MEDICAL FACULTY
| Researcher : Bruzzone R |
| Project Title: | Regulation of early steps of coronavirus infection by the ezrin ERM protein |
| Investigator(s): | Bruzzone R, Cheung CY, Nal-Rogier BTM |
| Department: | Medical Faculty |
| Source(s) of Funding: | General Research Fund (GRF) |
| Start Date: | 11/2008 |
| Abstract: |
| (1) To identify the determinants of interaction between the SARS-CoV Spike carboxy-terminal domain and cellular ezrin proteins - Definition of the amino-acids of Spike CT involved in ezrin binding by mutagenesis and GST pull-down assay - Differential binding of ezrin by SARS-CoV Spike versus other human coronavirus Spike (group 1: 229E, NL63; group 2: HKUI, OC43) - Synthesis of small peptides that mimic the Spike ezrin-binding motif and test for inhibition of Spike-ezrin interaction in GST-pull down experiments - Analysis of ezrin subcellular localization/recruitment by SARS-CoV Spike wild-type and mutant forms as well as other human coronavirus Spikes in transfected cells by immuno-fluorescence studies; (2) To test the role of ezrin in SARS-CoV virus infection - Measurement of SARS-CoV infection in susceptible FrHK4 cells where ezrin would have been either knocked-down by siRNA targeting or over-expressed (experiment performed in BSL3 laboratory). Both viral RNAs (positive and negative strands for N and ORF1ab genes) levels and virion production will be measured by quantitative RT-PCR and infectivity assays, respectively. - Effect of inhibitory peptides will be investigated on SARS-CoV life cycle; (3) To define the precise role of SARS-CoV Spike CT / ezrin interaction in the entry process of SARS-CoV - Production of lentiviral particles pseudotyped with wild-type and mutant forms of the SARS-CoV Spike protein (SARSpp and mSARSpp) - Infectivity assays using SARSpp and mSARSpp - Effect of inhibitory peptides on SARSpp infectivity - Analysis of ezrin recruitment at the site of SARS-CoV entry in infected cells by fluorescence microscopy. |
| Researcher : Chan YS |
| Project Title: | 30th Annual Conference of Society for Neuroscience Expression of N-Methyl-D-Aspartate Receptor Subunits and Induction of c-fos in Otolith Neurons in the Vestibular Nuclei of Postnatal Rats |
| Investigator(s): | Chan YS |
| Department: | Physiology |
| Source(s) of Funding: | URC/CRCG - Conference Grants for Teaching Staff |
| Start Date: | 11/2000 |
| Abstract: |
| N/A |
| Project Title: | 31st Annual Meeting of Society for Neuroscience Expression of Neurotrophin Receptors in Vestibular Nuclei During the Postnatal Development of the Rat |
| Investigator(s): | Chan YS |
| Department: | Physiology |
| Source(s) of Funding: | URC/CRCG - Conference Grants for Teaching Staff |
| Start Date: | 11/2001 |
| Abstract: |
| N/A |
| Project Title: | The role of central glial cells in the pathogenesis of Parkinson's Disease |
| Investigator(s): | Chan YS |
| Department: | Physiology |
| Source(s) of Funding: | Small Project Funding |
| Start Date: | 11/2003 |
| Abstract: |
| To employ immuno-hybridization histochemical methods to map the spatiotemporal distribution of different activated glial cells during the development of PD as induced by systemic administration of a neurotoxicant, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). |
| Project Title: | Functional maturation of excitatory and inhibitory synaptic receptors in canal-and otolith-related neurons of the inferior olive |
| Investigator(s): | Chan YS |
| Department: | Physiology |
| Source(s) of Funding: | General Research Fund (GRF) |
| Start Date: | 12/2006 |
| Completion Date: | 11/2009 |
| Abstract: |
| To examine developmental change of excitatory postsynaptic currents at glutamate synapses on canal- and otolith-related inferior olivary neurons; to examine developmental change of inhibitory postsynaptic currents at GABAergic synapses on canal- and otolith-related inferior olivary neurons. |
| Project Title: | XXIV Annual Conference of Indian Academy of Neurosciences Development Refinement of Spatial Recognition Circuits |
| Investigator(s): | Chan YS |
| Department: | Physiology |
| Source(s) of Funding: | URC/CRCG - Conference Grants for Teaching Staff |
| Start Date: | 12/2006 |
| Abstract: |
| N/A |
| Project Title: | Postnatal γ-aminobutyric acid transmission is critical for the formation of a three-dimensional spatial map. |
| Investigator(s): | Chan YS |
| Department: | Physiology |
| Source(s) of Funding: | General Research Fund (GRF) |
| Start Date: | 01/2008 |
| Abstract: |
| To determine whether functional organization of the gravity- and rotation-related spatial reference is perturbed by perinatal blockade of GABAergic synapses in the VN; to examine if the perturbations applied later in the postnatal period have any effect on the spatial coding capacities of VN and IO neurons in the mature brain; to examine if perinatal perturbations of GABA synapses has any effect on vestibular reflexes and behaviors in the adult. |
| Project Title: | Role of the thalamus in integrating spatial information and guiding navigation |
| Investigator(s): | Chan YS |
| Department: | Physiology |
| Source(s) of Funding: | Seed Funding Programme for Basic Research |
| Start Date: | 04/2009 |
| Abstract: |
| Vestibular cues arising from end organs within the inner ear are critical for providing directional signals to the central nervous system. These vestibular inputs, however, must be transformed considerably in order to signal head direction. Accurate perception of one's spatial orientation within the environment then constitutes the framework for navigation in space. Nevertheless, the neural circuitry that accomplishes this signal processing has not been fully established. Functional studies are therefore needed to determine whether thalamus, as an important ascending relay station of the vestibular pathway, mediates vestibular influences for the determination of head direction as well as guides behavior during spatial navigation. An emerging concept in sensory development is that sensory perturbation in the postnatal critical period will result in deficient neural connections that deter the orderly establishment of sensory functions in the mature animal. Studies in the visual, auditory and somatosensory systems have realized the importance of this concept. It remains to be determined whether a critical period exists for the developmental establishment of spatial reference within the vestibular system. Since neural networks within the vestibular nucleus (VN) is shaped by glutamatergic inputs arising from the vestibular afferent, we reason that modification of glutamatergic transmission during the critical period should lead to derangement of the spatial map in the ascending vestibular pathway, thereby resulting in behavioral dysfunction. The first specific aim is to determine whether thalamic neurons in the ascending vestibular circuitry process spatial information of different directions. Immunohistochemical expression of c-fos will be used as activity indicators for the identification of functionally activated neurons within the developing network of the thalamus. Both the critical maturation period and postnatal distribution of neuronal subpopulations within the thalamus will be mapped. These will serve as a reference framework for our second specific aim. Using the above approach, we will test the hypothesis that thalamic neurons are critical neural substrate for determining head direction and in spatial navigation. |
| Project Title: | Neuroscience 2009 Maturation profile of inhibitory and excitatory postsynaptic currents in central vestibular neurons of rats |
| Investigator(s): | Chan YS |
| Department: | Physiology |
| Source(s) of Funding: | URC/CRCG - Conference Grants for Teaching Staff |
| Start Date: | 10/2009 |
| Completion Date: | 10/2009 |
| Abstract: |
| N/A |
| Project Title: | Determinants of developmental plasticity in the vestibular system |
| Investigator(s): | Chan YS, Shum DKY |
| Department: | Physiology |
| Source(s) of Funding: | General Research Fund (GRF) |
| Start Date: | 11/2009 |
| Abstract: |
| To determine the role of AMPA and NMDA receptors in modulating functional maturation of VN neurons and otolith-related behavior; to examine if perinatal perturbations of glutamatergic synapses in the VN affect basal synaptic transmission and long-term synaptic plasticity in the adult cerebellum. |
| List of Research Outputs |
| Lai S.K., Lai C.H., Wong T.P., Yung W.H. and Chan Y.S., Developmental regulation of ionotropic glutamate receptors in central vestibular neurons in rats, The 32nd Annual Meeting of the Japan Neuroscience Society. 2009. |
| Researcher : Chen JHK |
| Project Title: | Influence of amino acid insertion at codon 35 in the protease region of the HIV-1 pol gene on drug resistance |
| Investigator(s): | Chen JHK, Yam WC |
| Department: | Microbiology |
| Source(s) of Funding: | Small Project Funding |
| Start Date: | 10/2008 |
| Completion Date: | 09/2009 |
| Abstract: |
| Protease insert HIV strains were reported in less than 0.1% patients worldwide and little is known about their impact on viral fitness and drug resistance towards protease inhibitors. Amino acid insertion at codon 35 of protease occurred in 0.04% among 25,330 patients (Kim et al, 2001; Paolucci et al, 2006). In collaboration with Integrated Treatment Centre of the Department of Health, a 3-year study supported by AIDS Trust Fund (project number MS099) revealed this insertion was more prevalent and occurred at 1.3% among 924 HIV+ patients in Hong Kong. Detailed investigation on the influence of this insertion to Protease inhibitor resistance will facilitate better clinical management of HIV infections in Hong Kong The specific objectives of this project emphasis on the association of amino acid insertion at the protease codon 35 position of the HIV-1 pol gene with drug resistance against different FDA-approved Protease inhibitors. |
| Project Title: | Molecular epidemiology study of HIV-1 among the men who have sex with men (MSM) population in Hong Kong |
| Investigator(s): | Chen JHK, Yam WC |
| Department: | Microbiology |
| Source(s) of Funding: | Council for the AIDS Trust Fund - General Award |
| Start Date: | 04/2009 |
| Abstract: |
| To elaborate the epidemiology of the local MSM population who is responsible for the local spread of HIV-1 in Hong Kong by: (1) Sequencing of the HIV-1 viral genes (pol and env) of 60 recently HIV-1 infected MSM in Hong Kong and performing phylogenetic analyses to identify the local MSM population who have close epidemiological relationships. (2) Development of a low costing in-house molecular method for monitoring of HIV-1 transmission among MSM in Hong Kong. (3) Monitoring the presence of primary resistance HIV-1 isolates in the local MSM population. |
| List of Research Outputs |
| Leung P.H.M., Chen J.H.K., Wong K.H., Chan K.C., Lam H.Y., Cheng V.C.C., Yuen K.Y. and Yam W.C., High prevalence of primary Enfuvirtide (ENF) resistance-associated mutations in HIV-1-infected patients in Hong Kong, Journal of Clinical Virology. 2010, 47: 273-275. |
| Researcher : Chen Z |
| Project Title: | A novel model for the study of lung pathogenesis of SARS |
| Investigator(s): | Chen Z |
| Department: | Medical Faculty |
| Source(s) of Funding: | National Institutes of Health, US Department of Health and Human Services - General Award |
| Start Date: | 08/2007 |
| Abstract: |
| To characterize the lung pathogenesis of SARS-CoV in Chinese rhesus monkeys. |
| Project Title: | Understanding the Ongoing HIV Epidemic in Yunnan China |
| Investigator(s): | Chen Z |
| Department: | Medical Faculty |
| Source(s) of Funding: | China AIDS Initiative - General Award |
| Start Date: | 05/2008 |
| Abstract: |
| To study the changing patterns of HIV-1 epidemic in Yunnan. We hypothesize that the identification of the dominant recombinant type of HIV-1 in Yunnan will play a fundamental role in the design of a relevant vaccine for the study region. While the virus spreads rapidly throughout the Yunnan province, the viral subtype of the dominant epidemic strains have also evolved in an unexpected dynamic way. In 1989, the subtype B virus was found to be the leading causative agent for the first HIV-1 epidemic in Yunnan. Two years later, subtype B′ strains were reported to have become the major epidemic strain. Thereafter, a rising epidemic of Indian subtype C viruses was reported. From our recent study, it is clear that none of these early strains of HIV-1 plays a major role in the epidemic today. Although the driving force for the viral selection remains unclear, the coexistence of multiple genotypes among the same IDU population has provided an ideal setting for the emergence of recombinant HIV-1 strains. We therefore propose to study the evolving HIV-1 epidemic in Yunnan. |
| Project Title: | Preventing HIV-1 infection using a novel vaccine immunogen |
| Investigator(s): | Chen Z |
| Department: | Medical Faculty |
| Source(s) of Funding: | Global Health Grants |
| Start Date: | 10/2008 |
| Abstract: |
| Despite over 25 years of efforts, the development of an effective AIDS vaccine to prevent HIV-1 infection remains the biggest challenge in HIV/AIDS research. Considering that conventional vaccine strategies are not successful for HIV-1 prevention, we propose to change the situation by exploring new approaches that follow the fundamental rules of primate evolution and immunology. Specifically, we hypothesize that a variant of simian CCR5 (sCCR5) would be an AIDS vaccine candidate for humans if it induces protective immune response in SHIV/macaque models. This hypothesis is based on findings that (1) CCR5-tropic HIV-1 is transmitted dominantly through sexual contacts; (2) individuals with homozygote delta32-CCR5 are resistant to HIV-1 infection; (3) some long-term non-progressors harboring anti-CCR5 antibodies have much delayed disease progression; and (4) HIV-infected women, who developed anti-CCR5 antibodies, display a lower rate of vertical transmission. Furthermore, we previously demonstrated that (1) both HIV and SIV use CCR5 of several simian species as a major co-receptor for entering target cells (Chen et al. JV. 97, 71:2705), and (2) CCR5 is dispensable in non-human primate species (e.g. red-capped mangabeys; Chen et al. JEM. 98, 188:2057) similar to human cases with homozygote delta32-CCR5. Importantly, our recent preliminary studies indicate that anti-rhesus CCR5 antibody blocks HIV-1 infection in cells expressing human CD4 and CCR5. Since anti-human CCR5 monoclonal antibody 2D7, that has potent neutralizing activity against HIV-1, does not recognize rhesus CCR5, our data indicate that there must be additional neutralizing determinants offering cross-protective response. The objective of the proposal is, therefore, to determine the efficacy of mutants of sCCR5 as AIDS vaccine candidates. The rationale is that if a sCCR5 mutant is protective in macaques against SHIV infection, it would be potentially effective in preventing HIV-1 infection in humans. The proposal includes two specific aims: (1) to design and construct mutants of sCCR5 which are capable of inducing neutralizing antibodies against HIV-1 infection in animals including rhesus macaques; and (2) to determine the efficacy of an optimized sCCR5 mutant using SHIV/Macaque models. |
| Project Title: | Mucosal Vaccine against HIV-1 Infection |
| Investigator(s): | Chen Z |
| Department: | Medical Faculty |
| Source(s) of Funding: | General Research Fund (GRF) |
| Start Date: | 10/2008 |
| Abstract: |
| (1) To study a MVTT-HIVenv/gag-pol vaccine which preferentially targets mucosa; (2) To study a MVTT-HIVenv/gag-pol vaccine which evades pre-existing anti-vaccinia immunity. |
| Project Title: | Role of the PD-1/PD-L pathway in HIV DNA vaccine design |
| Investigator(s): | Chen Z |
| Department: | Medical Faculty |
| Source(s) of Funding: | Seed Funding Programme for Basic Research |
| Start Date: | 06/2009 |
| Abstract: |
| The programmed death 1 (PD-1, also called PDCD1 or CD279) is a member of the CD28 family and is expressed on activated T cells, natural killer T cells (NKT), B cells, and macrophages. PD-1 is a 50-55 kDa type I transmembrane receptor consisting of a single immunoglobulin (Ig) variable-like domain and a cytoplasmic domain composed of two tyrosine-based signaling motifs. PD-1 interacts with its ligands PD-L1 (CD274 or B7-H1) and PD-L2 (CD273 or B7-DC), which are members of B7 family. PD-L1 is expressed on hematopoietic and non-hematopoietic cells, in immunoprivileged sites (eye, placenta), and is highly expressed in inflammatory environments. Upon general activation of the immune response, professional antigen presentation cells (APCs) and T cells further augment PD-L1 expression. By contrast, PD-L2 is expressed only on activated macrophages and dendritic cells (DCs). Some studies have demonstrated the inhibitory function of the PD-1/PD-L pathway (including PD-1/PD-L1 and PD-1/PD-L2). For example, PD-1 is persistently up-regulated on HBV and HCV-specific CD8+ T cells during chronic infection in humans. These virus-specific CD8+ T cells displayed poor proliferation, cytokines production and cytotoxicity. Critically, blocking the PD-1/PD-L1 interaction can reverse the exhausted cytokine production and proliferation of viral specific-CD8+ T cells. Therefore, PD-1 is a pivotal negative immune regulator associated with the establishment of viral chronic infection. Importantly, when antibodies were used to block the PD-1/PD-L pathway in vivo during chronic LCMV infection, virus-specific CD8 T cell responses were potently enhanced. Not only was the number of LCMV-specific CD8 T cells increased dramatically, but their function was also improved. After in vivo PD-1/PD-L blockade, virus-specific CD8 T cells produced more IFN- and TNF- on a per cell basis. The reversal of virus-specific CD8 T cell exhaustion has resulted in a considerable reduction in viral load. These findings provide scientific evidence for investigations into the PD-1/PD-L pathway for new vaccine design. An effective vaccine works by inducing memory immune responses that are capable of expanding to control an incoming infection to limit disease and transmission. B cells and T cells are the two major types of memory cells which need to be induced by the vaccine. B cells produce antibody that can block viral entry and infections. CD8 T cells, also called cytolytic T cells, recognize and kill virus-infected cells. CD4 T cells, often called helper T cells, produce growth and differentiation factors for CD8 T and B cells. To date, classical approaches to vaccine development have not yielded an effective HIV-1 vaccine. New approaches, however, using DNA vaccines, recombinant viral vectors, and combinations of different vectors in heterologous prime/boost regimens are encouraging and yielding vaccines capable of controlling pathogenic AIDS virus challenges in non-human primate models. Therefore, four major approaches have currently been used for the development of a HIV-1 vaccine: (1) delivering antigen in DNA vaccines; (2) delivering antigen in recombinant viral vectors; (3) delivering adjuvanted antigen; and (4) combining two or more modalities for antigen delivery in heterologous prime/boost regimens. DNA vaccines have the advantage of expressing only the vaccine insert. This advantage results in a highly focused immune response. They also have no issues of pre-existing immunity. However, the efficiency of DNA vaccines has been limited in humans probably due to several factors. One factor is the relatively poor ability of DNA to get into cells. This problem is being approached by a number of techniques, including lipofection, gene guns, attaching DNA to particles, and using in vivo electroporation techniques. Another factor is related to poor protein expression and therefore HIV-1 genes optimized for the codons preferred by human cells are used to enhance vaccine insert expression. An additional factor is related to antigen presentation and therefore much work has focused on adjuvants, many of which have been co-expressed by DNA. As a novel strategy, improving vaccine potency by promoting in vivo antigen targeting to dendritic cells has recently been described. By targeting the encoded protein to dendritic cells, a DNA vaccine encoding an HIV-1 gag p41–scFv DEC205 fusion protein induced 10-fold higher antibody levels and increased numbers of IFN- –producing CD4+ and CD8+ T cells. These studies open a new area of HIV-1 vaccine research and have provided scientific evidence in support of this proposed study. Till now, however, it remains unknown whether or not the efficacy of DNA vaccination would be much improved if the vaccine design engages DC targeting while blocks the PD-1/PD-L interaction. DNA vaccination remains at the forefront of efforts aimed at developing vaccine against viral infections including HIV-1. In this study, we hypothesize that targeting vaccine antigens at DCs and blocking the PD-1/PD-L pathway would increase the immunity and protection that result from DNA vaccines. To determine this hypothesis, we will generate a DNA vaccine encoding a fusion protein comprised of the vaccine antigen (e.g. HIV-1 Gag) and a soluble domain of PD-1 (sPD-1) specific for the DC-expressing ligand PD-L. We will focus on two specific objectives. Objective 1: To study the involvement of dendritic cells in sPD-1 based vaccine design in vitro. Objective 2: To study sPD-1-based HIV-1 DNA vaccine in vivo. |
