 1158: 123-134.

Ho Y.S., Yu M.S., Lai S.W., So K.F., Yuen W.H. and Chang R.C.C., Lycium barbarum as a potential drug to attenuate neurodegeneration in Alzheimer's disease, 2007 TWGHs Eddie Wang Symposium on Integrated Chinese and Western Medicine. 2007, 197.

Ho Y.S., Yu M.S., Yik S.Y., Lai S.W., So K.F., Yuen W.H. and Chang R.C.C., Lycium barbarum protects neurons against neurodegeneration in Alzheimer's disease through multiple approaches, Third International Symposium on Healthy Aging: Improving the Health of an Aging Population, March 1-2, 2008, Hong Kong. 2008, 44 OP10.

Yik S.Y., Yu M.S., Ho Y.S., Lai S.W., Cheung Y.T., So K.F. and Chang R.C.C., Significance of dsRNA-elicited neurotoxicity, neuroprotection of minocycline on viral induced neurodegeneration, Third International Symposium on Healthy Aging: Improving the Health of an Aging Population, March 1-2,2008, Hong Kong.. 2008, 52 P14.

Yu M.S., Lai S.W., Ho Y.S., Zee S.S.Y., So K.F., Yuen W.H. and Chang R.C.C., Characterization of the Effects of Anti-aging Medicine Fructus Lycii on b-amyloid Peptide Neurotoxicity , International Journal of Molecular Medicine . 2007, 20: 261-268.

Researcher : Howard EW

List of Research Outputs

Howard E.W., Leung C.L., Yuen H.F., Chua C.W., Lee D.T.W., Chan K.W., Wang X. and Wong Y.C., Decreased adhesiveness, resistance to anoikis and suppression of GRP94 are integral to the survival of circulating tumor cells in prostate cancer, Clinical and Experimental Metastasis. 2008, 25: 497-508.

Howard E.W., Camm K.D., Wong Y.C. and Wang X., E-cadherin upregulation as a therapeutic goal in cancer treatment, Mini reviews inMedicinal Chemistry. 2008, 8: 496-518.

Howard E.W., Lee D.T.W., Chiu Y.T., Chua C.W., Wang X. and Wong Y.C., Evidence of a novel docetaxel sensitizer, garlic-derived S-allylmercaptocysteine, as a treatment option for hormone refractory prostate cancer, International Journal of Cancer. 2008, 122: 1941-1948.

Wong Y.C., Howard E.W., Chu Q. and Wang X., Garlic derived compounds, S-allylcysteine (SAC) and S-allylmercaptocysteine (SAMC), synergise with Docetaxel to suppress growth of androgen refractory prostate cancer., BIT life Science’s 1st World Cancer Congress, June 12-17 2008, Shanghai, China.. 2008, 85.

Wong Y.C., Howard E.W., Chu Q. and Wang X., Garlic derived compounds, SAC and SAMC, synergise with docetaxel to inhibit the growth of hormone refractory prostate cancer, Proceeding of 5th APICA International Congress of Anatomists and the 8th Iranian congress of Anatomical Sciences, May 16-19, 2008. Tehran, Iran.. 2008, 79-80.

Wong Y.C., Howard E.W., Chu Q., Lee D.T.W. and Wang X., Garlic extract synergizes with docetaxel in suppressing the hormone refractory prostate cancer growth, Proceeding of 12th World Congress on Advances in Oncology and 10th International Symposium on Molecular Medicine held in Hersonissos, Crete, Greece from October 11-13, 2007.Int J Mol Medicine . 2007, 20, Suppl 1: S7.

Wong Y.C., Howard E.W. and Wang X., Garlic extracts working in concert with docetaxel to suppress the growth of androgen independent prostate cancer., XIX International Symposium on Morphological Sciences. Budapest, Hungary. 19-23/8 2007. Acta Biologica Szegediensis. 2007, 51 suppl 1: 57.

Researcher : Hu B

List of Research Outputs

Fu Q., Hu B., Wu W., Pepinsky R.B., Mi S. and So K.F., Blocking LINGO-1 function promotes retinal ganglion cell survival following ocular hypertension and optic nerve transection, Investigative Ophthalmology & Visual Science. 2008, 49(3): 975-985.

Mi S., Hu B., Hahm K., Luo Y., Hui S.K., Yuan Q.J., Wong W.M., Wang L., Su H., Chu T.H., Guo J., Zhang W., So K.F., Pepinsky B., Shao Z., Graff C., Garber E., Jung V., Wu E.X. and Wu W., LINGO-1 antagonist promotes spinal cord remyelination and axonal integrity in MOG-induced experimental autoimmune encephalomyelitis, Nature Medicine. 2007, 13(10): 1228-1233.

Researcher : Hugon J

List of Research Outputs

Yu M.S., Lai S.W., Suen K.C., So K.F., Hugon J. and Chang R.C.C., Neuronal apoptosis induced by extracellular accumulation of beta-amyloid peptides is independent of unfolded protein responses, 7th IBRO World Congress of Neuroscience. 2007.

Researcher : Kwok WK

List of Research Outputs

Kwok W.K., Oncogenic function of TWIST in the development and progression of prostate cancer. 2007, 185 pages.

Kwok W.K., Ling M.T., Yuen H.F., Wong Y.C. and Wang X., Role of p14^ARF in TWIST-mediated senescence in prostate epithelial cells, Carcinogenesis. 2007, 28(12): 2467-2475.

Researcher : Lai SW

List of Research Outputs

Chang R.C.C., Yik S.Y., Ho Y.S., Lai S.W. and So K.F., Direct neurotoxic effects of dsRNA: Implication of virus-induced neurodegeneration , Society for Neuroscience 2007. Program No. 605.23.

Chang R.C.C., Yu M.S., Ho Y.S., Lai S.W., Chiu K. and So K.F., Polysaccharides from medicinal herbs as potential drug lead in Alzheimer's disease, Neurobiology of Aging . 2008, 29S: S4-S5.

Cheung Y.T., Yu M.S., Lai S.W., So K.F. and Chang R.C.C., Global protein translation control in beta-amyloid peptide induced neurotoxicity, Third International Symposium on Healthy Aging: Improving the Health of an Aging Population, March 1-2, 2008 Hong Kong. 2008, 49 P2.

Cheung Y.T., Yu M.S., Lai S.W., So K.F. and Chang R.C.C., Global protein translation control in beta-amyloid peptide neurotoxicity, Federation of European Neurosciences Societies Abstracts. 2007, 4: Poster 014.3.

Ho Y.S., Yu M.S., Lai S.W., So K.F., Yuen W.H. and Chang R.C.C., Characterizing the neuroprotective effects of alkaline extract of Lycium barbarum on b-amyloid peptide neurotoxicity, Brain Research. 2007, 1158: 123-134.

Ho Y.S., Yu M.S., Lai S.W., So K.F., Yuen W.H. and Chang R.C.C., Lycium barbarum as a potential drug to attenuate neurodegeneration in Alzheimer's disease, 2007 TWGHs Eddie Wang Symposium on Integrated Chinese and Western Medicine. 2007, 197.

Ho Y.S., Yu M.S., Yik S.Y., Lai S.W., So K.F., Yuen W.H. and Chang R.C.C., Lycium barbarum protects neurons against neurodegeneration in Alzheimer's disease through multiple approaches, Third International Symposium on Healthy Aging: Improving the Health of an Aging Population, March 1-2, 2008, Hong Kong. 2008, 44 OP10.

Lai S.W., So K.F. and Chang R.C.C., Aggregation/collapse of endoplasmic reticulum prior activaton of programmed cell death, Society for Neuroscience 2007. Program No. 688.18.

Lai S.W., So K.F., Yuen W.H., So K.F., Zee S.S.Y. and Chang R.C.C., Antagonizing Beta-amyloid Peptide Neurotoxicity of the Anti-aging Fungus Ganoderma Lucidum, Brain Research . 2008, 1190: 215-224.

Lai S.W., Preisler J., Yu M.S., Lee D.H.S. and Chang R.C.C., Mechanism of b-amyloid-dependent neurotoxicity in primary hippocampal neurons: evidence for induction of endoplasmic reticulum aggregation, Alzheimer's Disease Keystone Symposia, March 24-29, Colorado, U. S. A.. 2008, 55 Poster 117.

Yik S.Y., Yu M.S., Ho Y.S., Lai S.W., Cheung Y.T., So K.F. and Chang R.C.C., Significance of dsRNA-elicited neurotoxicity, neuroprotection of minocycline on viral induced neurodegeneration, Third International Symposium on Healthy Aging: Improving the Health of an Aging Population, March 1-2,2008, Hong Kong.. 2008, 52 P14.

Yu M.S., Lai S.W., Ho Y.S., Zee S.S.Y., So K.F., Yuen W.H. and Chang R.C.C., Characterization of the Effects of Anti-aging Medicine Fructus Lycii on b-amyloid Peptide Neurotoxicity , International Journal of Molecular Medicine . 2007, 20: 261-268.

Yu M.S., Lai S.W., Suen K.C., So K.F., Hugon J. and Chang R.C.C., Neuronal apoptosis induced by extracellular accumulation of beta-amyloid peptides is independent of unfolded protein responses, 7th IBRO World Congress of Neuroscience. 2007.

Researcher : Lai SW

List of Research Outputs

Chang R.C.C., Yik S.Y., Ho Y.S., Lai S.W. and So K.F., Direct neurotoxic effects of dsRNA: Implication of virus-induced neurodegeneration , Society for Neuroscience 2007. Program No. 605.23.

Chang R.C.C., Yu M.S., Ho Y.S., Lai S.W., Chiu K. and So K.F., Polysaccharides from medicinal herbs as potential drug lead in Alzheimer's disease, Neurobiology of Aging . 2008, 29S: S4-S5.

Lai S.W., So K.F. and Chang R.C.C., Aggregation/collapse of endoplasmic reticulum prior activaton of programmed cell death, Society for Neuroscience 2007. Program No. 688.18.

Researcher : Lam AKM

Project Title:	Investigating the role of Epac in the differentiation of mouse and human embryonic stem cells into insulin-producing cells
Investigator(s):	Lam AKM, Chung SK, Lam KSL
Department:	Medical Faculty
Source(s) of Funding:	Small Project Funding
Start Date:	09/2006

Abstract:

In type 1 and late stage of type 2 diabetes, blood glucose level is dependent on the hormones of the pancreas, insulin, which is released from pancreatic beta cell. Insulin secretion from the beta cells is regulated positively and negatively by many intracellular signals generated by various factors, including nutrients, hormones and neurotransmitters. cAMP is thought to be a most critical intracellular signal in the mechanism of insulin secretion (1,2). Glucose is believed to act principally to stimulate mitochondrial ATP synthesis, leading to the closure of ATP-sensitive K channel, cell depolarization, calcium influx and exocytosis.GLP-1 is an insulinotropic hormone with blood glucose-lowering properties secreted by endocrine L cells of the intestinal tract. Binding of GLP-1 to the GLP-1 receptor stimulate the production of cAMP and the increase in intracellular Ca2+ for insulin secretion in pancreatic beta cells. Epac is a novel cAMP regulated guanine exchange factor for the Ras-like small GTPase Rap1 and Rap2 (3,4). It was shown that the GEF activity of Epac was strongly induced by cAMP besides protein kinase A. There are two isoforms of Epac, Epac1 and Epac2, in the mammalian cell. Both isoforms are expressed in pancreatic beta-cells (5) and is suggested to mediate the stimulatory actions of GLP-1 on Ca2+-dependent insulin secretion. Treatment with antisense oligonucleotide against Epac2 blocks the GLP-1-potentiated insulin secretion in the mouse pancreatic islets (6,7). Epac also acts as cAMP sensor, which specifically interacted with ATP-sensitive K+ channel (ATP sensor), Piccolo (Ca2+ sensor) and L-type voltage-dependent Ca2+ channels for insulin exocytosis (6,8). The Ca2+ release by GLP-1 agonist, exendin-4, is blocked by the overexpression of dominant negative Epac but increased by Epac selective analogue, 8-pCPT-2’-O-Me-cAMP (9). Therefore, by activating of Epac, GLP-1 sensitizes the beta cells to respond to the blood glucose level and stimulate insulin secretion. Therefore, it is hypothesized that the interaction of Epac and GLP-1 in insulin secretion may be relevant to the treatment of type 2 diabetes. In recent years, the potential use of mouse and human embryonic stem cells to generate insulin-producing cells in an attempt to treat type 1 and type 2 diabetes has received much attention (10-13). The differentiated insulin producing cells from mouse embryonic stem cells has been shown to reverse the hyperglycemia when transplanted into diabetic mice (14). However, the current issues for expression of insulin during in vitro beta-cell differentiation remain controversial since the amount of insulin produced by pure beta-cell population in the glucose dependent manner is considerably below that of native pancreatic islets. Epac is suggested to promote the beta-cell survival and mediate the regulation of beta-cell stimulus-secretion coupling. GLP-1 and cAMP analogue, which selectively activates Epac inhibited palmitate-mediated caspase-3 activation in a dose-dependent manner in beta-cell line RINm5F (15). Furthermore, Epac-specific analogue activated the PKA-dependent Erk1/2 signalling pathway and converts cAMP from a proliferative signal into differentiation signal in the neuronal cell line (16). Our preliminary data show that Epac1 and Epac2 are expressed as early in the undifferentiated stage of mouse embryonic stem cells (mESC). Moreover, the number of insulin positive cells from the differentiation of Epac1-/- mESC was significantly lower that that of wild type mESC. Therefore, it is proposed that Epac may be a growth and/or differentiation factor for the pancreatic beta-cells. We hypothesized that Epac plays an important role in the in vitro differentiation and proliferation of embryonic stem cells into beta-cells for the treatment of diabetes mellitus. The main objectives of this proposal are as follow: 1. To determine the role of Epac on the expression of beta-cell specific markers in the differentiation of mouse and human embryonic stem cells into pancreatic beta-cells 2. To determine the effect of Epac knockout in the differentiation of mouse embryonic stem cells to pancreatic beta cells 3. To determine the survival and in vivo function of Epac transduced or Epac analogue treated hESC-derived insulin-producing cells References: 1.Schuit, F. C., and Pipeleers, D. G. (1985) Endocrinology 117, 834-840 2.Pipeleers, D. G., Schuit, F. C., in't Veld, P. A., Maes, E., Hooghe-Peters, E. L., Van de Winkel, M., and Gepts, W. (1985) Endocrinology 117, 824-833 3.de Rooij, J., Zwartkruis, F. J., Verheijen, M. H., Cool, R. H., Nijman, S. M., Wittinghofer, A., and Bos, J. L. (1998) Nature 396, 474-477 4.Holz, G. G. (2004) Diabetes 53, 5-13. 5.Leech, C. A., Holz, G. G., Chepurny, O., and Habener, J. F. (2000) Biochem Biophys Res Commun 278, 44-47 6.Kashima, Y., Miki, T., Shibasaki, T., Ozaki, N., Miyazaki, M., Yano, H., and Seino, S. (2001) J Biol Chem 276, 46046-46053 7.Fujimoto, K., Shibasaki, T., Yokoi, N., Kashima, Y., Matsumoto, M., Sasaki, T., Tajima, N., Iwanaga, T., and Seino, S. (2002) J Biol Chem 277, 50497-50502 8.Shibasaki, T., Sunaga, Y., Fujimoto, K., Kashima, Y., and Seino, S. (2004) J Biol Chem 279, 7956-7961 9.Kang, G., Chepurny, O. G., Rindler, M. J., Collis, L., Chepurny, Z., Li, W. H., Harbeck, M., Roe, M. W., and Holz, G. G. (2005) J Physiol 566, 173-188 10.Lumelsky, N., Blondel, O., Laeng, P., Velasco, I., Ravin, R., and McKay, R. (2001) Science 292, 1389-1394 11.Blyszczuk, P., Asbrand, C., Rozzo, A., Kania, G., St-Onge, L., Rupnik, M., and Wobus, A. M. (2004) Int J Dev Biol 48, 1095-1104 12.Assady, S., Maor, G., Amit, M., Itskovitz-Eldor, J., Skorecki, K. L., and Tzukerman, M. (2001) Diabetes 50, 1691-1697 13.Segev, H., Fishman, B., Ziskind, A., Shulman, M., and Itskovitz-Eldor, J. (2004) Stem Cells 22, 265-274 14.Soria, B., Roche, E., Berna, G., Leon-Quinto, T., Reig, J. A., and Martin, F. (2000) Diabetes 49, 157-162 15.Kwon, G., Pappan, K. L., Marshall, C. A., Schaffer, J. E., and McDaniel, M. L. (2004) J Biol Chem 279, 8938-8945 16.Kiermayer, S., Biondi, R. M., Imig, J., Plotz, G., Haupenthal, J., Zeuzem, S., and Piiper, A. (2005) Mol Biol Cell 16, 5639-5648

Researcher : Lau HT

List of Research Outputs

Chiu K., Lau W.M., Lau H.T., So K.F. and Chang R.C.C., Micro-dissection of rat brain for RNA and protein extraction from specific brain region, Journal of Visualized Experiments. 2007, 7.

Researcher : Lau KW

List of Research Outputs

Lau K.W., Evaluation of using all-trans-retinoic acid to differentiate human neuroblastoma SH-SY5Y cells in neurodegeneration research . 2007, 101 pages.

Researcher : Lau TY

List of Research Outputs

Lau T.Y., Wang Y. and Chiu J., Reactive oxygen species: Current knowledge and applications in cancer research and therapeutic, Journal of Cellular Biochemistry. 2008, 104: 657-667.

Researcher : Lau WM

List of Research Outputs

Chiu K., Lau W.M., Lau H.T., So K.F. and Chang R.C.C., Micro-dissection of rat brain for RNA and protein extraction from specific brain region, Journal of Visualized Experiments. 2007, 7.

Chiu K., Lau W.M., Yeung S.C., Chang R.C.C. and So K.F., Retrograde labeling of reinal ganglion cells by application of Fluoro-Gold on the surafce of superior colliculus, Journal of Visualized Experiments. 2008.

Lau W.M., Tsao G.S.W., So K.F. and Yip H.K.F., Expression of telomerase reverse transcriptase in adult goldfish retina, Journal of Molecular Neuroscience. 2007, 32: 160-267.

Lau W.M., Wong A.O.L., Tsao G.S.W., So K.F. and Yip H.K.F., Molecular cloning and characterization of the Zebrafish (Danio rerio) telomerase catalytic subunit (Telomerase Reverse Transcriptase, TERT), Journal of Molecular Neuroscience. Humana Press Inc., 2007, 34: 63-75.

Researcher : Lee DTW

List of Research Outputs

Howard E.W., Leung C.L., Yuen H.F., Chua C.W., Lee D.T.W., Chan K.W., Wang X. and Wong Y.C., Decreased adhesiveness, resistance to anoikis and suppression of GRP94 are integral to the survival of circulating tumor cells in prostate cancer, Clinical and Experimental Metastasis. 2008, 25: 497-508.

Howard E.W., Lee D.T.W., Chiu Y.T., Chua C.W., Wang X. and Wong Y.C., Evidence of a novel docetaxel sensitizer, garlic-derived S-allylmercaptocysteine, as a treatment option for hormone refractory prostate cancer, International Journal of Cancer. 2008, 122: 1941-1948.

Wong Y.C., Howard E.W., Chu Q., Lee D.T.W. and Wang X., Garlic extract synergizes with docetaxel in suppressing the hormone refractory prostate cancer growth, Proceeding of 12th World Congress on Advances in Oncology and 10th International Symposium on Molecular Medicine held in Hersonissos, Crete, Greece from October 11-13, 2007.Int J Mol Medicine . 2007, 20, Suppl 1: S7.

Researcher : Lee VWH

List of Research Outputs

Fu Q., Wu W., Wang H., Li X., Lee V.W.H. and So K.F., Up-regulated endogenous erythropoietin/erythropoietin receptor system and exogenous erythropoietin rescue retinal ganglion cells after chronic ocular hypertension, Cellular and Molecular Neurobiology. 2008, 28: 317-329.

Li S.Y., Yau S.Y., Chen B., Tay D.K.C., Lee V.W.H., Pu M., Chan H.H.L. and So K.F., Enhanced Survival of Melanopsin-expressing Retinal Ganglion Cells After Injury is Associated with the PI3 K/Akt Pathway, Cellular and Molecular Neurobiology. 2008, 28: 1095-1107.

Researcher : Leong VYL

List of Research Outputs

Mak G.W.Y., Leong V.Y.L., Yau T.O., Ng I.O.L. and Ching Y.P., Functional characterization of C53 and its possible roles in tumorigenesis, Oncogenes and Human Cancer- The next 25 years / Nature-Centro Nacional de Investigaciones Oncologicas (CNIO) Conference . 2007.

Researcher : Leung CL

List of Research Outputs

Howard E.W., Leung C.L., Yuen H.F., Chua C.W., Lee D.T.W., Chan K.W., Wang X. and Wong Y.C., Decreased adhesiveness, resistance to anoikis and suppression of GRP94 are integral to the survival of circulating tumor cells in prostate cancer, Clinical and Experimental Metastasis. 2008, 25: 497-508.

Zhang X., Wang Q., Ling M.T., Wong Y.C., Leung C.L., Tsao G.S.W. and Wang X., Anti-apoptotic role of TWIST and its association with Akt pathway in mediating taxol resistance in nasopharyngeal carcinoma cells, International J Cancer. 2007, 120: 1891-1898.

Zhang X., Ling M.T., Wang Q., Lau C.K., Leung C.L., Lee T.K., Cheung A., Wong Y.C. and Wang X., Identification of a novel inhibitor of differentiation-1 (ID-1) binding partner, caveolin-1, and its role in epithelial-mesenchymal transition and resistance to apoptosis in prostate cancer cells, The Journal of Biological Chemistry. 2007, 282(46): 33284-33294.

Researcher : Leung TM

List of Research Outputs

Chan C.H., Shum D.K.Y., Tipoe G.L., Mak J.C.W., Leung T.M. and Ip M.S.M., Upregulation of ICAM-1 expression in bronchial epithelial cells by airway secretions in bronchiectasis, Respiratory Medicine. 2008, 102: 287-298.

Ho C.T., Tipoe G.L., Liong E.C., Leung T.M., Lau T.Y.H., Fung M.L. and Nanji A.A., Decreased adiponectin and antioxidant enzymes are associated with necroinflammatory changes and fibrosis in a rat model for non-alcoholic fatty liver disease (NAFLD), Hepatology International. 2008, 2: S151-S152.

Leung T.M., Tipoe G.L., Liong E.C., Lau T.Y.H., Fung M.L. and Nanji A.A., Nitric oxide inhibitor or donor reverses the induction of hypoxia-inducible factor (HIF-1á) in chronic liver fibrosis in mice, XIth International Congress of Toxicology, Montreal, Canada. 2007.

Tipoe G.L., Liong E.C., Casey C.A., Donohue Jr. T.M., Eagon P.K., So H.S.H., Leung T.M., Fogt F. and Nanji A.A., A voluntary oral enthanol-feeding rat model associated with necroinflammatory liver injury, Alcoholism: Clinical and Experimental Research. 2008, 32(4): 1-14.

Tipoe G.L., Liong E.C., Leung T.M. and Nanji A.A., A voluntary oral-feeding rat model for pathological alcoholic liver injury, Methods in Molecular Biology. 2008, 447: 11-31.

