Mechanisms of cellular injury and transformation

肝脏研究中心的研究人员参与了肝脏和神经系统疾病中细胞损伤和转化的分子机制的研究。有五个由初级教员进行的“微型项目”，每个具体目标都定义了一个由独立调查员进行的研究项目。具体目标1涉及利用转基因小鼠产生/鉴定禽流感病毒受体。她最近确定P170是一种主要的肝细胞受体，并计划建立一个小动物模型来研究病毒复制。这一转基因小鼠模型将用于了解宿主对肝炎病毒感染的免疫反应，并有助于抗病毒治疗的发展。具体目标#2，由童树平，医学博士，博士提交，将精确定义P170上介导病毒结合和细胞进入的氨基酸序列(S)。他计划通过盒式磁带交换、缺失分析和定点突变来绘制病毒结合位点的图谱。这项研究将允许寻找阻止病毒进入细胞的抗病毒药物，并有助于定义基本上未知的肝炎病毒生命周期的早期事件。具体目标#3将在一个独特的转基因小鼠模型中，研究次级细胞事件，如遗传突变(S)在肝细胞癌发展中的作用。在一个不转化的，但持续的，由人胰岛素受体底物-1基因(IRS-1)过表达产生的肝脏增殖刺激的背景下。这些研究将为体内肝癌发生的多步骤过程提供新的信息，以及评估生长因子信号转导通路和肿瘤抑制基因功能的相互作用。具体目的#4将分析转录因子肌细胞增强因子2(MEF2)在肝星状细胞激活中的作用，以及它在紫绪茂，M.D.，M.P.h调控纤维化形成中的潜在作用。这项拟议的研究将解决以下问题：1)MEF2蛋白或活性在星状细胞激活过程中是否受到调节？2)MEF2功能是星状细胞激活所必需的吗？3)在星状细胞激活过程中，哪些信号转导通路在调节MEF2活性方面起重要作用？特定目的#5将建立AD7C-NTP过表达的转基因小鼠模型，以研究Suzanne de la Monte，M.D.，M.P.H.在体内AD神经变性的机制。在体外，AD7C-NTP过表达在神经细胞中产生更多的凋亡和神经突起的生长(异常神经炎发芽)。本项目将试图建立一种转基因小鼠的神经退行性变模型，以确定AD7C-NTP在转基因小鼠脑中的神经元特异性表达所诱导的表型。

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.