| Project Title: | AIDS Vaccine 2009 Effective Control of a pathogenic SIVmac239 challenge by a novel heterologous mucosal prime intramuscular boost vaccination strategy |
| Investigator(s): | Chen Z |
| Department: | Medical Faculty |
| Source(s) of Funding: | URC/CRCG - Conference Grants for Teaching Staff |
| Start Date: | 10/2009 |
| Completion Date: | 10/2009 |
| Abstract: |
| N/A |
| Project Title: | Role of the PD-1/PD-L pathway in HIV-1 vaccine design |
| Investigator(s): | Chen Z |
| Department: | Medical Faculty |
| Source(s) of Funding: | General Research Fund (GRF) |
| Start Date: | 12/2009 |
| Abstract: |
| 1) To study HIV-1 DNA vaccine by blocking the PD-1/PD-L interaction and by promoting in vivo antigen targeting to dendritic cells (year 1-1.5); 2) To study vaccinia-based HIV-1 vaccine by blocking the PD-1/PD-L interaction and by promoting in vivo antigen targeting at dendritic cells (year 1.5-3). |
| Project Title: | Characterization of novel anti-HIV/TB natural product analogues |
| Investigator(s): | Chen Z |
| Department: | Medical Faculty |
| Source(s) of Funding: | Research Fund for the Control of Infectious Diseases - Full Grants |
| Start Date: | 03/2010 |
| Abstract: |
| To understand the functional characeristics of a novel class of anti-HIV/TB natural products, which are essential for the identification of new drugs for the treatment of AIDS and TB patients |
| List of Research Outputs |
| Chen Z., AIDS – Laboratory techniques and quality control Chapter 3: Specific immune response against HIV-1 infection. , Science Press, Beijing, People’s Republic of China. 2009, chapter: 3. |
| Chen Z., Acute infection of Chinese macaques by a CCR5-tropic SHIV carrying a primary HIV-1 subtype B’ envelope. , In: Wang H, Zhuang K, Liu L, Tang Z, Tang J, Tien P, Zhang L, and Chen Z*. , JAIDS.. 2010, Mar 1:53(3): 285-291. |
| Chen Z., Characterization of a Replication-competent Modified Vaccinia Tian Tan (MVTT) as a Vaccine Vector, 2nd Annual World Summit of Antivirals, Beijing, Jul 18-20, 2009. 2009. |
| Chen Z., Increased Genetic Diversity of HIV-1 Circulating in Hong Kong. , In: Chen JH-K, Wong K-H, Chen Z, Chan K, Lam H-Y, et al. , PLoS ONE . 2010, 5(8): e12198. |
| Chen Z., Journal of Antivirals and Antiretrovirals. OMICS Publishing Group, 2009. |
| Chen Z., One time intranasal vaccination with a modified vaccinia Tiantan strain MVTT (ZCI) protects animals against pathogenic viral challenge. , In: Yu W, Fang Q, Zhu W, Wang H, Tien P, Zhang L, and Chen Z*. , Vaccine.. 2010, 28(9): 2088-96. |
| Chen Z., The Development of an AIDS Mucosal Vaccine, Third Ditan International Conference on Infectious Diseases, Beijing, Jul 30 – Aug 2, 2009. 2009. |
| Chen Z., The development of an AIDS mucosal vaccine. , In: Tang X and Chen Z*. , Viruses.. 2010, 2(1): 283-297. |
| Chen Z., The development of anti-HIV drugs., In: Lu XF and Chen Z. , ACTA Pharmaceutica Sinica.. 2010, 45(2): 165-176. |
| Chen Z., The route of inoculation determines the tissue tropism of modified vaccinia Tiantan expressing the spike glycoprotein of SARS-CoV in mice. , In: Liu H, Yu W, Zhu W, Wang H, and Chen Z*, J Med Virol.. 2010, 82(5): 727-34. |
| Chen Z., Vasan S, Schlesinger SJ, Chen Z et al.. Phase 1 Safety and Immunogenicity Evaluation of ADMVA, a Multigenic, Modified Vaccinia Ankara-based Clade C/B’ HIV-1 Candidate Vaccine. , PLoS ONE. 2010, 5(1):e: 8816. |
| Chen Z., Vasan S, Schlesinger SJ, Huang Y, Hurley A, Lombardo A, Chen Z et al.. Phase 1 Safety and Immunogenicity Evaluation of ADVAX, a Multigenic, DNA-based Clade C/B’ HIV-1 Candidate Vaccine. , PLoS ONE. 2010, 5(1):e: 8617. |
| Chen Z., Xu L, Zhang Yf, Liu Y, Chen Z, Deng H, Ma Z, Wang H, Hu Z, And Fei Deng F. Angiotensin-converting Enzyme 2 (ace2) From Raccoon Dog Can Serve As An Efficient Receptor For The Spike Protein Of Severe Acute Respiratory Syndrome Coronavirus. , The Journal of General Virology (JGV). 2009, 90: 2695-2703. |
| Chen Z., Xue H, Lu XF, Zheng PR, Liu L, Han CY, Hu JP, Liu ZJ, Ma T, Li Y, Wang L, Chen Z* and Liu G*. Highly suppressing wild-type HIV-1 and Y181C Mutant HIV-1 Strains by 10-Chloromethyl-11-demethyl-12-oxo-calanolide A with druggable profile. , Journal of Medicinal Chemistry . 2010, 53(3): 1397-1401. |
| Wang H., Zhuang K., Liu L., Tang Z., Tang J., Zhang L. and Chen Z., Acute infection of Chinese macaques by a CCR5-tropic SHIV carrying a primary HIV-1 subtype B' envelope. , J Acquir Immune Defic Syndr. . 2010, 1;53(3): 285-91. |
| Xue H., Lu X., Zheng P., Liu L., Han C., Hu J., Liu Z., Ma T., Chen Z. and Liu G., Highly suppressing wild-type HIV-1 and Y181C mutant HIV-1 strains by 10-chloromethyl-11-demethyl-12-oxo-calanolide A with druggable profile, J Med Chem. . 2010, 11;53(3): 1397-401. |
| Researcher : Cheung BKW |
| List of Research Outputs |
| Chan L.L.Y., Cheung B.K.W. and Lau A.S.Y., A role for STAT3 in IL-10 downregulation of IFN-g-induced MHC class II molecule expression on primary human blood macrophages., Third Annual Scientific Meeting, The Hong Kong Society for Paediatric Immunology and Infectious Diseases Saturday, March 20, . 2010. |
| Chan L.L.Y., Cheung B.K.W. and Lau A.S.Y., A role for STAT3 in IL-10 downregulation of IFN-γ-induced MHC class II molecule expression on primary human blood macrophages., 14th Research Postgraduate Symposium, LKS Faculty of Medicine, The University of Hong Kong. December 2-3. 2009. |
| Chan L.L.Y., Cheung B.K.W. and Lau A.S.Y., A role for STAT3 in IL-10 downregulation of IFN-γ-induced MHC class II molecule expression on primary human blood macrophages., Tri-Society Annual Conference 2009 of the Society for Leukocyte Biology, International Cytokine Society & International Society for Interferon and Cytokine Research, (Tri-Society Conf of SLB, ICS & ISICR) Lisbon, Portugal 17-21 October 2009 [Cytokine 2009;46(1-2)PP1-0100]. 2009. |
| Cheung B.K.W., Yim H.C.H., Lee N.C.M. and Lau A.S.Y., A novel anti-mycobacterial function of mitogen-activated protein kinase phosphatase-1, BMC Immunology 2009 (17 Dec);10:64. 2009, 64: 1-10. |
| Cheung B.K.W., Yim H.C.H. and Lau A.S.Y., Positive role of mitogen-activated protein kinase phosphatase-1 in regulating the anti-mycobacterial immune response., Tri-Society Annual Conference 2009 of the Society for Leukocyte Biology, International Cytokine Society & International Society for Interferon and Cytokine Research, (Tri-Society Conf of SLB, ICS & ISICR) Lisbon, Portugal 17-21 October 2009 [Cytokine-the official journal of International Cytokine Society 2009;46(1-2)PP1-071]. 2009. |
| Yang L.H., Chik S.C.C., Li C.B., Cheung B.K.W. and Lau A.S.Y., Anti-inflammatory mechanisms of black cohosh on human primary blood macrophages via its downregulation of signal transduction and transcription factor activation., 8th Meeting of Consortium for Globalization of Chinese Medicine (CGCM), Nottingham, UK, August 26-28, . 2009. |
| Yang L.H., Chik S.C.C., Li C.B., Cheung B.K.W. and Lau A.S.Y., Identification of the bioactive constituent and its mechanisms of action in mediating the anti-inflammatory effects of black cohosh and related Cimicifuga species on human primary blood macrophages., Journal of Medical Chemistry. 2009, 52(21): 6707-6715. |
| Yim H.C.H., Cheung B.K.W. and Lau A.S.Y., Mitogen-activated protein kinase phosphatase-1 positively regulates the anti-mycobacterial immune responses (oral presentation)., 14th Research Postgraduate Symposium, LKS Faculty of Medicine, The University of Hong Kong. December 2-3,. 2009. |
| Researcher : Chik SCC |
| List of Research Outputs |
| Yang L.H., Chik S.C.C., Li C.B., Cheung B.K.W. and Lau A.S.Y., Identification of the bioactive constituent and its mechanisms of action in mediating the anti-inflammatory effects of black cohosh and related Cimicifuga species on human primary blood macrophages., Journal of Medical Chemistry. 2009, 52(21): 6707-6715. |
| Researcher : Chow KM |
| List of Research Outputs |
| Chow K.M., Chu A.C.Y., Poon R.T.P. and Pang R.W.C., Blockade of Raf/MEK/ERK Pathway by Raf265 Inhibits Tumor Growth in Colorectal Cancer, 101st Annual Meeting 2010 of American Association for Cancer Research. Washington DC, 2010. |
| Chow K.M., Chu A.C.Y., Poon R.T.P. and Pang R.W.C., Inhibition of Tumour Growth by Raf265 Via Blockade of Raf/MEK/ERK Pathway in Colorectal Cancer, 15th Medical Research Conference. Hong Kong, 2010. |
| Pang R.W.C., Law W.L., Chu A.C.Y., Poon J.T.C., Lam S.C., Chow K.M., Ng L., Cheung W.H., Lan X.R., Lan H.Y., Tan V.P.Y., Yau T.C.C., Poon R.T.P. and Wong B.C.Y., A Subpopulation of CD26+ Cancer Stem Cells with Metastatic Capacity in Human Colorectal Cancer, Cell Stem Cell. 2010, 6: 603-615. |
| Researcher : Chu ACY |
| List of Research Outputs |
| Chan K.H., Kwan S.C., Chu A.C.Y., Ho W.L., Ho W.M. and Ho S.L., Aquaporin-4 expression by thymoma of myasthenia gravis patients, 20th Meeting of the European Neurological Society, Berlin, 2010; Journal of Neurology. 2010, 257 (Supplement 1): S50. |
| Chow K.M., Chu A.C.Y., Poon R.T.P. and Pang R.W.C., Blockade of Raf/MEK/ERK Pathway by Raf265 Inhibits Tumor Growth in Colorectal Cancer, 101st Annual Meeting 2010 of American Association for Cancer Research. Washington DC, 2010. |
| Chow K.M., Chu A.C.Y., Poon R.T.P. and Pang R.W.C., Inhibition of Tumour Growth by Raf265 Via Blockade of Raf/MEK/ERK Pathway in Colorectal Cancer, 15th Medical Research Conference. Hong Kong, 2010. |
| Ho W.L., Liu H., Ho W.M., Zhang W., Chu A.C.Y., Kwok H.H., Ge X., Chan K.H., Ramsden D.B. and Ho S.L., Mitochondrial Uncoupling Protein-2 (UCP2) Mediates Leptin Protection Against MPP+ Toxicity in Neuronal Cells , Neurotoxicity Research. 2010, 17(4): 332-343. |
| Kwok H.H., Ho W.L., Chu A.C.Y., Ho W.M., Liu H., Yiu C.W., Chan K.H., Kung M.H.W., Ramsden D.B. and Ho S.L., Mitochondrial UCP5 is neuroprotective by preserving mitochondrial membrane potential, ATP levels, and reducing oxidative stress in MPP+ and dopamine toxicity., Free Radical Biology and Medicine. 2010, 49(6): 1023-1035. |
| Pang R.W.C., Law W.L., Chu A.C.Y., Poon J.T.C., Lam S.C., Chow K.M., Ng L., Cheung W.H., Lan X.R., Lan H.Y., Tan V.P.Y., Yau T.C.C., Poon R.T.P. and Wong B.C.Y., A Subpopulation of CD26+ Cancer Stem Cells with Metastatic Capacity in Human Colorectal Cancer, Cell Stem Cell. 2010, 6: 603-615. |
| Researcher : Fung TK |
| Project Title: | The role of NUP98 in hematopoiesis in zebrafish and generation of zebrafish model for NUP98-HOXA9 overexpression |
| Investigator(s): | Fung TK, Leung AYH |
| Department: | Medicine |
| Source(s) of Funding: | Small Project Funding |
| Start Date: | 09/2008 |
| Completion Date: | 02/2010 |
| Abstract: |
| See Attachment. |
| List of Research Outputs |
| Fung T.K., Cheung A.M., Kwong Y.L., Liang R.H.S. and Leung A.Y.H., Differential NOD/SCID mouse engraftment of peripheral blood CD34(+) cells and JAK2V617F clones from patients with myeloproliferative neoplasms., Leukemia Research. 2010. |
| Fung T.K., Liang R.H.S. and Leung A.Y.H., Functional characterization of novel gene NUP98 in zebrafish embryo, 15th Medical Research Conference, 2010. |
| Fung T.K. and Leung A.Y.H., Functional characterization of novel gene NUP98 in zebrafish embryo, 16th Hong Kong International Cancer Congresss 6th Annual Meeting Centre for Cancer Research. 2009. |
| Researcher : He M |
| Project Title: | Regulation of ion channels by angiotensin II in human cardiac fibroblasts |
| Investigator(s): | He M, Li GR |
| Department: | Medical Faculty |
| Source(s) of Funding: | Small Project Funding |
| Start Date: | 09/2009 |
| Abstract: |
| It is well recognized that cardiac fibroblasts play a central role in the maintenance of extracellular matrix in the normal heart and as mediators of inflammatory and fibrotic myocardial remodeling in the injured and failing heart. Excessive fibroblast proliferation induces an increase in the extra-cellular matrix and an increased myocardial stiffness, and therefore causes ventricular dysfunction and subsequent heart failure. Proliferation is an early step in cardiac fibroblasts activation and a major contributing factor to the collective fibrotic potential of these cells (1-4). Although cardiac fibroblasts are electrically unexcitable, they contribute to the cardiac electrophysiology (8, 9). Our previous study demonstrated that four types of ionic currents, IKDR (voltage-gated delayed rectifier K+ current), BKCa (big conductance Ca2+ -activated K+ current), ICl.vol (volume-sensitive chloride current), and INa were present in cultured human cardiac fibroblasts [Fig. 1 & 5]. Recently, we found that the blockade of IKDR, BKCa and ICl.vol, but not INa, inhibited proliferation of human cardiac fibroblasts by accumulating cells at G0/G1 phase [Fig. 2-4]. However, little is known about the detailed mechanism underlying the proliferation regulation by these ion channels in cardiac fibroblasts. It is believed that in addition to the stimulation of cardiac myocyte hypertrophy via paracrine release of TGF-β1 and endothelin-1 from fibroblasts, angiotensin II (Ang II) has been shown to be a potent activator of cardiac fibroblasts through activating Ang II type 1 receptor (AT1R) to stimulate both cellular proliferation and de novo collagen synthesis in the heart, and therefore plays a crucial role in myocardial remodeling. The major effect of Ang II stimulation in cardiac fibroblasts is to release Ca2+ from intracellular Ca2+ stores and produce diacylglycerol, which activates protein kinase C (PKC) and then promotes the transactivation of the extracellular signal regulated kinase (ERK) 1/2 cascade, a mediator of cell proliferation (2, 5-7). In addition, Ang II has been found to activate BKCa channels in guinea pig ileum myocytes by activating protein kinase C, and ICl.vol in rabbit ventricular myocytes via stimulating (AngII)-reactive oxygen species (ROS) signalling cascade (10, 11). Moreover, the chronic Ang II treatment reduced the expression of BKCa channel proteins in rat artery (12). These reports indicate that the effect of Ang II is closely related to the ion channel activity. However, it is unknown whether it is the case for human cardiac fibroblasts. Interestingly, we have recently found that Ang II initiates spontaneous intracellular Ca2+ oscillations at low concentration (100 pM) [Fig. 6] and increases the basal Ca2+ level at higher concentrations (>100 pM) in cultured human cardiac fibroblasts (data not shown). We hypothesize that the activity and protein expression of BKCa and ICl.vol would be modulated by Ang II via regulating Ca2+ signal activity and/or other signal pathways. We therefore propose 1) to determine the potential modulation of BKCa and ICl.vol by Ang II; 2) to examine the effects of Ang II on cell proliferation and BKCa and ICl.vol mRNA level and protein expression; and 3) to elucidate the signaling mechanism for the regulation of BKCa and ICl.vol channels by Ang II in cultured human cardiac fibroblasts. Objectives of the proposal: 1) To determine the potential modulation of BKCa and ICl.vol by Ang II using a whole-cell patch clamp technique. 2) To examine the effects of Ang II on cell proliferation and BKCa and ICl.vol mRNA level and protein expression using approaches of cell proliferation assay, RT-PCR, and Western blot. 3) To elucidate the signaling mechanisms for the regulation of BKCa and ICl.vol channels by Ang II using the approaches of electrophysiology, pharmacology, and molecular biology. References: 1. Porter KE, Turner NA 2009 Cardiac fibroblasts: at the heart of myocardial remodeling. Pharmacol Ther 123:255-278 2. Lijnen P 2008 Angiotensin II-induced proliferation of neonatal and adult rat cardiac fibroblasts. Hypertension 51:e50; author reply e51 3. Benson SC, Iguchi R, Ho CI, Yamamoto K, Kurtz TW 2008 Inhibition of cardiovascular cell proliferation by angiotensin receptor blockers: are all molecules the same? J Hypertens 26:973-980 4. Schnee JM, Hsueh WA 2000 Angiotensin II, adhesion, and cardiac fibrosis. Cardiovasc Res 46:264-268 5. Munoz V, Campbell K, Shibayama J 2008 Fibroblasts: modulating the rhythm of the heart. J Physiol 586:2423-2424 6. Fahrenbach JP, Mejia-Alvarez R, Banach K 2007 The relevance of non-excitable cells for cardiac pacemaker function. J Physiol 585:565-578 7. Olson ER, Shamhart PE, Naugle JE, Meszaros JG 2008 Angiotensin II-induced extracellular signal-regulated kinase 1/2 activation is mediated by protein kinase Cdelta and intracellular calcium in adult rat cardiac fibroblasts. Hypertension 51:704-711 8. Hansen JL, Aplin M, Hansen JT, Christensen GL, Bonde MM, Schneider M, Haunso S, Schiffer HH, Burstein ES, Weiner DM, Sheikh SP 2008 The human angiotensin AT(1) receptor supports G protein-independent extracellular signal-regulated kinase 1/2 activation and cellular proliferation. Eur J Pharmacol 590:255-263 9. Ostrom RS, Naugle JE, Hase M, Gregorian C, Swaney JS, Insel PA, Brunton LL, Meszaros JG 2003 Angiotensin II enhances adenylyl cyclase signaling via Ca2+/calmodulin. Gq-Gs cross-talk regulates collagen production in cardiac fibroblasts. J Biol Chem 278:24461-24468 10. Ren Z, Raucci FJ, Jr., Browe DM, Baumgarten CM 2008 Regulation of swelling-activated Cl(-) current by angiotensin II signalling and NADPH oxidase in rabbit ventricle. Cardiovasc Res 77:73-80 11. Hayabuchi Y, Nakaya Y, Yasui S, Mawatari K, Mori K, Suzuki M, Kagami S 2006 Angiotensin II activates intermediate-conductance Ca2+ -activated K+ channels in arterial smooth muscle cells. J Mol Cell Cardiol 41:972-979 12. Hilgers RH, Webb RC 2007 Reduced expression of SKCa and IKCa channel proteins in rat small mesenteric arteries during angiotensin II-induced hypertension. Am J Physiol Heart Circ Physiol 292:H2275-2284 |