Researcher : Leung TM

List of Research Outputs

Tipoe G.L., Liong E.C., Leung T.M. and Nanji A.A., A voluntary oral-feeding rat model for pathological alcoholic liver injury, Methods in Molecular Biology. 2008, 447: 11-31.

Researcher : Leung WC

List of Research Outputs

Leung W.C., Investigations into the role of endothelial endothelin-1 on transient focal cerebral ischemia. 2007, 222 pages.

Researcher : Li B

List of Research Outputs

Li B., Cheung P.Y., Wang X., Tsao G.S.W., Ling M.T., Wong Y.C. and Cheung A., Id-1 activation of PI3K/Akt/NFkB signaling pathway and its significance in promoting survival of esophageal cancer cells, Carcinogenesis. 2007, 28(11): 2313-2320.

Researcher : Li X

List of Research Outputs

Fu Q., Wu W., Wang H., Li X., Lee V.W.H. and So K.F., Up-regulated endogenous erythropoietin/erythropoietin receptor system and exogenous erythropoietin rescue retinal ganglion cells after chronic ocular hypertension, Cellular and Molecular Neurobiology. 2008, 28: 317-329.

Researcher : Liang Y

List of Research Outputs

Ellis-Behnke R.G., Liang Y., Chan K.C., Tay D.K.C., So K.F. and Wu E.X., Assessing the progression of functional regeneration of the visual system, 6th Picower-RIKEN Symposium, M.I.T., Cambridge USA. 2007.

Ellis-Behnke R.G., Liang Y., You S., Tay D.K.C., So K.F. and Schneider G.E., Beyond nano neuro knitting: creating a more permissive environment using SAPNS with Chondroitinase ABC for brain lesion repair and functional return of vision, International Brain Research Organization (IBRO), Melbourne, Australia. 2007.

Ellis-Behnke R.G., Liang Y., Tay D.K.C., You S.W., Schneider G.E. and So K.F., Beyond nano neuro knitting: creating of a more permissive environment using SAPNS with chondroitinase ABC for brain lesion repair and functional return of vision, 7th IBRO World Congress of Neuroscience , July 12-17, 2007, Melbourne, Australia. 2007, 272 POS-SUN-045.

Ellis-Behnke R.G., Liang Y., Cheung S.F., Tay D.K.C. and So K.F., Nano contrast enhancement agents used in the eye for tracing axons: Trauma or illlumination?, ARVO 2008 Annual Meeting, April 27-May 1, 2008, Florida, U. S. A.. 2008, No. 4014.

Ellis-Behnke R.G., Liang Y., Tay D.K.C. and So K.F., Nanomachines that help repair the brain, 1st IEEE International Conference on Nano/Molecular Medicine and Engineering, Macau SAR China. 2007.

Ellis-Behnke R.G., Liang Y., Tay D.K.C., Schneider G.E. and So K.F., The impact of nanotechnology on eye treatments, 7th International Symposium on Ocular Pharmacology and Therapeutics, Budapest, Hungary . 2008.

Ellis-Behnke R.G., Liang Y., Tay D.K.C., Schneider G.E. and So K.F., Using Nanotechnology For Tissue Bioengineering In Ophthalmology, 31st World Ophthalmology Congress, Symposium on Nanotechnology. 2008.

Ellis-Behnke R.G., Liang Y., Tay D.K.C., Schneider G.E. and So K.F., Using Nanotechnology To Repair The CNS: From The 4 Ps Of Regeneration To Crystal Clear Surgery To In Vivo Non-invasive Imaging Of Regenerating Axons , 1st Unither Nanomedical and Telemedical Technology conference. 2008.

Ellis-Behnke R.G., Liang Y., Tay D.K.C., So K.F. and Wu E.X., Using a 7 Tesla fMRI and Nano Contrast Agent to Visualize Regeneration of Axons in vivo after Chronic Injury in the Hamster Optic Tract , Society for Neuroscience, San Diego USA . 2007.

Guo J., Su H., Zeng Y., Liang Y., Wong W.M., Ellis-Behnke R.G., So K.F. and Wu W., Reknitting The Injured Spinal Cord By Self Assembling Peptide Nanofiber Scaffold, Nanomedicine: Nanotechnology, Biology and Medicine. 2007, 3(4): 311-321.

Guo J., Liang Y., Zeng Y., Ellis-Behnke R.G., So K.F. and Wu W., Reknitting the spinal cord using a self-assembling peptide nanofiber scaffold to promote functional recovery, Society for Neuroscience, San Diego USA. 2007.

So K.F., Liang Y., Tay D.K.C. and Ellis-Behnke R.G., Regenerative Medicine in Vision, 1st Pan Pacific Symposium on Stem Cells Research 2008, May 31-June 2, 2008. 98.

Researcher : Liao S

List of Research Outputs

Liao S., Leptin expression in embryos sired by male golden hamsters (Mesocricetus auratus) with accessory sex glands removed. 2007, 176 pages.

Researcher : Ling MT

Project Title:	The regulation and role of Id-1 in prostate cancer progression
Investigator(s):	Ling MT, Wong YC, Wang X
Department:	Anatomy
Source(s) of Funding:	Small Project Funding
Start Date:	09/2005

Abstract:

Background: Prostate cancer remains the most commonly diagnosed cancer in Western countries and recent reports indicated that the incidence and mortality rate of prostate cancer are rising significantly in Asian countries including Hong Kong. Nearly all the patients diagnosed with advanced stage prostate cancer will be treated with hormone ablation therapy, but most, if not all of them will inevitably progress to an androgen independent stage after a period of 2-3 years. The failure of the treatment is mainly due to the lost of dependency on androgen for the survival and proliferation of the cancer cells. Unfortunately, prostate cancer is relatively resistant to the chemotherapeutic drugs commonly used in the treatment of other cancers, making the disease virtually incurable at this stage. Therefore, to stop or at least delay the development of androgen independency could be the best way to improve the survival of prostate cancer patients. While the molecular events during the progression of prostate cancer have been studied intensively, the exact mechanism for the development of androgen independent disease is still unclear. Key issues: In the past 5 years, I have been studying the role of Id-1, which encodes an inhibitor of differentiation, in the development and progression of prostate cancer. We have recently shown that the Id-1 gene plays an important role in the development of androgen independent prostate cancer cell growth in tissue culture models [Ling et al., Carcinogenesis, 25:517, 2004]. We have demonstrated that Id-1 expression in prostate cancer cells is essential for the survival [Ling et al., Oncogene, 22:4498, 2003] and proliferation of the cells [Ling et al., Oncogene, 21:8498, 2002]. In prostate cancer cell lines as well as xenograft that grow independent of androgen, we have been able to detect very high level of Id-1 expression [Ling et al., Carcinogenesis, 25:517, 2004]. More interestingly, we have shown that over-expression of Id-1 in an androgen dependent prostate cancer cell line promotes the development of the androgen independent phenotype [Ling et al., Carcinogenesis, 25:517, 2004] i.e. androgen independent PSA expression and reduction of androgen responsiveness. These findings suggested that upregualtion of Id-1 is involved in the development of androgen independent prostate cancer. Purpose of the proposed project: The long-term goal of this proposal is to elucidate the molecular mechanism responsible for the upregulation of Id-1 during the progression of prostate cancer to the androgen independent stage and eventually facilitate the development of new therapeutic strategies against this disease. Hypothesis: The major hypothesis of this proposal is that expression of Id-1 in prostate cancer cells is negatively regulated by the androgen signaling pathway. This hypothesis is based on the following findings. Firstly, we found that androgen dependent prostate cancer cells LNCaP expressed very low level of Id-1 when cultured with fetal calf serum (FCS) [Ouyang et al, Carcinogenesis, 23:721, 2002], but the level of Id-1 increase sharply when steroids (including androgen) were removed from the FCS (unpublished data). Secondly, we have recently showed in human prostate cancer xenograft model that Id-1 expression was significantly upregulated in human prostate cancers soon after castration of the host [Ling et al., Carcinogenesis, in press, 2005]. Finally, the TGF-beta/Smad signaling pathway has been implicated as the major pathway controlling the transcription of the Id-1 gene [Kang et al., Mol Cell, 11:915, 2003]. Recently, Smad protein has been shown to be the coregulator of the androgen receptor (AR) signaling which enhances the androgen mediated PSA gene transcription [Kang et al., Proc. Natl. Acad. Sci.U.S.A, 98:3018, 2001]. Therefore, it was believed that AR and TGF-beta/Smad signaling pathway may regulate a number of their target genes synergistically. Based on these observations, the main focus of the proposed experiments will be on studying how androgen regulates the expression of Id-1 in prostate cancer cells and the significance of this regulation in the development of androgen independent prostate cancer. There are three specific aims in this study: 1. To determine the effect of androgen on the in vitro expression of Id-1 in prostate cancer cells. 2. To elucidate the signaling pathway involved in the regulation of Id-1 expression by androgen in prostate cancer cells. 3. To test the effect of Id-1 inactivation on the inhibition of prostate cancer progression.

Project Title:	The role of EMI1 in prostate carcinogenesis
Investigator(s):	Ling MT, Wang X
Department:	Anatomy
Source(s) of Funding:	Seed Funding Programme for Basic Research
Start Date:	02/2007

Abstract:

Background: Prostate cancer is currently the most commonly diagnosed male cancer in Western countries and recent statistic data suggests that the incidence is increasing in Asian countries, including Hong Kong [1]. When presented at early stage where the tumor is still localized, prostate cancer can be treated effectively with surgical or radio-prostatectomy. However, when the cancer reached the metastatic stage, the only frontline treatment available is chemical or surgical castration, which normally results in rapid relief of symptoms. Unfortunately, more than 70% of the patients will suffer again from the disease due to the development of hormone refractory stage[1]. Currently, there is no effective second line treatment available that can significantly enhance the overall survival of the prostate cancer patients once they reached that stage. Therefore, it is important to identify a better prognostic marker as well as to develope an alternative therapeutic strategy against the disease. Key issues: 1. EMI1 is a cell cycle regulatory protein which promotes the S-phase entry of the cell cycle. Previously, EMI1 expression has been shown to be upregulated in several types of tumor, including breast, ovary and colon[2]. Meanwhile, ectopic expression of EMI1 has recently been shown to induced tetraploidy and genomic instability[3], which are the hallmarks of cancer cells, suggesting that EMI1 may play role in cancer development. In addition, EMI1 overexpression has also been demonstrated to be associated strongly with ER negative breast tumors and poor clinical outcome of breast cancer patients[4], suggesting that EMI1 may have function in tumor progression. However, the role of EMI1 in prostate cancer is so far unclear. 2. Recently, by examining the protein level of EMI1 in a series of prostate epithelial cell lines, we found that EMI1 was significantly upregulated in all the cancer cell lines that we tested, and the level was highest in the androgen independent prostate cancer cells. From limited archival materials examined, EMI1 was most highly expressed in AI prostate cancer tissue. These results suggest that EMI1 may play important roles in the development as well as the progression of prostate cancer. Hypothesis: EMI1 may play a promoting role in prostate carcinogensis and may be a novel prognostic marker as well as therapeutic target against prostate cancer. Objectives 1. To examine EMI1 expression in prostate cancer tissues. 2. To examine if EMI1 over-expression would promote the tumorigenesis of the prostate epithelial cells. 3. To test the inhibitory effect of EMI1 knockdown on prostate cancer development. References 1. Krongrad,A., Lai,S. and Vidal,E.M. The significance of changing trends in prostate cancer incidence and mortality, Semin.Urol.Oncol., 16: 30-34, 1998. 2. Hsu,J.Y., Reimann,J.D., Sorensen,C.S., Lukas,J. and Jackson,P.K. E2F-dependent accumulation of hEmi1 regulates S phase entry by inhibiting APC(Cdh1), Nat.Cell Biol., 4: 358-366, 2002. 3. Lehman,N.L., Verschuren,E.W., Hsu,J.Y., Cherry,A.M. and Jackson,P.K. Overexpression of the anaphase promoting complex/cyclosome inhibitor Emi1 leads to tetraploidy and genomic instability of p53-deficient cells, Cell Cycle, 5: 1569-1573, 2006. 4. van,'., V, Dai,H., van,d., V, He,Y.D., Hart,A.A., Mao,M., Peterse,H.L., van der,K.K., Marton,M.J., Witteveen,A.T., Schreiber,G.J., Kerkhoven,R.M., Roberts,C., Linsley,P.S., Bernards,R. and Friend,S.H. Gene expression profiling predicts clinical outcome of breast cancer, Nature, 415: 530-536, 2002.

List of Research Outputs

Chiu Y.T., Wong Y.C. and Ling M.T., Identification of a novel androgen receptor corepressor, CDC25A, in prostate cancer cells., 12th Research Postgraduate Symposium, HKU Medical Faculty, Dec 12 and 14 2007. . 2007, 95.

Kwok W.K., Ling M.T., Yuen H.F., Wong Y.C. and Wang X., Role of p14^ARF in TWIST-mediated senescence in prostate epithelial cells, Carcinogenesis. 2007, 28(12): 2467-2475.

Li B., Cheung P.Y., Wang X., Tsao G.S.W., Ling M.T., Wong Y.C. and Cheung A., Id-1 activation of PI3K/Akt/NFkB signaling pathway and its significance in promoting survival of esophageal cancer cells, Carcinogenesis. 2007, 28(11): 2313-2320.

To K.W., Cheung H.W., Ling M.T., Wong Y.C. and Wang X., MAD2ΔC induces aneuploidy and promotes anchorage-independent growth in human prostate epithelial cells. , Oncogene. 2008, 27: 347-357.

Wong Y.C., Zhang X., Ling M.T. and Wang X., Caveolin 1, a novel Id-1 binding partner and its role on Id-1 induced behavioral change in prostate cancer cells, AACR annual meeting, San Diego, USA, April 12-16, 2008. 1082.

Wong Y.C., Zhang X., Ling M.T. and Wang X., Inactivation of Id-1 gene induces sensitivity of prostate cancer cells to chemotherapeutic drugs, In: JJ Li, Sara A Li, Suresh Mohla, Henri Rochefort and Thierry Maudelonde., Hormonal Carcinogenesis . Springer, 2008, V: 565-572.

Yu S., Wong Y.C., Wang X., Ling M.T., Chen S. and Chan F.L., Orphan nuclear receptor β suppresses in vitro and in vivo growth of prostate cancer cells via p21WAF1/CIP1 induction and as a potential therapeutic target in prostate cancer., Oncogene. 2008, 27: 2313-2320.

Zhang X., Wang Q., Ling M.T., Wong Y.C., Leung C.L., Tsao G.S.W. and Wang X., Anti-apoptotic role of TWIST and its association with Akt pathway in mediating taxol resistance in nasopharyngeal carcinoma cells, International J Cancer. 2007, 120: 1891-1898.

Zhang X., Ling M.T., Wong Y.C. and Wang X., Evidence of a novel anti-apoptotic factor: role of inhibitor of differentiation or DNA binding in anticancer drug-induced apoptosis, Cancer Science. 2007, 98: 308-314.

Zhang X., Ling M.T., Wang Q., Lau C.K., Leung C.L., Lee T.K., Cheung A., Wong Y.C. and Wang X., Identification of a novel inhibitor of differentiation-1 (ID-1) binding partner, caveolin-1, and its role in epithelial-mesenchymal transition and resistance to apoptosis in prostate cancer cells, The Journal of Biological Chemistry. 2007, 282(46): 33284-33294.

Researcher : Liong EC

List of Research Outputs

Ho C.T., Tipoe G.L., Liong E.C., Leung T.M., Lau T.Y.H., Fung M.L. and Nanji A.A., Decreased adiponectin and antioxidant enzymes are associated with necroinflammatory changes and fibrosis in a rat model for non-alcoholic fatty liver disease (NAFLD), Hepatology International. 2008, 2: S151-S152.

Lam S.S.Y., Tipoe G.L., Liong E.C. and Fung M.L., Chronic hypoxia enhances the expression and function of proinflammatory cytokines in the rat carotid body, 12th Research Postgraduate Symposium, HKU. 2007, 1-12.

Lam S.S.Y., Tipoe G.L., Liong E.C. and Fung M.L., Differential expressions and roles of hypoxia-inducible factor-1a, -2a and -3a in the rat carotid body during chronic and intermittent hypoxia, Histology and Histopathology. 2008, 23: 271-280.

Lam S.S.Y., Tipoe G.L., Liong E.C. and Fung M.L., Functional upregulation of proinflammatory cytokines and local inflammation in the rat carotid body during chronic hypoxia, The 11th Annual Scientific Meeting of the Institute of Cardiovascular Science and Medicine (Journal of the Hong Kong College of Cardiology). 2007, 15(2):91: 18.

Lam S.Y.S., Tipoe G.L., Liong E.C. and Fung M.L., Chronic hypoxia upregulates the expression and function of proinflammatory cytokines in the rat carotid body, Histochemistry and Cell Biology. 2008, 130: 549-559.

Leung T.M., Tipoe G.L., Liong E.C., Lau T.Y.H., Fung M.L. and Nanji A.A., Nitric oxide inhibitor or donor reverses the induction of hypoxia-inducible factor (HIF-1á) in chronic liver fibrosis in mice, XIth International Congress of Toxicology, Montreal, Canada. 2007.

Tipoe G.L., Liong E.C., Casey C.A., Donohue Jr. T.M., Eagon P.K., So H.S.H., Leung T.M., Fogt F. and Nanji A.A., A voluntary oral enthanol-feeding rat model associated with necroinflammatory liver injury, Alcoholism: Clinical and Experimental Research. 2008, 32(4): 1-14.

Tipoe G.L., Liong E.C., Leung T.M. and Nanji A.A., A voluntary oral-feeding rat model for pathological alcoholic liver injury, Methods in Molecular Biology. 2008, 447: 11-31.

Researcher : Lo ACY

List of Research Outputs

Cheung A.K.H., Lo A.C.Y., So K.F., Chung S.S.M. and Chung S.K., Gene deletion and pharmacological inhibition of aldose reductase protect against retinal ischemic injury, Experimental Eye Research. 2007, 85: 608-616.

Researcher : Lok CN

List of Research Outputs

Lok C.N., Ehrlich H.P., White S.L., Buttolph T.R., Cultroneo K.R. and Chiu J., Oligodeoxynucleotide decoy therapy blocks type 1 procollagen transcription and the prolyl hydroxylase b subunit translation, Journal of Cellular Biochemistry. 2008, 103: 1066-1075.

Researcher : Lucas PW

List of Research Outputs

Cheng A.C.O., Lucas P.W., Yuen H.K.L., Lam D.S.C. and So K.F., Surgical anatomy of the Chinese orbit, Ophthalmic Plastic and Reconstructive Surgery. 2008, 24(2): 136-141.

Researcher : Mak GWY

List of Research Outputs

Mak G.W.Y., Leong V.Y.L., Yau T.O., Ng I.O.L. and Ching Y.P., Functional characterization of C53 and its possible roles in tumorigenesis, Oncogenes and Human Cancer- The next 25 years / Nature-Centro Nacional de Investigaciones Oncologicas (CNIO) Conference . 2007.

Researcher : Man CWY

List of Research Outputs

Law G.L., Wong K.L., Man C.W.Y., Wong W.T., Tsao G.S.W., Lam M.H.W. and LAM P.K.S., Emissive Terbium Probe for Multiphoton in Vitro Cell Imaging , Journal of the American Chemical Society. 2008, 130: 3714-3715.

Man C.W.Y., Rosa J., Yip Y.L., Cheung A., Kwong Y.L., Doxsey S.J. and Tsao G.S.W., Id1 overexpression induces tetraploidization and multiple abnormal mitotic phenotypes by modulating Aurora A , Molecular Biology Of The Cell. USA, The American Society for Cell Biology, 2008, 19: 2389-2401.

Tong P.H., Man C.W.Y., Tsao G.S.W. and Chan G.C.F., Arsenic Trioxide Induced All Cycle Arrest in Neuroblastoma Cells with or without MYCN Over-Expression & the Response Had No Correlation with their Effect on Chromosomal Passenger Complex, Advances in Neuroblastoma Research 2008, Chiba, Japan, 21-24 May 2008. 140.

Researcher : Man WYC

List of Research Outputs

Man W.Y.C., Induction of genomic instability and mitotic dysregulation in immortalized nasopharyngeal epithelial cells. 2007, 273 pages.

Researcher : Niu C

List of Research Outputs

Yip H.K.F., Niu C. and Wu G., Neuronal injury affects telomerase activity and expression in the adult rat nervous system, US Society of Neuroscience Annual Meeting . 2007.

Researcher : O WS

Project Title:	LEPTIN AND HUMAN SPERM FUNCTION
Investigator(s):	O WS, Yeung WSB, Li HWR
Department:	Anatomy
Source(s) of Funding:	Seed Funding Programme for Basic Research
Start Date:	12/2005

Abstract:

1. To demonstrate the expression pattern of different leptin receptor isoforms in human spermatozoa.2. To confirm the correlation of leptin concentration in seminal plasma and leptin receptor expression in spermatozoa with semen parameters (sperm concentration, motility, morphology, velocity curve linear, velocity average path and velocity straight line).3. To study the correlation of leptin concentration in seminal plasma and leptin receptor expression in spermatozoa with capacitation and acrosome reaction.4. To study the correlation of leptin concentration in seminal plasma and leptin receptor expression in spermatozoa with fertilisation outcome.

Project Title:	In vitro maturation - Mitochondria and oocyte competence
Investigator(s):	O WS, Yeung WSB
Department:	Anatomy
Source(s) of Funding:	Small Project Funding
Start Date:	09/2006

Abstract:

Objectives:(1) To establish a preantral follicle culture model system using rat oocytes;(2) To investigate the qunatitiy, function and distribution of mitochondria in oocytes matured in vitro; (3) To study the correlation of the mitochondria copies, functions and distribution in oocytes with fertilization outcome.BackgroundIt is evident from clinical IVF outcome that each embryo has a unique developmental potential. Current investigations suggested that physiological factors during oocyte development can have dowstream consequences for development (Cotichhio et al., 2004). Mitochondria dysfunctions or abnormalities in the oocyte have been found to be a critical determinant of embryo developmental competence (van Blerkom, 2004). The accumulation of mitochondria is a feature of oocyte maturation (Chen et al., 1995). During oogenesis, the mitochondrial copy number in primordial oocytes is

List of Research Outputs

Chan Y.F., Tang F. and O W.S., Adrenomedullin in the Rat Testis. II: Its Production, Actions on Inhibin Secretion, Regulation by Follicle-Stimulating Hormone, and Its Interaction with Endothelin 1 in the, Sertoli Cell Biol Reprod . 2008, 78: 780-5.

Chan Y.F., O W.S. and Tang F., Adrenomedullin in the rat testis. I: Its production, actions on testosterone secretion, regulation by human chorionic conadotropin, and its interaction with endothelin 1 in the Leydig cell, Biology of Reproduction. 2008, 78: 773-779.

Chan Y.F., Tang F. and O W.S., Adrenomedullin in the rat testis. II: Its production, actions on inhibin secretion, regulation by follicle-stimulating hormone, and its interaction with endothelin 1 in the sertoli cell, Biology of Reproduction. 2008, 78: 780-785.

