Chang, Ming-fu

Biography

1976,B.Sc. Kaohsiung Medical College, ROC. (Pharmacy) 1981,M.Sc. National Taiwan University, ROC. (Biochemistry) 1986,M.A. University of California at Los Angeles, CA, USA. (Biology) 1989,Ph.D. University of Southern California, CA, USA.(Microbiology)

Research Interest

We are interested in understanding the molecular mechanisms by which cellular factors and viral proteins are involved in the multiplication and pathogenesis of human hepatitis viruses and SARS coronavirus. The results provide new molecular targets for virus therapy. In collaboration with Dr. PH Lee at the Department of Surgery, we recently identified a novel genetic association of MMP-7(Asp-137) variant with risk of liver cirrhosis in HCC patients. This additional marker is in a category different from previous findings that have focused on liver-cirrhosis-associated genetic factors in inflammatory and immunoregulatory pathways. The study is interesting and has explored a mechanism-based approach of the single nucleotide polymorphism found in human subjects. The MMP-7(Asp-137) variant increased association with CD151 on cell surface when expressed in stellate cells and has increased its enzymatic activity. We also found that MMP-7(Asp-137) confers a gain-of-function phenotype in cell migration critical for the progression of cirrhosis. The MMP-7 variant may be used as a new marker for liver cirrhosis. A. Molecular virology and pathogenesis of human hepatitis delta virus (HDV). Hepatitis delta virus (HDV) may cause severe chronic hepatitis and fulminant hepatitis. Our previous studies have addressed several interesting questions regarding the viral multiplication. We demonstrated that delta antigens (HDAgs) interact with nucleolin, which is important for the replication of HDV. In addition, large HDAg interacts with clathrin heavy chain at trans-Golgi network where the assembly of HDV takes place. In addition, cytoplasm-localized HDAg-L inhibited the clathrin- mediated endocytosis, endosome trafficking, and exocytosis. Furthermore, we identified a novel CRM1-independent nuclear export signal of the large HDAg. By performing yeast-two hybrid analysis, we recently identified a novel nuclear export signal-interacting protein (NESI) critical for HDV assembly. Recent studies showed that the behavior was abnormal in heterologous knockout mice. The molecular mechanisms of NESI protein involved in the nuclear export of host proteins and associated with diseases are being examined. B. Molecular virology and pathogenesis of human hepatitis C virus (HCV). Hepatitis C virus (HCV) infection often develops chronic hepatitis, cirrhosis, and is strongly associated with hepatocellular carcinoma. Towards understanding the viral proteins and cellular factors involved in the oncogenesis of HCV, we have established HCV mouse models by using hydrodynamics-based transfection. By performing microarray analysis of LCM- (Laser Capture Microdissection) mouse hepatocytes, we identified a spindle gene aspm that are regulated by NS5A via PKR-p38 pathway, and resulted in G2/M exit delay, suggesting a role of HCV NS5A in hepatocellular carcinoma (HCC) through inhibition of PKR-dependent pathway. Biological significances of other cellular factors involved in the cell growth, differentiation, apoptosis, steatosis, and hepatocellular carcinoma (HCC) are currently under investigated. C. Molecular virology and pathogenesis of SARS coronavirus. During the outbreak of SARS in 2003, we also joined the studies on SARS coronavirus. In collaboration with CL Kao at the Department of Clinical Laboratory Science and Medical Biotechnology, we have completed the sequences of the whole genome of SARS-CoV (TW1 strain) and successfully expressed the viral structural proteins in both mammalian and insect cells. The virus-like-particle (VLP) systems in both mammalian and insect cells were established. Results demonstrated that an RNA packaging signal of SARS-CoV was identified and the virus assembly is nucleocapsid-dependent. In addition, we demonstrated that the SARS-CoV VLPs can induce neutralization and protection activity in mouse system. To examine whether the SARS-CoV VLPs can be used as a vaccine for clinical use, monkey model for testing the neutralization of SARS-CoV VLPs is also in progress. Furthermore, we are currently working on understanding the molecular mechanisms involved in the virus infection and pathogenesis of SARS-CoV