| List of Research Outputs |
| He M., Lau C.P., Tse H.F. and Li G.R., Regulation of cell proliferation by large-conductance calcium-activated potassium and volume-sensitive chloride channels in human cardiac fibroblasts, 15th Medical Research Conference. 2010, 16(1): 23. |
| Hu R., He M., Hu H., Yuan B.X., Zang W.J., Lau C.P., Tse H.F. and Li G.R., Characterization of calcium signaling pathways in human preadipocytes, J Cell Physiol. 2009, 220(3): 765-770. |
| Researcher : Hui EC |
| Project Title: | A survey of viewpoints regarding medical decision-making capacity of adolescents in Hong Kong |
| Investigator(s): | Hui EC, Kuan HY |
| Department: | Medical Faculty |
| Source(s) of Funding: | Seed Funding for New Staff |
| Start Date: | 09/2004 |
| Abstract: |
| To investigate healthcare providers' attitudes and perspectives regarding AP and their capacity for and right to MDM; to investigate the attitudes and perspectives of parents of both well and sick adolescents regarding AP and their capacity for and right to MDM; to investigate the attitudes and perspectives of well and sick adolescents and young adults in age groups between 12 to 21 regarding capacity for and right to MDM; to make a comparison of the attitudes and perspectives of healthcare providers, parents and adolescents regarding AP and their capacity for and right to MDM. |
| Project Title: | Promotion of the reflection, dialogue and teaching of ethical issues related to the development and uses of biotechnologies among students and faculty members of health-related sciences at the University of Hong Kong |
| Investigator(s): | Hui EC |
| Department: | Medical Faculty |
| Source(s) of Funding: | Teaching Development Grants |
| Start Date: | 03/2005 |
| Abstract: |
| (1) To enhance in the HKU campus an awareness of the ethical issues related to the rapid advances of bio-technology and to promote among students and faculty members moral dialogues and discourses of the impacts of bio-technoogy on the Hong Kong society, socially, medically, legally, economically and environmentally. (2) To develop skills in clinical ethics analysis based on a Case-Based Learning approach for medical, nursing and Chinese Medicine students in the Faculty of Medicine as well as dental students from the Faculty of Dentistry. (3) To train and support faculty members in biological, physical, and social sciences, law, bio-engineering, environmental students, psychology, medicine, nursing, dentistry, and Chinese Medicine to engage in ethical reflections and to stimulate students to think ethically as they teach in their respective disciplines of learning. (4) To provide a "venue", a university website on ethics and biotechnology, to encourage a campus-wide dialogue, discussion and debate of bioethical issues, as well as dissemination of information. |
| Project Title: | Ethical decision-making and the potential use of advance directives by Hong Kong Chinese patients with meta-static and/or recurrent cancer: a prospective study |
| Investigator(s): | Hui EC, Chua DTT, Yau CC |
| Department: | Medical Faculty |
| Source(s) of Funding: | Seed Funding Programme for Basic Research |
| Start Date: | 03/2005 |
| Abstract: |
| The overall goal of this study is to develop an ethical framework for the management of cancer patients in Hong Kong that takes into consideration the Chinese cultural background that informs and shapes patients' values, beliefs, preferences, goals and decisions. |
| Project Title: | Ethical decision-making and potential use of advance directives by HongKong Chinese patients with newly diagnosed, recurrent, meta-static or terminal cancer |
| Investigator(s): | Hui EC, Chua DTT, Liu KY |
| Department: | Medical Faculty |
| Source(s) of Funding: | General Research Fund (GRF) |
| Start Date: | 09/2007 |
| Completion Date: | 12/2009 |
| Abstract: |
| To find out different Chinese cancer patients’physical, mental, emotional, social and spiritual needs and concerns and their relative importance in MDM; to find out different patients' attitude towards truthful disclosure, preferred sources of medical information, “traffic”of information among patient, doctor, and family, and family’s right to influence/control the “traffic”; to find out different patients' preferences for autonomous or shared MDM, their rationale for MDM partner(s), and family’s role or right in patient MDM; to identify medico-socio-cultural factors that impact on the use of “advance directives”in Hong Kong; to find out different patients' attitude towards and preferences for Chinese herbal medicine and how using herbs may affect patients' MDM process. |
| List of Research Outputs |
| Hui E.C., Invited discussant on ethical issues of clinical application of human stem cell therapy, International Course on Stem Cell Biology and Regenerative Medicine, LKS Faculty of Medicine, HKU. 2009. |
| Wang C. and Hui E.C., Ethical, legal and social implications of prenatal and preimplantation genetic testing for cancer susceptibility, Reproductive Bio Medicine Online. 2009, Vol 19, Suppl 2: 23-33. |
| Wang C.R. and Hui E.C., Ethical, Legal, Social Implications of prenatal and preimplantation genetic testing for cancer susceptibility, In: Robert Edwards, Reproductive BioMedicine Online. EBSCO Publishing, 2009, Vol. 19, Supplement 2. |
| Researcher : Kong MCW |
| Project Title: | Proliferation of stem cell-derived cardiomyocyte (CM) |
| Investigator(s): | Kong MCW, Tse HF |
| Department: | Medical Faculty |
| Source(s) of Funding: | Small Project Funding |
| Start Date: | 08/2009 |
| Abstract: |
| In many mammalian tissues, reactivation of committed progenitor or stem cell or of proliferation of differentiated cells capable of reenter the cell cycle is a common response to injury. Cardiomyocyte (CM) in the heart, unfortunately, possesses its robust proliferative activity solely in utero, thereafter the proliferative capability markedly reduces in the postnatal heart. Those observations have led to a general belief that CMs in adult are terminally differentiated cells possessing no further division throughout a life span. This notion, however, was recently challenged by the emerging evidences supporting the existence of cardiogenic stem/progenitor cells, which are capable of generating CMs in vitro, in adult myocardium [1]. A later retrospective birth dating study of 14C concentrations in humans CMs estimated a renewal rate of about 1% at the age of 25 and gradually reduced to 0.45% at the age of 75, summing up to an estimation that fewer than 50% of CMs are exchanged during a normal life span [2]. Such modest proliferative potential of adult CM is reflected on the very limited functional recovery after loss of myocardium in various kinds of myocardial injury and points directly to a need of CM replacement, either by cell transplantation or by the promotion of endogenous regenerative processes, in those disease states. CMs derived from stem cell, especially from induced pluripotent stem cell (iPS), which possesses no ethical and immunological issues, could be an ideal source of cell replacement therapy for the injured heart. Currently one of the major obstacles of therapeutic applications of the stem cell-derived CMs is the low efficiency in generating the cells in general [3, 4]. Therefore in this proposal, we aim to study the proliferation of CMs and its manipulation (stimulation in particular) by various protocols such as cell cycle regulators, pharmacological inhibitor of signaling molecules and in particular, microRNA, a novel regulatory molecule that emerging as a central regulator of many cardiogenic processes [5]. 1. Martin-Puig, S., et al., Cell Stem Cell, 2008. 2(4): p. 320-31. 2. Bergmann, O., et al., Science, 2009. 324(5923): p. 98-102. 3. Fukuda, K. and Yuasa, S., Circ Res, 2006. 98(8): p. 1002-13. 4. Zhang, J., et al., Circ Res, 2009. 104(4): p. e30-41. 5. Cordes, K. R. and Srivastava, D., Circ Res, 2009. 104(6): p. 724-32. |
| List of Research Outputs |
| Fu J.D., Kong M.C.W., Rushing S.N., Lieu D.K., Chan C.W.Y., Tse H.F., Wilson K., Chiamvimonvat N., Boheler K.R., Wu J.C., Keller G. and Li R.A., Distinct Roles of MicroRNA-1 and -499 in ventricular specification and maturation of human embryonic stem cells, Fifth International Symposium on Healthy Aging. 2010. |
| Jiang P., Rushing S.N., Kong M.C.W., Fu J., Lieu D.K., Chan C.W.Y., Deng W. and Li R.A., Electrophysiological Properties of Human induced Pluripotent Stem Cells (iPSCs), Fifth International Symposium on Healthy Aging. 2010. |
| Jiang P., Rushing S.N., Kong M.C.W., Fu J., Lieu D.K., Chan C.W.Y., Deng W. and Li R.A., Electrophysiological properties of human induced pluripotent stem cells, Am J Physiol Cell Physiol. 2010, 298: 486-495. |
| Kong M.C.W., Jiang P., Rushing S.N., Tse H.F. and Li R.A., MicroRNA and cell cycle of embryonic stem (ES) and induced pluripotent stem (iPS) cells: Insights for eliminating tumorgenicity, Fifth International Symposium on Healthy Aging. 2010. |
| Researcher : Lai WWK |
| Project Title: | The use of a conjugate of mushroom (Agaricus bisporus) lectin and 5-fluorouracil as an inhibitry aget against proliferative vitreoretinopathy |
| Investigator(s): | Lai WWK, Wong DSH |
| Department: | Medical Faculty |
| Source(s) of Funding: | Seed Funding Programme for Basic Research |
| Start Date: | 12/2007 |
| Abstract: |
| Rhegmatogenous retinal detachment (RRD) occurs when fluid from the vitreous cavity passes through a tear in the retina and results in the separation of the neurosensory retina from the underlying retinal pigment epithelium (RPE). Nearly all patients with a symptomatic RRD will progressively lose vision unless the detachment is surgically repaired. Once a RRD occurs the eye undergoes a modified healing process, or proliferative vitreoretinopathy (PVR), which involves cellular proliferation, tissue contraction and laying down of collagen. Although most cases of RRD can be successfully repaired by surgery, PVR is the cause of surgical failure in up to 15% of patients.In PVR, contraction of membranes that develop on both surfaces of the retina leads to retinal redetachment and surgical failure. Despite the increase in success rate with the introduction of sophisticated microsurgery, 25% of all initially successful PVR cases result in redetachment. Even in cases where the retina is reattached, the final visual results are often disappointing. Recent attempts by members of our group using adjunctive therapy during PVR surgery that consists of 5-fluorouracil (5-FU), an antimetabolite, and low molecular weight heparin, showed some promise in preventing PVR in patients who were at high risk of developing PVR, but not once the process had become established. It has been proposed that a higher concentration of 5-FU may be useful in established PVR by modulating the various cell types involved, but the dosage would exceed that could be tolerated by the RPE and photoreceptors. Thus, newer and targeted treatment is necessary that would allow delivery of an efficacious yet non-toxic concentration of 5-FU. De-differentiated RPE cells have emerged as key players in PVR. These cells behave like wound fibroblasts and therefore proliferate, migrate and adhere to extracellular matrix in order to generate the contractile forces in PVR tissue. Newer agents are thus required, not only as prophylaxis, but which address these key wound healing properties of RPE cells. Lectins are carbohydrate-binding proteins of non-immune origin that agglutinate cells or precipitate polysaccharides or glycoconjugates. The lectin of the edible mushroom, Agaricus bisporus (ABL), which binds the cell membrane TF antigen, is a reversible nontoxic inhibitor of epithelial cell proliferation. Recently, our group has shown this lectin to be antiproliferative to bovine15 and human RPE in vitro. Our group has recently synthesized a novel conjugate of ABL and 5-FU. It has been shown to be antiproliferative to RPE cells and without cytotoxicity. In this study, we will investigate the role of the conjugate on the wound healing properties of RPE cells in vitro. Specifically, we will examine whether the conjugate would modulate the proliferation, migration, adhesion, and contraction of RPE cells in vitro. |
| Project Title: | Open label, prospective, double arm, randomized, pilot study to evaluate the safety and efficacy of the same day administration of PDT with verteporfin and an intravitreal injection of ranibizumab vs. ranibizumab monotherapy for the treatment of subfoveal CNV secondary to neovascular age related macular degeneration in the Asian population |
| Investigator(s): | Lai WWK, Li KKW, Wong DSH, McGhee S, Lam CLK, Chan CWS |
| Department: | Medical Faculty |
| Source(s) of Funding: | Pharmaceutical Industry - General Award |
| Start Date: | 07/2008 |
| Abstract: |
| To evaluate the safety and efficacy of same day administration of PDT with verteporfin and an intravitreal injection of ranibizumab vs. intravitreal ranibizumab monotherapy for the treatment of subfoveal CNV secondary to exudative AMD in the Asian population; to assess the quality of life and utility values of patients with exudative AMD before and after intravitreal injection of ranibizumab +/- PDT in Hong Kong. |
| Project Title: | Production of Iris Pigment Epithelial Cells for transplantation to treat Age-Related Macular Degeneration |
| Investigator(s): | Lai WWK, Lo ACY, Fletcher C, Wong DSH |
| Department: | Eye Institute |
| Source(s) of Funding: | Seed Funding Programme for Basic Research |
| Start Date: | 06/2009 |
| Abstract: |
| 1. To isolate iris pigment epithelial (IPE) cells from non-dystrophic rats 2. To optimize growth kinetics and investigate the characteristics of IPE cells 3. To evaluate a range of differentiation factors and growth factors that influence cell behavior by either enhancing or neutralizing specific growth factors, human serum levels and differentiating agents (e.g. retinoic acid) for RPE cell production from rat IPE cells 4. To measure a range of quantifiable changes in order to determine if cellular rejuvenation has been successful. |
| List of Research Outputs |
| Woo T.T.Y., Li S.Y., Lai W.W.K., Wong D.S.H. and Lo A.C.Y., Lutein Inhibition Of Photoreceptor Death In A Rat Model Of Retinal Detachment, Joint Annual Scientific Meeting of the Hong Kong Society of Neurosciences and the Biophysical Society of Hong Kong. 2010. |
| Researcher : Lam SK |
| Project Title: | Biotech Company in the Faculty of Medicine, The University of Hong Kong |
| Investigator(s): | Lam SK |
| Department: | Medicine |
| Source(s) of Funding: | The University of Hong Kong Foundation Seed Grant |
| Start Date: | 07/2003 |
| Abstract: |
| To enable the Faculty of Medicine of The University of Hong Kong to establish itself as the regional centre of excellence in the provision of complete solutions to industry from laboratory research services to clinical trials, setting standards and quality benchmarks comparable to the best international practices for other similar centres in the region to follow. |
| Project Title: | Treatment of gastrointestinal cancer by targeting survivin using adeno-associated virus gene delivery system |
| Investigator(s): | Lam SK, Wong BCY, Lin MC |
| Department: | Medical Faculty |
| Source(s) of Funding: | General Research Fund (GRF) |
| Start Date: | 09/2004 |
| Abstract: |
| To elucidate the molecular mechanisms of survivin in tumor angiogenesis, to will investigater the effect of overexpression of survivin on the migration and capillary tuber-like networks of endothelial cells, expression of angiogenic factors in gastrointestinal cancer cells and angiogenesis in Chorioallantoic membrane angiogenesis (CAM) model and nude mice xenograft; to establish a novel gene therapy for gastrointestinal cancer by targeting survivin gene with adeno-associated virus vector. We will further study the therapeutic effect of rAAV-mediated survivin mutant on gastrointestinal cancer in vivo and evaluate long-term effect and safety of the rAAV virus. |
| List of Research Outputs |
| Yee Y.K., Wong K.W., Hui C.K., Chan C.K., Chan A.O.O., Lam S.K., Fung F.M.Y., Hung I.F.N. and Wong B.C.Y., Prevalence and time trend of intestinal metaplasia in Hong Kong, J Gastorenterol Hepatol . 2009, 24: 896-9. |
| Researcher : Lau YL |
| Project Title: | A community-based educational program on thalassaemias to enhance awareness with the aim to reduce burden of thalassaemia related health problems in Hong Kong |
| Investigator(s): | Lau YL, Ha SY |
| Department: | Paediatrics & Adolescent Med |
| Source(s) of Funding: | Health Promotion Projects |
| Start Date: | 09/1997 |
| Abstract: |
| To enhance the awareness of the community regarding thalassaemias; to counsel, screen and/or refer clinets who come forward to the Unit after the educational sessions; to decrease the disease burden of thalassaemias in Hong Kong as well as to serve as a possible model for southern China. |
| Project Title: | Comparison of process upgrade varicella vaccine (Puvv) with VARILRIX-TM |
| Investigator(s): | Lau YL |
| Department: | Paediatrics & Adolescent Med |
| Source(s) of Funding: | Other Funding Scheme |
| Start Date: | 07/1999 |
| Abstract: |
| To evaluate and provide information on the safety, tolerability, and immunogenicity of the Process Upgrade Varicella Vaccine (PUVV) at ~16,000 or ~50,000 PFU/0.5ml compared to VARILRIX ( estimated at a release dosage of ~50,000PFU/dose) when they are concomitantly with MMRII at separate injection sites. |
| Project Title: | Association of cytokine and chemokine genes polymorphism with susceptibility to SARS and severity of SARS |
| Investigator(s): | Lau YL, Peiris JSM |
| Department: | Paediatrics & Adolescent Med |
| Source(s) of Funding: | Research Fund for the Control of Infectious Diseases - Full Grants |
| Start Date: | 09/2005 |
| Abstract: |
| To test the association of single nucleotide polymorphisms (SNPs) and microsatellites of 6 cytokine and chemokine genes, i.e. interferon-gamma (IFN-gamma), interluekin-12 (IL-12), interleukin-10 (IL-10), tumour necrosis factor-alpha (TNF-alpha), monocyte chemoattractant protein-1 (MCP-1), and interferon gamma-induced protein-10 (IP-10) with susceptibility to SARS; To test the association of these SNPs and microsatellites with mortality from SARS. |
| Project Title: | p21 gene polymorphism with systemic lupus erythematosus and rheumatoid arthritis |
| Investigator(s): | Lau YL, Lau WCS |