Chan Y.F., O W.S. and Tang F., Adrenomedullin in the rat testis. I: its production, actions on testosterone secretion, regulation by human chorionic gonadotropin, and its interaction with endothelin 1 in the, Leydig cell.Biol Reprod. 2008, 78: 773-9.

Li Y.Y., Li L., Hwang I.S.S., Tang F. and O W.S., Coexpression of Adrenomedullin and Its Receptors in the Reproductive System of the Rat, Effects on Steroid Secretion in Rat Ovary,Biol Reprod. 2008, 79:200.

Li Y.Y., Li L., Hwang I.S.S., Tang F. and O W.S., Coexpression of adrenomedullin and its receptors in the reproductive system of the rat: Effects on steroid secretion in rat ovary, Biology of Reproduction. 2008, 79: 200-208.

Li Y.Y., O W.S. and Tang F., Effect of aging on the expression of adrenomedullin and its receptor component proteins in the male reproductive system of the rat., The Journals of Gerontology Series A: Biological Sciences and Medical Sciences. 2007, 62: 1346-1351.

Li Y.Y., O W.S. and Tang F., Effect of aging on the expression of adrenomedullin and its receptor component proteins in the male reproductive system of the rat, J Gerontol A Biol Sci Med Sci. 2007, 62: 1346-51.

Li Y.Y., O W.S. and Tang F., Effect of aging on the expression of adrenomedullin and its receptor component proteins in the male reproductive system of the rat, Journal of Gerontology: Biological Sciences. 2007, 62A(12): 1346-1351.

O W.S., Li S.L. and Tang F., Adrenomedullin in female reproduction: folliculogenesis, luteogenesis and pregnancy, Society for Reproduction and Fertility Abstract Series June 2008. 74 P62.

Wong C.L., Chan O.C., Lee K.H., O W.S. and Chow P.H., Absence of paternal accessory sex glands dysregulates preimplantation embryo cell cycle and causes early oviductal-uterine transit in the golden hamster in vivo, Fertility and Sterility. 2008, 89(4): 1021-1024.

Zhao W., O W.S. and Fung Y.S., Quantitation of Mitochondria Separated by Capillary Electrophoresis , 7th Asia-Pacific Internationa Symposium on Microscale Separation and Analysis (APCE 2007), Singapore, December 16-19, 2007. Paper 5:50, pp 5:141.

Researcher : Pu M

List of Research Outputs

Li S.Y., Yau S.Y., Chen B., Tay D.K.C., Lee V.W.H., Pu M., Chan H.H.L. and So K.F., Enhanced Survival of Melanopsin-expressing Retinal Ganglion Cells After Injury is Associated with the PI3 K/Akt Pathway, Cellular and Molecular Neurobiology. 2008, 28: 1095-1107.

Researcher : Qiu G

List of Research Outputs

Lau W.M., Qiu G., Yau S.Y., Helmeste D.M., Lee T.M.C., Tang S.W. and So K.F., Neuroprotection in steroid therapy: An animal model, Health Research symposium 2007, September 29, 2007. Poster P10.

Researcher : Schneider GE

List of Research Outputs

Ellis-Behnke R.G., Liang Y., You S., Tay D.K.C., So K.F. and Schneider G.E., Beyond nano neuro knitting: creating a more permissive environment using SAPNS with Chondroitinase ABC for brain lesion repair and functional return of vision, International Brain Research Organization (IBRO), Melbourne, Australia. 2007.

Ellis-Behnke R.G., Liang Y., Tay D.K.C., Schneider G.E. and So K.F., The impact of nanotechnology on eye treatments, 7th International Symposium on Ocular Pharmacology and Therapeutics, Budapest, Hungary . 2008.

Ellis-Behnke R.G., Liang Y., Tay D.K.C., Schneider G.E. and So K.F., Using Nanotechnology For Tissue Bioengineering In Ophthalmology, 31st World Ophthalmology Congress, Symposium on Nanotechnology. 2008.

Ellis-Behnke R.G., Teather L.A., Schneider G.E. and So K.F., Using Nanotechnology To Design Potential Therapies For CNS Regeneration, Current Pharmaceutical Design. 2007, 13(24): 2519-2538.

Ellis-Behnke R.G., Liang Y., Tay D.K.C., Schneider G.E. and So K.F., Using Nanotechnology To Repair The CNS: From The 4 Ps Of Regeneration To Crystal Clear Surgery To In Vivo Non-invasive Imaging Of Regenerating Axons , 1st Unither Nanomedical and Telemedical Technology conference. 2008.

Researcher : So KF

Project Title:	Molecular signaling of PKR/EiF2-[alpha] and GSK3[beta] in the pathophysiology of glaucoma
Investigator(s):	So KF, Hugon J, Chang RCC
Department:	Anatomy
Source(s) of Funding:	Incentive Award for RGC CERG Fundable But Not Funded Projects
Start Date:	07/2003

Abstract:

N/A

Project Title:	Neuroprotection in steroid therapy: an animal model
Investigator(s):	So KF, Lee TMC, Tang SW
Department:	Anatomy
Source(s) of Funding:	Research Fund for the Control of Infectious Diseases - Full Grants
Start Date:	01/2005

Abstract:

To investigate the effect of Lithium and paroxetine in arresting hippocampal damages associated with high dosage of steroid through quantitative neuro-anatomical and immunohistochemical methods.

Project Title:	Nanobiomedical manufacturing: the workforce of tomorrow
Investigator(s):	So KF, Ellis-Behnke RG, Tay DKC, Liang Y
Department:	Anatomy
Source(s) of Funding:	Innovation and Technology Support Programme
Start Date:	09/2006

Abstract:

The goal is to not only understand the variation in the manufacturing process, but to understand how to remove that variation. At the same time the process needs to be optimized for cost, purity and the quantities that will be needed for use in humans.

Project Title:	Hemostasis and Hong Kong: The future hub of Nanomedicine
Investigator(s):	So KF, Ellis-Behnke RG, Liang Y, Tay DKC
Department:	Anatomy
Source(s) of Funding:	Innovation and Technology Support Programme
Start Date:	09/2006

Abstract:

In order to progress the work to humans we need to perform four additional experiements: 1. Identify the mechanism of action 2. Perform large animal trials in pigs with a liver laceration model 3. Determine the best way to measure the quality of the material during manufacturing 4. Follow up the breakdown of the material by radio labeling the material in the brain and liver

Project Title:	The role of endothelin-1 in chronic ocular hypertension and retinal ischemia-reperfusion
Investigator(s):	So KF, Chung SK
Department:	Anatomy
Source(s) of Funding:	Seed Funding Programme for Basic Research
Start Date:	03/2007

Abstract:

Glaucoma is an ocular degenerative disease and characterized by progressive damage of optic nerve fibers and retinal ganglion cells (RGC), resulting in progressive visual field loss and excavation of the optic nerve head. As a leading cause of blindness worldwide, glaucoma continues to be a clinical problem. Optic nerve damage in most forms of glaucoma is commonly associated with increased intraocular pressure (IOP) caused by impairment in the normal aqueous humor outflow pathway. Yet, increased IOP may not be the sole risk factor for glaucomatous disease, and because the eye is a highly perfused organ, the vascular system may also play a key role in disease progression. Indeed, death of RGC is thought to be initiated after ischemia resulting from a prolonged vasoconstriction and/or vasospasms from abnormal auto-regulation of the retinal microcirculation. Recent experimental evidence suggests that endothelin-1 (ET-1), a potent vasoconstrictor, may be an important contributor to glaucoma pathophysiology. Studies indicate that perfusion instability, resulted from a disturbed auto-regulation in the context of a general vascular dysregulation, might contribute to glaucoma. Indeed, ET-1 levels in the aqueous humor and plasma are higher in patients with primary open-angle glaucoma. Both vascular (endothelial) and glial (astrocytic) ET-1 are involved in the regulation of retinal micro-circulation; yet, the involvement of these two components in pathophysiology of glaucoma retinopathy is poorly understood. Transient ischemia-related diseases, such as central retinal artery occlusion, angle-closure glaucoma and carotid artery disease, also affect vision. Various methods, such as raising the IOP through cannulation of the eye and ligation of the central retinal artery together with the optic nerve, have been used to create a model of retinal ischemia-reperfusion, but they have drawbacks and limitations. In light of this, we decided to investigate the contribution of vascular and glial ET-1 to the pathogenesis of glaucoma and retinal ischemia-reperfusion using animal models. As validation and interpretation of the published data on human studies are difficult, animal systems may provide insights into exploring the underlying molecular mechanisms of development of glaucoma. Dogs and rats have provided valuable information on the pathogenesis of experimental glaucoma in the form of ocular hypertension, but they are poorly suited for these studies using modern methods of genetic manipulations. Building on our longstanding expertise in studies using transgenic mice, we propose to use transgenic mouse models to study the involvement of ET-1 in retinal structural and functional lesions in ocular hypertension. With the availability of the Tie1-ET-1 (TET-1) and GFAP-ET1 (GET-1) transgenic mice that we generated, we plan to use these animals in our experiments proposed below. The TET-1 mice over-express ET-1 in the endothelial cells under the control of the tie-1 promoter whereas the GET-1 mice carry a transgene in which ET-1 expression is targeted by the GFAP promoter to the astrocytes and Muller cells. Here, we propose to challenge these two lines of transgenic mice to ocular hypertension and assay for retinal structural lesions and functional deficits. In addition, we will challenge these mice with middle cerebral artery occlusion (MCAO) using the intraluminal method, a well established model that is shown to result in retinal ischemia. In so doing, we will be able to investigate the differential contribution of vascular and glial ET-1 in experimental glaucoma and retinal ischemia-reperfusion. Our approach is outlined as follows: 1.To determine the expression of ET-1 and its related genes in chronic ocular hypertension and retinal ischemia-reperfusion. 2.To determine the effects of vascular ET-1 and glial ET-1 in retinal development using transgenic mouse models. 3.To determine the effects of vascular ET-1 and glial ET-1 in ocular hypertension and retinal ischemia-reperfusion. 4.To understand the underlying mechanism behind the observed effects of endothelial and astrocytic ET-1 in chronic ocular hypertension and retinal ischemia-reperfusion using proteomics analyses

List of Research Outputs

Cen L.P., Luo J.M., Zhang C.W., Fan Y.M., Song Y., So K.F., Rooijen N.V., Pang C.P., Lam D.S.C. and Cui Q., Chemotactic effect of ciliary neurotrophic factor on macrophages in retinal ganglion cell survival and axonal regneration, Investigative Ophthalmology & Visual Science. 2007, 48(9): 4257-4266.

Chan B.P., Chan C.M. and So K.F., Collagen-based microspheres incorporating bioactive molecules, methods for preparation and modification, and applications., Provisional Patent Application (filed on 7 July 2007). 2007.

Chan B.P., Chan C.M. and So K.F., Effects of photochemical crosslinking on the microstructure of collagen and a feasibility study on controlled protein release, Acta Biomaterialia. Elsevier Ltd., 2008, 4: 1627-1636.

Chan C.M., So K.F. and Chan B.P., Fabrication of nano-fibrous collagen microspheres for protein delivery and effects of photochemical crosslinking on release kinetics, Journal of Controlled Release. Elsevier B.V., 2008, 129: 135-143.

Chan C.M., So K.F. and Chan B.P., Photochemically crosslinked collagen microspheres for controlled protein release, The 34th Annual Meeting and Exposition of the Controlled Release Society. 7-11 Jul 2007. Long Beach, California, USA. 2007, p558.

Chang M.P., Chang R.C.C., Wang M. and So K.F., A review on the laboratory investigations and epidemiological studies of black tea, In: Chi-Tang Ho, James E. Simon, Fereidoon Shahidi and Yu Shao, ACS Symposium Series 987, Dietary Supplements. Washington, DC, American Chemical Society, 2008.

Chang R.C.C., Yik S.Y., Ho Y.S., Lai S.W. and So K.F., Direct neurotoxic effects of dsRNA: Implication of virus-induced neurodegeneration , Society for Neuroscience 2007. Program No. 605.23.

Chang R.C.C., Yu M.S., Ho Y.S., Lai S.W., Chiu K. and So K.F., Polysaccharides from medicinal herbs as potential drug lead in Alzheimer's disease, Neurobiology of Aging . 2008, 29S: S4-S5.

Chang R.C.C. and So K.F., Use of anti-aging herbal medicine, Lycium barbarum, against aging-associated diseases. What do we know so far?, Cellular Molecular Neurobiology. 2008, 28: 643-652.

Cheng A.C.O., Lucas P.W., Yuen H.K.L., Lam D.S.C. and So K.F., Surgical anatomy of the Chinese orbit, Ophthalmic Plastic and Reconstructive Surgery. 2008, 24(2): 136-141.

Cheung A.K.H., Lo A.C.Y., So K.F., Chung S.S.M. and Chung S.K., Gene deletion and pharmacological inhibition of aldose reductase protect against retinal ischemic injury, Experimental Eye Research. 2007, 85: 608-616.

Cheung Y.T., Yu M.S., Lai S.W., So K.F. and Chang R.C.C., Global protein translation control in beta-amyloid peptide induced neurotoxicity, Third International Symposium on Healthy Aging: Improving the Health of an Aging Population, March 1-2, 2008 Hong Kong. 2008, 49 P2.

Cheung Y.T., Yu M.S., Lai S.W., So K.F. and Chang R.C.C., Global protein translation control in beta-amyloid peptide neurotoxicity, Federation of European Neurosciences Societies Abstracts. 2007, 4: Poster 014.3.

Cheung Z.H., Leung M.C.P., Yip H.K.F., Wu W., Siu F.K.W. and So K.F., A neuroprotective herbal mixture inhibits caspase-3-independent apoptosis in retinal ganglion cells, Celular and Molecular Neurobiology. 2008, 28: 137-155.

Chiu K., Yeung S.C., Ho Y.S., Chan W., So K.F. and Chang R.C.C., Best Poster Award, Hong Kong Society of Immunology. 2008.

Chiu K., Chang R.C.C. and So K.F., Intravitreous injection for establishing ocular disease model , Journal of Visualized Experiments. 2007, 8.

Chiu K., Chang R.C.C. and So K.F., Laser induced chronic ocular hypertension model on SD rats, Journal of Visualized Experiments. 2007, 10.

Chiu K., Lau W.M., Lau H.T., So K.F. and Chang R.C.C., Micro-dissection of rat brain for RNA and protein extraction from specific brain region, Journal of Visualized Experiments. 2007, 7.

Chiu K., Yeung S.C., Ho Y.S., Chan W., So K.F. and Chang R.C.C., Neuroprotective effect of IL-10 on retinal ganglion cell survival in experimental glaucoma model, Hong Kong Society for Immunology 2008 Annual General Meeting and Scientific Meeting, April 19, 2008, Hong Kong.. 2008, 26.

Chiu K., Lau W.M., Yeung S.C., Chang R.C.C. and So K.F., Retrograde labeling of reinal ganglion cells by application of Fluoro-Gold on the surafce of superior colliculus, Journal of Visualized Experiments. 2008.

Ellis-Behnke R.G., Liang Y., Chan K.C., Tay D.K.C., So K.F. and Wu E.X., Assessing the progression of functional regeneration of the visual system, 6th Picower-RIKEN Symposium, M.I.T., Cambridge USA. 2007.

Ellis-Behnke R.G., Liang Y., You S., Tay D.K.C., So K.F. and Schneider G.E., Beyond nano neuro knitting: creating a more permissive environment using SAPNS with Chondroitinase ABC for brain lesion repair and functional return of vision, International Brain Research Organization (IBRO), Melbourne, Australia. 2007.

Ellis-Behnke R.G., Liang Y., Tay D.K.C., You S.W., Schneider G.E. and So K.F., Beyond nano neuro knitting: creating of a more permissive environment using SAPNS with chondroitinase ABC for brain lesion repair and functional return of vision, 7th IBRO World Congress of Neuroscience , July 12-17, 2007, Melbourne, Australia. 2007, 272 POS-SUN-045.

Ellis-Behnke R.G., Liang Y., Cheung S.F., Tay D.K.C. and So K.F., Nano contrast enhancement agents used in the eye for tracing axons: Trauma or illlumination?, ARVO 2008 Annual Meeting, April 27-May 1, 2008, Florida, U. S. A.. 2008, No. 4014.

Ellis-Behnke R.G., Liang Y., Tay D.K.C. and So K.F., Nanomachines that help repair the brain, 1st IEEE International Conference on Nano/Molecular Medicine and Engineering, Macau SAR China. 2007.

Ellis-Behnke R.G., Liang Y., Tay D.K.C., Schneider G.E. and So K.F., The impact of nanotechnology on eye treatments, 7th International Symposium on Ocular Pharmacology and Therapeutics, Budapest, Hungary . 2008.

Ellis-Behnke R.G., Liang Y., Tay D.K.C., Schneider G.E. and So K.F., Using Nanotechnology For Tissue Bioengineering In Ophthalmology, 31st World Ophthalmology Congress, Symposium on Nanotechnology. 2008.

Ellis-Behnke R.G., Teather L.A., Schneider G.E. and So K.F., Using Nanotechnology To Design Potential Therapies For CNS Regeneration, Current Pharmaceutical Design. 2007, 13(24): 2519-2538.

Ellis-Behnke R.G., Liang Y., Tay D.K.C., Schneider G.E. and So K.F., Using Nanotechnology To Repair The CNS: From The 4 Ps Of Regeneration To Crystal Clear Surgery To In Vivo Non-invasive Imaging Of Regenerating Axons , 1st Unither Nanomedical and Telemedical Technology conference. 2008.

Ellis-Behnke R.G., Liang Y., Tay D.K.C., So K.F. and Wu E.X., Using a 7 Tesla fMRI and Nano Contrast Agent to Visualize Regeneration of Axons in vivo after Chronic Injury in the Hamster Optic Tract , Society for Neuroscience, San Diego USA . 2007.

Fu Q., Hu B., Wu W., Pepinsky R.B., Mi S. and So K.F., Blocking LINGO-1 function promotes retinal ganglion cell survival following ocular hypertension and optic nerve transection, Investigative Ophthalmology & Visual Science. 2008, 49(3): 975-985.

Fu Q., Wu W., Wang H., Li X., Lee V.W.H. and So K.F., Up-regulated endogenous erythropoietin/erythropoietin receptor system and exogenous erythropoietin rescue retinal ganglion cells after chronic ocular hypertension, Cellular and Molecular Neurobiology. 2008, 28: 317-329.

Guo J., Su H., Zeng Y., Liang Y., Wong W.M., Ellis-Behnke R.G., So K.F. and Wu W., Reknitting The Injured Spinal Cord By Self Assembling Peptide Nanofiber Scaffold, Nanomedicine: Nanotechnology, Biology and Medicine. 2007, 3(4): 311-321.

Guo J., Liang Y., Zeng Y., Ellis-Behnke R.G., So K.F. and Wu W., Reknitting the spinal cord using a self-assembling peptide nanofiber scaffold to promote functional recovery, Society for Neuroscience, San Diego USA. 2007.

Ho Y.S., Yu M.S., Lai S.W., So K.F., Yuen W.H. and Chang R.C.C., Characterizing the neuroprotective effects of alkaline extract of Lycium barbarum on b-amyloid peptide neurotoxicity, Brain Research. 2007, 1158: 123-134.

Ho Y.S., Yu M.S., Lai S.W., So K.F., Yuen W.H. and Chang R.C.C., Lycium barbarum as a potential drug to attenuate neurodegeneration in Alzheimer's disease, 2007 TWGHs Eddie Wang Symposium on Integrated Chinese and Western Medicine. 2007, 197.

Ho Y.S., Yu M.S., Yik S.Y., Lai S.W., So K.F., Yuen W.H. and Chang R.C.C., Lycium barbarum protects neurons against neurodegeneration in Alzheimer's disease through multiple approaches, Third International Symposium on Healthy Aging: Improving the Health of an Aging Population, March 1-2, 2008, Hong Kong. 2008, 44 OP10.

Lai S.W., So K.F. and Chang R.C.C., Aggregation/collapse of endoplasmic reticulum prior activaton of programmed cell death, Society for Neuroscience 2007. Program No. 688.18.

Lai S.W., So K.F., Yuen W.H., So K.F., Zee S.S.Y. and Chang R.C.C., Antagonizing Beta-amyloid Peptide Neurotoxicity of the Anti-aging Fungus Ganoderma Lucidum, Brain Research . 2008, 1190: 215-224.

Lau W.M., Helmeste D.M., Lee T.M.C., Tang S.W. and So K.F., Differential effect of chronic corticosterone and antidepressant treatment on amygdale cell proliferation and depression-like behavior, Hong Kong Society of Biological Psychiatry Conference 2007, October 18-20, 2007, Hong Kong. 2007, 20 A0007.

Lau W.M., Tsao G.S.W., So K.F. and Yip H.K.F., Expression of telomerase reverse transcriptase in adult goldfish retina, Journal of Molecular Neuroscience. 2007, 32: 160-267.

Lau W.M., Wong A.O.L., Tsao G.S.W., So K.F. and Yip H.K.F., Molecular cloning and characterization of the Zebrafish (Danio rerio) telomerase catalytic subunit (Telomerase Reverse Transcriptase, TERT), Journal of Molecular Neuroscience. Humana Press Inc., 2007, 34: 63-75.

Lau W.M., Qiu G., Yau S.Y., Helmeste D.M., Lee T.M.C., Tang S.W. and So K.F., Neuroprotection in steroid therapy: An animal model, Health Research symposium 2007, September 29, 2007. Poster P10.

Li S.Y., Yau S.Y., Chen B., Tay D.K.C., Lee V.W.H., Pu M., Chan H.H.L. and So K.F., Enhanced Survival of Melanopsin-expressing Retinal Ganglion Cells After Injury is Associated with the PI3 K/Akt Pathway, Cellular and Molecular Neurobiology. 2008, 28: 1095-1107.

Mi S., Hu B., Hahm K., Luo Y., Hui S.K., Yuan Q.J., Wong W.M., Wang L., Su H., Chu T.H., Guo J., Zhang W., So K.F., Pepinsky B., Shao Z., Graff C., Garber E., Jung V., Wu E.X. and Wu W., LINGO-1 antagonist promotes spinal cord remyelination and axonal integrity in MOG-induced experimental autoimmune encephalomyelitis, Nature Medicine. 2007, 13(10): 1228-1233.

Schneider G.E., Ellis-Behnke R.G. and So K.F., Nano neuro knitting of the severed optic tract with return of function, ARVO 2008 Annual Meeting, April 27-May 1, 2008, Florida, U. S. A.. 2008, 371.

Shen J., Rong J., So K.F., Lau A.S.Y. and Tam P.K.H., Integration of multiple comprehensive approaches for exploration of therapeutic principle of BHD-01 in post-stroke treatment, HKU TCM Workshop 2007.

Shen J., Rong J., Tong Y., So K.F., Lau A.S.Y., Liu K.J., Tam P.K.H. and Cheng Y.C., Integration of systemic biology, chemical profile fingerprint and functional imaging technology for understanding therapeutic principle of Chinese medicinal formula: a study on classical Post-Stroke Formula, The Sixth Meeting of Consortium for Globalization of Chinese Medicine (CGCM). Beijing, China, 2007.

Shi Y., So K.F., Man R.Y.K. and Vanhoutte P.M.G.R., Oxygen-derived free radicals mediate endothelium-dependent contractions in femoral arteries of rats with streptozotocin-induced diabetes, British Journal of Pharmacology. 2007, 152: 1033-1041.

