特聘研究員 / 本院分生所

EDUCATION AND POSITIONS HELD:

• B.M., Medicine, National Taiwan University (1968)
• Ph.D., Molecular Biology, University of California, Berkeley (1973)
• Assistant Professor through Distinguished Professor, Dept of Microbiology and Dept. of Neurology, University of Southern California School of Medicine, Los Angeles, California (1973-present)
• Investigator, Howard Hughes Medical Institute (1990-2003)
• Distinguished Research Fellow, Institute of Molecular Biology, Academia Sinica (2003-present)

HONORS:

• Society of Chinese Bioscientists in America-Cathay Hospital Award on Hepatitis Research (1990)
• Academician, Academia Sinica, R.O.C. (1992)
• USC Associates Award for Creativity in Research and Scholarship (1998)
• Fellow, American Academy of Microbiology (2002)
• Taiwanese-American Foundation Science-Technology Achievement Award (2003)
• Honorary Degree in Science, The Central University, Taiwan (2004)

RESEARCH INTERESTS:

Molecular biology and pathogenesis of RNA viruses

The primary research interests of our laboratory are the studies of the mechanisms of replication and pathogenesis of several medically important RNA viruses. Our current interest is on three different viruses:

1. Coronavirus: This virus family includes the SARS coronavirus, which causes severe acute respiratory syndrome. This virus contains the largest genome among RNA viruses. Our laboratory has previously performed many pioneering studies on the structure and replication of this virus, particularly viral RNA synthesis. We discovered the phenomenon of high-frequency RNA recombination in this virus. We are focusing on understanding the viral and cellular factors involved in the viral RNA replication. In the immediate future, we will focus on studying the properties of gene products and mechanism of pathogenesis of the SARS coronavirus.

2. Hepatitis C virus (HCV): This virus is one of the most common causes of chronic hepatitis, liver cirrhosis and hepatocellular carcinoma. Our laboratory is interested in understanding the mechanism of viral RNA replication. Currently we are focusing on studying the structure and mechanism of formation of the viral RNA replication complex. We are also investigating the properties of the various viral gene products in order to identify the potential targets for developing antiviral agents. Finally, my laboratory has developed an in vitro cell culture system for this virus based on the in vivo association of HCV with B-cell lymphoma. This culture system allows for the first time the study of the biology of HCV infection. We have found that HCV infection induces DNA breaks and enhances DNA mutation frequencies, thus explaining the mechanism of oncogenesis of this RNA virus. We are further exploring the detailed mechanisms of these virus-induced effects.

3. Hepatitis delta virus (HDV): This virus contains a small (1.7 kb) circular RNA genome, which is unique among animal viruses. It replicates by an RNA-dependent RNA replication mechanism, which is carried out by a cellular enzyme. The dilemma is that the mammalian cells do not have RNA-dependent RNA polymerases. It appears that the cellular DNA-dependent polymerase II and possibly other polymerases, together with a unique viral protein hepatitis delta antigen, are involved in this process. This is a novel aspect of cellular machinery. We are further investigating the precise mechanisms of such a process.

我們的研究重點是各種RNA病毒的分子生物學及致病機制。

本實驗室現在所研究的病毒包括三種病毒：第一種是冠狀病毒。此病毒包括引起嚴重急性呼吸道症候群（severe acute respiratory syndrome, SARS）的病毒。我們過去發現許多這類病毒的基因構造及繁殖的方法。近年來特別專注於研究這些病毒RNA複製過程中所需要的細胞因素。未來的研究將注重 於SARS病毒的基因與蛋白質的性質，以及它引起嚴重症狀的原因。

第二種病毒是C型肝炎病毒。此病毒引起慢性肝炎而會引發肝硬化及肝癌，為近年所發現最嚴重及最常見的肝炎病毒之一。本實驗室要了解這個病毒如何複製 RNA，我們將從分析RNA複製所需的蛋白質（包括病毒蛋白及細胞因素）著手，進而瞭解哪些步驟可以用以發展抗病毒的藥品。我們已經發展出一種培養C型肝 炎病毒的細胞，能用以研究這個病毒在感染細胞後所引起的變化。目前已發現這個病毒會改變細胞基因修補的功能，因而引起染色體的斷裂及細胞基因的變化。這些 變化可以用來解釋病毒致癌的機制。

第三種病毒是D型肝炎病毒。這個病毒帶有圓形的RNA，是在自然界很奇特的RNA，特別是它的複製需要用細胞的RNA聚合酶。而這個酶必須和病毒的蛋白 （D型抗原）合作才能用來複製 RNA。這是在自然界嶄新的基因複製機制（即由細胞酶素來複製RNA），我們正在進行用分子生物學及細胞學的方法來瞭解這個機制。