| Department: | Paediatrics & Adolescent Med |
| Source(s) of Funding: | Small Project Funding |
| Start Date: | 09/2005 |
| Abstract: |
| Systemic lupus erythematosus (SLE ) is a complex, multifactorial autoimmune disease that is characterized by the production of various autoantibodies. Dysregulated T cell-dependent induction of autoreactive B cells is considered to play a critical role in the development of SLE (1). The etiology and pathogenesis of SLE remain unclear, but the increased concordance rate in monozygotic twins, familial aggregation and high heritability suggested that the genetic factor is involved in the development of SLE (2-4). Cyclin-dependent kinase inhibitor 1A (also known as p21, WAF1 or CDKN1A) is a negative regulator of cyclin dependent kinases (CDKs) (5). The p21 protein encodes a 21 kDa cell cycle regulatory protein that forms quaternary complexes with the entire cyclin/CDK holoenzyme and acts as pancyclin inhibitors (6). It interacts with CDK2, CDK3, CDK4 and CDK6, thereby inhibiting the progression from the G1 to the S phase of the cell cycle (7-9). It can also bind to the replication factor proliferating cell nuclear antigen (PCNA) and inhibit DNA replication (10). The p21 gene contains the p53 binding site that is localized at 2.4 kb upstream from the translational start site and expression of p21 gene was found to be inducible by wild-type p53 gene expression (11). Moreover, several growth factors and cytokines, including interferon (IFN)-α and -γ, can modify p21 expression (12,13). As p21 is an important molecule in mediating cell cycle arrest, loss of function in p21 may favor cell proliferation. Mutations in the p21 gene have been reported to associate with development of various cancers (14-17). And cells lacking p21 gene are defective in DNA repair, which might induce impaired regulation in cell proliferation (18). Inactivating mutations of p21 lead to overexpression and hyperactivation of low-avidity, autoreactive T cells that are found in abundance in the peripheral lymphoid organs of normal individuals (19). These findings suggested that dysregulated p21 gene expression might contribute to defective cell cycle regulation and therefore lead to excessive cell proliferation and activation. The human p21 gene maps on chromosome 6p21.2 (11), which is a susceptibility region for SLE (20,21). A significant reduction in p21 gene expression is found in SLE patients as compared to controls (22). A lower expression in SLE patients is detected at various points from the G1 to G2/M phase through the S phase when compared with controls (22). Therefore, malfunction of p21 protein may contribute to the pathogenesis of systemic autoimmunity through a variety of primary or secondary mechanisms. Indeed, the p21-/- female mice with 129/Sv x C57BL/6 mixed backgrounds show development of severe lupus-like diseases followed by early mortality, high levels of anti-dsDNA antibodies and kidney immune complex deposits (23). However, the p21-/- lupus-prone BXSB mice show inhibition for the development of systemic autoimmunity (24). The p21-/- BXSB lupus-prone mice show enhancement of the Fas/FasL-mediated activation-induced T cell death and therefore promote the apoptosis of the accumulated autoreactive T and B cells, which inhibit spontaneous systemic autoimmunity (24). Although the above findings showed conflicting results for p21 deficiency, they suggested p21 gene is involved in the pathogenesis of SLE. Similar to SLE, rheumatoid arthritis (RA) is also a complex autoimmune diseases that involves genetic factors. Although disease pathogenesis remains unclear, we have previously identified the mannose binding lectin (MBL) gene as susceptibility gene in both SLE and RA (25-27) and recently, we have demonstrated that the low producing genotype of IL-10 promoter is associated with disease susceptibility and serositis in Hong Kong Chinese patients with SLE (28). The identification of susceptibility allele in SLE and RA by case-control study offers the potential for early prediction of risk of disease progression. This should also provide an approach to select the most appropriate candidate genes for intervention with new biological agents which may prevent or arrest disease progression in those at highest risk. References: Please refer to attachment [05-CRCG-SLE-References.doc] |
| Project Title: | Association of STAT4, ITGAM, BLK and PXK gene polymorphisms with systemic lupus erythematosus (SLE) |
| Investigator(s): | Lau YL, Yang W |
| Department: | Paediatrics & Adolescent Med |
| Source(s) of Funding: | Small Project Funding |
| Start Date: | 09/2008 |
| Abstract: |
| Systemic lupus erythematosus (SLE) is a complex, multi-factorial autoimmune disease with strong genetic involvement. Siblings of SLE patients are of 30 times higher risk of being affected than the general population [1]. Compared to Caucasians, Asians have a higher disease prevalence and more renal involvement [2, 3]. Strong population differences in genetic risk factors towards the disease have been documented by us and others [4, 5]. Recent work on genome-wide association (GWA) studies has discovered new susceptibility genes for SLE [6-9]. However, these studies were mainly conducted in populations of European origin, and it is important to examine whether those genes are also risk factors for populations of other origins. In this study, we will examine whether STAT3, ITGAM, BLK and PXK confer susceptibility risk to Chinese in Hong Kong by a case-control design of association study. We will be using the 900 plus SLE patient samples we have collected and 1,000 healthy controls obtained from Red Cross. We will choose the SNPs that were found to be associated with the disease in GWA studies but also have minor allele frequency of at least 5% in our population (based on Han Chinese in Beijing (HCB) data from HapMap) and only use the tag SNPs which don’t have good linkage disequilibrium with each other (r2<0.8). PXK is a Phox homology domain-containing serine/threonine kinase with unknown function. The gene locates in chromosome 3p14.3. SNP rs6445975 in intron 4 of PXK was found to be associated with SLE in all four sets of samples used in the study of Harley et al with P values for each set all reached below 0.05 (joint P = 7.01X10-9) [8]. The SNP has a minor allele frequency of 16.7% in HCB, so our study will have good power to detect an association if the gene also plays a role in our population. A recent study reported an association of STAT4 with disease risks of both rheumatoid arthritis and SLE. The haplotype marked by rs7574865 was found strongly associated with lupus [9]. Association of STAT4 with SLE was also confirmed in an independent study by Harley et al, both on rs7574865 and another SNP, rs7601754, which is 24 kb downstream of rs7574865 in intron 4 of the gene [8]. Both rs7574865 and rs7601754 have good MAF in Chinese population (33.3% and 14.4%, respectively), and the two SNPs has low LD with each other. So in this study we will genotype both SNPs in our samples and test whether they have independent effect on the association with the disease. BLK is a src family tyrosine kinase involved in signal transduction downstream of B cell receptor, and expression of BLK is highly restricted to B cells. The minor allele of rs13277113, a SNP located in the promoter region of BLK, was found to be associated with SLE in populations of European origin. The risk allele is also found to be related to reduced expression of BLK and increased expression of C8orf13, a gene 25 kb away from the SNP on the opposite strand [7]. Association of BLK with SLE was also confirmed by the study of Harley et al on SNP rs2248932 (OR = 1.22 P = 7X10-10) and rs10903340 (OR = 1.18, P = 1.46E-7)[8]. Rs2248932 and rs10903340 have good LD with each other and only one will be examined together with rs13277113 in our population. The product of ITGAM, integrin-M, is a molecule that combines with integrin-2 to form a leukocyte-specific integrin. The M2-integrin is important in the adherence of neutrophils and monocytes to stimulated endothelium, and in the phagocytosis of complement coated particles. The expression level of M2-integrin was found to be correlated directly with SLE disease activity [10]. In three recent studies, this gene has been found to be associated with SLE [6-8]. Harley et al showed that SNP rs9888739 located in intron 14 of ITGAM has the most significant association with SLE, but rs1143679 was not genotyped directly in this study [8]. In the study of Nath et al, both rs1143679 and rs9888739 were genotyped in the same set of samples and rs1143679 showed the most significant association in Caucasians and also in two African American populations, and was proposed to be a functional variant in the association of this gene with the disease[6]. In this study, we will genotype both rs1143679 and rs9888739 and test their association with the disease as well as any independent effect from the two variants. Reference 1. Danchenko N, et al: Epidemiology of systemic lupus erythematosus: a comparison of worldwide disease burden. Lupus 2006, 15:308-318. 2. Chong WP, et al: Association of interleukin-10 promoter polymorphisms with systemic lupus erythematosus. Genes Immun 2004, 5:484-492. 3. Mok CC, et al: Lupus in Hong Kong Chinese. Lupus 2003, 12:717-722. 4. Willcocks LC, et al: Copy number of FCGR3B, which is associated with systemic lupus erythematosus, correlates with protein expression and immune complex uptake. J Exp Med 2008. 5. Clatworthy MR, et al: Systemic lupus erythematosus-associated defects in the inhibitory receptor FcgammaRIIb reduce susceptibility to malaria. Proc Natl Acad Sci U S A 2007, 104:7169-7174. 6. Nath SK, et al: A nonsynonymous functional variant in integrin-alpha(M) (encoded by ITGAM) is associated with systemic lupus erythematosus. Nat Genet 2008, 40:152-154. 7. Hom G, et al: Association of systemic lupus erythematosus with C8orf13-BLK and ITGAM-ITGAX. N Engl J Med 2008, 358:900-909. 8. Harley JB, et al: Genome-wide association scan in women with systemic lupus erythematosus identifies susceptibility variants in ITGAM, PXK, KIAA1542 and other loci. Nat Genet 2008, 40:204-210. 9. Remmers EF, et al: STAT4 and the risk of rheumatoid arthritis and systemic lupus erythematosus. N Engl J Med 2007, 357:977-986. 10. Molad Y, et al: Intravascular neutrophil activation in systemic lupus erythematosus (SLE): dissociation between increased expression of CD11b/CD18 and diminished expression of L-selectin on neutrophils from patients with active SLE. Clin Immunol Immunopathol 1994, 71:281-286. |
| Project Title: | Immune Responses to Influenza Viruses in the Patients with X-linked Agammaglobulinemia |
| Investigator(s): | Lau YL, Tu W |
| Department: | Paediatrics & Adolescent Med |
| Source(s) of Funding: | General Research Fund (GRF) |
| Start Date: | 10/2008 |
| Abstract: |
| (1) To determine the maturation and function of influenza virus activated dendritic cells from XLA patients in vitro We hypothesize that there are impaired maturation and function of the influenza virus activated monocyte-derived dendritic cells (MDDC) from XLA patients as defined by phenotype, cytokine production and mixed lymphocyte reaction (MLR), compared to that from normal controls; (2) To determine the influenza virus-specific CD4 and CD8 T cells responses in XLA patients in vitro We hypothesize that there are differences in influenza virus-specific CD4 and CD8 T cell responses between XLA patients and age-matched normal controls in terms of their cell number and cytokine production; (3) To determine the influenza virus-specific memory/effector CD4 and CD8 T cells in XLA patients before and after administrations of inactivated influenza vaccines. We hypothesize that XLA patients have different influenza virus-specific memory and effector CD4 and CD8 T cell responses before and after vaccination as defined by multiple phenotypic markers, cytokine secretion and tetramer staining, compared to normal controls. |
| Project Title: | Case-control study of Sichuan and Hong Kong children with melamine associated renal stones - renal ultasounds and urinary IL-8 and MCP-1 |
| Investigator(s): | Lau YL, Tu W |
| Department: | Paediatrics & Adolescent Med |
| Source(s) of Funding: | Studies Related to Melamine Incident |
| Start Date: | 04/2009 |
| Abstract: |
| To compare the renal ultrasound findings and the urinary IL-8 and MCP-1 in Sichuan children suffering from melaine associated renal stones with the Hong Kong chilgdren suspected to have such stones. |
| Project Title: | Functional characterization of two genetic variants associated with SLE identified in the Hong Kong SLE collection |
| Investigator(s): | Lau YL, Yang W |
| Department: | Paediatrics & Adolescent Med |
| Source(s) of Funding: | Small Project Funding |
| Start Date: | 01/2010 |
| Abstract: |
| Systemic Lupus Erythematosus (SLE) is a prototypic systemic autoimmune disease characterized by autoantibody production and involvement of multiple organ systems. It shows a striking female predominance, and is more prevalent in the African and Asian populations. Genetic factors are known to play important roles to disease susceptibility [1, 2]. Work in our own group has recently documented both similarities and differences in disease susceptibility genes between our population and the Caucasians [3-5]. Our recent work, based on GWAS from Hong Kong SLE samples, identified two single nucleotide polymorphisms (SNPs), rs7859667 and rs10814451, located between the paired box 5 gene (PAX5) and maternal embryonic leucine zipper kinase (MELK) at chromosome 9, to be associated with the disease. This finding was further confirmed in four independent cohorts collected from Hong Kong, mainland China and Thailand comprising a large collection of 2953 SLE cases and 4280 controls at genome level significance (OR = 0.80, P = 1.19 x 10-9; OR = 0.76, P = 3.32 x 10-8 respectively). PAX5 and MELK demonstrated potential roles in autoimmunity developments. PAX5 encodes the transcription factor B-cell-specific activator protein (BSAP), essential to B-cell differentiation and function. The significance of PAX5 in autoimmune disease has also been suspected in a recent study of psoriasis [6, 7]. MELK is a Ser/Thr kinase that has been implicated in stem cell renewal, cell cycle progression and pre-mRNA splicing. Overexpression of wild-type MELK suppressed Bcl-GL-induced apoptosis, and thus was associated with carcinogenesis. Ineffective apoptosis can also results in accumulation of autoreactive antigens which may play a role in pathogenesis of autoimmune disease. Despite the genetic findings, the role of the two genetic variants and the potential function of the two surrounding genes in SLE pathogenesis remain unclear. In this proposal, we aim to characterize the roles of the genetic variants in the expression of PAX5 and MELK, and further, how potentially changed expression level of PAX5 and MELK may involve in SLE pathogenesis. Specifically, we will test the effect of the haplotypes formed by the two SNPs on the expression level of PAX5 and MELK in control samples and SLE patients. We will also compare the effect on healthy individuals and SLE patients and also relate any potential effect to other factors such as disease activity, and subphenotypes of the patients. Reference 1. Mok CC, et al: Lupus in Hong Kong Chinese. Lupus 2003, 12:717-722. 2. Harley I. T, et al: Genetic susceptibility to SLE: new insights from fine mapping and genome-wide association studies. Nat Rev Genet 2009, 10: 285-290. 3. W Yang, Minghui Zhao, Nattiya Hirankarn, Chak Sing Lau, Chi Chiu Mok, Tak Mao Chan, Raymond W.S. Wong, Ka Wing Lee, Mo Yin Mok, Sik Nin Wong, Yingyos Avihingsanon, Irene Oi Lin NG, Tsz Leung Lee, Marco Hok Kung Ho, Pamela Pui Wah Lee, Wilfred Hing Sang Wong, Pak Chung Sham, Yu Lung Lau, ITGAM is associated with disease susceptibility and renal nephritis of systemic lupus erythematosus in Hong Kong Chinese and Thai (Human Molecular Genetics, 18: 2063-2070, 2009) 4. Yuk Kwan Chang, W Yang, Minghui Zhao, Chi Chiu Mok, Tak Mao Chan, Raymond W.S. Wong, Ka Wing Lee, Mo Yin Mok, Sik Nin Wong, Irene Oi Lin NG, Tsz Leung Lee, Marco Hok Kung Ho, Pamela Pui Wah Lee, Wilfred Hing Sang Wong, Chak Sing Lau, 6Pak Chung Sham, Yu Lung Lau, Association of BANK1 and TNFSF4 with Systemic Lupus Erythematosus in Hong Kong Chinese (Genes and Immunity, 2009, in press) 5. W. Yang , Ping Ng , MingHui Zhao , Nattiya Hirankarn , Chak Sing Lau , Chi Chiu Mok , Tak-Mo Chan , Raymond Wong , Ka Wing Lee , Mo Yin Mok , Sik Nin Wong , Yingyos Avihingsanon , Tsz Leung Lee , Marco Ho , Pamela Lee , Hing-Sang Wong, Yulung Lau, Population differences in SLE susceptibility genes--STAT4 and BLK, but not PXK, are associated with Systemic Lupus Erythematosus in Hong Kong Chinese (Genes & Immunity, 10: 219-226, 2009) 6. Smith, R. L, et al: Polymorphisms in the PTPN22 region are associated with psoriasis of early onset. Br J Dermatol 2008, 5: 962-968. 7. Kingo, K, et al: Association analysis of IL20RA and IL20RB genes in psoriasis. Genes Immun 2008, 5: 445-451. |
| List of Research Outputs |
| Anderson H.R., Ruggles R., Pandey K.D., Kapetanakis V., Brunekreef B., Lai C.K., Strachan D.P., Weiland S.K., ISSAAC P.H.A.S.E. .1. and Lau Y.L., Ambient particulate pollution and the world-wide prevalence of asthma, rhinoconjunctivitis and eczema in children: Phase One of the International Study of Asthma and Allergies in Childhood (ISAAC)., Occupational and Environmental Medicine. 2010, 67: 293-300. |
| Asher M.I., Stewart A.W., Mallol J., Montefort S., Lai C.K.W., Ait-Khaled N., Odhiambo J., ISSAC Phase One Study Group and Lau Y.L., Which population level environmental factors are associated with asthma, rhinoconjunctivitis and eczema? Review of the ecological analyses of ISAAC Phase One., Respiratory Research. 2010, 11: 8. |
| Ellwood P., Williams H., Ait-Khaled N., Bjorksten B., ISSAC Phase III Study Group I.S.A.A.C. and Lau Y.L., Translation of questions: the international study of asthma and allergies in childhood (ISAAC) experience, International Journal of Tuberculosis and Lung Diseases. 2009, 13: 1174-1182. |
| Odhiambo J.A., Williams H.C., Clayton T.O., Robertson C.F., Asher M.I., ISSAC Phase Three Study Group I.S.S.A.C. and Lau Y.L., Global variations in prevalence of eczema symptoms in children from ISAAC Phase Three, Journal of Allergy and Clinical immunology. 2009, 124: 1251-1258. |
| Yang W., Ying D. and Lau Y.L., In-depth cDNA Library Sequencing Provides Quantitative Gene Expression Profiling in Cancer Biomarker Discovery, Genomics Proteomics Bioinformatics. 2009, 7: 1-12. |
| Researcher : Li CB |
| Project Title: | Enhancement of innate immunity to the pathogen infection: anti-mycobacterial effect of IL-17 |
| Investigator(s): | Li CB, Lau ASY |
| Department: | Medical Faculty |
| Source(s) of Funding: | Research Fund for the Control of Infectious Diseases - Full Grants |
| Start Date: | 12/2009 |
| Abstract: |