So K.F. and Chang R.C.C., Molecular mechanism of neuroprotection in glaucoma and Alzheimer's disease using Gouqizi, HKU TCM Workshop, December 14, 2007. 24.

So K.F. and Ellis-Behnke R.G., Nanomedicine for CNS regeneration and instant hemostasis, 2nd congress of International Society of Reconstructive Neurosurgery and 5th Scientific Meeting of the WFNS Neurorehabilitation Committee, September 13-16, 2007, Taipei, Taiwan. 2007, 79 S15-3.

So K.F., Nanomedicine for CNS regeneration and instant hemostasis, The 2nd Beijing International Forum on Rehabilitation, August 17-20, 2007, China. 2007, 14.

So K.F. and Ellis-Behnke R.G., Nanomedicine for CNS regeneration and instant hemostasis, The 5th Asian-Pacific International Congress of Anatomists & The 8th Iranian Congress of Anatomical Sciences, May 16-19, 2008, Iran. 2008, 126-127.

So K.F., Pharmacological study and its mechanism of chinese herbs on treatment of eye diseases, International Conference & Exhibition of the Modernization of Chinese Medicine & Health Products, August 16-20, 2007, Hong Kong. 2007, 23-24.

So K.F., Liang Y., Tay D.K.C. and Ellis-Behnke R.G., Regenerative Medicine in Vision, 1st Pan Pacific Symposium on Stem Cells Research 2008, May 31-June 2, 2008. 98.

Wang H., Wang N.L. and So K.F., Recent advances in research on the use of stem cells in the retina of adult rodents, International Review of Ophthalmology. 2008, 32(3): 153-156.

Wu M., Hou B., Yang H., Luo N., Jiao X.Y., So K.F., Ju G. and You S.W., Neuroprotective effects of transplanted olfactory ensheathing cells on axotimized retinal ganglion cells in adult rats, Neuroscience Research. 2007, 58S: S90 P1-d37.

Yik S.Y., Yu M.S., Ho Y.S., Lai S.W., Cheung Y.T., So K.F. and Chang R.C.C., Significance of dsRNA-elicited neurotoxicity, neuroprotection of minocycline on viral induced neurodegeneration, Third International Symposium on Healthy Aging: Improving the Health of an Aging Population, March 1-2,2008, Hong Kong.. 2008, 52 P14.

You S., Lau W.M., Tang S.W., Lee T.M.C. and So K.F., Effect of different doses of corticosterone on hippocampal cell proliferation, Hong Kong Society of Biological Psychiatry Conference 2007, October 18-20, 2007, Hong Kong. 2007, 19 A0006.

Yu M.S., Lai S.W., Ho Y.S., Zee S.S.Y., So K.F., Yuen W.H. and Chang R.C.C., Characterization of the Effects of Anti-aging Medicine Fructus Lycii on b-amyloid Peptide Neurotoxicity , International Journal of Molecular Medicine . 2007, 20: 261-268.

Yu M.S., Lai S.W., Suen K.C., So K.F., Hugon J. and Chang R.C.C., Neuronal apoptosis induced by extracellular accumulation of beta-amyloid peptides is independent of unfolded protein responses, 7th IBRO World Congress of Neuroscience. 2007.

Yu M.S., So K.F., Fang J.N., Yuen W.H. and Chang R.C.C., Neuroprotective polysaccharides from Nerium indicum rescue cultured neurons from beta-amyloid peptides-induced apoptosis via different mechanisms, Society for Neuroscience 2007. Program No. 169.8.

Yuan Q.J., Scott D.E., So K.F. and Wu W., Differential activation of c-fos immunoreactivity after hypophysectomy in developing and adult rats, The Anatomical Record. 2007, 290: 1050-1056.

Researcher : Su H

List of Research Outputs

Guo J., Su H., Zeng Y., Liang Y., Wong W.M., Ellis-Behnke R.G., So K.F. and Wu W., Reknitting The Injured Spinal Cord By Self Assembling Peptide Nanofiber Scaffold, Nanomedicine: Nanotechnology, Biology and Medicine. 2007, 3(4): 311-321.

Mi S., Hu B., Hahm K., Luo Y., Hui S.K., Yuan Q.J., Wong W.M., Wang L., Su H., Chu T.H., Guo J., Zhang W., So K.F., Pepinsky B., Shao Z., Graff C., Garber E., Jung V., Wu E.X. and Wu W., LINGO-1 antagonist promotes spinal cord remyelination and axonal integrity in MOG-induced experimental autoimmune encephalomyelitis, Nature Medicine. 2007, 13(10): 1228-1233.

Su H., Chu T.H. and Wu W., Lithium enhances proliferation and neuronal differentiation of neural progenitor cells in vitro and after transplantation into the adult rat spinal cord, The 37 Annual Meeting Society for Neuroscience, U.S.A., Nov. 2007.

Researcher : Su H

List of Research Outputs

Researcher : Suen KC

List of Research Outputs

Yu M.S., Lai S.W., Suen K.C., So K.F., Hugon J. and Chang R.C.C., Neuronal apoptosis induced by extracellular accumulation of beta-amyloid peptides is independent of unfolded protein responses, 7th IBRO World Congress of Neuroscience. 2007.

Researcher : Tay DKC

List of Research Outputs

Ellis-Behnke R.G., Liang Y., Chan K.C., Tay D.K.C., So K.F. and Wu E.X., Assessing the progression of functional regeneration of the visual system, 6th Picower-RIKEN Symposium, M.I.T., Cambridge USA. 2007.

Ellis-Behnke R.G., Liang Y., You S., Tay D.K.C., So K.F. and Schneider G.E., Beyond nano neuro knitting: creating a more permissive environment using SAPNS with Chondroitinase ABC for brain lesion repair and functional return of vision, International Brain Research Organization (IBRO), Melbourne, Australia. 2007.

Ellis-Behnke R.G., Liang Y., Tay D.K.C., You S.W., Schneider G.E. and So K.F., Beyond nano neuro knitting: creating of a more permissive environment using SAPNS with chondroitinase ABC for brain lesion repair and functional return of vision, 7th IBRO World Congress of Neuroscience , July 12-17, 2007, Melbourne, Australia. 2007, 272 POS-SUN-045.

Ellis-Behnke R.G., Liang Y., Cheung S.F., Tay D.K.C. and So K.F., Nano contrast enhancement agents used in the eye for tracing axons: Trauma or illlumination?, ARVO 2008 Annual Meeting, April 27-May 1, 2008, Florida, U. S. A.. 2008, No. 4014.

Ellis-Behnke R.G., Liang Y., Tay D.K.C. and So K.F., Nanomachines that help repair the brain, 1st IEEE International Conference on Nano/Molecular Medicine and Engineering, Macau SAR China. 2007.

Ellis-Behnke R.G., Liang Y., Tay D.K.C., Schneider G.E. and So K.F., The impact of nanotechnology on eye treatments, 7th International Symposium on Ocular Pharmacology and Therapeutics, Budapest, Hungary . 2008.

Ellis-Behnke R.G., Liang Y., Tay D.K.C., Schneider G.E. and So K.F., Using Nanotechnology For Tissue Bioengineering In Ophthalmology, 31st World Ophthalmology Congress, Symposium on Nanotechnology. 2008.

Ellis-Behnke R.G., Liang Y., Tay D.K.C., Schneider G.E. and So K.F., Using Nanotechnology To Repair The CNS: From The 4 Ps Of Regeneration To Crystal Clear Surgery To In Vivo Non-invasive Imaging Of Regenerating Axons , 1st Unither Nanomedical and Telemedical Technology conference. 2008.

Ellis-Behnke R.G., Liang Y., Tay D.K.C., So K.F. and Wu E.X., Using a 7 Tesla fMRI and Nano Contrast Agent to Visualize Regeneration of Axons in vivo after Chronic Injury in the Hamster Optic Tract , Society for Neuroscience, San Diego USA . 2007.

Li S.Y., Yau S.Y., Chen B., Tay D.K.C., Lee V.W.H., Pu M., Chan H.H.L. and So K.F., Enhanced Survival of Melanopsin-expressing Retinal Ganglion Cells After Injury is Associated with the PI3 K/Akt Pathway, Cellular and Molecular Neurobiology. 2008, 28: 1095-1107.

So K.F., Liang Y., Tay D.K.C. and Ellis-Behnke R.G., Regenerative Medicine in Vision, 1st Pan Pacific Symposium on Stem Cells Research 2008, May 31-June 2, 2008. 98.

Researcher : Tipoe GL

Project Title:	Glycolytic adaptive response mediated by hypoxic inducible factors in chronic liver hypoxia
Investigator(s):	Tipoe GL, Fung ML
Department:	Anatomy
Source(s) of Funding:	Small Project Funding
Start Date:	11/2005

Abstract:

Prolonged hepatic hypoxia is a common underlying event in most chronic liver diseases. The metabolic response for adaptation in chronic liver hypoxia is poorly understood. Chronic hypoxia results in an increase in nutrient supply which provides cells with energy for survival. This is accomplished by increase uptake of glucose through the plasma membrane via glucose transporter 1, 2 and 3. Hypoxia-inducible factors (HIFs) activate transcription of genes encoding proteins that mediate the adaptive response to hypoxia. These genes include erythropoietin, VEGF and glycolytic enzymes. Hypoxia inducible factors are the key transcriptional factor that regulate vascular motor response and cellular metabolism through their down-stream genes carrying hypoxic response element (HRE). HIFs play an essential role in embryonic development, tumor pathogenesis and tissue ischemia (Huang & Bunn, 2003). In our previous study, we have shown that chronic hypoxia induces upregulation of HIF-1 alpha and their down-stream HRE genes involved in the regulation of the vasomotor response such as VEGF, eNOS and iNOS (Tipoe et al., 2004). These genes produce and maintain the levels of nitric oxide which counteracts the vasoconstrictive effect of ET-1 (Lau et al., 2005). Apart from the vasodilation at the sinosiodal level, the HRE genes mentioned above also support cellular proliferation and survival either direcctly acting on the liver cells or indirectly by increasing hepatic perfusion. Up todate, these findings have not been demonstrated by others. Hence we would like to extend the current work in relation to the metabolic adaptive mechainism in chronic liver hypoxia by assessing the diffenrent types of glucose transporter genes that regulate the uptake of glucose in the liver cells. The transport of glucose in mammalian cells is mediated by a class of proteins known as glucose transporters. There are 13 isoforms of glucose transporter and classsified into three clasess (Joost et al., 2002). Our major interest is on class I [Glucose transporter 1-4] because Glucose transporter 1 and 3 are induced by hypoxia and Glucose transporter -2 is also found in liver (Heidbreder et al., 2003). Glucose transporter 1 and 3 are transcriptionlly regulated by HIF-1 alpha and are considered HRE genes whereas Glucose transporter -2 is a non-HRE gene. Glucose transporter -1 is upregulated in glucose deprivation under hypoxic condition in cultured myocytes and 3T3 fibroblasts and alveolar epithelial cells (Wertheimer et al., 1991). Alterations in Gluts 1 has been observed in an alcoholic rat liver from Glucose transporter -2 to Glucose transporter -1 activity in the centrilobular hepatocytes where hypoxia is more severe (Nanji et al., 1995). As to date, there are no studies that show the regulation of Glucose transporter 1, 2 and 3 in prolonged deprivation of oxygen in the liver. We have shown the upregulation of HIF-1 alpha in our previous study (Tipoe et al., 2004; Lau et al., 2005) but not HIF-2 alpha and HIF 3 alpha. Other studies have shown that HIF-2 alpha and HIF-3 alpha are also induced in moderate hypoxia (Heidbreder et al., 2003; Wiessner et al., 2003). The objectives of the present study are: 1) To localize the expression of glucose transporters (1-3) in the normoxic and chronic hypoxic liver cells. 2) To quantify the protein and mRNA expression of glucose transpoters 1-3 in the normoxic and chronic hypoxic liver. 3) To assess the expression of HIF isoforms 2 and 3 in the normoxic and chronic hypoxic liver. References: Heidbreder M, Frohlich F, Johren O, Dendorfer A, Qudri F, Dominiak P. (2003) The FASEB Journal 17; 1541-1543. Huang EL & Bunn FH (2003) Hypoxia-inducble factor and its biomedical relevance. JBC (In press, online). Joost H-G, Bell GI, Best JD, Birhbaum MJ, et al., (2002) American Journal of Physiology- Endocrinology and metabolism 282; E974-E976. Lau TYH, Tipoe GL, Fung ML, Liong E.C. et al. (2005) Journal of Pathology 205 Supplement 1: 11. Nanji A.A., Fogt F, Griniuviene B. (1995) American Journal of Pathology 146; 329-334. Tipoe GL, Lau YH, Fung, ML, Liong EC, Nanji, AA (2004) Journal of Gastroenterology 19; 2:85. Wertheimer E, Sassoon S, Cerasi E, Ben-Neriah Y (1991) Proc. Natl. Acad. Sci. USA 88; 2525-2529. Wiessner MS, Jurgrnsen JS, Rosenberger C, Scholze CK et al. (2003) The FASEB Journal 17; 271-273.

Project Title:	(-) Epigallocatechinc-3- gallate (EGCG) modulates the progression of liver fibrosis in vivo
Investigator(s):	Tipoe GL, Fung ML
Department:	Anatomy
Source(s) of Funding:	Small Project Funding
Start Date:	10/2006

Abstract:

Our in vivo model, the induction of hepatoxin (CCl4) would initiate lipid peroxidation and oxidative stress. In prolonged carbon tetrachloride [CCl4] administration, the presence of oxidative stress would induce chronic inflammation and later would initiate repair and remodelling process in the liver known as fibrosis. Tumor ncerosis factor alpha, iNOS and COX-2 are some of the pro-inflammatory mediators that are commonly induced in chronic liver injury. These pro-inflamatory mediators are mediated by nuclear transcription factors such NF-kB. The extent of liver remodelling would depend on the balance between collagen formatoin and degradation. The key molecules are TGF-beta 1 (mainly produced by the Kupffer cells), metalloproteinases and tissue inhibitor metalliproteinases (mainly produced by hepatic stellate cells). Green tea polyphenols has been known to possess anti-inflammatory, anti-oxidative, anti-fibrongenetic and anti-carcinogenic effects (Hertog et al., 1997; Alvarez et al., 2002; Higdon and Frei, 2003). (-) Epigallocatechins-3-gallate is one of the components of green tea polyphenols which has the strongest anti-oxidant effect. Currently, there are a few studies that investigate the effects of EGCG in liver fibrosis. Most of these studies are in vitro models (Nakamuta et al., 2005; Sakata et al., 2004). Our current study hypothesize that EGCG could modulate the oxidative stress, inflammation and pro-fibrotic mediators by down-regulating the nuclear transcription factors, thereby attenuate the development of liver fibrosis in vivo.The present study has three main objectives: 1) To determine whether EGCG could reduce the level of oxidative stress and the degree of inflammation during the development of liver fibrosis. 2) To investigate whether EGCG could modulate the expression of pro-fibrotic factors such as TGF-beta, procollagen, MMP-2, MMP-9, TIMP-1 and TIMP-2 during the development liver fibrosis.. 3) To evaluate whether EGCG could down-regulate the expression of nuclear transcirption factor, NF-kB, in liver fibrosis. Our group previously showed that EGCG effectively downregulated carbon tetrachloride (CCl4)-induced acute liver injury in association with reduced expression of proinflammatory mediators (iNOS and COX-2) (Chen et al., 2004). Our preliminary findings on the effect of EGCG in CCl4-induced liver fibrosis showed that CCl4-induced liver fibrosis was significantly reduced with EGCG treatment as indicated by the reduced serum ALT level, expression of TNF-alpha and the amount of collagen accumulated in the liver (Sirius Red staining). EGCG also effectively suppressed the formation of nitrotyrosine (as determined by Western Blotting analysis), which is an oxidative stress marker, indicating the antioxidant effect of EGCG. Furthermore, administration of EGCG decreased the expression of iNOS, COX-2 and alpha-smooth muscle actin (alpha-SMA; a marker of activated hepatic stellate cell) . These preliminary results revealed the potent effect of EGCG in mitigating the progression of liver fibrosis by inhibiting inflammatory response and oxidative stress. The future work will adress the last two objectives of this study.References:Alvarez E et al., 2002 Int Immunopharmacol. 2(6):849-855.Chen et al., 2004 Am J Clin Nutr 80: 742-751.bHertog MG et al., 1997 Lancet. 349(9053):699.Higdon JV and Frei B. 2003 Crit Rev Food Sci Nutr. 43(1):89-143.Nakamuta M et al., 2005 Int J Mol Med. 16:677-681.Sakata R et al., 2004 J Hepatol. 40:52-59.

List of Research Outputs

Chan C.H., Shum D.K.Y., Tipoe G.L., Mak J.C.W., Leung T.M. and Ip M.S.M., Upregulation of ICAM-1 expression in bronchial epithelial cells by airway secretions in bronchiectasis, Respiratory Medicine. 2008, 102: 287-298.

Ho C.T., Tipoe G.L., Liong E.C., Leung T.M., Lau T.Y.H., Fung M.L. and Nanji A.A., Decreased adiponectin and antioxidant enzymes are associated with necroinflammatory changes and fibrosis in a rat model for non-alcoholic fatty liver disease (NAFLD), Hepatology International. 2008, 2: S151-S152.

Hung M.W., Tipoe G.L., Poon A.M.S., Reiter R.J. and Fung M.L., Protective effect of melatonin against hippocampal injury of rats with intermittent hypoxia, Journal of Pineal Research. 2008, 44: 214-221.

Lam S.S.Y., Tipoe G.L., Liong E.C. and Fung M.L., Chronic hypoxia enhances the expression and function of proinflammatory cytokines in the rat carotid body, 12th Research Postgraduate Symposium, HKU. 2007, 1-12.

Lam S.S.Y., Tipoe G.L., Liong E.C. and Fung M.L., Differential expressions and roles of hypoxia-inducible factor-1a, -2a and -3a in the rat carotid body during chronic and intermittent hypoxia, Histology and Histopathology. 2008, 23: 271-280.

Lam S.S.Y., Tipoe G.L., Liong E.C. and Fung M.L., Functional upregulation of proinflammatory cytokines and local inflammation in the rat carotid body during chronic hypoxia, The 11th Annual Scientific Meeting of the Institute of Cardiovascular Science and Medicine (Journal of the Hong Kong College of Cardiology). 2007, 15(2):91: 18.

Lam S.Y.S., Tipoe G.L., Liong E.C. and Fung M.L., Chronic hypoxia upregulates the expression and function of proinflammatory cytokines in the rat carotid body, Histochemistry and Cell Biology. 2008, 130: 549-559.

Leung T.M., Tipoe G.L., Liong E.C., Lau T.Y.H., Fung M.L. and Nanji A.A., Nitric oxide inhibitor or donor reverses the induction of hypoxia-inducible factor (HIF-1á) in chronic liver fibrosis in mice, XIth International Congress of Toxicology, Montreal, Canada. 2007.

Tipoe G.L., Liong E.C., Casey C.A., Donohue Jr. T.M., Eagon P.K., So H.S.H., Leung T.M., Fogt F. and Nanji A.A., A voluntary oral enthanol-feeding rat model associated with necroinflammatory liver injury, Alcoholism: Clinical and Experimental Research. 2008, 32(4): 1-14.

Tipoe G.L., Liong E.C., Leung T.M. and Nanji A.A., A voluntary oral-feeding rat model for pathological alcoholic liver injury, Methods in Molecular Biology. 2008, 447: 11-31.

Researcher : To KW

List of Research Outputs

To K.W., MAD2 inactivation on chromosomal instability and tumorigenesis in prostate epithelial cells. 2007, 216 pages.

To K.W., Cheung H.W., Ling M.T., Wong Y.C. and Wang X., MAD2ΔC induces aneuploidy and promotes anchorage-independent growth in human prostate epithelial cells. , Oncogene. 2008, 27: 347-357.

Researcher : Tsao GSW

Project Title:	Defining the genetic elements involved in immortalization and malignant transformation of primary nasopharyngeal epithelial cells
Investigator(s):	Tsao GSW, Jin Y
Department:	Anatomy
Source(s) of Funding:	Competitive Earmarked Research Grants (CERG)
Start Date:	10/2004

Abstract:

To examine the roles of inactivation of the P16 and RASSFIA genes, overexpression of deltaNp63 and telomerase reconstitution in the immortatlization of primary nasopharyngeal epithelial cells; to establish an immortalized nasopharyngeal epithelial cells using defined genetic elements for NPC oncogenesis study; to examine the susceptibility of immortalized nasopharyngeal cells to the malignant transformation by EBV latent genes/EBV infection.

Project Title:	Functional study of EBV infection and genetic alterations in immortalized epithelial cells
Investigator(s):	Tsao GSW, Chen H
Department:	Anatomy
Source(s) of Funding:	NSFC/RGC Joint Research Scheme
Start Date:	12/2004

Abstract:

To study intracellular signaling events regulating latent infection of EBV infection in nasopharyngeal epithelial cells; to study the role of the EBV encoded LMP1 in the immortalization and transformaton of premalignant nasopharyngeal epithelial cells.

