Mechanisms of cellular injury and transformation

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Investigators at the Liver Research Center are involved in studies on the molecular mechanisms of cellular injury and transformation in liver and neurologic disease. There are five "mini-projects" conducted by junior faculty, and each Specific Aim defines a research project conducted by an independent investigator. Specific Aim #1 involves the generation/characterization of the avian hepatitis B viral receptor in transgenic mice by Ji Su Li, M.D., Ph.D. She recently identified p170 as a major hepatocyte receptor, and plans to create a small animal model to study viral replication. This transgenic mouse model will be used to understand the host immune response to hepadnaviral infection, and aid in the development of antiviral therapy. Specific Aim #2, submitted by Shuping Tong, M.D., Ph.D. will precisely define the amino acid sequence(s) on p170 that mediate viral binding and cellular entry. He plans to map the viral binding site by cassette exchange, deletion analysis, and site-directed mutagenesis. This study will permit a search for antiviral agents that block viral entry into the cell, and aid in the definition of the largely unknown early events of the hepadnaviral life cycle. Specific Aim #3 will study the role of secondary cellular events such as genetic mutation(s) in the development of hepatocellular carcinoma (HCC) in the setting of a non-transforming, but continuous, hepatic proliferative stimulus generated by over-expression of the human insulin receptor substrate-1 gene (IRS-1) in a unique transgenic mouse model. These studies should provide new information on the multi-step process of hepatocarcinogenesis in vivo, as well as to assess the interactions of a growth factor signal transduction pathway, and tumor suppressor gene function. Specific Aim #4 will analyze the role of transcription factor myocyte enhance factor 2 (MEF2) in hepatic stellate cell activation, and its potential role in regulating fibrogenesis by Zixu Mao, M.D., m.p.h. This proposed research will address the following issues: 1) are MEF2 proteins or activity regulated during stellate cell activation? 2) is MEF2 function required for stellate cell activation? And 3) which signal transduction pathways are important for mediating MEF2 activity during stellate activation? Specific Aim #5 will generate a transgenic mouse model of AD7C-NTP over-expression to study the mechanisms of AD neurodegeneration in vivo by Suzanne de la Monte, M.D., M.P.H. Over- expression of AD7C-NTP in neuronal cells in vitro produces increased apoptosis and growth of neuritic process' (aberrant neuritic sprouting). This project will attempt to establish a transgenic mouse model of neural degeneration defining the phenotype induced by neuronal specific expression of AD7C-NTP in the transgenic mouse brain.