| (1) To further examine the mechanisms underlying how IL-17 contributes to the anti-mycobacterial activities of macrophages including production of nitric oxide and cytokines, induction of signaling kinases and bactericidal actions against MTB and Mycobacteria avium complex (MAC); (2) to study the effects of IL-17 in optimizing anti-mycobacterial effects such as nitric oxide production and induction of cytokines; (3) to test whether exogenous IL-17 can be used to enhance the innate immune system in a mouse model and further considered for use as an adjunctive therapy for MTB or MAC |
| List of Research Outputs |
| Au K.Y., Li C.B., Yim H.C.H., Fang J.W. and Lau A.S.Y., Travel Award, 2010 Annual General Meeting and Scientific Meeting, Hong Kong Society for Immunology, Hong Kong, April 17, 2010 . 2010. |
| Chan L.L.Y., Cheung B.K.W., Li C.B. and Lau A.S.Y., A role for STAT3 and cathepsin S in IL-10 down-regulation of IFN-γ-induced MHC class II molecule on primary human blood macrophages., Journal of Leukocyte Biology. 2010, 88: 1-9. |
| Researcher : Li G |
| Project Title: | The 10th International Conference on Alzheimer's Disease and Related Disorders High Field MRI Study of the Beta Amyloid and Plaque Desposits in the Brain of APP/PS1 Mice CoQ10 Delays the Brain Atrophy in Transgenic Aged Mice: in Vivo Volume MRI Study |
| Investigator(s): | Li G |
| Department: | Medical Faculty |
| Source(s) of Funding: | URC/CRCG - Conference Grants for Teaching Staff |
| Start Date: | 07/2006 |
| Abstract: |
| N/A |
| Project Title: | Effect of imbalance of kinases and protein phosphatases on deposit of B amyloid and Tau Pathology in double transgenic APP/PS1 Mice |
| Investigator(s): | Li G, Yang X, Yang ES |
| Department: | Medical Faculty |
| Source(s) of Funding: | Germany/Hong Kong Joint Research Scheme |
| Start Date: | 01/2007 |
| Abstract: |
| 1. To investigate the effect of the overactivation of GSK-3 on deposit of amyloid and tau pathology in APP/PS1 double transgenic mice 2. To investigate the effect of the suppression of the two major proteins - phosphatase 2A and phosphatase 1 on deposit of amyloid and tau pathology in APP/PS1 double transgenic mice This is the first of systematical study on effects of GSK-3/PP2A and PP1 on the main two defining pathological feature-SPs and tau pathology in transgenic mice |
| Researcher : Li GR |
| Project Title: | Volume-sensitive chloride current and cell volume regulation in human atrial myocytes |
| Investigator(s): | Li GR, Lau CP, Chiu SW, Tse HF |
| Department: | Medicine |
| Source(s) of Funding: | General Research Fund (GRF) |
| Start Date: | 12/2001 |
| Abstract: |
| To determine the intracellular signaling pathways that regulate ICl.vol and cell volume in human atrium; to determine whether ICl.vol is persistently activated in atrial myocytes from patients with dilated atrial cardiomyopathy. |
| Project Title: | Studies on ion channels and cell proliferation in human cardiac fibroblasts |
| Investigator(s): | Li GR, Lau CP |
| Department: | Medical Faculty |
| Source(s) of Funding: | General Research Fund (GRF) |
| Start Date: | 01/2007 |
| Completion Date: | 12/2009 |
| Abstract: |
| To analyze the molecular identities of IKCa, IKDR, ICI.vol, and INa, in human cardiac fibroblasts with RT-PCR, Western blot analysis, and patch clamp technique; to test the hypothesis that these four types of channels (IKCa, IKDR, ICI.vol, and INa are involved in the proliferation of human cardiac fibroblasts. Cell proliferation assays will be conducted in the absence and presence of channel blockers, short interfering RNA (siRNA) oligos targeted to IKDR, IKCa, ICI.vol, and INa and channels, and/or signal modulators. |
| Project Title: | Calcium Signals and Cell Proliferation in Human Cardiac Fibroblasts |
| Investigator(s): | Li GR, Lau CP, Lee HC, Tse HF |
| Department: | Medicine |
| Source(s) of Funding: | General Research Fund (GRF) |
| Start Date: | 01/2009 |
| Abstract: |
| (1) To determine the effects of calcium signals on proliferation and the modulation of calcium signals and cell cycle progression by extracellular ATP in human cardiac fibroblasts. |
| Project Title: | Calcium Signaling Pathways in Human Preadipocytes |
| Investigator(s): | Li GR |
| Department: | Medicine |
| Source(s) of Funding: | Seed Funding Programme for Basic Research |
| Start Date: | 03/2009 |
| Completion Date: | 02/2010 |
| Abstract: |
| It is well known that calcium (Ca2+) is a universal second messenger that modulates numerous diverse cellular processes in excitable, non-excitable and proliferative cells. In excitable cells Ca2+ signal participates in motility, secretion, and learning and memory: in proliferative cells it plays an important role in maintaining physiological homeostasis and regulating proliferation. It is well known that white adipose tissue plays a crucial role in the regulation of energy balance and acts as a secretory/endocrine (leptin, adiopnectin, resistin, etc.) organ that mediates numerous physiological and pathological processes. Dysregulation of adipose mass (i.e. size and number of white adipocyte) causes obesity and lipatrophy, that are closely associated with life-threatening pathologies including cardiovascular disease and type 2 diabetes. Preadipocytes (i.e. pre-fat cells) are a type of highly proliferating cell and the origin of fat cells (adipocytes); however, cell biology of this type of cell is not fully understood, especially in human preadipocytes. An understanding of Ca signals and their physiological activity is important in the study on obesity, the major risk factor for type 2 diabetes and cardiovascular disease. Nonetheless, little or no study appears to have been made of Ca signal pathways of preadipocytes. In a preliminary experiment we found that spontaneous intracellular Ca oscillations were observed in a small population of human preadipocytes without any inducing agent. Fetal bovine serum (FBS) in the bath medium increased the cell number with Ca oscillations (please refer the attached Research Background), suggesting that Ca activity is significant in human preadipocytes. However, it is unknown what Ca signal pathways are involved in the Ca oscillations. The objectives of the present proposal are therefore: 1) to characterize calcium signal pathways in human cardiac fibroblasts; and 2) to determine whether calcium signals regulate proliferation of human cardiac fibroblasts. |
| Project Title: | Biophysical Society 54th Annual Meeting PURINOCEPTOR ACTIVATION AND CELL PROLIFERATION IN HUMAN CARDIAC FIBROBLAST |
| Investigator(s): | Li GR |
| Department: | Medicine |
| Source(s) of Funding: | URC/CRCG - Conference Grants for Teaching Staff |
| Start Date: | 02/2010 |
| Completion Date: | 02/2010 |
| Abstract: |
| N/A |
| Project Title: | Study on the Natural Anti-Atrial Fibrillation Compound Acacetin and Its Analogues/Derivatives |
| Investigator(s): | Li GR, Vanhoutte PMGR |
| Department: | Medicine |
| Source(s) of Funding: | Innovation and Technology Support Programme (Tier 3) |
| Start Date: | 03/2010 |
| Abstract: |
| 1) To investigate pharmacokinetic profile of acacetin. The bioavailability, metabolites of acacetin will be studied in the two animal species, the non-rodent dog and the rodent rat, using classical approaches of pharmacokinetics to provide pharmacokinetic information for the potential clinical trial, in addition, tissue distribution wull be determined in rats. 2) To determine pharmacological efficacy and ion channel selectivity of acacetin's analogues/derivatives. The pharmacological efficacy of analogues/derivatives (including its major metabolite) on Kv1.5 channel and Kv4.3 will be studied to find out the compound(s) that has more potent inhibitory effect on Kv1.5 and Kv4.3 channels than acacetin, and ion channel selectivity will be then studied for the selected compound(s) using patch clamp technique. |
| Researcher : Liu L |
| Project Title: | Screening and mechanism study of novel anti-HIV natural product analogues |
| Investigator(s): | Liu L |
| Department: | Medical Faculty |
| Source(s) of Funding: | Seed Funding Programme for Basic Research |
| Start Date: | 06/2008 |
| Completion Date: | 06/2010 |
| Abstract: |
| Human immunodeficiency virus (HIV) is the cause of acquired immunodeficiency syndrome (AIDS). Since its first report in 1981, AIDS has spread rapidly through the world. In 2006 approximately 4.3 million people became infected with HIV-1 leading to over 39.5 million adults and children living with HIV-1/AIDS. More than 2.9 million are estimated to have died of AIDS in 2006 alone. The development of chemotherapeutic strategies for AIDS has recently been considered one of the most challenging scientific projects. The United States Food and Drug Administration (FDA) has approved several anti-HIV drugs, including seven nucleoside reverse transcriptase inhibitors (NRTIs), one nucleotide reverse transcriptase inhibitor (NtRRTI), three nonnucleoside reverse transcriptase inhibitors (NNRTIs), nine protease inhibitors (PIs), and one fusion inhibitor. Although highly active antiretroviral therapy (HAART) using a combination of anti-HIV drugs has been highly effective in suppressing the HIV load and decreasing mortality in AIDS patients, the emergence of drug resistance among HIV carriers, and the unavoidable viral recurrency after drug treatments and the toxicity of the therapies have made the continued search for novel anti-HIV drugs necessary. In China, there are only limited HAART regimens available, the finds of new cost effective anti-HIV drugs reminds one of the highest priority for HIV/AIDS research for our nation. For these reasons, the overall objective of this grant proposal is to search for novel anti-HIV natural product analogues and study the mechanism of the anti-HIV activity of the identified compound. (+)-Calanolide A is Originally isolated from species Calophyllum lanigerum var. austrocoriaceum , and was previously found as an inhibitor of HIV-1 reverse transcriptase. It is the first natural product which is under clinical development for AIDS (IC50 = 0.2 M), due to its low toxicity and broadly anti-HIV activity. Previous investigation of its template indicate, racemic 11-demethyl-12-oxo calanolide A, which had two fewer chiral carbon centers at C-11 and C-12 positions than that of (+)-Calanolide A, had the comparably inhibitory activity and better therapeutic index (EC50= 0.11 uM, TI=818) against HIV-1 in vitro. A library base on its structural core was then designed and synthesized with introduction of nine diversity points by Dr. Liu Gang and his group in Department of Synthetic Medicinal Chemistry, Institute of Materia Medica, Chinese Academy of Medical Sciences, China. Our group has been cooperating with Dr. Liu Gang and his group in searching of novel anti-HIV-1 compounds by screening this new library. The evaluations of anti-HIV-1 activity in vitro concluded their structure-activity relationships (SARs). And a novel compound (10-bromomethyl-11- demethyl-12-oxo calanolide A, 123) was identified to have much higher inhibitory activity and therapeutic index (EC50= 2.85 nM, TI>10,526) than that of the class compound against HIV-1, and two papers have been published. One was published in Journal of Medicinal Chemistry, another is published in Bioorganic & Medicinal Chemistry Letters . Based on the newly identified anti-HIV compound (10-bromomethyl-11- demethyl-12-oxo calanolide A, 123) as previous described , in this study, a new library have been designed and synthesized by Dr. Liu Gang and his group in Department of Synthetic Medicinal Chemistry, Institute of Materia Medica, Chinese Academy of Medical Sciences, China. Therefore in this application, we will focus on following special aims: Specific Aim 1: To screen the 10-bromomethyl-11- demethyl-12-oxo calanolide A, 123 based library and determine the activity of novel anti-HIV compounds against major HIV-1 subtypes in the world. Considering that the new drugs should be beneficial to the majority of AIDS patients, we hypothesize that these lead compounds should have broad anti-HIV activities against the dominant HIV-1 subtypes in the world. Based on the lead anti-HIV compounds indentified, a novel library will be further generated for test. Specific Aim 2: To study the mechanism of the anti-HIV activity of the identified novel compounds ((+)-calanolide A analogues). (+)-Calanolide A was previously defined as a member of HIV-1 (non-nucleoside reverse transcriptase inhibitor (NNRTI). (+)-Calanolide A exhibits enhanced activity against HIV-1 isolates with the Y181C mutation and retains activity against HIV-1 isolates with dual Y181C and K103N mutations. However, when virological failure occurs following treatment with an NNRTI, the resistance mutations can confer reduced sensitivity to the entire class of antivirals. It is therefore important to develop next generation NNRTIs with improved potencies against the clinically relevant viral mutants. Under this aim, we will determine the anti-HIV mechanism of novel calanolide A analogues. We hypothesize that the newly sythesized 11-Demethyl-12-oxo-calanolide A analogues are also members of HIV-1 NNRTI but with unique anti-HIV mechanism. |
| Project Title: | Early HIV-1 diagnosis using in-house real-time PCR amplification on dried blood spots for men who have sex with men in Hong Kong |
| Investigator(s): | Liu L |
| Department: | Medical Faculty |
| Source(s) of Funding: | Council for the AIDS Trust Fund - General Award |
| Start Date: | 09/2009 |
| Abstract: |
| 1. To develop an assay for early HIV-1 diagnosis on dried blood spots for MSM, which is rapid, cheap, sensitive, reproducible, and Hong Kong specific; 2. To investigate the HIV-1 epidemic with emphasis on the sexually active high-risk group in MSM: targeting on the population of early infection before seroconversion; 3. To contribute to timely estimates of HIV incidence, a better understanding of the HIV epidemic on MSM, and to appropriate targeting of care and prevention efforts. |
| List of Research Outputs |
| Wang H., Zhuang K., Liu L., Tang Z., Tang J., Zhang L. and Chen Z., Acute infection of Chinese macaques by a CCR5-tropic SHIV carrying a primary HIV-1 subtype B' envelope. , J Acquir Immune Defic Syndr. . 2010, 1;53(3): 285-91. |
| Xue H., Lu X., Zheng P., Liu L., Han C., Hu J., Liu Z., Ma T., Chen Z. and Liu G., Highly suppressing wild-type HIV-1 and Y181C mutant HIV-1 strains by 10-chloromethyl-11-demethyl-12-oxo-calanolide A with druggable profile, J Med Chem. . 2010, 11;53(3): 1397-401. |
| Researcher : Ng KM |
| List of Research Outputs |
| Siu D.C.W., Waston T., Lai K.W.H., Lee Y.K., Chan Y.H., Ng K.M., Lau C.P., Lip G.Y. and Tse H.F., Relationship of circulating endothelial progenitor cells to the recurrence of atrial fibrillation after successful conversion and maintenance of sinus rhythm., Europace. 2009, 12(4): 460-1. |
| Researcher : Rong J |
| Project Title: | The 7th International Conference on Systems Biology Genome-wide Biological Response Fingerprinting (BioReF) of Traditional Chinese Medicine Formula ISF-1 Reveals a Potential Role of Heme Oxygenase-1 Pathway in the Antioxidant Therapy |
| Investigator(s): | Rong J |
| Department: | Medical Faculty |
| Source(s) of Funding: | URC/CRCG - Conference Grants for Teaching Staff |
| Start Date: | 10/2006 |
| Abstract: |
| N/A |
| Project Title: | Molecular characterization of the transcriptional regulatory elements involved in the synergistic induction of heme oxygenase-1 expression by traditional Chinese medicines |
| Investigator(s): | Rong J, Chen Y, Lau ASY, Tam PKH, Tong Y |
| Department: | Medical Faculty |
| Source(s) of Funding: | General Research Fund (GRF) |
| Start Date: | 09/2007 |
| Completion Date: | 02/2010 |
| Abstract: |
| To characterize the regulatory responsive elements contributing to the synergistic regulation of HO-1 expression; to isolate the active components responsible for the synergistic induction of HO-1 expression; to evaluate the biological importance of synergistic induction of HO-1 expression in animal model. |
| Project Title: | Synergistic induction of leukotriene B4 12-hydroxydehydrogenase (LTB4DH) by Chinese medicines Radix Astragali and Radix Paeoniae Rubrae: Identification of the active compounds and their intracellular targets |
| Investigator(s): | Rong J |
| Department: | School of Chinese Medicine |
| Source(s) of Funding: | Seed Funding Programme for Basic Research |
| Start Date: | 04/2009 |
| Completion Date: | 08/2010 |
| Abstract: |