Project Title:	Chromosome instabiliy induced by Id1 expression in nasopharyngeal epithelial cells
Investigator(s):	Tsao GSW
Department:	Anatomy
Source(s) of Funding:	Small Project Funding
Start Date:	12/2005

Abstract:

BackgroundChromosome instability is a hallmark of human cancers. Immortalization is a pre-requisite property of all cancer cells and is considered an early event in the carcinogenesis process. Events occurring at the immortalization process may be earlier steps involved in carcinogenesis. Nasopharyngeal carcinoma is a common cancer among Southern Chinese. Our laboratory has been involved in investigation of critical events underlying the immortalization and malignant transformation of human nasopharyngeal epithelial cells. Several events are critical for immortalization of nasopharyngeal epithelial cells. Among them are telomerase activation, p16 inactivation and downregulation of p21 gene which are commonly observed in our immortalized nasopharyngeal epithelial cells. In addition, we observed that Id1 expression is common in immortalized nasopharyngeal epithelial cells. Id1 expression could suppress p16 and p21 expression in cells and may play a role in cell immortalization. We have previously reported that Id1 is commonly overexpressed in nasopharyngeal carcinoma (Wang et al., 2002). Id1 expression could accelerate cell cycle progression in nasopharyngeal carcinoma cell. Interestingly, we observed that an Epstein Barr virus encoded protein- LMP1 could effectively upregulate Id1 expression in an immortalized nasopharyngeal epithelial cell established in our laboratory (Tsao et al., 2002; Li HM et al., 2004 ). In order to study the functional significance of Id1 expression in nasopharyngeal epithelial cells, we have overexpressed Id1 in another immortalizaed nasopharyngeal cell line recently established in our laboratory using telomerase alone. The telomerae immortalized nasopharyngeal epithelial cell line is diploid in karyotype and harbours minimal genetic alterations compared to all other established nasopharyngeal epithelial cells previously established. Interestingly, overexpressing Id1 effectively induced polyploidy in this telomerase immortalized nasopharyngeal epithelial cells. This would suggest that Id1 may be involved in inducing the chromosome instability in nasopharyngeal epithelial cells. Examination of the these Id1 expressing cells revealed upregulation of Aurora A, supernumerary centrosome and microtubules stability, all of are implicated in maintenance of chromosome stability and integrity. This Id1 expressing cell system hence provide us an unique opportunity to examine the role of Id1 in inducing chromosome instablity in nasopharyngeal epithelial cells. Recently, we were able to confirm the induction of Aurora A by Id1 in a transient expression cell system. This allows us to dissect the detail mechanism involved in the transduction of signal from Id1 expression to Aurora A expression. Aurora A is an important kinase involved in mitosis. Overexpression of Aurora A has been known to associate with centrosome abnormality. Upstream events regulating its expression are also unknown. Our observatioin that Id1 expression is an upstream event to upregulate Aurora A expression is a novel finding. We propose to elucidate the detail signaling pathways involved. Microtubule plays essential role in mitotic by involvement in spindle assembly and segregation of chromosome. The effects of Id1 in mirotubule disturbances have not been previosly reported. We have preliminary data showing that upregulation of Aurora A may induce microtubule abnormality. This would results in disruption of mitotic spindle assembly and mitotic exit. Failure of mitotic exit will result in polyploidy which may be the mechanism underlying the polyploidy phenotype observed our Id1 expressing nasopharyngeal epithelial cells. To confirm the role of Id1 in chromosomal instability in the development of nasopharyngeal carcinoma, the following objectives will be pursued. Details of the research plan and methodology are described in separate section.Specific objectives:o To identify downstream signaling events of Id1 overexpression leading to overexpression of Aurora A in nasopharyngeal epithelial cellso To examine the effects of Id1 in centrosome abnormality, microtubules disruption and chromososme instability in nasopharyngeal epithelial cells by live cell imaging techniqueso To examine the effects of downregulation of Aurora A by interference RNA and their effects on Id1 induced chromosomal abnormality.References: Li, H. M., Zhuang, Z. H., Wang, Q., Pang, J. C. S., Wang, X. H., Wong, H. L., Feng, H. C., Jin, D. Y., Ling, M. T., Wong, Y. C., Eliopoulos, A. G., Young, L. S., Huang, D. P., and Tsao, S. W. Epstein-Barr virus latent membrane protein 1 (LMP1) upregulates Id1 expression in nasopharyngeal epithelial cells. Oncogene, 23: 4488-4494, 2004.Tsao, S. W., Wang, X. H., Liu, Y., Cheung, Y. C., Feng, H. C., Zheng, Z., Wong, N., Yuen, P. W., Lo, A. K. F., Wong, Y. C., and Huang, D. P. Establishment of two immortalized nasopharyngeal epithelial cell lines using SV40 large T and HPV16E6/E7 viral oncogenes. Biochimica et Biophysica Acta-Molecular Cell Research, 1590: 150-158, 2002.Wang, X. H., Xu, K. X., Ling, M. T., Wong, Y. C., Feng, H. C., Nicholls, J., and Tsao, S. W. Evidence of increased Id-1 expression and its role in cell proliferation in nasopharyngeal carcinoma cells. Molecular Carcinogenesis, 35: 42-49, 2002.

Project Title:	Mechanisms involved in Id1 induced centrosome abnormalities
Investigator(s):	Tsao GSW, Wong YC
Department:	Anatomy
Source(s) of Funding:	Competitive Earmarked Research Grants (CERG)
Start Date:	09/2006

Abstract:

(1) To examine and confirm the involvement of Aurora A expression and NFkB in Id1 induced centrosome abnormalities in cells. (2) To elucidate the events involved in the actigvation of NFkB by Id1.

Project Title:	Downregulation of RASSF1A by the Epstein Barr virus encoded-LMP1 in nasopharyngeal epithelial cells
Investigator(s):	Tsao GSW, Deng W, Cheung A
Department:	Anatomy
Source(s) of Funding:	Small Project Funding
Start Date:	01/2007

Abstract:

Background and Objectives: Nasopharyngeal carcinoma (NPC) is a common disease among Cantonese population living in Hong Kong and southern China. Infection of EBV is closely associated with NPC and is believed to be a major etiological factor for NPC. EBV infection could be detected in most if all nasopharyngeal carcinoma. The EBV encoded-LMP1 has been shown to have oncogenic properties. Expression of LMP1 activates multiple cellular signaling pathways and transforms rodent fibroblasts in vitro. Our laboratory has been involved in the elucidation of mechanism involved in the oncogene transformation activity of LMP1 on nasopharyngeal epithelial cells (Tsao et al., Seminar in Cancer Biology, 2002, Lo AKF et al., Lab. Investigation, 2004, Li et al., Oncogene, 2004). We have recently identify a novel function of LMP1 in downregulation of expression of , RASSF1A, a tumour suppression gene commonly inactivated in nasopharyngeal carcinoma. RASSF1A is a potent tumour suppressor gene located on chromosome 3p21. Inactivation of RASSF1A is common in human cancers. The downregulation of RASSF1A by LMP1 does not involve promoter methylation and represents a novel mechanism of inactivation of RASSF1A in nasopharyngeal carcinoma. Inactivation of RASSF1A facilitates tumour development and progression. RASSF1A has been reported to be associated with regulating events involved in mitosis. It has been shown that expression of RASSF1A stabilizes microtubules in cells. RASSF1A also interacts with multiple centrosomal proteins and regulate events in mitosis. Mitotic spindle is involved in the regulation of chromosome segregation during mitotis. Disruption of mitotic spindle may induce chromosome instability and facilitate oncogenic transformation. Downregulation of RASSF1A by LMP1 may disrupt the normal function and behavior of mitotic spindle and induce chromosomal aberrations in EBV infected nasopharyngeal epithelial cells. In this study, we propose to examine the molecular mechanisms involved in the downregulation of RASSF1A by LMP1 and its effects on chromosome instability. Specific aims: 1. To characterize the key cell signaling events involved in the downregulation of RASSF1A by LMP1 2. To examine the effect of LMP1-induced RASSF1A inactivation on microtubule dynamics and mitotic spindle formation in nasopharyngeal epithelial cells 3. To examine if RASSF1A downregulation may mediate the chromosomal aberration in LMP1 expressing nasopharyngeal epithelial cells.

List of Research Outputs

Chan S.L., Cui Y., van Hasselt A., Li H., Srivastava G., Jin H., Ng K.M., Wang Y., Lee K.Y., Tsao G.S.W., Zhong S., Robertson K.D., Rha S.Y., Chan A.T. and Tao Q., The tumor suppressor Wnt inhibitory factor 1 is frequently methylated in nasopharyngeal and esophageal carcinomas, Lab Invest. 2007, 87(7): 644-50.

Chan S.Y., Choy K.W., Tsao G.S.W., Tao Q., Tang T., Chung G.T. and Lo K.W., Authentication of nasopharyngeal carcinoma tumor lines., International Journal of Cancer. 2008, 122: 2169-2171.

Chan W.Y., Yu C.L., Nicholls J.M., Tsao G.S.W., Peiris J.S.M. and Chan M.C.W., Innate immune response and virus replication in human nasopharyngeal epithelial cells infected with influenza A (H5N1) virus, American Society for Microbiology general meeting 2008.

Cheung A., Deng W., Tsao G.S.W. and Guan X.Y., Centromeric instability in human cells undergoing immortalization., Proceedings of American Association for Cancer Research Annual Meeting; 2008 Apr 12-16; San Diego, CA. Abstract nr 4318. 2008, 4318.

Cheung P.Y., Deng W., Tsao G.S.W. and Cheung A., Role of cyclin D1 in conferring malignant phenotypes on immortalized esophageal epithelial cells., Proceedings of the American Association for Cancer Research Annual Meeting, San Diego, U. S. A., April 12-16, 2008. Abstract 5581.. 2008, 5581.

Choy E.Y.W., Siu K.L., Kwong D.L.W., Tsao G.S.W. and Jin D., Epstein-Barr virus-encoded microRNA targets PUMA to promote tumor cell survival , 2008 Miami Winter Symposium, A Nature Conference on Regulatory RNA in Biology and Human Health. Miami Beach, Florida, USA, 2008.

Choy E.Y.W., Siu K.L., Kwong D.L.W., Tsao G.S.W. and Jin D., First place in poster competition, 2008 Miami Winter Symposium, A Nature Conference on Regulatory RNA in Biology and Human Health. Miami Beach, Florida, USA, 2008.

Choy E.Y.W., Kok K.H., Tsao G.S.W. and Jin D., Utility of Epstein-Barr virus-encoded small RNA promoters for driving the expression of fusion transcripts harboring short hairpin RNAs., gne Ther.. 2008, 15: 191-202.

Choy E.Y.W., Kok K.H., Tsao G.S.W. and Jin D., Utility of Epstein-Barr virus-encoded small RNA promoters for driving the expression of fusion transcripts harboring small hairpin RNAs., Gene Therapy. 02/2008, 2007, 15: 191-202.

Deng W., Tsao G.S.W., Guan X.Y. and Cheung A., Microtubule breakage is not a major mechanism for resolving end-to-end chromosome fusions generated by telomere dysfunction during the early process of immortalization, Chromosoma. 2007, 116: 557-568.

Feng H., Tsao G.S.W., Ngan H.Y.S., Xue W., Kwan H.S., Siu K.Y., Liao X., Wong E.S.Y. and Cheung A.N.Y., Over-expression of Prostatic Stem Cell Antigen (PSCA) is associated with Gestational Trophoblastic neoplasia. , Histopathology. 2007, 52: 167-174.

Feng H., Tsao G.S.W., Ngan H.Y.S., Xue W., Kwan H.S., Siu K.Y., Liao X., Wong E.S.Y. and Cheung A.N.Y., Overexpression of prostate stem cell antigen is associated with gestational trophoblastic neoplasia, Histopathology. 2008, 52(2): 167-174.

Feng Y., Tsao G.S.W., Tong Y. and Ng K.M., Matching Grant (4th Phase)-Research project on alternative drug for bear bile, UGC (Government Matching Grant Scheme). 2008, HK$402,500.

Feng Y., Tsao G.S.W., Tong Y. and Ng K.M., Research project on alternative drug for bear bile, Yiqingzhai Foundation (The Pong Ding Yueng Endowment Fund for Education & Research in Chinese-Western Medicine). 2008, HK$805,000.

Fu L., Qin Y.R., Xie D., Hu L., Kwong D.L.W., Srivastava G., Tsao G.S.W. and Guan X.Y., Characterization of a novel tumor-suppressor gene PLC delta 1 at 3p22 in esophageal squamous cell carcinoma, Cancer Res. 2007, 67(22): 10720-6.

Ko J.M.Y., Chan P.L., Yau W.L., Chan H.K., Chan K.C., Yu Z.Y., Kwong F.M., Miller L.D., Liu E.T., Yang L.C., Lo P.H.Y., Stanbridge E.J., Tang J.C.O., Srivastava G., Tsao G.S.W., Law S.Y.K. and Lung M.L., Monochromosome transfer and microarray analysis identify a critical tumor-suppressive region mapping to chromosome 13q14 and THSD1 in esophageal carcinoma, Molecular Cancer Research. 2008, 6(4): 592-603.

Lau W.M., Tsao G.S.W., So K.F. and Yip H.K.F., Expression of telomerase reverse transcriptase in adult goldfish retina, Journal of Molecular Neuroscience. 2007, 32: 160-267.

Lau W.M., Wong A.O.L., Tsao G.S.W., So K.F. and Yip H.K.F., Molecular cloning and characterization of the Zebrafish (Danio rerio) telomerase catalytic subunit (Telomerase Reverse Transcriptase, TERT), Journal of Molecular Neuroscience. Humana Press Inc., 2007, 34: 63-75.

Law F.B.F., Chen W.Y.W., Wong K.Y., Ying J., Tao Q., Langford C., Lee P.Y., Law S.Y.K., Cheung R.W.L., Chui C.H., Tsao G.S.W., Lam A.K.Y., Wong J., Srivastava G. and Tang J.C.O., Identification of a novel tumor transforming gene GAEC1 at 7q22 which encodes a nuclear protein and is frequently amplified and overexpressed in esophageal squamous cell carcinoma, Oncogene. 2007, 26(40): 5877-5888.

Law G.L., Wong K.L., Man C.W.Y., Wong W.T., Tsao G.S.W., Lam M.H.W. and LAM P.K.S., Emissive Terbium Probe for Multiphoton in Vitro Cell Imaging , Journal of the American Chemical Society. 2008, 130: 3714-3715.

Leung A.C.C., Wong V.C.L., Yang L.C., Chan P.L., Daigo Y., Nakamura Y., Qi R.Z., Miller L.D., Liu E.T.B., Wang L.D., Li J.L., Law S.Y.K., Tsao G.S.W. and Lung M.L., Frequent decreased expression of candidate tumor suppressor gene, DEC1, and its anchorage-independent growth properties and impact on global gene expression in esophageal carcinoma, International Journal of Cancer. 2008, 122(3): 587-594.

Li B., Cheung P.Y., Wang X., Tsao G.S.W., Ling M.T., Wong Y.C. and Cheung A., Id-1 activation of PI3K/Akt/NFkB signaling pathway and its significance in promoting survival of esophageal cancer cells, Carcinogenesis. 2007, 28(11): 2313-2320.

Li L., Zhou S., Chen X., Guo L., Li Z., Hu D., Luo X., Ma X., Yi W., Tsao G.S.W. and Cao Y., The activation of p53 mediated by Epstein-Barr virus latent membrane protein 1 in SV40 large T-anigen transformed cells., FEBS Lett.. 2008, 582: 755-762.

Lung H.L., Lo P.H., Xie D., Apte S.S., Cheung A.K., Cheng Y., Chua D.T.T., Zeng Y.X., Tsao G.S.W., Standbridge E.J. and Lung M.L., Characterization of a novel epigenetically-silenced, growth-suppressive gene, ADAMTS9, and its association iwthlymph node metastases in nasopharyngeal carcinoma, International Journal of Cancer. 2008, 123: 401-408.

Man C.W.Y., Rosa J., Yip Y.L., Cheung A., Kwong Y.L., Doxsey S.J. and Tsao G.S.W., Id1 overexpression induces tetraploidization and multiple abnormal mitotic phenotypes by modulating Aurora A , Molecular Biology Of The Cell. USA, The American Society for Cell Biology, 2008, 19: 2389-2401.

Monkkonen K.S., Aflatoonian R., Lee C.K.F., Yeung W.S.B., Tsao G.S.W., Laitinen J.T. and Fazeli A., Hormonal regulation of G{alpha}i2 and mPR{alpha} in immortalized human oviductal cell line OE-E6/E7., Mol Hum Reprod. 2007, 13: 845-51.

Siu K.Y., Woo N.W., Wong E.S.Y., Chan H.Y., Chan K.Y.Q., Ngan H.Y.S., Tsao G.S.W. and Cheung A.N.Y., p21-activated kinase 4 in Ovarian Cancer: Its expression, localization and possible functional role, 16th Annual Growth Factor and Signal Transduction Symposium titled "Senescence, Aging and Cancer",Iowa, 26-29 July . 2007.

Tong P.H., Man C.W.Y., Tsao G.S.W. and Chan G.C.F., Arsenic Trioxide Induced All Cycle Arrest in Neuroblastoma Cells with or without MYCN Over-Expression & the Response Had No Correlation with their Effect on Chromosomal Passenger Complex, Advances in Neuroblastoma Research 2008, Chiba, Japan, 21-24 May 2008. 140.

Tong P.H., Man C.W.Y., Tsao G.S.W. and Chan G.C.F., Arsenic Trioxide induced G2/M phase arrest in neuroblastoma cells with or without MYCN over-expression & the response had no correlation with their effect on chromosomal passenger complex., 第七屆粵港兒科學術文流會暨第一屆港粵滬渝學術交流會, 香港. 28 June 2008, 2008.

Tsao G.S.W., Current Cancer Drug Targets. 2007.

Tsao G.S.W., Latent membrane protein 1 suppresses RASSF1A expression, disrupts microtubule structues and induces chromosomal aberrations in human epithelial cells., East-West Symposium on Nasopharyngeal carcinoma . 2007.

Tse W.W., Deng W., Tsao G.S.W. and Cheung A., Methylation status of tumor related genes during immortalization of human cervical epithelial cell lines. , Proceedings of American Association for Cancer Research Annual Meeting; 2008 Apr 12-16; San Diego, CA. Abstract nr 48.. 2008, 48.

Wang Y., He Q.Y., Che C.M., Tsao G.S.W., Sun R.W.Y. and Chiu J., Modulation of gold(III) porphyrin 1a-induced apoptosis by mitogen-activated protein kinase signaling pathways, Biochemical Pharmacology. 2008, 75: 1282-1291.

Woo N.W.S., Wong E.S.Y., Chan H.Y., Chan K.Y.Q., Ngan H.Y.S., Tsao G.S.W. and Cheung A.N.Y., p21-activated kinase 4 in Ovarian Cancer: Its expression, localization and possible functional role, 16th annual Growth Factor and Signal Transduction Symposium, Iowa, 26-29 July. 2007.

Wu G., Tsao G.S.W. and Yip H.K.F., Characteristics of Telomerase Expression in Neurogenic Sites of Adult Central Nervous System, 12th Research Postgraduate Symposium, The University of Hong Kong, Faculty of Medicine. 2007.

Wu G., Tsao G.S.W. and Yip H.K.F., Characteristics of Telomerase Expression in Neurogenic Sites of Adult Central Nervous System, The University of Hong Kong Li Ka Shing Faculty of Medicine, Research Centre of Heart, Brain, Hormone & Healthy Aging, 3rd International Symposium on Healthy Aging: “Improving the Health of an Aging Population. 2008.

Ye X., Feng Y., Tong Y. and Tsao G.S.W., The effects of coptis extract on hepatoprotection in rats with liver damage., 2007 Hong Kong-Macau postgraduate Symposium on Chinese Medicine. Hong Kong, 2007, 92-93.

Zhang X., Wang Q., Ling M.T., Wong Y.C., Leung C.L., Tsao G.S.W. and Wang X., Anti-apoptotic role of TWIST and its association with Akt pathway in mediating taxol resistance in nasopharyngeal carcinoma cells, International J Cancer. 2007, 120: 1891-1898.

Researcher : Tse WW

List of Research Outputs

Tse W.W., Deng W., Tsao G.S.W. and Cheung A., Methylation status of tumor related genes during immortalization of human cervical epithelial cell lines. , Proceedings of American Association for Cancer Research Annual Meeting; 2008 Apr 12-16; San Diego, CA. Abstract nr 48.. 2008, 48.

Researcher : Wang H

List of Research Outputs

Fu Q., Wu W., Wang H., Li X., Lee V.W.H. and So K.F., Up-regulated endogenous erythropoietin/erythropoietin receptor system and exogenous erythropoietin rescue retinal ganglion cells after chronic ocular hypertension, Cellular and Molecular Neurobiology. 2008, 28: 317-329.

Researcher : Wang L

List of Research Outputs

Mi S., Hu B., Hahm K., Luo Y., Hui S.K., Yuan Q.J., Wong W.M., Wang L., Su H., Chu T.H., Guo J., Zhang W., So K.F., Pepinsky B., Shao Z., Graff C., Garber E., Jung V., Wu E.X. and Wu W., LINGO-1 antagonist promotes spinal cord remyelination and axonal integrity in MOG-induced experimental autoimmune encephalomyelitis, Nature Medicine. 2007, 13(10): 1228-1233.

Researcher : Wang Q

List of Research Outputs

Zhang X., Wang Q., Ling M.T., Wong Y.C., Leung C.L., Tsao G.S.W. and Wang X., Anti-apoptotic role of TWIST and its association with Akt pathway in mediating taxol resistance in nasopharyngeal carcinoma cells, International J Cancer. 2007, 120: 1891-1898.

Zhang X., Ling M.T., Wang Q., Lau C.K., Leung C.L., Lee T.K., Cheung A., Wong Y.C. and Wang X., Identification of a novel inhibitor of differentiation-1 (ID-1) binding partner, caveolin-1, and its role in epithelial-mesenchymal transition and resistance to apoptosis in prostate cancer cells, The Journal of Biological Chemistry. 2007, 282(46): 33284-33294.

Researcher : Wang X

Project Title:	Downregulation of MAD2 expression and its significance in chemodrug sensitization in nasopharyngeal carcinoma cells
Investigator(s):	Wang X, Nicholls JM, Tsao GSW, Jin D
Department:	Anatomy
Source(s) of Funding:	Competitive Earmarked Research Grants (CERG)
Start Date:	09/2003

Abstract:

To confirm that MAD2 expression is downregulated in clinical samples of NPC; to determine the mechanism by which MAD2 is downregulated in NPC; to establish whether upregulation of MAD2 expression can sensitize NPC cells to chemotherapy.

Project Title:	The role fo MAD2 in overcoming cisplatin resistance in testicular germ cell tumors
Investigator(s):	Wang X, Jin D
Department:	Anatomy
Source(s) of Funding:	Lance Armstrong Foundation - General Award
Start Date:	10/2003

Abstract:

To investigate the association between decreased MAD2 protein expression and cisplatin resistance in TGCT cells; to study if exogenous expression of the MAD2 gene in TGCT cells can lead to chemosensitization to cisplatin in TGCT cells; to demonstrate that downregulation of MAD2 results in resistance ot cisplatin in TGCT cells; to characterize the role of MAD2 in cisplatin-induced cell death inTGCT cells; to identify binding partners of MAD2 in response to cisplatin-induced DNA damage.

Project Title:	Significance of MAD2 expression to chromosomal instability in prostate cancer
Investigator(s):	Wang X, Jin D Y
Department:	Anatomy
Source(s) of Funding:	Association for International Cancer Research - General Award
Start Date:	04/2004

Abstract:

To correlate MAD2 expression with genomic instability in prostate cancer specimens; to show that MAD2 expression is essential for a functional mitotic checkpoint in prostate cancer cells; to demonstrate that downregulation of MAD2 leads to mitotic checkpoint defect and increased CIN in prostate cancer cells. • To investigate if promoter hypermethylation contributes to decreased MAD2 expression in prostate cancer

Project Title:	Molecular mechanisms involved in the suppressive effects of garlic derivatives on cell growth and motility in prostate cancer cells
Investigator(s):	Wang X, Jin D Y
Department:	Anatomy
Source(s) of Funding:	American Institute for Cancer Research (AICR) - General Award
Start Date:	08/2005

Abstract:

To study the role of the mitotic checkpoint in SAC and SAMC-induced androgen independent prostate cancer cell death; to investigate if SAC and SAMC have any inhibitory effect on the invasive ability of prostate cancer cells and to determine the molecular mechanisms responsible. Specific Aim 3. To examine if SAC and SAMC can enhance the sensitivity of prostate cancer cells to chemotherapeutic drugs.