| Stroke causes increasing incidence of severe disabilities and mortalities worldwide [1]. Stroke-induced brain damage is mainly resulted from uncontrolled immunological and inflammatory responses [2, 3]. Leukotriene B4 (LTB4) is a chemoattractant and proinflammatory lipid mediator generated from arachidonic acids by 5-lipoxygenase and leukotriene A hydrolase [4, 5]. The production of LTB4 is elevated in ischemic stroke [6-8]. LTB4 is a chemoattactant for neutrophiles, macrophages, mast cells, eosinophiles and T-cells. LTB4 stimulates granulocytes and macrophages to release lysosomal enzymes and to generate reactive oxygen species [9]. Thus, uncontrolled recruitment of immune cells often causes tissue damage in the inflammatory diseases. Although the role of LTB4 in ischemic stroke has not fully characterized yet, a previous study demonstrated that LTB4 induced reduction of voltage-dependent potassium outward currents resulted in the neuronal dysfunction in the inflammatory sites [10]. Inhibition of the production of various lipid mediators including LTB4 conferred the reduced neuronal death after transient focal cerebral ischaemia [11]. On the other hand, LTB4 12-hydroxydehydrogenase (LTB4DH) catalyzes the conversion of LTB4 to the less bioactive metabolite 12-keto-LTB4 in the presence of NADP+ and thus LTB4DH plays a critical role in activating LTB4 [12-14]. Similarly, LTB4DH also degrades the lipoxins (LX), the autacoids that dampen neutrophil recruitment and promote resolution within a local inflammatory milieu [15]. In fact, the activation of LTB4 catabolism via enhanced LTB4DH activity by several chemopreventive agents such as dithiolethione may suppress inflammatory processes implicated in tumorigenesis [16, 17]. Owing to its ability to reduce the alpha, beta-carbon=carbon double bond to a single bond in various exogenous and endogenous compounds, LTB4DH was suggested as the fourth class of detoxication enzyme [18]. LTB4DH activity determines the sensitivity of cancer cells to the chemotherapeutic alkylating agent irofulven [19]. These results stimulate us to question if pharmacological induction of LTB4DH expression could inhibit LTB4-mediated inflammatory responses in ischemic stroke. Several herbal medicines are known to inhibit the biosynthesis of LTB4 [20-22]. Little is known about the regulation of LTB4 metabolism by herbal compounds. As an example, Panax notoginseng Buck F.H. Chen. (Arialiaceae) root is widely used to treat haemorrhages and to promote health in traditional Chinese medicine. A recent study demonstrated that Panax notoginseng extract inhibited neutrophil functions such as degranulation, superoxide generation and leukotriene B4 production [23]. By investigating the cellular response to Chinese traditional medicines at the genome-wide scale, we found that a well-documented post-stroke rehabilitation formulation ISF-1 induced heme oxygenase-1 in a synergistic fashion, conferring the cytoprotection of neurons from oxidant-induced injuries in the post-stroke rehabilitation [24, 25]. In addition, the formulation ISF-1 also induced several anti-inflammatory genes such as LTB4DH [24]. These results suggest that LTB4DH may play a potential role in the post-stroke rehabilitation by degrading LTB4. Consequently, we further studied the regulation of LTB4DH expression by the herbal ingredients of the formulation ISF-1. It is intriguing that both Radix Astragali and Radix Paeoniae Rubrae are required to induce LTB4DH expression and none of the ingredients in the formulation ISF-1 alone showed any activity. Thus, we hypothesize that LTB4DH expression is synergistically regulated by two different signals that are triggered by Radix Astragali and Radix Paeoniae Rubrae, respectively. Due to the chemical complexity of herbal extracts, we will apply a bioactivity-guided fractionation strategy to isolate the active compounds from Radix Astragali and Radix Paeoniae Rubrae. When the active compounds are identified, we will subsequently elucidate the mechanisms by which Radix Astragali and Radix Paeoniae Rubrae induce LTB4DH expression. The long term objective of this project is to develop new chemically defined formulations for the treatment of ischemic stroke by inducing LTB4DH expression. Specific Aim 1: To isolate the active compounds from Chinese medicines Radix Astragali and Radix Paeoniae Rubrae. Radix Astragali and Radix Paeoniae Rubrae are widely used as anti-inflammatory, anti-oxidant, anti-cancer and immunomodulatory drugs in traditional Chinese medicine [26-28]. However, the underlying mechanisms remain largely unknown. We recently demonstrated that the post-stroke rehabilitation formulation ISF-1 containing both herbs significantly upregulated LTB4DH, known as an anti-oxidant and anti-inflammatory gene [24]. In our subsequent effort to identify the active ingredients from the formulation ISF-1, both Radix Astragali and Radix Paeoniae Rubrae were found to be essential for effective induction of LTB4DH expression, suggesting a synergistic mechanism. The objective of this study is to isolate the active compounds for inducing LTB4DH expression. We will adapt a bioactivity-guided fractionation strategy to isolate the compounds capable of inducing LTB4DH expression. Induction of LTB4DH expression will be assayed by RT-PCR technique using specific primers. The results will be verified by Western blot analysis using anti-human LTB4DH antibody. The active fractions will be subjected to further chemical identification by mass spectrometry and NMR technique. Specific Aim 2. To elucidate the molecular mechansims underlying the regulation of LTB4DH. Leukotrienes (e.g. LTB4) are important proinflammatory lipid mediators in the cardiovascular diseases including arteriosclerosis, myocardial infarction, and stroke [29, 30]. LTB4DH is an endogenous regulator of LTB4-mediated inflammatory signals by converting the LTB4 to the less bioactive metabolite [31]. Previous studies showed that LTB4DH expression could be induced pharmacologically. Our preliminary results showed that Radix Astragali and Radix Paeoniae Rubrae may induce LTB4DH expression in a synergistic fashion. However, little is known about the cellular signaling pathways that regulate LTB4DH expression. Following the identification of the active compounds in Specific Aim 1, this study is designed to elucidate the molecular mechansims underlying the regulation of LTB4DH by the active herbal compounds. Transcriptomics is widely used to study the molecular mechanisms undelying the action of various drugs. We will fingerprint the cellular responses to the active compounds by DNA GeneChips at the genome-wide scale. The transcriptional profile will reveal the target genes for the active compounds. Subsequently, we will verify the candidate targets by introducing the full length cDNA sequence into the neuronal cells or knocking down the expression of the candidate genes by RNAi contructs. Alternatively, we will clone the promoter sequence of LTB4DH gene from the genomic DNA library purchased from Stratagene earlier. Our hypothesis is that LTB4DH gene carries with specific transcriptional regulatory elements responsive to Radix Astragali and Radix Paeoniae Rubrae. Identification of transcriptional regulatory elements may be helpful to decipher the intracellular signaling networks regulated by the active compounds. Thus, this study will make it possible to develop chemically defined and mechanism specific new Chinese medicine formulation for the prevention and treatment of post-stroke disorders. |
| Project Title: | Inhibitory effect of gallic acid and caffeoyl glucose in combination on the proliferation of human liver cancer HepG2 cells: A role of leukotriene B4 12-hydroxydehydrogenase (LTB4DH) |
| Investigator(s): | Rong J |
| Department: | School of Chinese Medicine |
| Source(s) of Funding: | Seed Funding Programme for Basic Research |
| Start Date: | 05/2010 |
| Abstract: |
| Hepatocarcinogenesis is a multistep process including initiation, promotion and progression [1, 2]. Although multiple etiologies exist, viral infection and chronic inflammation are the major risk factors for the pathogenesis of hepatocellular carcinoma [3, 4]. Chronic inflammation is characterized by aberrant arachidonic acid metabolism that is implicated in the development of various cancers [5]. Arachidonic acids are converted to prostaglandins (PGs) and leukotrienes (LTs) by cyclooxygenase (COX) and lipoxygenase (LOX) pathways, respectively [6]. Leukotriene B4 (LTB4) is a key proinflammatory mediator derived from arachidonic acid by 5-lipoxygenase (5-LOX) pathway [7, 8]. It was recently found that LTB4 level could be 10-30 fold higher in oral squamous cell cancers compared to control normal tissues [6, 9]. LTB4 also promotes the growth and survival of cancer cells [5, 10]. These results suggest a role for LTB4 in the pathogenesis of various cancers. Recent in vitro and in vivo studies also showed that blockage of LTB4 production resulted in the suppression of tumor development [10, 11]. However, selective control of the cellular LTB4 level is an ongoing challenge. With the support of a previous internal seed grant, we recently discovered that gallic acid and 1-O-caffeoyl-β-D-glucose in combination strongly induced the expression of LTB4 12-hydroxydehydrogenase (LTB4DH) mRNA and protein (Figure 1&2). LTB4DH is a key endogenous enzyme converting LTB4 to less active metabolite 12-keto-LTB4. Remarkably, we confirmed that elevated LTB4DH expression either through transfection of LTB4DH cDNA or synergistic induction of by gallic acid and 1-O-caffeoyl-β-D-glucose inhibited the growth of cancer cells (Figure 3&4). The inhibition of the growth of HepG2 cells by gallic acid and 1-O-caffeoyl-β-D-glucose was largely attenuated by RNAi-mediated knockdown of LTB4DH expression (Figure 5). These preliminary results suggest a role for LTB4DH in the anticancer activity of gallic acid and 1-O-caffeoyl-β-D-glucose. Thus, we hypothesize that LTB4DH induction may attenuate the proliferation of cancer cells via specific control of LTB4 level. We will test this hypothesis through addressing two specific questions: (1) Does LTB4DH play a role in the inhibitory effect of gallic acid and 1-O-caffeoyl-β-D-glucose on the proliferation of cancer cells? (2) Is it possible to use gallic acid and 1-O-caffeoyl-β-D-glucose in the treatment of hepatocarcinogenesis in vivo? The goal of this project is to demonstrate a novel anticancer mechanism by pharmacological induction of LTB4DH. The results from this project will improve current understanding on the role of LTB4DH in the selective control of LTB4 levels and subsequent inhibition of hepatocellular carcinoma. Objectives 1. To investigate the role of LTB4DH in the inhibitory effect of gallic acid and caffeoyl glucose on the proliferation of liver cancer HepG2 cells. Our pilot results suggest that LTB4DH is highly induced by gallic acid and caffeoyl glucose in cultured HepG2 cells, which is positively correlated with the inhibition of cell proliferation. Importantly, RNAi-mediated downregulation of LTB4DH expression attenuated the inhibitory effects of gallic acid and caffeoyl glucose on the growth of HepG2 cells. Thus, the objective of this study is to investigate the role of LTB4DH in the inhibition of cell proliferation by gallic acid and caffeoyl glucose in liver cancer HepG2 cells. We will determine the effects of LTB4DH induction on the focus formation, colony formation, morphological changes and cell motility as described [12-14]. The results of this study will not only demonstrate the chemopreventive role of LTB4DH in hepatocarcinogenesis, but also open a new avenue for the therapeutic intervention of hepatocarcinogenesis based on traditional Chinese medicines. 2. To examine the effect of gallic acid and caffeoyl glucose on hepatocarcinogenesis in an animal model We recently discovered that gallic acid and caffeoyl glucose inhibited the proliferation of cancer cells in cell culture. Others showed that Radix Astragali extracts inhibited carcinogenesis in animal models [15, 16]. Thus, this study is designed to further investigate the effects of gallic acid and caffeoyl glucose on tumor growth in vivo. Human hepatoma xenograft will be made in nude mice as described [17]. This study will demonstrate the therapeutic potential of gallic acid and caffeoyl glucose in liver cancer. |
| Researcher : Sham PC |
| Project Title: | Optimal design of genome-wide association studies for multifactorial diseases |
| Investigator(s): | Sham PC, Ng MKP, Tang NLS |
| Department: | Psychiatry |
| Source(s) of Funding: | General Research Fund (GRF) |
| Start Date: | 01/2007 |
| Completion Date: | 12/2009 |
| Abstract: |
| To focus on the following issues in the design of genome-wide association studies: (1) multi-stage, multi-platform study designs; (2) function-informed selection of tag SNPs and haplotype tagging; to quantitative evaluation of subject informativeness; marker-based derivation of homogeneous sub-populations. |
| Project Title: | Replication study of susceptibility genes for colorectal cancer |
| Investigator(s): | Sham PC, Ho JWC, Cheng KK |
| Department: | Medical Faculty |
| Source(s) of Funding: | Small Project Funding |
| Start Date: | 10/2007 |
| Abstract: |
| To conduct replication studies in the Hogn Kong Chinese population of potential suscepstibility genes identified by whole-genome association studies performed in European populations. |
| Project Title: | Genome-wide association study of schizophrenia |
| Investigator(s): | Sham PC, Chen EYH, Chen RYL, Cherny SS, Tam PKH |
| Department: | Medical Faculty |
| Source(s) of Funding: | General Research Fund (GRF) |
| Start Date: | 01/2008 |
| Abstract: |
| To identify susceptibility loci for schizophrenia by a genome-wide association screen using 500 case-control pairs and 500 case-parents trios; to examine the possible impact of the detected susceptibility genes on disease outcome in a sample of 130 schizophrenic patients who have been studied since the onset of psychosis. |
| Project Title: | Genomics |
| Investigator(s): | Sham PC |
| Department: | Medical Faculty |
| Source(s) of Funding: | Seed Funding for Strategic Research Theme |
| Start Date: | 06/2008 |
| Completion Date: | 05/2011 |
| Abstract: |
| n/a |
| Project Title: | Visiting Research Professors Scheme 2009-10 |
| Investigator(s): | Sham PC |
| Department: | Medical Faculty |
| Source(s) of Funding: | Visiting Research Professors Scheme |
| Start Date: | 09/2009 |
| Abstract: |
| To support the appointment of Professor Michael Q. Zhang as Visiting Research Professor in the Department of Psychiatry and SRT on Genomics. |
| Project Title: | The 59th Annual Meeting of the American Society of Human Genetics A RET founder mutation in Chinese Hirschsprung’s patients |
| Investigator(s): | Sham PC |
| Department: | Medical Faculty |
| Source(s) of Funding: | URC/CRCG - Conference Grants for Teaching Staff |
| Start Date: | 10/2009 |
| Completion Date: | 10/2009 |
| Abstract: |
| N/A |
| List of Research Outputs |
| Cheung C.Y.Y., Tso A.W.K., Cheung B.M.Y., Xu A., Ong K.L., Fong H.Y., Wat N.M.S., Janus E.D., Sham P.C. and Lam K.S.L., Obesity susceptibility genetic variants identified from recent genome-wide association studies: implications in a Chinese population, J Clin Endocrinol Meta. 2010, 95: 1395-403. |
| Ong K.L., Tso A.W.K., Cherny S.S., Sham P.C., Lam K.S.L., Jiang C.Q., Thomas G.N., Lam T.H. and Cheung B.M.Y., A genetic variant in the gene encoding fibrinogen beta chain predicted incident hypertension in Chinese men, Annual Scientific Meeting and Annual General Meeting of Hong Kong Society of Endocrinology, Metabolism and Reproduction, Nov 2009, Hong Kong. 2009. |
| Ong K.L., Tso A.W.K., Cherny S.S., Sham P.C., Lam K.S.L., Jiang C.Q., Thomas G.N., Lam T.H. and Cheung B.M.Y., Association of a genetic polymorphism in the gene encoding fibrinogen β chain with hypertension in Hong Kong Chinese, 14th Research Postgraduate Symposium, Faculty of Medicine, HKU, Dec 2009, Hong Kong. 2009. |
| Ong K.L., Li M., Tso A.W.K., Xu A., Cherny S.S., Sham P.C., Tse H.F., Cheung B.M.Y. and Lam K.S.L., Association of a genetic variant in the adiponectin gene with persistent hypertension in Hong Kong Chinese, 1st International Congress on Abdominal Obesity, Jan 2010, Hong Kong. 2010. |
| Ong K.L., Tso A.W.K., Leung R.Y., Cherny S.S., Sham P.C., Cheung B.M.Y. and Lam K.S.L., Association of a genetic variant in the adiponectin gene with persistent hypertension in Hong Kong Chinese, Annual Scientific Meeting and Annual General Meeting of Hong Kong Society of Endocrinology, Metabolism and Reproduction, Nov 2009, Hong Kong. 2009. |
| Ong K.L., Tso A.W.K., Leung R.Y., Xu A., Cherny S.S., Sham P.C., Lam K.S.L. and Cheung B.M.Y., C-reactive Protein As A Predictor Of Hypertension In The Hong Kong Cardiovascular Risk Prevalence Study (crisps) Cohort, International Congress of Cardiology (ICC), Feb 2010, Hong Kong. 2010. |
| Ong K.L., Tso A.W.K., Leung Y.K., Cherny S.S., Sham P.C., Cheung B.M.Y. and Lam K.S.L., Relationship of genetic variants in gene encoding adrenomedullin with hypertension and dysglycaemia in Hong Kong Chinese, 13th Annual Scientific Meeting of the Institute of Cardiovascular Science and Medicine, Co-morbidity Hypertension / Diabetes: which one do we treat, Dec 2009, Hong Kong. 2009. |
| Ong K.L., Tso A.W.K., Leung Y.H., Cherny S.S., Sham P.C., Cheung B.M.Y. and Lam K.S.L., Relationship of plasma interleukin-6 and its genetic variants with hypertension in Hong Kong Chinese., 15th Medical Research Conference, HKU. Hong Kong Medical Journal.. 2010, 16: 50. |
| Yang S., Agrawal K.R., Lam T.W., Sham P.C., Cheah K.S.E. and Wang J.J., Novel Profile Hidden Markov Model to predict microRNAs in Degenerative Disc Disease. University Grants Council site visit for Area of Excellence Programme "Developmental Genomics & Skeletal Research". January 25, 2010. |
| Researcher : Tai LS |
| List of Research Outputs |
| Fu L., Dong S., Xie Y.W., Tai L.S., Chen L., Kwong D.L.W., Man K., Xie D., Li Y., Cheng Y., Tao Q. and Guan X.Y., Down-regulation of tyrosine aminotransferase at a frequently deleted region 16q22 contributes to the pathogenesis of hepatocellular carcinoma, Hepatology. 2010, 51: 1624-34. |
| Researcher : Wang H |
| List of Research Outputs |
| Liu H., Wang H., Yu W., Zhu W. and Chen Z., The route of inoculation determines the tissue tropism of modified vaccinia Tiantan expressing the spike glycoprotein of SARS-CoV in mice., J. Med. Virol.. 2010, 82(5): 727-734. |
| Yu W., Fang Q., Zhu W., Wang H., Tien P., Zhang L. and Chen Z., One time intranasal vaccination with a modified vaccinia Tiantan strain MVTT (ZCI) protects animals against pathogenic viral challenge., Vaccine. 2010, 28(9): 2088-96. |
| Researcher : Wong DSH |
| Project Title: | Inhibition of provisional matrix synthesis in proliferative vitreoretinopathy (PVR) prevention |
| Investigator(s): | Wong DSH, Lo ACY |
| Department: | Medical Faculty |
| Source(s) of Funding: | Seed Funding Programme for Basic Research |
| Start Date: | 02/2008 |
| Abstract: |
| The research direction of our project has been changed and the new project title is: Chromosomal analysis in ocular adnexal lymphoma The ocular adnexal lymphomas (OAL) are malignant lymphoid neoplasms that develop in the orbit, conjunctiva, eyelid and lacrimal gland. They constitute less than 1% of all non-Hodgkin lymphoma (NHL), but represent 8% of those NHL occurring in extra-nodal sites[1]. According to the new WHO Classification[2] and the Revised European and American Lymphoma (R.E.A.L) Classification, 60% to 70% of all OAL are of extra-marginal zone B-cell lymphomas (EMZL) subtype. The less common subtypes of OAL include diffuse large B-cell (DLBCL) and follicular lymphoma (FL), each representing approximately 10% of the total OAL. In this project, we mainly focus on OAL of EMZL subtype; those OAL, such as FL, DLBCL and mantle cell lymphoma (MCL) are grouped together as “non-EMZL”. EMZL are low-grade B-cell lymphomas, which were first described in the stomach, and then subsequently in other extra-nodal sites e.g. lung, ocular adnexa, salivary and thyroid glands[3]. EMZL are thought to arise from neoplastic B-cells, which are located in the marginal zone of a secondary lymphoid follicle. This monoclonal B-cell population is comprised typically of centrocyte-like cells, monocytoid cells as well some with a plasmacellular differentiation. Infiltration of an adjacent epithelium or mucosa by the neoplastic B-cells has resulted in some of these tumors being termed as mucosa-associated lymphoid tissue (MALT) lymphomas[4]. The majority of the patients with OAL present with Stage IE tumors (Ann Arbor staging), and are usually treated with low-dose radiotherapy. The clinical course of these tumors is an indolent one, characterised by recurrent tumor occurring at other extranodal sites, including the contralateral ocular adnexa [5]. It is difficult to predict both histomorphologically and clinically, in which patient the NHL will recur or possibly spread systemically. Some prognostic markers have been suggested on the basis of large cohorts [6-8], and include serum lactate dehydrogenase, age and gender of the patient, EMZL versus non-EMZL tumors, and the Ki-67 growth fraction of the neoplastic B-cells [9, 10]. EMZL demonstrate several cytogenetic alterations. These include trisomies 3 and 18, and the translocations t(11;18)(q21;q21), t(1;14)(p22;q32), t(14;18)(q32;q21) and t(3;14)(p13;q32)[11-13]. Most of these cytogenetic alterations are linked with a dysregulation of of the BCL10 and MALT1 genes, which in turn affect a common signaling mechanism, the NF-kB signaling pathway. Dysregulation of the NF-kB pathway results in an uncontrolled proliferation of lymphocytes [12, 13]. EMZL at different locations show distinctive cytogenetic mutation profiles[13], and EMZL OAL is particularly related with t(11;18) and t(14;18) translocations, 10% and 7%, respectively [12]. Recently reported loss of TNFAIP3 and A20, both at 6q23, are associated with the pathogenesis of EMZL of the ocular adnexa via enhanced activation of the NF-kB signaling mechanism [14, 15]. To date, it has not been determined whether any of these chromosomal abnormalities are of clinical prognostic significance. Although cytogenetic mutations of EMZL have been studied in detail, little research has been performed on the hypermethylation status of tumor suppressor genes in OAL. Chromosomal methylation involves the addition of methyl groups on the deoxyribonucleotide base cytosine, specifically at Cytosine-Guanine (CG)-rich sites, i.e. CpG islands in the promoter regions. Such hypermethylation can prevent the binding of transcription factors and lead to down-regulation of the expression of the affected gene. Hypermethylation of tumor suppressor genes is a common epigenetic phenomenon that leads to such “gene silencing”, and plays an important role in development of many tumors, including lymphomas. Hypermethylation status of various genes in different subtypes of lymphoma was studied, such as p16, p15, DAP-kinase, androgen receptor, SHP1, MLH1 and MGMT have shown hypermethylation, and the levels of methylation can be variable among different subtypes [16-19]. Many studies have showed a correlation between EMZL pathogenesis and microorganism infection. Helicobacter pylori infection is well known to be associated with gastric EMZL development: growth of the neoplastic B-cells can be stimulated by intratumoral H. pylori specific T-cells [12, 13, 20]. Several recent studies have shown Chlamydia psitacci is present in some ocular adnexal EMZL [21-23]. The correlation between C. psitacci and ocular adnexal EMZL is, however, variable among different geographical regions, being most frequently in Italy (80%), followed by Germany (47%), the East Coast of USA (35%) and the Netherlands (29%)[21, 22]. As yet there is no evidence showing microbial DNA contributing to EMZL OAL pathogenesis[24]. In this project, our aims include: - To investigate whether hypermethylation pattern in OAL EMZL and compare it with the reactive lymphoproliferative lesions of the OAL as well as with the OAL non-EMZL - To investigate whether hypermethylation pattern in OAL EMZL is similar (or not) to that of EMZL in other locations, such as gastric and pulmonary EMZL - To correlate methylation status with anatomical location within the ocular adnexa using the novel TNM-based staging system for OAL [25], and with the subsequent clinical course in a well-defined cohort of OAL - To assess what the functional result of hypermethylation of any genes in OAL: e.g. subsequent dysregulation of signalling pathways - To assess whether the methylation pattern of the OAL EMZL may be related to the presence or absence of microorganisms, such as Chlamydia psitacci infection. Similarly, we plan to correlate the methylation status in stomach EMZL with the clinical history with and without Helicobacter pylori infection. |
| Project Title: | To introduce bevacizumab for the treatment of macular degeneration and diabetic retinopathy to Queen Mary Hospital |
| Investigator(s): | Wong DSH, Lai WWK, Li KKW |
| Department: | Medical Faculty |
| Source(s) of Funding: | S.K. Yee Medical Foundation - General Award |
| Start Date: | 03/2008 |
| Abstract: |
| To introduce this new treatment to public patients; to use the drug appropriately in the patients best interest; to demonstrate that a high quality service can be delivered effectively and cost effectively. |
| Project Title: | To develop a tool that can be used to study patients with eye diseases in Hong Kong, namely a translated Chinese version of the established Visual Function Questionnaire (VFQ-25) |
| Investigator(s): | Wong DSH, Lai WWK, McGhee S, Lam CLK, Chan CWS |
| Department: | Medical Faculty |
| Source(s) of Funding: | Seed Funding Programme for Applied Research |
| Start Date: | 07/2008 |
| Abstract: |
| To develop a tool that can be used to study patients with eye diseases in Hong Kong, namely a translated Chinese version of the established Visual Function Questionnaire (VFQ-25) |
| Project Title: | The Royal College of Ophthalmologists Annual Congress 2009 Can Lutein Protect the Outer Retina? |
| Investigator(s): | Wong DSH |
| Department: | Medical Faculty |
| Source(s) of Funding: | URC/CRCG - Conference Grants for Teaching Staff |
| Start Date: | 05/2009 |
| Abstract: |
| N/A |
| Researcher : Wong JGWS |
| Project Title: | What makes a good clinical teacher in the new medical curriculum? A focus group study on student perception |
| Investigator(s): | Wong JGWS, Lam TP, Mak-Lieh F |
| Department: | Psychiatry |
| Source(s) of Funding: | Other Funding Scheme |
| Start Date: | 01/2002 |
| Abstract: |
| To examine medical student perceptions on what makes a good clinical teacher; to explore the concept of a good role model. |
| Project Title: | A follow-up study on the severity of psychological sequelae in SARS patients |
| Investigator(s): | Wong JGWS, Sham PC, Wong PC, McAlonan GM, Chu CM, Lee AM, Lee PWH, Tsang KWT, Chua SE |
| Department: | Psychiatry |
| Source(s) of Funding: | Small Project Funding |
| Start Date: | 11/2004 |
| Abstract: |
| To assess severity of psychological sequelae in SARS patients (including infected HCWS after recovery from the infection; to assess severity of psychological sequelae in high risk and low risk HCWs after the SARS outbreak; to inform psychological intervention in the event of a future outbreak. |
| List of Research Outputs |
| Lam T.P., Wong J.G.W.S., Ip M.S.M., Lam K.F. and Pang S.L., Psychological wellbeing of interns in Hong Kong: What causes them stress and what helps them, Medical Teacher . Taylor & Francis, 2010, 32: e120-e126. |
| Researcher : Xia F |
| Project Title: | Roles of liver-secreted factors, FGF21 and adropin, in energy homeostasis and insulin sensitivity |
| Investigator(s): | Xia F, Xu A, Lam KSL |
| Department: | Medical Faculty |
| Source(s) of Funding: | Small Project Funding |
| Start Date: | 08/2009 |
| Abstract: |
| Obesity has been increasingly prevalent in virtually all the developed countries worldwide, and is closely linked to a set of medical disorders commonly referred to metabolic syndrome that increases the risk of developing cardiovascular diseases and diabetes. The mechanisms that link obesity and nutrient / energy homeostasis are not fully elucidated. An intensive research has been focusing on exploring the factors that regulate energy homeostasis, and novel therapeutic intervention of these disorders. Peptides secreted from peripheral organs regulate lipid metabolism in key insulin-target tissues, playing an important role in energy homeostasis and maintaining insulin sensitivity (Reitman, 2007;Scherer, 2006;Sharma & Staels, 2007). Adipose tissue-produced cytokines, termed adipokines, have gained much attention for their actions as paracrine factors within white adipose tissue, as well as endocrine hormones acting on the liver, muscles, and central nerve system (Scherer, 2006). Among those adipokines, adiponectin and leptin have been intensively studied as positive regulators for energy homeostasis. Adiponectin enhances insulin sensitivity and promotes fat oxidation in the liver and muscle (Scherer, 2006;Sharma & Staels, 2007). Leptin regulates ingestive behaviour, peripheral lipid metabolism, and insulin sensitivity through its actions on hypothalamic neurons (Morton et al., 2006). During past five years, we have well established in the studies of aipokines in regulating metabolism with over 30 publications in peer-reviewed journals (Xu et al., 2006;Wang et al., 2007;Wang et al., 2008;Wang et al., 2009;Xu et al., 2007;Xu et al., 2009a;Zhu et al., 2008). Compared to adipose tissue-derived peptides, liver-secreted factors have only drawn attention recently and implicated critical for energy homeostasis (Kumar et al., 2008;Reitman, 2007). Fibroblast growth factor-21 (FGF21) is produced predominantly by the liver and to a lesser extent by adipose tissue, and has beneficial effects on several metabolic parameters in different mouse models of obesity (Kharitonenkov et al., 2005). The beneficial metabolic effects of FGF21 include stimulation on insulin-dependent glucose uptake by increasing GLUT-1 expression in adipocytes, lowering blood glucose and triglyceride levels of genetic models of murine obesity, protecting against diet-induced obesity (DIO) and insulin resistance, and reducing body weight (Coskun et al., 2008;Kharitonenkov et al., 2005;Xu et al., 2009b). The beneficial effects of FGF21 on hyperglycemia and hyperlipidemia have also been reported on diabetic rhesus monkeys (Kharitonenkov et al., 2007). The observation that FGF21 does not cause hypoglycemia and weight gain (reduced body weight) makes this factor an intriguing candidate for the treatment of metabolic syndrome. However, some issues remain further investigations. Firstly, there is no highly specific immunoassay available for studying circulating FGF levels in mouse and human. Secondly, the roles of FGF21 in human remain elusive. a few recent human studies from us and others have shown discrepancy of the roles of FGF21 in mouse and human (Chavez et al., 2009;Christodoulides et al., 2009;Li et al., 2009;Zhang et al., 2008). Furthermore, all the human studies are of cross-sectional nature in small study cohorts, and therefore prospective study with a large cohort is needed to evaluate the role of FGF21 in regulating energy homeostasis. Most recently, Kumar et al reported another novel liver-secreted peptide adropin involved in energy homeostasis (Kumar et al., 2008). Adropin is encoded by a gene Energy Homeostasis Associated (Enho), and expressed in the liver and brain. The expression of adropin in the liver is regulated by nutrition. They found that adropin mRNA in the liver increased by 9-fold in lean C57BL/6J mice fed high fat diet (HFD) for 2 days, while fasting reduced expression compared to control. However, the expression of adropin mRNA declined with diet induced obesity (DIO) by feeding the mice with HFD for 3 months, indicating that the metabolic disorders are associated with obesity. This is further confirmed by the observation that transgenic overexpression or systemic administration of synthesized adropin on the DIO mice attenuated hepatosteatosis and insulin resistance independently from the effects on adiposity or food intake. Furthermore, adropin was found to regulate expression of hepatic lipogenic genes and a major regulator of lipogenesis in adipose tissue, peroxisome proliferator-activated receptor gamma (PPARgamma) (Kumar et al., 2008). Those effects of adropin in energy homeostasis and lipid metabolism could form basis for the development of novel therapeutic intervention for the treatment of metabolic disorders related to obesity. Although adropin may be a promising target for treating metabolic syndrome, many issues remain further investigations. The mechanism of adropin action is almost unknown, and its receptor remains to be identified. The secretion of adropin is speculated based on the analysis of the peptide structure and by in vitro transgenic overexpression of the recombined DNA. It will be critical to detect the occurrence of adropin in circulation, and to further verify the roles of circulating adropin in regulating metabolism. FGF21 and adropin are the two novel discovered peptides secreted by liver with the potential application for therapeutic intervention on metabolic disorders related with obesity. The major purpose of this project is to further characterize the roles of these two peptides in energy homeostasis and insulin sensitivity, and specifically we aim to address the following key issues: - To establish highly specific immunoassays for serum levels of FGF21 and adropin in mouse and human; - To explore roles of circulating FGF21 and adropin in physiological and pathological conditions in mouse models; - To evaluate the association of serum FGF21 and adropin with classical metabolic parameters and indexes of insulin sensitivity in human subjects. |
| Project Title: | 70th Scientific Sessions of American Diabetes Association Serum Levels of Fibroblast Growth Factor 21 are Elevated in both Rodents and Humans in Response to Acute Fasting |
| Investigator(s): | Xia F |
| Department: | Medical Faculty |
| Source(s) of Funding: | URC/CRCG - Conference Grants for Teaching Staff |
| Start Date: | 06/2010 |
| Completion Date: | 06/2010 |
| Abstract: |
| N/A |
| List of Research Outputs |
| Xia F., Lam K.S.L., Zhang J., Zhou P. and Xu A., Serum Levels Of Fibroblast Growth Factor 21 Are Elevated In Both Rodents And Humans In Response To Acute Fasting, Diabetes. 2010, 59 supplement: 1661-P. |
| Researcher : Yang LH |
| Project Title: | Anti-inflammatory mechanisms of Ligusticum Chuangxiong |
| Investigator(s): | Yang LH, Lau ASY, Cheung BKW |
| Department: | Medical Faculty |
| Source(s) of Funding: | Small Project Funding |
| Start Date: | 01/2009 |
| Abstract: |
| Introduction: Cerebral ischemia (stroke) is a leading cause of death and long-term disability worldwide. It occurs when there is interruption of blood supply to the brain or when there is bleeding in the brain. Within minutes of reduced cerebral blood flow, brain cells begin to die. Two groups of therapeutic agents are currently being developed for the treatment of stroke: one for antiplatelet aggregation and the other for anticoagulation. These drugs can effectively prevent stroke from further deterioration. However, there are associated adverse effects including gastrointestinal irritation and severe bleeding. Therefore, alternative therapies for the treatment of early and intermediate stages of stroke are desirable. Although different mechanisms are involved in the pathogenesis of stroke, there are increasing evidences demonstrating that inflammation partly accounts for its progression and complications (Barone and Feuerstein, 1999; Samson et al., 2005). Some studies have suggested that inflammation of the brain is due to reduction of cerebral blood flow leading to energy depletion as well as necrotic neuronal death. These events trigger immune responses which ultimately lead to activation of immune cells including macrophages. In turn, these activated macrophages secrete small intercellular signaling molecules known as proinflammatory cytokines including interferon-γ (IFN-γ), interleukin-1 (IL-1), IL-6, and tumor necrosis factor alpha (TNF-α). Among these cytokines, TNF-α is considered as the key mediator that is implicated in the pathogenesis of cerebral ischemia (Barone and Feuerstein, 1999; del Zoppo et al., 2000). Several studies have shown that there is a rapid upregulation of TNF-α mRNA and protein in activated microglia and macrophages after focal stroke (Buttini et al., 1996). Also, in an in vivo study, Siren (1992) showed that hypertensive rats with propensity for stroke have higher levels of TNF-α production in the brain than that of the normotensive rats. The involvement of mitogen-activated protein (MAP) kinase cascades and transcription factors NF-kB in TNF-α expression has been demonstrated (Trede et al., 1995). Therefore, these results implicated that development of therapies directed towards the inhibition of TNF-α production and/or deactivation of the MAP kinase signaling pathways may help to ameliorate the severity of cerebral ischemia. The use of medicinal plants or their crude extracts in the prevention and/or treatment of diseases has been traditionally practiced worldwide. Recently, the use of traditional Chinese medicines (TCM) is gaining popularity and it is important to investigate the scientific basis of their therapeutic actions. In our previous studies in collaboration with Prof. Robert Ko of HKUST, Prof. A. Lau’s group showed that extracts from a post-stroke rehabilitation (PSR) formula demonstrated anti-inflammatory effects. This PSR formula includes eight traditional Chinese herbs. Among them, the extracts of Ligusticum Chuangxiong (LCX) exhibited a very significant suppressive effect on TNF-α production. In light of these preliminary results, we hypothesize that specific chemical constituents of LCX modulate the inflammatory responses via regulation of specific signaling kinase activities and transcription factors, which lead to reduced cytokine expressions in immune cells. Objectives: First, we will find out the most suitable method for extracting and fractionating LCX extracts until a definable list of compounds with anti-inflammatory effect is obtained. Second, we will investigate the anti-inflammatory mechanisms of LCX in immune cells such as macrophages. Our Specific aims are: Aim 1. To determine the most suitable extraction method of LCX Aim 2. To fractionate and isolate anti-inflammatory compounds from LCX Aim 3. To investigate the mechanisms of anti-inflammatory effects of compounds isolated from LCX in primary human blood macrophages (PBM) References: 1. Barone FC, Feuerstein GZ. (1999). Inflammatory mediators and stroke: new opportunities for novel therapeutics. J Cereb Blood Flow Metab 19:819–834. 2. Buttini M, Appel K, Sauater A, Gebicke-Haerter P-J, Boddeke HWGM. (1996). Expression of tumour necrosis factor alpha after focal cerebral ischemia in the rat. Neuroscience 71:1−16. 3. del Zoppo G, Ginis I, Hallenbeck JM, Iadecola C, Wang X, Feuerstein GZ. (2000). Inflammation and stroke: putative role for cytokines, adhesion molecules and iNOS in brain response to ischemia. Brain Pathol 10:95–112. 4. Siren AL, Heldman E, Doron D, Lysko PG, Yue T-L, Liu T, Feuerstein GZ, Hallenbeck J. (1992). Release of proinflammatory and prothrombotic mediators in the brain and peripheral circulation in spontaneously hypertensive and normotensive Wistar-Kyoto rats. Stroke 23:1643−1651. 5. Samson Y, Lapergue B, Hosseini H. (2005). Inflammation and ischaemic stroke: current status and future perspectives. Rev Neurol 161:1177–1182. 6. Trede NS, Tsytsykova AV, Chatila T, Goldfeld AE, Geha RS. (1995). Transcriptional activation of the human TNF-alpha promoter by superantigen in human monocytic cells: Role of NF-kappaB. J Immunol 155:902–908. |
| Project Title: | The 8th Consortium for Globalization of Chinese Medicine Meeting Anti-inflammatory mechanisms of Black Cohosh on human primary blood macrophages via its downregulation of signal transduction and transcription factor activation |
| Investigator(s): | Yang LH |
| Department: | Medical Faculty |
| Source(s) of Funding: | URC/CRCG - Conference Grants for Teaching Staff |
| Start Date: | 08/2009 |
| Completion Date: | 08/2009 |
| Abstract: |
| N/A |
| List of Research Outputs |
| Lee D.C.W., Yang L.H., Chik S.C.C., Li C.B. and Lau A.S.Y., Bioactivity-guided identification and cell signaling analysis to investigate the immunomodulatory effects of ginseng on U937 cells., Tri-Society Annual Conference 2009 of the Society for Leukocyte Biology, International Cytokine Society & International Society for Interferon and Cytokine Research, (Tri-Society Conf of SLB, ICS & ISICR) Lisbon, Portugal 17-21 October 2009 [Cytokine 2009;46(1-2)PP2-046]. 2009. |