Project Title:	Significance of Id-1 upregulation and its association with EGFR in bladder cancer
Investigator(s):	Wang X
Department:	Anatomy
Source(s) of Funding:	Seed Funding Programme for Basic Research
Start Date:	06/2006

Abstract:

Background: Bladder cancer is one of the common urological cancers. Although majority of bladder cancers are superficial at presentation, 20% of the bladder cancer patients present with muscle invasive disease at diagnosis (i.e. stage T2-T4 tumours). If untreated, fewer than 15% of those patients can survive more than two years. Two main challenges remain for the treatment of this cancer which are (i) the ability to identify the small but significant number of patients with non-muscle-invasive disease who will progress to muscle-invasive disease, and (ii) to improve current treatment of the muscle invasive bladder cancer. Recently, our group identified a potential oncogene, Id-1 (inhibitor of differentiation or DNA binding), and demonstrated its significance in the development of human prostate cancer (Ouyang et al., J Urol 167: 2598, 2002), nasopharyngeal carcinoma (Wang et al., 35:42-49, 2002) and ovarian cancer (Zhang et al., Br J Cancer 91: 2042, 2004). Since then, upregulation of Id-1 has been reported in over 20 types of human cancer such as breast, pancreas, cervical, melanoma, and head and neck (Reviewed by Wong et al., 9:279-289, 2004). In addition, increased Id-1 expression levels are associated with advanced tumour stage as well as poor prognosis (Maruyama et al., Am J Pathol 155: 815, 1999; Schindl et al., Cancer Res 61: 5703, 2001; Ouyang et al., J Urol 167: 2598, 2002). Furthermore, patients with higher levels of Id-1 have much shorter overall survival than the patients with relatively lower Id-1 expression in ovarian cancer (Schindl et al., Clin Cancer Res 9:779, 2003). Recent evidence also shows that Id-1 is able to induce epidermal growth factor receptor (EGFR) expression, indicating that the oncogenic effect of Id-1 may be mediated through activation of the EGFR pathway (Ling et al., Carcinogenesis 25: 517, 2004; Zhang et al., Br J Cancer 91: 2042, 2004). In bladder cancer, upregulation of EGFR has been frequently reported in tissue samples (Neal et al., Lancet 1: 366, 1985; Mellon et al., J Urol 153: 919, 1995). Several studies have correlated EGFR positively with tumour stage, tumour progression, and poor clinical outcome in bladder cancer patients (Neal et al., Cancer 65: 1619, 1990; Mellon et al., J Urol 153: 919, 1995; Nguyen et al., Am J Clin Pathol 101: 166, 1994). Furthermore, it was recently reported that treatment of bladder cancer cells with ZD1839 (or Iressa), a highly selective EGFR inhibitor, resulted in radiosensitization to ionizing radiation (Maddineni et al., Br J Cancer 92: 125, 2005), indicating that EGFR may be a potential therapeutic target in improving treatment efficiency of bladder cancer. Based on the evidence that Id-1 is able to activate EGFR pathway, we hypothesized that activation of the EGFR pathway observed in bladder cancer may be a result of overexpression of Id-1, as indicated in other cancers (Ling et al., Carcinogenesis 25: 517, 2004; Zhang et al., Br J Cancer 91: 2042, 2004 ). Purpose of the project: The aim of this project is to study the significance of Id-1 in bladder cancer and provide an alternative target of the EGFR pathway for the treatment of bladder cancer. This will be achieved through the following objectives: 1). To study differential Id-1 protein expression between normal and malignant bladder cancer specimens and correlate its expression levels with EGFR in different stage bladder cancer specimens. 2). To study if ectopic Id-1 expression in bladder cancer cell lines could lead to upregulation of EGFR and demonstrate the significance of Id-1 overexpression in bladder cancer cell proliferation. 3). To study if inactivation of Id-1 could suppress EGFR expression and investigate if downregulation of Id-1 could lead to inhibition of bladder cancer cell growth.

List of Research Outputs

Di K., Wong Y.C. and Wang X., Id-1 promotes TGF-b1-induced cell motility through HSP27 activation and disassembly of adherens junction in prostate epithelial cells, Experimental Cell Research. 2007, 313: 3983-3999.

Fung K.L., Wong Y.C., Cheung A. and Wang X., MAD2 expression and its significance in mitotic checkpoint control in testicular germ cell tumour, AACR Centennial conference, LA, USA, April 14-18 2007. 2008, 1233.

Howard E.W., Leung C.L., Yuen H.F., Chua C.W., Lee D.T.W., Chan K.W., Wang X. and Wong Y.C., Decreased adhesiveness, resistance to anoikis and suppression of GRP94 are integral to the survival of circulating tumor cells in prostate cancer, Clinical and Experimental Metastasis. 2008, 25: 497-508.

Howard E.W., Camm K.D., Wong Y.C. and Wang X., E-cadherin upregulation as a therapeutic goal in cancer treatment, Mini reviews inMedicinal Chemistry. 2008, 8: 496-518.

Howard E.W., Lee D.T.W., Chiu Y.T., Chua C.W., Wang X. and Wong Y.C., Evidence of a novel docetaxel sensitizer, garlic-derived S-allylmercaptocysteine, as a treatment option for hormone refractory prostate cancer, International Journal of Cancer. 2008, 122: 1941-1948.

Kwok W.K., Ling M.T., Yuen H.F., Wong Y.C. and Wang X., Role of p14^ARF in TWIST-mediated senescence in prostate epithelial cells, Carcinogenesis. 2007, 28(12): 2467-2475.

Li B., Cheung P.Y., Wang X., Tsao G.S.W., Ling M.T., Wong Y.C. and Cheung A., Id-1 activation of PI3K/Akt/NFkB signaling pathway and its significance in promoting survival of esophageal cancer cells, Carcinogenesis. 2007, 28(11): 2313-2320.

To K.W., Cheung H.W., Ling M.T., Wong Y.C. and Wang X., MAD2ΔC induces aneuploidy and promotes anchorage-independent growth in human prostate epithelial cells. , Oncogene. 2008, 27: 347-357.

Wang X., Cheung H.W., Chun C.S., Jin D. and Wong Y.C., Mitotic checkpoint defects in human cancers and their implications to chemotherapy, Frontiers in Bioscience. 2008, 13: 2103-2114.

Wong Y.C., Zhang X., Ling M.T. and Wang X., Caveolin 1, a novel Id-1 binding partner and its role on Id-1 induced behavioral change in prostate cancer cells, AACR annual meeting, San Diego, USA, April 12-16, 2008. 1082.

Wong Y.C., Howard E.W., Chu Q. and Wang X., Garlic derived compounds, S-allylcysteine (SAC) and S-allylmercaptocysteine (SAMC), synergise with Docetaxel to suppress growth of androgen refractory prostate cancer., BIT life Science’s 1st World Cancer Congress, June 12-17 2008, Shanghai, China.. 2008, 85.

Wong Y.C., Howard E.W., Chu Q. and Wang X., Garlic derived compounds, SAC and SAMC, synergise with docetaxel to inhibit the growth of hormone refractory prostate cancer, Proceeding of 5th APICA International Congress of Anatomists and the 8th Iranian congress of Anatomical Sciences, May 16-19, 2008. Tehran, Iran.. 2008, 79-80.

Wong Y.C., Howard E.W., Chu Q., Lee D.T.W. and Wang X., Garlic extract synergizes with docetaxel in suppressing the hormone refractory prostate cancer growth, Proceeding of 12th World Congress on Advances in Oncology and 10th International Symposium on Molecular Medicine held in Hersonissos, Crete, Greece from October 11-13, 2007.Int J Mol Medicine . 2007, 20, Suppl 1: S7.

Wong Y.C., Howard E.W. and Wang X., Garlic extracts working in concert with docetaxel to suppress the growth of androgen independent prostate cancer., XIX International Symposium on Morphological Sciences. Budapest, Hungary. 19-23/8 2007. Acta Biologica Szegediensis. 2007, 51 suppl 1: 57.

Wong Y.C., Zhang X., Ling M.T. and Wang X., Inactivation of Id-1 gene induces sensitivity of prostate cancer cells to chemotherapeutic drugs, In: JJ Li, Sara A Li, Suresh Mohla, Henri Rochefort and Thierry Maudelonde., Hormonal Carcinogenesis . Springer, 2008, V: 565-572.

Yu S., Wong Y.C., Wang X., Ling M.T., Chen S. and Chan F.L., Orphan nuclear receptor β suppresses in vitro and in vivo growth of prostate cancer cells via p21WAF1/CIP1 induction and as a potential therapeutic target in prostate cancer., Oncogene. 2008, 27: 2313-2320.

Yuen H.F., Chan Y.P., Chan K.K., Chu Y.Y., Wong M.L.Y., Law S.Y.K., Srivastava G., Wong Y.C., Wang X. and Chan K.W., Id-1 and Id-2 are markers for metastasis and prognosis in oesophageal squamous cell carcinoma, Br J Cancer. 2007, 97(10): 1409-15.

Zhang X., Wang Q., Ling M.T., Wong Y.C., Leung C.L., Tsao G.S.W. and Wang X., Anti-apoptotic role of TWIST and its association with Akt pathway in mediating taxol resistance in nasopharyngeal carcinoma cells, International J Cancer. 2007, 120: 1891-1898.

Zhang X., Ling M.T., Wong Y.C. and Wang X., Evidence of a novel anti-apoptotic factor: role of inhibitor of differentiation or DNA binding in anticancer drug-induced apoptosis, Cancer Science. 2007, 98: 308-314.

Zhang X., Ling M.T., Wang Q., Lau C.K., Leung C.L., Lee T.K., Cheung A., Wong Y.C. and Wang X., Identification of a novel inhibitor of differentiation-1 (ID-1) binding partner, caveolin-1, and its role in epithelial-mesenchymal transition and resistance to apoptosis in prostate cancer cells, The Journal of Biological Chemistry. 2007, 282(46): 33284-33294.

Researcher : Wang Y

List of Research Outputs

Lau T.Y., Wang Y. and Chiu J., Reactive oxygen species: Current knowledge and applications in cancer research and therapeutic, Journal of Cellular Biochemistry. 2008, 104: 657-667.

Wong C.C., Wang Y., He Q., Chiu J.F. and Chen S.F., Anticancer activity of indioside d: insights from proteomic analysis, Abstracts of the 32nd FEBS Congress, 7-12 July, Vienna, Austria. 2007, p. 375.

Wong C.C., Wang Y., Cheng K.W., Chiu J., He Q. and Chen S.F., Comparative proteomic analysis of indioside D-triggered cell death in HeLa cells, Journal of Proteome Research. 2008, 7: 2050-2058.

Researcher : Wong WM

List of Research Outputs

Guo J., Su H., Zeng Y., Liang Y., Wong W.M., Ellis-Behnke R.G., So K.F. and Wu W., Reknitting The Injured Spinal Cord By Self Assembling Peptide Nanofiber Scaffold, Nanomedicine: Nanotechnology, Biology and Medicine. 2007, 3(4): 311-321.

Mi S., Hu B., Hahm K., Luo Y., Hui S.K., Yuan Q.J., Wong W.M., Wang L., Su H., Chu T.H., Guo J., Zhang W., So K.F., Pepinsky B., Shao Z., Graff C., Garber E., Jung V., Wu E.X. and Wu W., LINGO-1 antagonist promotes spinal cord remyelination and axonal integrity in MOG-induced experimental autoimmune encephalomyelitis, Nature Medicine. 2007, 13(10): 1228-1233.

Researcher : Wong YC

Project Title:	Induction of breast carcinogenesis by a combination of androgens and oestrogens
Investigator(s):	Wong YC, Xie B
Department:	Anatomy
Source(s) of Funding:	Other Funding Scheme
Start Date:	07/1997

Abstract:

To examine the role of both oestrogens and androgens in the initiation and progression of breast carcinogenesis in an animal model.

Project Title:	The Beijing, Hong Kong and UK Collaborative Study on the Molecular Genetic Basis of Differential Susceptibility of Prostate Cancer Between Chinese and Caucasian
Investigator(s):	Wong YC, Wang X, Ho KMT
Department:	Anatomy
Source(s) of Funding:	The University of Hong Kong Foundation Seed Grant
Start Date:	07/2003

Abstract:

To investigate molecular mechanisms responsible for racial differences in prostate cancer incidence.

Project Title:	Id-1 activation of NF-[kappa]B and its role in development of androgen-independent prostate cancer
Investigator(s):	Wong YC, Tsao GSW, Wang X
Department:	Anatomy
Source(s) of Funding:	Competitive Earmarked Research Grants (CERG)
Start Date:	09/2003

Abstract:

To investigate the correlation between the over-expression of Id-1 and activation of NF-[kappa]B in prostate cancer progression; to examine the sensitivity of LNCaP-Id-1 clones towards TNF-[alpha] induced apoptosis; to explore the effect of inhibition of Id-1 expression by antisense Id-1 oligonucleotide on TNF[alpha] induced apoptosis; to study the role of Id-1 gene in development of AI prostate cancer in vivo; to investigate the effect of Id-1 gene silencing on growth of prostate cancer using RNA interference on human prostate cancer xenograft, CWR22.

Project Title:	Identification and evaluation of specific marker proteins from secretions of benign prostatic hyperplasia (BPH)
Investigator(s):	Wong YC, Tam PC, Wang X
Department:	Anatomy
Source(s) of Funding:	NSFC/RGC Joint Research Scheme
Start Date:	12/2003

Abstract:

To confirm and characterize these proteins in the secretion of BPH by 2-D gel electrophoresis followed by mass spectrometry and mass sequencing; to examine the sources of these differetially expressed proteins including the PSP61, lwPSA and protein X, and to investigate the value of these proteins as markers of BPH; to examine whether these proteins are present in serum and to examine the potential of using these proteins as markers in clinical diagnosis of PBPH; to assess correlation of the levels of these newly identified proteins to PSA levels in prostate cancer and BPH patient and to examine their association with PSA.

Project Title:	The role of Id-1 gene in initiation of prostate carcinogenesis
Investigator(s):	Wong YC, Wang X
Department:	Anatomy
Source(s) of Funding:	Competitive Earmarked Research Grants (CERG)
Start Date:	01/2005

Abstract:

To investigate whether over-expression of Id1 could lead to extension of the life span, possibly immortalization, of HPrE cells; to examine whether Id1 expression in combination with additional factors is able to induce malignant transformation of HPrE cells; to study the molecular mechanisms responsible for the Id1-induced malignant transformation of HPrE cells; to identify novel factors (pathways) responsbile for Id1-induced malignant transformation of HPrE cells.

Project Title:	The role of ld-1 gene in prostate cancer angiogenesis
Investigator(s):	Wong YC
Department:	Anatomy
Source(s) of Funding:	Small Project Funding
Start Date:	11/2006

Abstract:

Id-1 (inhibitor of differentiation/DNA synthesis) protein belongs to the Id family of helix-loop-helix proteins. It lacks the basic domain for DNA binding and functions mainly as a dominant inhibitor of the bHLH transcription factor through heterodimerization (1). Id-1 has been shown to play a critical role in the regulation of cell proliferation (2), differentiation (3) and senescence (4-6), and recent studies suggest that Id-1 may function as an oncogene. For example, Id-1 is shown to inhibit replicative senescence and promotes life span of primary cells through inactivation of p16/RB pathway (6). In addition, elevated Id-1 expression either at transcriptional or translational levels has been reported in over 20 types of human cancer including prostate, breast, cervical, colon, liver cancers (7). Furthermore, ectopic expression of Id-1 is able to promote cancer cell proliferation and protect against apoptosis under sub-optimal culture conditions (2, 8). In addition to its potential oncogenic actions, Id-1 has also been suggested to take part in the malignant progression of human cancer. For example, in breast cancer, Id-1 is found to be constitutively expressed in the highly aggressive but not the non-aggressive cancer cells (9). In endometrial carcinoma, Id-1 expression is high in high grade and invasive tumors (10). Early stage cervical cancer patients with high Id-1 expression have poor prognosis compared with patients with relatively low Id-1 expression (11). In breast and cervical cancers, increased Id-1 is associated with more aggressive clinical behavior as well as poor clinical outcome in patients (9, 11, 12). In our previous studies, in human prostate cancer, Id-1 expression is found to be increased with increased Gleason score of the tumors (12) and ectopic expression of Id-1 in the androgen sensitive prostate cancer cells leads to decreased sensitivity to androgen-induced growth stimulation (13), which is a characteristic of prostate cancer progression. Furthermore, Id-1 is shown to stimulate MAPK and NFkeppaB pathways which are frequently activated in more advanced and aggressive cancers (8, 14). These lines of evidence strongly suggest that Id-1 may be a key factor not only in promoting human tumorigenssis but it may also play an important part in tumor progression. One of the striking characteristics of the aggressive cancer cells is their ability to metastasis and develop an ectopic growth. The most convincing evidence associating Id-1 with tumor metastasis are the results generated from knockout mice that Id-1 and Id-3 double knockout results in embryonic lethality in mice due to display poor blood vessel formation in the brain. The Id-1-/-Id3+/- mice also failed to support the growth of tumor xenografts due to poor vascularization leading to necrosis of tumor cells (15). In addition, loss of Id-1 is also associated with downregulation of several proangiogenic genes such as integrinα6 and beta4 in tumor endothelial cells (16). Furthermore, downregulation of Id-1 in a breast cancer animal model leads to decreased metastasis ability of xenografts and reduced invasion ability in cultured cells (17). These results raise a hypothesis that Id-1 may play a positive role in cancer metastasis through promoting angiogenesis and inactivation of Id-1 may be a therapeutic target for the treatment of metastatic cancers. Prostate cancer is the most commonly diagnosed cancer in American men representing one-third of all new cancer cases each year. This means that one out of six American men being diagnosed with prostate cancer over the course of their lifetimes. As the result, over 30,000 men die each year from prostate cancer in the United States (18). Like majority of human cancers, early stage androgen sensitive prostate cancer is manageable with androgen depletion therapy. However, approximately 33% of prostate cancer patients have micro-metastatic disease at the time of presentation, this group of patients will eventually progress to clinical detectable metastatic and androgen independent diseases at which point the median survival is only 12-15 months (19). Therefore, metastatic prostate cancer remains the main cause of prostate cancer related death in men. However, the molecular mechanisms leading to metastatic progression of prostate cancer are not known. In this study, we propose ti investigate the role of Id1 in prostate cancer angiogenesis through activation of secretion of VEGF. Our preliminary results suggest that overexpression of Id-1 may provide an autocrine signal to facilitate ectopic growth of prostate cancer cells through promoting angiogenesis.

List of Research Outputs

Chiu Y.T., Wong Y.C. and Ling M.T., Identification of a novel androgen receptor corepressor, CDC25A, in prostate cancer cells., 12th Research Postgraduate Symposium, HKU Medical Faculty, Dec 12 and 14 2007. . 2007, 95.

Di K., Wong Y.C. and Wang X., Id-1 promotes TGF-b1-induced cell motility through HSP27 activation and disassembly of adherens junction in prostate epithelial cells, Experimental Cell Research. 2007, 313: 3983-3999.

Fung K.L., Wong Y.C., Cheung A. and Wang X., MAD2 expression and its significance in mitotic checkpoint control in testicular germ cell tumour, AACR Centennial conference, LA, USA, April 14-18 2007. 2008, 1233.

Howard E.W., Leung C.L., Yuen H.F., Chua C.W., Lee D.T.W., Chan K.W., Wang X. and Wong Y.C., Decreased adhesiveness, resistance to anoikis and suppression of GRP94 are integral to the survival of circulating tumor cells in prostate cancer, Clinical and Experimental Metastasis. 2008, 25: 497-508.

Howard E.W., Camm K.D., Wong Y.C. and Wang X., E-cadherin upregulation as a therapeutic goal in cancer treatment, Mini reviews inMedicinal Chemistry. 2008, 8: 496-518.

Howard E.W., Lee D.T.W., Chiu Y.T., Chua C.W., Wang X. and Wong Y.C., Evidence of a novel docetaxel sensitizer, garlic-derived S-allylmercaptocysteine, as a treatment option for hormone refractory prostate cancer, International Journal of Cancer. 2008, 122: 1941-1948.

Kwok W.K., Ling M.T., Yuen H.F., Wong Y.C. and Wang X., Role of p14^ARF in TWIST-mediated senescence in prostate epithelial cells, Carcinogenesis. 2007, 28(12): 2467-2475.

Li B., Cheung P.Y., Wang X., Tsao G.S.W., Ling M.T., Wong Y.C. and Cheung A., Id-1 activation of PI3K/Akt/NFkB signaling pathway and its significance in promoting survival of esophageal cancer cells, Carcinogenesis. 2007, 28(11): 2313-2320.

To K.W., Cheung H.W., Ling M.T., Wong Y.C. and Wang X., MAD2ΔC induces aneuploidy and promotes anchorage-independent growth in human prostate epithelial cells. , Oncogene. 2008, 27: 347-357.

Wang X., Cheung H.W., Chun C.S., Jin D. and Wong Y.C., Mitotic checkpoint defects in human cancers and their implications to chemotherapy, Frontiers in Bioscience. 2008, 13: 2103-2114.

Wong Y.C., Zhang X., Ling M.T. and Wang X., Caveolin 1, a novel Id-1 binding partner and its role on Id-1 induced behavioral change in prostate cancer cells, AACR annual meeting, San Diego, USA, April 12-16, 2008. 1082.

Wong Y.C., Howard E.W., Chu Q. and Wang X., Garlic derived compounds, S-allylcysteine (SAC) and S-allylmercaptocysteine (SAMC), synergise with Docetaxel to suppress growth of androgen refractory prostate cancer., BIT life Science’s 1st World Cancer Congress, June 12-17 2008, Shanghai, China.. 2008, 85.

Wong Y.C., Howard E.W., Chu Q. and Wang X., Garlic derived compounds, SAC and SAMC, synergise with docetaxel to inhibit the growth of hormone refractory prostate cancer, Proceeding of 5th APICA International Congress of Anatomists and the 8th Iranian congress of Anatomical Sciences, May 16-19, 2008. Tehran, Iran.. 2008, 79-80.

Wong Y.C., Garlic extract synergizes with docetaxel in suppressing the hormone refractory prostate cancer growth, 12th World Congress on Advances in Oncology and 10th International Symposium on Molecular Medicine held in Hersonissos, Crete, Greece from October 11-13, 2007. 2007.

Wong Y.C., Howard E.W., Chu Q., Lee D.T.W. and Wang X., Garlic extract synergizes with docetaxel in suppressing the hormone refractory prostate cancer growth, Proceeding of 12th World Congress on Advances in Oncology and 10th International Symposium on Molecular Medicine held in Hersonissos, Crete, Greece from October 11-13, 2007.Int J Mol Medicine . 2007, 20, Suppl 1: S7.

Wong Y.C., Garlic extracts working in concert with docetaxel in suppressing the hormone refractory prostate cancer growth, XIX International Symposium on Morphological Sciences, in Budapest, Hungary. August 19-23, 2007. 2007.

Wong Y.C., Howard E.W. and Wang X., Garlic extracts working in concert with docetaxel to suppress the growth of androgen independent prostate cancer., XIX International Symposium on Morphological Sciences. Budapest, Hungary. 19-23/8 2007. Acta Biologica Szegediensis. 2007, 51 suppl 1: 57.

Wong Y.C., Garlic-derived compounds, SAC (S-allylcysteine) and SAMC (S-allylmercaptocysteine), synergise with docetaxel to inhibit the growth of hormone independent prostate cancer, The World Cancer Congress 2008, June 12-17 2008 Shanghai. 2008.

Wong Y.C., Garlic-derived compounds, SAC and SAMC, synergise with docetaxel to inhibit the growth of hormone independent prostate cancer, Plenary lecture. the 5th APICA held in Tehran, Iran from May 16-20, 2008. 2008.