| Yang L.H., Wang L., Or C.T., Chik S.C.C., Li C.B. and Lau A.S.Y., Anti-inflammatory compounds from medicinal herbs capable of modulating cytokines expression in human primary blood macrophages, Tri-Society Annual Conference 2009 of the Society for Leukocyte Biology, International Cytokine Society & International Society for Interferon and Cytokine Research, (Tri-Society Conf of SLB, ICS & ISICR) Lisbon, Portugal 17-21 October 2009 [Cytokine 2009;46(1-2)PP1-088]. 2009. |
| Yang L.H., Chik S.C.C., Li C.B., Cheung B.K.W. and Lau A.S.Y., Anti-inflammatory mechanisms of black cohosh on human primary blood macrophages via its downregulation of signal transduction and transcription factor activation., 8th Meeting of Consortium for Globalization of Chinese Medicine (CGCM), Nottingham, UK, August 26-28, . 2009. |
| Researcher : Yau JMH |
| Project Title: | Angiopoietin-like proteins 3 and 4 as novel inhibitors of lipoprotein lipase: functional and structural studies |
| Investigator(s): | Yau JMH, Xu A, Lam KSL |
| Department: | Medical Faculty |
| Source(s) of Funding: | Small Project Funding |
| Start Date: | 11/2006 |
| Abstract: |
| Angiopoietin-like proteins (ANGPTLs) are a family of secreted proteins consisting of six members, denominated as ANGPTL1 to ANGPTL6. These factors are secreted mainly from the liver and act as endocrine signals in the peripheral tissues. Three members of this family, including ANGPTL3, 4 and 6, have recently been shown to play important roles in regulating insulin sensitivity and lipid metabolism [1-3]. These proteins represent a novel class of pharmacological targets for treating obesity and related metabolic disorders, including hyperlipidemia, type 2 diabetes mellitus (T2DM) and cardiovascular diseases. Many recent studies from others and our laboratory have demonstrated that ANGPTL3 and ANGPTL4 may contribute to obesity-related dyslipidemia in mice. ANGPTL3 expression is increased in obese or diabetic mice [4,5]. Transgenic overexpression of ANGPTL3 or direct intravenous injection of this protein increases plasma levels of triglycerides [6], and while ablation of this gene alleviates dyslipidemia associated with diabetic mice [6,7]. We have recently shown that adenovirus-mediated expression of ANGPTL4 could also induce a severe hyperlipidemia and fatty liver in mice, despite its beneficial effects on insulin sensitivity [8]. The hyperlipidemic effects of both ANGPTL3 and ANGPTL4 are mediated by their ability to inhibit lipoprotein lipase (LPL) [7,9,10], an apolipoprotein associated enzyme responsible for triglyceride clearance in blood. The molecular and structural basis whereby ANGPTL3 and ANGPTL4 inhibit plasma LPL activity and induce hyperlipidemia remains to be determined. All the six members of the ANGPTL proteins share a common modular design, with a secretory signal peptide followed by an NH2-terminal helical coiled-coil domain (CCD) and a COOH-terminal fibrinogen-like domain. However, only ANGPTL3 and ANGPTL4 can inhibit LPL activity. In both animal models and human subjects, ANGPTL3 and ANGPTL4 are cleaved into NH2-terminal CCD and COOH-terminal fibrinogen-like domain in the blood stream [11,12]. Recent studies have shown that the NH2-terminal CCD of ANGPTL3 is sufficient in inhibiting LPL activity and inducing hyperlipidemia in mice [13], while its COOH-terminal domain lacks such activities. Although the NH2-terminal CCD of human ANGPTL3 and ANGPTL4 share only around 30% amino acid sequence homology, we have identified a short sequence motif (Leu-Ala-X-Gly-Leu-Leu-Gln-Leu-Gly-X-Gly-Leu, where X represents those residues with positively charged or nucleophilic side chains; the sequence corresponding to amino acid resiudes 46-57 and 44-55 in mouse ANGPTL3 and ANGPTL4 respectively) that is highly conserved among all known ANGPTL3 and ANGPTL4 from different species (see Figure 1 in section 'Research plan and methodology). This motif is not conserved in the NH2-terminal CCD of ANGPTL6, which does not have any hyperlipidemic effect. Notably, both ANGPTL3 and ANGPTL4, but not ANGPTL6, have been found to be physically associated with very low density lipoproteins (VLDLs) [14]. Based on these evidence, we hypothesize that ANGPTL3 and ANGPTL4 might inhibit LPL activity in VLDL particles, which will prevent lipid clearance from the circulation and cause hyperlipidemia. The conserved sequence motif identified in ANGPTL3 and ANGPTL4 is responsible for mediating the inhibitory effects of these two proteins on LPL activity. The study seeks to address the molecular and structural basis that underlies the hyperlipidemic effects of ANGPTL3 and ANGPTL4. Our specific objectives are: 1.To investigate whether the NH2-terminal CCDs of ANGPTL3 and ANGPTL4 can inhibit LPL activity by direct interaction with this enzyme in an in vitro system. 2.To generate various forms of recombinant ANGPTL3 and ANGPTL4 with mutations at the conserved sequence motif, and to investigate whether this sequence motif alone is sufficient in inhibiting LPL activity in vitro. 3.To use adenovirus delivery system to evaluate the effects of wild-type ANGPTL3 and ANGPTL4, and their various mutants on lipid metabolism and insulin sensitivity in animal models. |
| Researcher : Yu W |
| List of Research Outputs |
| Liu H., Wang H., Yu W., Zhu W. and Chen Z., The route of inoculation determines the tissue tropism of modified vaccinia Tiantan expressing the spike glycoprotein of SARS-CoV in mice., J. Med. Virol.. 2010, 82(5): 727-734. |
| Yu W., Fang Q., Zhu W., Wang H., Tien P., Zhang L. and Chen Z., One time intranasal vaccination with a modified vaccinia Tiantan strain MVTT (ZCI) protects animals against pathogenic viral challenge., Vaccine. 2010, 28(9): 2088-96. |
| Researcher : Zhang H |
| Project Title: | Identification of anti-HIV receptor and co-receptor human neutralizing monoclonal antibodies |
| Investigator(s): | Zhang H, Zhang M |
| Department: | Medical Faculty |
| Source(s) of Funding: | Small Project Funding |
| Start Date: | 12/2009 |
| Abstract: |
| The objective of this project is to identify anti-HIV receptor and co-receptor human monoclonal antibodies with high specificity and affinity. The potential application of these antibodies, in combination with anti-HIV envelope human monoclonal antibodies, will be explored. The impact of combinational use of these antibodies for prevention and therapy will be tested in cell culture and animal models. This project is composed of 3 inter-related parts: 1. Based on the panel of anti-CD4 antibodies we selected, chain shuffling, random mutagenesis or targeted mutagenesis will be carried out to improve their affinity and specificity. The most specific and efficacious antibody will be identified. 2. Synthesize 2nd loop of CCR5 and pan antibody library, identify anti-CCR5 monoclonal antibody with highest efficacy, carry out chain shuffling, random mutagenesis or targeted mutagenesis if necessary. 3. Test the impact of combination of these antibodies, plus the anti-HIV envelope antibodies, and explore their potential use in prevention and therapy. |
| List of Research Outputs |
| Zhang H., Wang Y., Wu H., Jin D., Wen Y. and Zheng B., The Y271 And I274 Amino Acids In Reverse Transcriptase Of Human Immunodeficiency Virus-1 Are Critical To Protein Stability, In: Olivier Schwartz, Plos One. 2009, 4. |
| Researcher : Zhang M |
| Project Title: | 20th Annual Antibody Engineering Conference Construction and Characterization of a Chimeric Monoclonal Antibody against the Insulin-like Growth Factor-I Receptor |
| Investigator(s): | Zhang M |
| Department: | Medical Faculty |
| Source(s) of Funding: | URC/CRCG - Conference Grants for Teaching Staff |
| Start Date: | 12/2009 |
| Completion Date: | 12/2009 |
| Abstract: |
| N/A |
| Project Title: | Identification of HIV-1 vaccine immunogens by antibody in vitro maturation |
| Investigator(s): | Zhang M |
| Department: | Medical Faculty |
| Source(s) of Funding: | Seed Funding Programme for Basic Research |
| Start Date: | 12/2009 |
| Abstract: |
| Over two decades after the discovery of Human Immunodeficiency Virus type I (HIV-1) in 1981, the development of vaccine immunogens that can elicit high-titer, potent, and broadly cross-reactive HIV-1-neutralizing antibodies (bcnAbs) remains a major challenge. Such antibodies are rare in HIV-infected individuals, and usually emerge after years of chronic infection. The lag of antibody maturation behind viral mutation often leads to viral escape and eventual disease progression. There are a small percentage of HIV-1 infected individuals whose sera exhibit high titers of bcnAbs, which contribute to their long-term no disease progression. Several monoclonal bcnAbs have been isolated from such long-term nonprogressors (LTNPs), but the immunogens designed to include their conserved epitopes did not generate the same or similar bcnAbs. Further analyses of known HIV-1 bcnAbs revealed their distinguish characteristics when compared with potent nAbs against SARS and Niphendra viruses, including high sequence diversification from the corresponding germlines, autoantibody properties, suggesting that elicitation of HIV-specific bcnAbs may require a prolonged period of time or it may never occur in most individuals. Sequence analysis of antibody libraries constructed using the mRNA isolated from the bone marrow and peripheral blood mononuclear cells (PBMCs) of subtype B LTNPs whose sera exhibited high titers of bcnAbs further revealed that the antibody gene repertoires in those subtype B LTNPs are biased to certain VH families and the third heavy chain complementary determination region (HCDR3) is on average significantly longer than the average length of HCDR3 in healthy human subjects. To explore the mechanism for elicitation of HIV-1 envelope glycoprotein (Env)-specific bcnAbs in vivo, we recently synthesized the germline antibodies of three known bcnAbs b12, 2G12 and 2F5. We found that the germline antibodies of b12, 2G12 and 2F5 did not bind HIV-1 Env, suggesting that immunization with immunogens containing b12, 2G12 and 2F5 epitopes may not trigger the naive B cells bearing the corresponding germline genes for antibody maturation and B cell proliferation. Based on these observations, we hypothesize that those LTNPs may have antibody intermediates of bcnAbs due to pre-exposure to certain immunogen(s) prior to HIV-1 infection and this “pre-existing immunity” allows the immune system to rapidly and efficiently respond to HIV-1 infection and contain the virus. The purpose of this proposed study is to identify such “pre-existing immunity” and the possible immunogens that can serve as primary immunogens leading to generation of such “pre-existing immunity”. HIV-1 Envs can serve as second immunogens leading to elicitation of potent HIV-1-specific bnAbs. To prove the concept, we will use b12 and 2F5 as model antibodies for antibody in vitro maturation study which mimics antibody maturation in vivo. B12 recognizes gp120 subunit of HIV-1 Env and its epitope overlaps the CD4 binding site (CD4bs). 2F5 recognizes the membrane proximal external region (MPER) of gp41 subunit of HIV-1 Env. The rational of this study is shown in the scheme below. Although HIV-1 isolates vary in groups, subtypes, the newly transmitted HIV-1 viruses were found to be restricted to R5-tropic virus and relatively easy to be neutralized by antibodies. We suppose that the intermediate Abs of b12 and 2F5 can bind to transmitted viruses and neutralize them. We have obtained a panel of newly transmitted HIV-1 virus isolates from NIH AIDS repository and used them in pseudovirus assay to test the isolated intermediate antibodies. Therefore, this study has two specific objectives. Objective 1: identify intermediate antibodies of b12 and 2F5 that can bind HIV-1 Env and neutralize newly transmitted HIV-1 virus. Objective 2: identify the primary immunogens that can bind b12 and 2F5 germline antibodies and elicit the coresponding intermediate antibodies. Through this study, we intend to address the question why elicitation of HIV-1-specific bcnAbs does not occur in most natural infections. We also intend to seek a solution to induction of HIV-1 specific bcnAbs by two step immunization using primary immunogens and HIV-1 Env trimers as shown in the above scheme, a novel approach for development of effective HIV-1 vaccine. |
| Project Title: | Development of “Two-in-One (TiO)” dual specific antibodies targeting both IGF-IR and Her 2 |
| Investigator(s): | Zhang M |
| Department: | Medical Faculty |
| Source(s) of Funding: | Seed Funding Programme for Applied Research |
| Start Date: | 06/2010 |
| Abstract: |
| Cancer and infectious diseases are the two leading global causes of human mortality. Statistics from 1975 to 2004 by National Cancer Institute, NIH indicates that lifetime risk of being diagnosed with cancer is 1 out of 2 in man and 1 out of 3 in women. Over 30% of cancer patients have died from cancer. Monoclonal antibody (mAb) and antibody-based therapy targeting abnormal pathways have been proven to be effective in cancer diagnosis and treatment. Activation of tyrosine kinase receptors from the human epidermal growth factor receptor family (EGFR, Her2, Her3, Her4) and the insulin-like growth factor receptor type I (IGF-IR) plays a key role in the initiation and progression of breast cancer. Her2 overexpression is a validated therapeutic target, as shown by the clinical efficacy of anti-Her2 mAb trastuzumab. However, only 25–30% of patients with Her2-overexpressing tumors respond to single-agent trastuzumab, and resistance develops even in responding patients. Accumulating evidence showed that cross-talk between Her2 and IGF-IR, including receptor heterodimerization and transactivation, and elevated IGF-IR signaling have been associated with trastuzumab resistance. Therefore, co-targeting IGF-IR and Her 2 could be of clinical benefit to improve anti-Her2 therapeutic efficacy. The purpose of the proposed project is to develop dual specific antibodies, in which two antigen-binding sites are integrated into one IgG molecule, in order to co-targeting IGF-IR and Her2. Such “Two-in-One” (TiO) dual specific antibodies are expected to be more effective than monotherapy targeting Her2 alone in treatment of Her2-overexpressing breast cancer patients and in prevention of generation of resistance to anti-Her2 therapy. Furthermore, “TiO” antibodies have advantages over the conventional bi-specific antibodies in antibody production and clinical application. The conventional bi-specific antibodies, e.g. knob-hole Ig, BiTE, dAB, DVD and scFv-IgG, are in non-natural antibody format and their production is usually problematic. “TiO” Abs preserve natural IgG structure with the known pharmacokinetic behavior and in vivo effector functions. We have previously reported a human/mouse chimeric antibody, m590 that specifically bound with high affinity to cell-associated IGF-IR, blocked the binding of IGF-I and IGF-II to IGF-IR and inhibited both IGF-I and IGF-II induced phosphorylation of IGF-IR in MCF-7 breast cancer cells, suggesting its great potential for diagnosis and treatment of breast cancer. To explore the potential of m590 for clinical use, we are humanizing m590 by grafting m590 CDRs to a human antibody framework. We found that an intermediate Fab construct, in which only m590 HCDR1-3 grafted human antibody, designated Fab H10, bound to MCF-7 cells as efficiently as the parent m590, suggesting that only the heavy chain of m590 contributed to the binding to IGF-IR. This hybrid antibody can serve as a template for constructing “TiO” dual specific antibodies by grafting Her2-binding determinants (CDRs) into the light chain. To develop novel anti-Her2 mAbs, we have immunized rabbits with membrane protein extracts from human epithelial ovarian cancer cell line, SKOV-3, that over expresses Her2 and IGF-IR. The immune rabbit sera bound to SKOV-3 and MCF-7 cells in FACS analysis and inhibited the growth of both cell lines, suggesting successful immunization. We are constructing an immune rabbit Fab and VH domain antibody (dAb) libraries using PBMC and bone marrow obtained from the immunized rabbits and will select Her2-specific rabbit Abs from the library by using phage display technology. Selected anti-Her2 Fab or dAb will be used to construct TiO antibodies. Therefore, the proposed project has two specific objectives: 1. Identification of anti-Her2 neutralizing antibodies from the immune rabbit Fab and VH dAb libraries. 2. Engineering humanized anti-IGF-IR Fab H10 by grafting Her2-specific antibody CDRs to the light chain framework and optimizing the framework of the dual specific antibodies for improved biological properties to target both IGF-IR and Her2. |
| List of Research Outputs |
| Borges A.R., Ptak R.G., Wang Y., Dimitrov A.S., Alam S.M., Wieczorek L., Bouma P., Fouts T., Jiang S. and Zhang M., Potent And Broad Neutralizing Activity Of A Single Chain Antibody Fragment Against Cell-free And Cell-associated Hiv-1, In: Janice M. Reichert, Ph.D., MAbs. • 1002 West Ave., Austin, TX 78701, Landes Bioscience, 2010, 2. |
| Zhang M., Characterization of a Chimeric Monoclonal Antibody against the Insulin-like Growth Factor-I Receptor, 16th Hong Kong International Cancer Congress, Hong Kong, China. Hong Kong, 2009. |
| Zhang M., Characterization of a Chimeric Monoclonal Antibody against the Insulin-like Growth Factor-I Receptor, 7th Annual Congress of International Drug Discovery Science and Technology, 2009, Beijing, China. Beijing, China, 2009. |
| Zhang M., Collaboration Agreement between NCI and HKU, NCI MTA#27832-09. 2009. |
| Zhang M., Construction and Characterization of a Chimeric Monoclonal Antibody against the Insulin-like Growth Factor-I Receptor, 20th Annual International Conference On Antibody Engineering, 2009, San Diego, US. San Diego, 2009. |
| Zhang M., Materials Transfer Agreement Between HKU And Huazhong Agricultural University, 2009. |
| Zhang M. and Dimitrov D.S., Sequential Antigen Panning for Selection of Broadly Cross-Reactive HIV-1-Neutralizing Human Monoclonal Antibodies, In: Robert Aitken, Methods in Molecular Biology Methods and Protocols . Humana Press, 2009, 562: 143-154. |
| Researcher : Zhang X |
| List of Research Outputs |
| Lam K.S.L., Zhang X. and Xu A., Selective Inactivation Of C-jun Nh2 Terminal Kinase (jnk) In Adipose Tissue Is Sufficient To Alleviate Metabolic Disorders Associated With Dietary Obesity In Mice , The 5th Scientific Meeting of the Asia-Pacific Diabetes and Obesity Study Group, Japan. 2009. |
| Lam K.S.L., Zhang X., Wong L.C. and Xu A., Selective Inactivation of c-Jun NH2 Terminal Kinase (JNK) in the Adipose Tissue Is Sufficient To Protect Against Diet-Induced-Obesity and Its Associated Metabolic Disorders in Mice, Endocrine Society Annual Meeting, 19-22 June, San Diego, USA. 2010. |
| Zhang X., Lam K.S.L., Chung S.K. and Xu A., Hypoxia Inducible Factor 1α Plays An Indispensible Role In Maintaining The Thermogenic Functions Of Brown Adipose Tissue In Mice, Endocrine Society Annual Meeting, 19-22 June, San Diego, USA. 2010. |
| Zhang X., Lam K.S.L., Chung S.K. and Xu A., Hypoxia Inducible Factor 1 Plays an Indispensible Role in the Thermogenic Functions of Brown Adipose Tissue in Mice, Diabetes. 2010, 59 supplement 1: A47. |