Wong Y.C., Zhang X., Ling M.T. and Wang X., Inactivation of Id-1 gene induces sensitivity of prostate cancer cells to chemotherapeutic drugs, In: JJ Li, Sara A Li, Suresh Mohla, Henri Rochefort and Thierry Maudelonde., Hormonal Carcinogenesis . Springer, 2008, V: 565-572.

Wong Y.C., Mechanism involved in garlic extract suppressed prostate cancer growth, The seventh Central and Southern China Anatomical Conference in Zhengzhou, Henan, China. July 20-24 2007.. 2007.

Wong Y.C., Morphological Science research: Where do we go from here?, 9th National Histology and Embryology Congress with International Contribution held in Adana, Turkey from May 20-23 2008. Opening ceremony lecture. 2008.

Wong Y.C., Morphological science research: Where do we go from here?, Proceeding of 9th National Histology and Embryology Congress with International Contribution May 20-23, 2008, Adana, Turkey.Cell and Tissue Biology Research (Turkish Histology and Embryology Association) . 2008, 1 Suppl C1: 8.

Yu S., Wong Y.C., Wang X., Ling M.T., Chen S. and Chan F.L., Orphan nuclear receptor β suppresses in vitro and in vivo growth of prostate cancer cells via p21WAF1/CIP1 induction and as a potential therapeutic target in prostate cancer., Oncogene. 2008, 27: 2313-2320.

Yuen H.F., Chan Y.P., Chan K.K., Chu Y.Y., Wong M.L.Y., Law S.Y.K., Srivastava G., Wong Y.C., Wang X. and Chan K.W., Id-1 and Id-2 are markers for metastasis and prognosis in oesophageal squamous cell carcinoma, Br J Cancer. 2007, 97(10): 1409-15.

Zhang X., Wang Q., Ling M.T., Wong Y.C., Leung C.L., Tsao G.S.W. and Wang X., Anti-apoptotic role of TWIST and its association with Akt pathway in mediating taxol resistance in nasopharyngeal carcinoma cells, International J Cancer. 2007, 120: 1891-1898.

Zhang X., Ling M.T., Wong Y.C. and Wang X., Evidence of a novel anti-apoptotic factor: role of inhibitor of differentiation or DNA binding in anticancer drug-induced apoptosis, Cancer Science. 2007, 98: 308-314.

Zhang X., Ling M.T., Wang Q., Lau C.K., Leung C.L., Lee T.K., Cheung A., Wong Y.C. and Wang X., Identification of a novel inhibitor of differentiation-1 (ID-1) binding partner, caveolin-1, and its role in epithelial-mesenchymal transition and resistance to apoptosis in prostate cancer cells, The Journal of Biological Chemistry. 2007, 282(46): 33284-33294.

Researcher : Wu EX

Project Title:	Magnetic resonance imaging for biomedical research
Investigator(s):	Wu EX
Department:	Engineering Faculty
Source(s) of Funding:	Seed Funding for New Staff
Start Date:	02/2004

Abstract:

To develop and acquire the basic and necessary software and hardware required for the MRI research at HKU.

Project Title:	Manganese-enhanced Magnetic Resonance Imaging of Rodent Brain Function and Pathology
Investigator(s):	Wu EX
Department:	Engineering Faculty
Source(s) of Funding:	Small Project Funding
Start Date:	10/2005

Abstract:

Manganese ions (Mn++) have been recently discovered as a Ca++ analog in neuronal transport that tracks various active neuronal pathways and cortical projections. The primary objective of this project is to explore and develop in vivo Mn-enhanced MRI (MEMRI) technology that is suitable for interrogation of rodent brain functions in normal and pathological states. The specific aims are to (1) establish an optimal high-resolution MEMRI protocol to detect neural activity in various regions of normal rodent brain; (2) define and characterize altered patterns of MEMRI enhancement associated with neonatal hypoxia ischemia in mouse model and glaucoma in rat model.

Project Title:	MRI of gas-filled microbubbles for microbubble-based therapeutic applications
Investigator(s):	Wu EX, Xu B, Khong PL
Department:	Engineering Faculty
Source(s) of Funding:	Competitive Earmarked Research Grants (CERG)
Start Date:	09/2006

Abstract:

To characterize MRI sensitivity in detecting gas-filled microbubbles; to evaluate the ability of MRI to monitor microbubble cavitation procedure in real time; to explore and evaluate a new gas-filled microbubble design that has enhanced MRI detectability.

Project Title:	Magnetic Resonance Measurement of Heart and Liver Iron
Investigator(s):	Wu EX
Department:	Electrical & Electronic Engg
Source(s) of Funding:	The National Institute of Diabetes and Digestive and Kidney Diseases
Start Date:	11/2006

Abstract:

1. Implementation and optimization of projection-reconstruction, gradient- and spin-echo imaging sequences to map T2 and T2* in test phantoms. The work initially will be performed at 7 Tesla for testing and then implemented for clinical imaging at 3 Tesla. This component of the research work will also include development of necessary software toolkits for image data analysis. 2.Optimization of clinical protocols at 3 Tesla for T2 and T2* measurements using projection-reconstruction, gradient- and spin-echo sequences in the anterior pituitary, pancreas and gonads. 3. Estimates of iron deposition in the anterior pituitary, pancreas and gonads using the optimized MRI protocols will be compared with the results of clinical evaluation of endocrine function in a group of thalassaemia patients with a wide range of body iron burdens.

Project Title:	Cell labeling for In Vivo MRI Monitoring after Transplantation in Cell Based Therapies
Investigator(s):	Wu EX
Department:	Engineering Faculty
Source(s) of Funding:	Small Project Funding
Start Date:	01/2007

Abstract:

In vivo monitoring of stem cells after grafting is essential for a better understanding of their migrational dynamics and differentiation processes and of their therapeutic potential. High-field magnetic resonance imaging (MRI) is potentially capable of tracking transplanted stem cells, and characterizing resulting anatomical, physiological and functional recovery in vivo, intact, and with high spatial resolution. We propose to develop such cellular imaging methodology on a 7 Tesla MRI scanner by (i) designing various techniques to label cells in vitro and quantitatively monitoring their in vivo distribution and activity after transplantation in stem cell therapy in rat stroke model; (ii) characterizing the therapeutic outcome in terms of anatomical structures and physiological functions using various MRI methods.

Researcher : Wu G

List of Research Outputs

Wu G., Tsao G.S.W. and Yip H.K.F., Characteristics of Telomerase Expression in Neurogenic Sites of Adult Central Nervous System, 12th Research Postgraduate Symposium, The University of Hong Kong, Faculty of Medicine. 2007.

Wu G., Tsao G.S.W. and Yip H.K.F., Characteristics of Telomerase Expression in Neurogenic Sites of Adult Central Nervous System, The University of Hong Kong Li Ka Shing Faculty of Medicine, Research Centre of Heart, Brain, Hormone & Healthy Aging, 3rd International Symposium on Healthy Aging: “Improving the Health of an Aging Population. 2008.

Yip H.K.F., Niu C. and Wu G., Neuronal injury affects telomerase activity and expression in the adult rat nervous system, US Society of Neuroscience Annual Meeting . 2007.

Researcher : Wu W

Project Title:	Effects of chondroitinase ABC and lithium chloride on neuronal survival and regeneration after spinal cord injury
Investigator(s):	Wu W, Yick LW, So KF
Department:	Anatomy
Source(s) of Funding:	Matching Fund for National Key Basic Research Development Scheme (973 Projects)
Start Date:	11/2003

Abstract:

To study the effects of chondroitinase ABC and lithium chloride on neuronal survival and regneration after spinal cord injury.

Project Title:	The role of neuronal nitric oxide synthase in motoneuron degeneration
Investigator(s):	Wu W, Huang J
Department:	Anatomy
Source(s) of Funding:	Competitive Earmarked Research Grants (CERG)
Start Date:	09/2004

Abstract:

To examine the effect of nNOS inhibitors on the expression of injury-induced nNOS and the effect on motoneuron survival and regeneration in adult animals following spinal root avulsion; to investigate the effect of blockage of nNOS expression by antisense nNOS oligodeoxynuleotide (ODN) on motoneuron degeneration and regeneration after root avulsion; to examine how motoneurons respond to axonal injury and whether they can regenerate after root avulsion in nNOS knockout animals; to investigate the effect of nNOS gene silencing on survival and growth of cultured spinal motoneurons using RNA interference technique.

Project Title:	Effect of LINGO-1 antibody on demyelinating desease
Investigator(s):	Wu W
Department:	Anatomy
Source(s) of Funding:	Seed Funding Programme for Basic Research
Start Date:	01/2006

Abstract:

Backgroud: Demyelinating diseases are characterized by the loss of myelin sheath due to extensive inflammation and gliosis in the central nervous system (CNS). A typical example of demyelinating diseases is multiple sclerosis (MS). The main pathological characteristics of MS are widespread demyelination and oligodendrocyte degeneration [1]. Degeneration of oligodendrocytes not only results in demyelination but also cause degeneration of axons and neurons in the late stage of MS [2]. Axonal loss and neuronal degeneration in MS contribute directly to the disability motor and sensory functions [3]. The key issue in MS is the degenrartion of oligodendrocytes. Therefore, preventing degeneration of oligodendrocytes may be critical for the progress of MS and could become a potential theraputical procedure. The control of myelination by oligodendrocytes in the CNS is poorly understood. Recently, a study in Mi's group [4,5] demonstrated that LINGO-1 (LRR and Ig domain-containing, Nogo Receptor-interacting proten) is an important negative regulator of myelination. LINGO-1 is expressed in oligodendrocytes. Overexpression of LINGO-1 leads to inhibition of oligodendrocyte differentiation and myelination. Attenuation of its function by dominat-negative LINGO-1, LINGO-1 RNA-mediated interference (RNAi) or soluble human LINGO-1 (LINGO-1-Fc) leads to differentiation of oligodendrocytes and myelination competence [5]. The ability to recapitulate CNS myelination is verified in vivo through the analsis of LINGO-1 knochout mice [5], which indicate that LINGO-1 signaling may be critical for CNS myelination. However, precise mechanisms of LINGO-1 in demyelinating disease models have not been studied. Objectives: Objectives of the present study are 1) to test whether attenuation of LINGO-1 (by application of antibody to LINGO-1) can prevent the degeneration of oligodendrocytes and the onset of demyelination in a MS model; and 2) to investigate whether such treatment can slow down the progress and prevent the demyelination after the onset of demyelination in a MS model. Key issues and problems in the proposal are 1) establishment of the MS model and 2) attenuation of LINGO-1 by its antibody. To address these problems, we have run a preliminary study by collaboration with Dr. Mi Sha of Biogen Idec, Inc, USA and an experimental autoimmune encephalomyelitis (EAE) rat model has been adapted in Dr Wu's laboratory for the proposed study. The EAE model is the principal model for MS [6]. Antibody against LINGO-1 has been purified and produced in Dr. Mi's laboratory and is ready to be used in the proposed study. In addition to the main ojectives mentioed above in the proposed study, we will also test the best dosage level, the best time zone and duration, and the best administration way for the use of LINGO-1 antibody for the prevention of demyelination. Reference:[1]. Merrill JE et al., Neuropathol Appl Neurobiol 1999; 25:435-58.[2]. Rieckmann P et al., Trends Neurosci 2001; 24:435-7.[3]. De Stefano N et al., Brain 1998; 121:1469-77.[4]. Mi S et al., Nature Neurosci 2004; 7:221-28.[5]. Mi S et al., Nature Neurosci 2005; 8:745-51.[6]. Wekerle M et al., Ann Neurol Suppl 1994; 36:S47-53.

Project Title:	Axonal regeneration of CNS neurons after spinal cord injury
Investigator(s):	Wu W
Department:	Anatomy
Source(s) of Funding:	Competitive Earmarked Research Grants (CERG)
Start Date:	10/2006

Abstract:

The aim of this study is to examine the effects of combined treatments, lithium chloride (LiC1) plus chondroitinase ABC (ChABC), on neuronal regeneration after spinal cord injury (SCI) and to investigate the potential mechanisms of the treatments. Work programme: by using in vivo model the proposed study will investigate: (1) effects of combined treatment of ChABC and Lithium on axonal regeneration after SCI; (2) potential mechanisms of combined treatments on axonal regeneration after SCI.

Project Title:	Effects of lithium on the survival, proliferation and differentiation of neural stem cells transplanted into the rat spinal cord.
Investigator(s):	Wu W
Department:	Anatomy
Source(s) of Funding:	Seed Funding Programme for Basic Research
Start Date:	09/2007

Abstract:

Objectives: Objectives of the present study are: 1) to investigate whether lithium could induce neurogenesis and promote endogenous progenitor cells in injured spinal cord and, 2) to examine the effects of lithium on the survival, migration, proliferation and differentiation of grafted neural stem cells into the spinal cord. Rationale for the objectives: Why neural stem cells? Neural stem cell transplantation is a promising therapeutic strategy for the treatment of neurological diseases including brain and spinal cord injuries. The cell replacement of damaged neurons and oligodendrocytes and the production of neurochemically supportive molecules by engrafted cells could be the rational for using transplantation as a therapeutic approach (Bjorklund, 2000; Okano., 2002). Adult spinal cord shows very limited ability for spontaneous repair after injury. Although endogenous neural stem cells (NSCs) have been demonstrated to be present in the adult spinal cord (Horner et al., 2000), this cell type is clearly insufficient for significant repair of the injured spinal cord. Therefore, NSCs transplantation shows great potential for treating spinal cord injury. Many studies have shown that grafting NSCs into the lesion site of spinal cord after injury leads to improve structure growth and functional recovery. Delayed transplantation of neural progenitor cells into the contused spinal cord could induce neurogenesis and functional recovery (Ogawa et al., 2002), and promote remyelination (Karimi-abdolrezaee et al., 2006). Neural and glial restricted precursors transplantation into the injured spinal cord has been shown to improve bladder and motor functions and decrease thermal hypersentivity (Mitsui et al., 2005). However, the efficacy of NSCs transplantation in cell replacement and function restore is quite limited (Cao et al., 2002; Enzmann et al., 2005). Adult spinal cord is a hostile milieu for the grafted neural stem cells and the injured cord does not appear to support the long-term survival of transplanted stem cells (Chow et al., 2000). Transplantation of multipotent NSCs into the spinal cord leads to poor survival (Lepore et al., 2005), incomplete differentiation (Cao et al., 2001). Environmental factors, programmed cell death of grafted NSCs and host rejection would be the reasons contributing to the ultimate survival and differentiated phenotypes of grafted cells. Therefore, how to enhance survival, proliferation and differentiation of transplanted NSCs in the host spinal cord is essential for the application of NSCs transplantation therapy. Immune suppression, inflammation control, apoptosis inhibition and lesion environment modification as well as mobilization of endogenous stem cells are believed to benefit the application of cell transplantation therapy. Why lithium? Recently, increasing documents have shown that small molecules are capable of inducing neurogenesis and promoting proliferation, survival, migration or maturation of neural precursor cells (Longo et al., 2006). Lithium, a widely used antidepressant drug, is reported to markedly increase the proliferation and neuronal differentiation of cultured hippocampal neural progenitor cells (Kim et al., 2004). It can also stimulate progenitor proliferation in cultured brain neurons (Hashimoto et al., 2003) and inhibit apoptosis of mouse neural progenitor cells (Shimomura et al., 2003). In vivo lithium has been demonstrated to enhance hippocampal neurogenesis (Chen et al., 2000) as well as proliferation of dentate gyrus progenitor cells (Son et al., 2003). On the other hand, little literature was reported whether lithium could induce neurogenesis, modify glial reaction, alleviate the inflammation and promote activation of endogenous progenitor cells in injured spinal cord. It is also not clear whether lithium could exert promotive effects on the survival, migration, proliferation and differentiation of grafted neural stem cells into the spinal cord. Therefore, objectives of the present study focuses on the effects of lithium on endogenous progenitor cells and transplanted NSCs in injured spinal cord and. Preliminary results Since this is a new research project for the PI, in order to achieve the objectives of the study we have performed a few preliminary experiments, which include 1) establishing methods for isolating and culturing fetal NSCs from GFP rats; and 2) establishing method for transplantation of cultured NSCs into the rat spinal cord. Results of these preliminary studies demonstrated that NSCs from GFP fetal rat can be isolated, cultured, identified and transplanted into wild type rat spinal cord in our lab (Fig 1, attachment 1). With these successful preliminary results we are sure we can achieve the objectives of the proposed project. Reference: Bjorklund A . Novartis Found Symp. (2000), 231:7-15. Cao et al., Exp. Neurol. (2001) 167:48-58. Cao et al., J Neurosci. Res. (2002) 68:501-510. Chen et al., J Neurochem. (2000) 75(4):1729-34. Chow et al., Brain Res. (2000), 874:87-106. Enzmann et al., Exp. Neurol. (2005), 195:293-304. Hashimoto et al., Neuroscience. (2003), 117(1):55-61. Horner et al., J Neurosci. (2000) 20(6):2218-28. Karimi-abdolrezaee et al., J Neurosci. (2006), 26(13):3377-89. Kim et al., J Neurochem. (2004) 89(2):324-36. Lepore et al., Exp. Neurol. (2005), 194:230-242. Longo et al., Curr Alzheimer Res. (2006), 3(1):5-10. Mitsui et al., J Neurosci. (2005) 25(42):9624-36. Ogawa et al., J Neurosci. Res. (2002), 69:925-933. Okano., Keio J Med. (2002) 51(3):115-28. Shimomura et al., Neuroreport. (2003) 14(14):1779-82. Son et al., 2003 J Neurochem. (2003) 85(4):872-81.

List of Research Outputs

Cheung Z.H., Leung M.C.P., Yip H.K.F., Wu W., Siu F.K.W. and So K.F., A neuroprotective herbal mixture inhibits caspase-3-independent apoptosis in retinal ganglion cells, Celular and Molecular Neurobiology. 2008, 28: 137-155.

Fu Q., Hu B., Wu W., Pepinsky R.B., Mi S. and So K.F., Blocking LINGO-1 function promotes retinal ganglion cell survival following ocular hypertension and optic nerve transection, Investigative Ophthalmology & Visual Science. 2008, 49(3): 975-985.

Fu Q., Wu W., Wang H., Li X., Lee V.W.H. and So K.F., Up-regulated endogenous erythropoietin/erythropoietin receptor system and exogenous erythropoietin rescue retinal ganglion cells after chronic ocular hypertension, Cellular and Molecular Neurobiology. 2008, 28: 317-329.

Guo J., Su H., Zeng Y., Liang Y., Wong W.M., Ellis-Behnke R.G., So K.F. and Wu W., Reknitting The Injured Spinal Cord By Self Assembling Peptide Nanofiber Scaffold, Nanomedicine: Nanotechnology, Biology and Medicine. 2007, 3(4): 311-321.

Guo J., Liang Y., Zeng Y., Ellis-Behnke R.G., So K.F. and Wu W., Reknitting the spinal cord using a self-assembling peptide nanofiber scaffold to promote functional recovery, Society for Neuroscience, San Diego USA. 2007.

Guo J., Pu J.K.S., Wu W. and Leung G.K.K., Self-assembling peptide promotes the recovery of acute injured brain, The 14th Annual Scientific Meeting, The Hong Kong Neurosurgical Society. 2007.

Mi S., Hu B., Hahm K., Luo Y., Hui S.K., Yuan Q.J., Wong W.M., Wang L., Su H., Chu T.H., Guo J., Zhang W., So K.F., Pepinsky B., Shao Z., Graff C., Garber E., Jung V., Wu E.X. and Wu W., LINGO-1 antagonist promotes spinal cord remyelination and axonal integrity in MOG-induced experimental autoimmune encephalomyelitis, Nature Medicine. 2007, 13(10): 1228-1233.

Su H., Chu T.H. and Wu W., Lithium enhances proliferation and neuronal differentiation of neural progenitor cells in vitro and after transplantation into the adult rat spinal cord, The 37 Annual Meeting Society for Neuroscience, U.S.A., Nov. 2007.

Xiao Q., Wu W. and Yip H.K.F., The Roles of Bone Morphogenetic Proteins (BMPs) in the Acute Spinal Cord Injury in Adult Mice, 12th Research Postgraduate Symposium, The University of Hong Kong, Faculty of Medicine. 2007.

Yuan Q.J., Scott D.E., So K.F. and Wu W., Differential activation of c-fos immunoreactivity after hypophysectomy in developing and adult rats, The Anatomical Record. 2007, 290: 1050-1056.

Researcher : Xiao Q

List of Research Outputs

Xiao Q., Wu W. and Yip H.K.F., The Roles of Bone Morphogenetic Proteins (BMPs) in the Acute Spinal Cord Injury in Adult Mice, 12th Research Postgraduate Symposium, The University of Hong Kong, Faculty of Medicine. 2007.

Researcher : Yau SY

List of Research Outputs

Lau W.M., Qiu G., Yau S.Y., Helmeste D.M., Lee T.M.C., Tang S.W. and So K.F., Neuroprotection in steroid therapy: An animal model, Health Research symposium 2007, September 29, 2007. Poster P10.

Li S.Y., Yau S.Y., Chen B., Tay D.K.C., Lee V.W.H., Pu M., Chan H.H.L. and So K.F., Enhanced Survival of Melanopsin-expressing Retinal Ganglion Cells After Injury is Associated with the PI3 K/Akt Pathway, Cellular and Molecular Neurobiology. 2008, 28: 1095-1107.

Researcher : Yeung SC

List of Research Outputs

Chiu K., Yeung S.C., Ho Y.S., Chan W., So K.F. and Chang R.C.C., Best Poster Award, Hong Kong Society of Immunology. 2008.

Chiu K., Yeung S.C., Ho Y.S., Chan W., So K.F. and Chang R.C.C., Neuroprotective effect of IL-10 on retinal ganglion cell survival in experimental glaucoma model, Hong Kong Society for Immunology 2008 Annual General Meeting and Scientific Meeting, April 19, 2008, Hong Kong.. 2008, 26.

Chiu K., Lau W.M., Yeung S.C., Chang R.C.C. and So K.F., Retrograde labeling of reinal ganglion cells by application of Fluoro-Gold on the surafce of superior colliculus, Journal of Visualized Experiments. 2008.

Researcher : Yick LW

Project Title:	Defining the roles of epidermal growth factor (EGF) in the regulation of chondrocyte differentiation and endochondral bone formation
Investigator(s):	Yick LW, Chan SY
Department:	Paediatrics & Adolescent Med
Source(s) of Funding:	Small Project Funding
Start Date:	11/2004

Abstract:

To understand the role of EGF in chondrocyte differentiation using our 'knock-in mice' with targeted expression of EGF in prehypertrophic chondrocytes.

Researcher : Yik SY

List of Research Outputs

Chang R.C.C., Yik S.Y., Ho Y.S., Lai S.W. and So K.F., Direct neurotoxic effects of dsRNA: Implication of virus-induced neurodegeneration , Society for Neuroscience 2007. Program No. 605.23.

Ho Y.S., Yu M.S., Yik S.Y., Lai S.W., So K.F., Yuen W.H. and Chang R.C.C., Lycium barbarum protects neurons against neurodegeneration in Alzheimer's disease through multiple approaches, Third International Symposium on Healthy Aging: Improving the Health of an Aging Population, March 1-2, 2008, Hong Kong. 2008, 44 OP10.

Yik S.Y., Yu M.S., Ho Y.S., Lai S.W., Cheung Y.T., So K.F. and Chang R.C.C., Significance of dsRNA-elicited neurotoxicity, neuroprotection of minocycline on viral induced neurodegeneration, Third International Symposium on Healthy Aging: Improving the Health of an Aging Population, March 1-2,2008, Hong Kong.. 2008, 52 P14.

Researcher : Yip HKF

Project Title:	The role of microglia in the survival of retinal ganglion cells (RGCs) following transient retinal ishemia
Investigator(s):	Yip HKF, Chang RCC
Department:	Anatomy
Source(s) of Funding:	Small Project Funding
Start Date:	11/2002

Abstract:

To study the effects of: (1) Ischemia on the survival of RGCs and microglial response; (2) Neurotrophic factors (CNTF, BDNF, and bFGF) and cytokines (TGF-[gamma], IL-4, IL-10, TNF-[gamma], CSF-1, and IFN-/LPS) on the survival of RGCs and microglial response after transient retinal ischemia; (3) Neurotrophic factors and cytokines on the microglia from ischemic retina in vitro.

Project Title:	In vivo gene transfer of the catalytic subunit of telomerase protects retinal ganglion cells against axotomy-induced cell death
Investigator(s):	Yip HKF, Tsao GSW, Chung SK
Department:	Anatomy
Source(s) of Funding:	Seed Funding Programme for Basic Research
Start Date:	05/2005

Abstract:

To compare TERT mRNA expression levels in axotomized mouse and fish RGCs; to determine whether TERT upregulation protects mouse RGCs from axotomy-induced cell death; to determine signaling pathways involved in the TERT-induced survival of axotomized RGCs.

Project Title:	The role of telomerase in protecting retinal ganglion cells against axonal injury
Investigator(s):	Yip HKF, Tsao GSW, Leung AYH
Department:	Anatomy
Source(s) of Funding:	Competitive Earmarked Research Grants (CERG)
Start Date:	09/2005

Abstract:

To establish the anti-apoptotic role of telomerase in regulating RGC survival after optic nerve (ON) lesion in fish and mice; to examine the possibility that telomerase mediate RGC survival-promoting actions of brain-derived neurotrophic factor (BDNF); to determine possible mechanisms whereby telomerase prevent apoptosis.

Project Title:	The interaction of Id2, bHLH and retinoblastoma proteins in the neurogenesis of zebrafish retina
Investigator(s):	Yip HKF, Chung SK, Wong YC, Wang X
Department:	Anatomy
Source(s) of Funding:	Seed Funding Programme for Basic Research
Start Date:	04/2006

Abstract:

During development of the retina, progenitor cells change their competency over time under the control of extrinsic (such as neurotrophic factors) and intrinsic regulators (such as transcription factors). In mouse, retinal progenitors initially proliferate extensively to increase the cell number but, from embryonic day (E) 10.5 onward, proliferating progenitors start cell differentiation. In the neural retina, there are six types of neurons and one type of glial cells (Müller cells). These seven types of cells are differentiated from common progenitors in an order conserved among many species: ganglion cells first and Müller cells last. Thus, retinal development consists of three successive processes: (i) proliferation of progenitors, (ii) neurogenesis, and (iii) gliogenesis. It has been shown that these processes are controlled by a number of basic helix-loop-helix (bHLH) genes, which function as intrinsic regulators (1). Another family of HLH genes, which lack the basic DNA-binding domain, is known as inhibitors of DNA binding or Id genes. In mammals, there are four known Id gene family members. Id1, Id2, Id3, and Id4 are expressed in progenitors of the central nervous system (CNS) in overlapping but distinctive patterns. The proteins encoded by these genes form inactive heterodimeric complexes and negatively influences the ability of tissue-specific bHLH transcription factors to bind to DNA. Thus, Id proteins function as negative regulators by sequestering cell type-restricted bHLH transcription factors, and act as a negative regulator of differentiation (2). Similarly, expression of the mammalian prototype Id gene Id1 is down-regulated upon differentiation in many cell types, including neurons (3). Inconsistent with the model mentioned above, however, is the expression of Id genes in functional, mature cells of several types. For example, Id2 expression is not restricted to early newborn neurons but is also found in specific neurons throughout the development and adulthood in the mouse brain (4). Id1, Id2 and Id3 have been shown to interact with cell cycle regulatory molecules (5). In addition, both genetic and biochemical evidence indicates that Id2 inhibits retinoblastoma (pRb) protein function to enhance the G1 to S transition in proliferating cells (6). Together, these data suggest that Id proteins perform a dual function in the control of cell proliferation and differentiation. We have provided the first evidence that Id3 protein is present in the postnatal and adult mouse retina. Id3 are found in the retinal ganglion cells and amacrine cells (7). The spatial expression pattern of Id2 overlaps and yet is distinct with the pattern of Id3. Id2 expression is restricted to the amacrine and bipolar cells (8). Basic helix-loop-helix (bHLH) genes play a key role in the induction of cell type-specific gene expression. During early development, retinal progenitor cells proliferate in the ventricular zones and eventually commit to a neuronal fate, progenitor cells then exit cell cycle and undergo terminal mitosis and at the same time induce neuron-specific genes. Retinoblastoma tumor suppressor protein (pRb) has been indicated in this transition. Because pRb plays a role in cell cycle regulation, inactivation of pRb results in ectopic mitoses and extensive cell death in the developing nervous system (9). Studies demonstrated a crucial temporal requirement for the pRb during neuronal phenotypic determination; these cell cycle regulatory molecules were pivotal for termination of mitosis and survival of progenitor cells, however, it is not required for the induction of neurogenesis. The role of pRB and the molecular mechanisms responsible for coordinately inducing neuronal gene expression are largely unknown. Interestingly, both positive bHLH and dominant-inhibitory HLH proteins Id2 are thought to interact with pRb to regulate muscle and brain development, although it is not known whether similar interactions between transcription factors and cell cycle proteins regulate neurogenesis in the retina. Towards this aim, we propose the following objectives: 1. To examine the expression of endogenous and exogenous Id2 in the developing Zebrafish retina. 2. To determine whether positively acting HLH transcription factors are essential for induction of retinal neuron-specific gene expression. 3. To determine whether constitutively activated pRb rescues both the loss of neuronal gene expression and the progenitor cell apoptosis induced by Id2.

Project Title:	Bone morphogenetic proteins (BMPs) regulation of the Id gene family in neural progenitors and glial cells of the rat spinal cord following contusion injury
Investigator(s):	Yip HKF, Wu W
Department:	Anatomy
Source(s) of Funding:	Seed Funding Programme for Basic Research
Start Date:	04/2007

Abstract:

Injury to the spinal cord leads to a complex sequence of cellular responses, including axonal degeneration, demyelination, marcrophage/microglia activation, astrocyte hypertrophy, and neuronal cell death (1). Reactive astrocytes and activated microglia are histological hallmarks of central nervous system (CNS) disease or injury. Pronounced increases in the number of reactive astrocytes form the glial scars at the lesioned site (2). It is generally believed that failure of axonal regeneration in the CNS is attributed to the formation of astroglial scars after injury. In addition, activated astrocytes and reactive marcophates/microglia can also cause neuronal and oligodendrocyte cell death by releasing neurotoxins and cytokines (3). This combination of events leads to severe secondary degeneration in the lesioned spinal cord. Thus, it is thought that spinal cord regeneration after injury cannot readily occur. Neural progenitors in the subventricular/ventricular zone of the brain proliferate and give rise to neurons, astrocytes and oligodendrocytes during CNS development (4). Recent studies indicate that neural progenitors in adult CNS retain the ability to proliferate and differentiate (5). Although the neuronal cell death and activation of astrocyte/microglial after CNS injury are extensively studied, the response of neural progenitors to CNS injury remains to be elucidated. Cell fate determination during development and after injury usually involves transcription factors (6). In the nervous system, neurogenesis is promoted by proneural basic helix-loop-helix (bHLH) transcription factors such as NeuroD, neurogenin, and Mash1. These tissue specific bHLH proteins form heterodimers with E box binding proteins (E12/E47) and in turn activate gene transcription (7). Functions of bHLH are negatively regulated by the Id (inhibitor of DNA) family of proteins. Ids, including Id1-Id4, lack a basic domain (8). Id proteins inhibit neurogenic bHLH by binding to its heterodimeric bHLH partners and E12/E47 (14). The expression of Id gene is high in proliferating cells during embryogenesis, but decrease in differentiating cells in the CNS (9). We have recently demonstrated that Ids are expressed by differentiated neurons in the adult mouse retina (10). Id gene family is involved in the regulation of cell proliferation and differentiation. Studies had shown that Id gene was expressed in immature and mature astrocytes during development and upregulated in reactive astrocytes after spinal cord injury (11). These results suggest that Id genes may play an important role in regulating astrocyte development and in the formation of reactive astrocytes after CNS injury; however, little is known about the factors regulating Id expression in astrocytes. Precise mechanisms by which neurogenesis and gliogenesis are regulated in the CNS are not fully understood. Embryonic subventricular zone progenitor cells give rises to the neuronal lineage and glial lineage, which include astrocytes and oligodendrocytes (12). The fate of neural precursors in the developing brain is determined by intrinsic cellular programs and by external cues, such as bone morphogenetic proteins (BMPs) (12). BMPs are members of the large transforming growth factor-ß (TGF-ß) superfamily. BMPs have recently emerged as important regulators of nervous system development. Several lines of evidence have been implicating BMPs in neuronal and glial development (13). BMPs mediate their effects by heterotetrameric serine/threonine kinase receptors (BmprI and BmprII) and downstream transcription factors Smad-1, -5 or -8. The transcription factors are phosphorylated and form a complex with Smad-4, and the complex is translocated into the nucleus to activate transcription of specific genes (14). BMP-2 and BMP-7 are highly expressed in the developing nervous system (13). It has also been demonstrated that BMP-2 and BMP-7 can induce cortical neuroepithelial or stem cells to differentiate as astrocytes (15), but the molecular mechanisms underlying this effect remain largely elusive. BMP expression in the adult CNS is relatively low, but is dramatically increased in glial cells and neurons after insult or injury to the CNS (16). The rapid increase of BMP expression in the CNS after injury is analogous to the effects of BMP during development, and it may be responsible for the astrocytic response and gliosis that accompany to many CNS insults. As Smad binding elements are found on the promoter of Id gene (17), and BMPs have been shown to regulate Id expression in several cell types, including embryonic stem cells (17). We therefore propose that the antineurogenic effect of BMP is induced by a mechanism by which BMP signaling activates Id genes and in turn suppresses neurogenesis of progenitor cells mediated by inhibiting the function of neurogenic bHLH, suggesting that injury-induced increase of BMP expression may regulate glial cell differentiation from progenitor cells, which are present in the adult spinal cord, and may induce gliosis after CNS injury. Objectives: 1. To examine whether injury can induce upregulation of BMP-2, -4, -7 and BmprII expression and to identify BMP-expressing cells in adult rat spinal cord and in neural stem cells isolated from adult spinal cord. 2. To examine whether BMP-2, -4 and -7 mediates cell fate alteration from neurogenesis to astrocytogenesis of adult spinal cord neural stem cells. 3. To examine whether repression of neurogenesis by BMP-2, -4 and -7 is mediated by Ids. Reference: 1. Young W (1993) J Emerg Med 11:13-22. 2. Reier PJ et al (1989) In: Seil FJ, ed. Neural regeneration and transplantation. New York: Alan R Liss, p183-209. 3. Eitan S et al (1992) PNAS 89:5442-5446. 4. Levison SW & Goldman JE (1993) Neuron 10:201-212. 5. Kuhn HG et al (1997) J Neurosci 17:5820-5829. 6. Herdegen T et al (1997) Trends in Neurosci 20:227-231. 7. Kageyama R & Nakanishi S (1997) Curr Opin Genet Dev 7:659-665. 8. Norton JD (2000) J Cell Sci 113:3897-3905. 9. Jen Y et al (1992) Genes Dev 6:1466-1479. 10. Yeung SC & Yip HK (2005) NeuroReport 16:673-676. 11. Tzeng SF et al (2001) J Neurosci Res 66:1161-1172. 12. Gage FH (2000) Science 287:1433-1438. 13. Mehler MF et al (1997) Trends Neurosci 20:309-317. 14. Heldin CH et al (1997) Nature 390:465-471. 15. Gross, RE et al (1996) Neuron 17:595-606. 16. Martinez G et al (2001) Brain Res 894:1-11. 17. Hollnagel A et al (1999) JBC 274:19838-19845. 18. Hua H et al (2006) JBC 281:13574.

List of Research Outputs

Cheung Z.H., Leung M.C.P., Yip H.K.F., Wu W., Siu F.K.W. and So K.F., A neuroprotective herbal mixture inhibits caspase-3-independent apoptosis in retinal ganglion cells, Celular and Molecular Neurobiology. 2008, 28: 137-155.

Lau W.M., Tsao G.S.W., So K.F. and Yip H.K.F., Expression of telomerase reverse transcriptase in adult goldfish retina, Journal of Molecular Neuroscience. 2007, 32: 160-267.

Lau W.M., Wong A.O.L., Tsao G.S.W., So K.F. and Yip H.K.F., Molecular cloning and characterization of the Zebrafish (Danio rerio) telomerase catalytic subunit (Telomerase Reverse Transcriptase, TERT), Journal of Molecular Neuroscience. Humana Press Inc., 2007, 34: 63-75.

Wu G., Tsao G.S.W. and Yip H.K.F., Characteristics of Telomerase Expression in Neurogenic Sites of Adult Central Nervous System, 12th Research Postgraduate Symposium, The University of Hong Kong, Faculty of Medicine. 2007.

Wu G., Tsao G.S.W. and Yip H.K.F., Characteristics of Telomerase Expression in Neurogenic Sites of Adult Central Nervous System, The University of Hong Kong Li Ka Shing Faculty of Medicine, Research Centre of Heart, Brain, Hormone & Healthy Aging, 3rd International Symposium on Healthy Aging: “Improving the Health of an Aging Population. 2008.

Xiao Q., Wu W. and Yip H.K.F., The Roles of Bone Morphogenetic Proteins (BMPs) in the Acute Spinal Cord Injury in Adult Mice, 12th Research Postgraduate Symposium, The University of Hong Kong, Faculty of Medicine. 2007.

Yip H.K.F., Niu C. and Wu G., Neuronal injury affects telomerase activity and expression in the adult rat nervous system, US Society of Neuroscience Annual Meeting . 2007.

Researcher : Yip YL

List of Research Outputs

Man C.W.Y., Rosa J., Yip Y.L., Cheung A., Kwong Y.L., Doxsey S.J. and Tsao G.S.W., Id1 overexpression induces tetraploidization and multiple abnormal mitotic phenotypes by modulating Aurora A , Molecular Biology Of The Cell. USA, The American Society for Cell Biology, 2008, 19: 2389-2401.

Researcher : You S

List of Research Outputs

Ellis-Behnke R.G., Liang Y., You S., Tay D.K.C., So K.F. and Schneider G.E., Beyond nano neuro knitting: creating a more permissive environment using SAPNS with Chondroitinase ABC for brain lesion repair and functional return of vision, International Brain Research Organization (IBRO), Melbourne, Australia. 2007.

You S., Lau W.M., Tang S.W., Lee T.M.C. and So K.F., Effect of different doses of corticosterone on hippocampal cell proliferation, Hong Kong Society of Biological Psychiatry Conference 2007, October 18-20, 2007, Hong Kong. 2007, 19 A0006.

Researcher : Yu MS

List of Research Outputs

Chang R.C.C., Yu M.S., Ho Y.S., Lai S.W., Chiu K. and So K.F., Polysaccharides from medicinal herbs as potential drug lead in Alzheimer's disease, Neurobiology of Aging . 2008, 29S: S4-S5.

Chao J., Yu M.S., Ho Y.S., Wang M. and Chang R.C.C., Dietary oxyresveratrol attenuates neurotoxicity induced by 6-hydroxydopamine in SH-SY5Y cells, Federation of European Neurosciences Societies Abstracts. 2007, 4: Poster 184.15.

Chao J., Yu M.S., Ho Y.S., Wang M. and Chang R.C.C., Dietary oxyresveratrol prevents 6-hydroxydopamine-induced neurotoxicity in SH-SY5Y cells, Third International Symposium on Healthy Aging: Improving the Health of an Aging Population, March 1-2, 2008, Hong Kong. 2008, 51 P11.

Cheung Y.T., Yu M.S., Lai S.W., So K.F. and Chang R.C.C., Global protein translation control in beta-amyloid peptide induced neurotoxicity, Third International Symposium on Healthy Aging: Improving the Health of an Aging Population, March 1-2, 2008 Hong Kong. 2008, 49 P2.

Cheung Y.T., Yu M.S., Lai S.W., So K.F. and Chang R.C.C., Global protein translation control in beta-amyloid peptide neurotoxicity, Federation of European Neurosciences Societies Abstracts. 2007, 4: Poster 014.3.

Ho Y.S., Yu M.S., Lai S.W., So K.F., Yuen W.H. and Chang R.C.C., Characterizing the neuroprotective effects of alkaline extract of Lycium barbarum on b-amyloid peptide neurotoxicity, Brain Research. 2007, 1158: 123-134.

Ho Y.S., Yu M.S., Lai S.W., So K.F., Yuen W.H. and Chang R.C.C., Lycium barbarum as a potential drug to attenuate neurodegeneration in Alzheimer's disease, 2007 TWGHs Eddie Wang Symposium on Integrated Chinese and Western Medicine. 2007, 197.

Ho Y.S., Yu M.S., Yik S.Y., Lai S.W., So K.F., Yuen W.H. and Chang R.C.C., Lycium barbarum protects neurons against neurodegeneration in Alzheimer's disease through multiple approaches, Third International Symposium on Healthy Aging: Improving the Health of an Aging Population, March 1-2, 2008, Hong Kong. 2008, 44 OP10.

Lai S.W., Preisler J., Yu M.S., Lee D.H.S. and Chang R.C.C., Mechanism of b-amyloid-dependent neurotoxicity in primary hippocampal neurons: evidence for induction of endoplasmic reticulum aggregation, Alzheimer's Disease Keystone Symposia, March 24-29, Colorado, U. S. A.. 2008, 55 Poster 117.

Yik S.Y., Yu M.S., Ho Y.S., Lai S.W., Cheung Y.T., So K.F. and Chang R.C.C., Significance of dsRNA-elicited neurotoxicity, neuroprotection of minocycline on viral induced neurodegeneration, Third International Symposium on Healthy Aging: Improving the Health of an Aging Population, March 1-2,2008, Hong Kong.. 2008, 52 P14.

Yu M.S., Lai S.W., Ho Y.S., Zee S.S.Y., So K.F., Yuen W.H. and Chang R.C.C., Characterization of the Effects of Anti-aging Medicine Fructus Lycii on b-amyloid Peptide Neurotoxicity , International Journal of Molecular Medicine . 2007, 20: 261-268.

Yu M.S., Lai S.W., Suen K.C., So K.F., Hugon J. and Chang R.C.C., Neuronal apoptosis induced by extracellular accumulation of beta-amyloid peptides is independent of unfolded protein responses, 7th IBRO World Congress of Neuroscience. 2007.

Yu M.S., So K.F., Fang J.N., Yuen W.H. and Chang R.C.C., Neuroprotective polysaccharides from Nerium indicum rescue cultured neurons from beta-amyloid peptides-induced apoptosis via different mechanisms, Society for Neuroscience 2007. Program No. 169.8.

Yu M.S., Travel award to attend the IBRO (International Brain Research Organization) Workshop, “Neurodegenerative Diseases: Different Phenotypes, Shared Mechanism of Pathogenesis” and the 7th IBRO World Congress held in Melbourne, Australia (10-17 July 2007), Society for Neuroscience (SfN). 2007.

Researcher : Yu MS

List of Research Outputs

Chang R.C.C., Yu M.S., Ho Y.S., Lai S.W., Chiu K. and So K.F., Polysaccharides from medicinal herbs as potential drug lead in Alzheimer's disease, Neurobiology of Aging . 2008, 29S: S4-S5.

Researcher : Yuan QJ

List of Research Outputs

Mi S., Hu B., Hahm K., Luo Y., Hui S.K., Yuan Q.J., Wong W.M., Wang L., Su H., Chu T.H., Guo J., Zhang W., So K.F., Pepinsky B., Shao Z., Graff C., Garber E., Jung V., Wu E.X. and Wu W., LINGO-1 antagonist promotes spinal cord remyelination and axonal integrity in MOG-induced experimental autoimmune encephalomyelitis, Nature Medicine. 2007, 13(10): 1228-1233.

Yuan Q.J., Scott D.E., So K.F. and Wu W., Differential activation of c-fos immunoreactivity after hypophysectomy in developing and adult rats, The Anatomical Record. 2007, 290: 1050-1056.

Researcher : Zhang W

List of Research Outputs

Mi S., Hu B., Hahm K., Luo Y., Hui S.K., Yuan Q.J., Wong W.M., Wang L., Su H., Chu T.H., Guo J., Zhang W., So K.F., Pepinsky B., Shao Z., Graff C., Garber E., Jung V., Wu E.X. and Wu W., LINGO-1 antagonist promotes spinal cord remyelination and axonal integrity in MOG-induced experimental autoimmune encephalomyelitis, Nature Medicine. 2007, 13(10): 1228-1233.

Researcher : Zhang X

List of Research Outputs

Wong Y.C., Zhang X., Ling M.T. and Wang X., Caveolin 1, a novel Id-1 binding partner and its role on Id-1 induced behavioral change in prostate cancer cells, AACR annual meeting, San Diego, USA, April 12-16, 2008. 1082.

Wong Y.C., Zhang X., Ling M.T. and Wang X., Inactivation of Id-1 gene induces sensitivity of prostate cancer cells to chemotherapeutic drugs, In: JJ Li, Sara A Li, Suresh Mohla, Henri Rochefort and Thierry Maudelonde., Hormonal Carcinogenesis . Springer, 2008, V: 565-572.

Zhang X., Wang Q., Ling M.T., Wong Y.C., Leung C.L., Tsao G.S.W. and Wang X., Anti-apoptotic role of TWIST and its association with Akt pathway in mediating taxol resistance in nasopharyngeal carcinoma cells, International J Cancer. 2007, 120: 1891-1898.

Zhang X., Ling M.T., Wong Y.C. and Wang X., Evidence of a novel anti-apoptotic factor: role of inhibitor of differentiation or DNA binding in anticancer drug-induced apoptosis, Cancer Science. 2007, 98: 308-314.

Zhang X., Ling M.T., Wang Q., Lau C.K., Leung C.L., Lee T.K., Cheung A., Wong Y.C. and Wang X., Identification of a novel inhibitor of differentiation-1 (ID-1) binding partner, caveolin-1, and its role in epithelial-mesenchymal transition and resistance to apoptosis in prostate cancer cells, The Journal of Biological Chemistry. 2007, 282(46): 33284-33294.

Zhang X., Significance and molecular basis of Id-1 in regulation of cancer cell survival and invasion. 2007, 174 pages.

Researcher : Zhou Y

List of Research Outputs

Zhou Y., Bhatia I., Cai Z., He Q., Cheung P.T. and Chiu J., Proteomic analysis of neonatal mouse brain: evidence for hypoxia- and ischemia-induced dephosphorylation of collapsin response mediator proteins, J Proteome Research. 2008, 7: 2507.

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