HEPATITIS C VIRUS CORE PROTEIN AND HOST DEFENSE

丙型肝炎病毒(丙型肝炎病毒)导致非常高的频率的持续性 感染，导致慢性肝炎、肝硬变和 肝细胞癌。病毒的致病机制和作用机制 持久力尚不清楚。我们实验室已经初步获得了 研究发现，丙型肝炎病毒核心蛋白可以与几个成员相互作用 肿瘤坏死因子受体(TNFR)家族，包括TNFR I、TNFR II、 淋巴毒素-β受体(LTbetaR)和Fas。这些受体是 细胞免疫防御机制的重要组成部分 参与了细胞的凋亡。因此，丙型肝炎病毒之间的相互作用 核心蛋白和这些受体可能会破坏细胞 防御，占病毒持续感染的比例。或者， 这些相互作用可以使肝细胞对肿瘤坏死因子敏感，导致 肝炎。这些发现为研究丙型肝炎病毒提供了新的途径。 持久力和致病力。 在这个项目中，计划了四个具体目标： 1.表征这些相互作用的生化性质。 2.研究这些相互作用的生物效应，包括 丙型肝炎病毒核心蛋白对肿瘤坏死因子及其信号转导的影响 这些受体的转导。 3.用丙型肝炎病毒(+)肝来源的原代肝细胞检测 细胞因子或激素对丙型肝炎病毒复制的可能影响。 4.鉴定在酵母中检测到的TNFR以外的其他分子 双杂交系统，可能与丙型肝炎病毒核心蛋白相互作用。 这些项目预计将揭示核心的潜在作用 蛋白在丙型肝炎病毒中的持久性和致病机制，并可能有助于 丙型肝炎病毒体外培养体系的建立这两个目标 都是这个丙型肝炎合作研究中心的主要主题。 我们提出的项目代表了这方面研究的新方向。 区域。它们也构成了项目II的基础(丙型肝炎病毒核心转基因 小鼠)和项目IV(肿瘤坏死因子受体、淋巴细胞和 丙型肝炎病毒治疗。)

Hepatitis C virus (HCV) causes a very high frequency of persistent infection, which leads to chronic hepatitis, cirrhosis and hepatocellular carcinoma. The mechanisms of viral pathogenesis and persistency are not clear. Our laboratory has obtained preliminary findings that the HCV core protein can interact with several members of tumor necrosis factor receptor (TNFR) family, including TNFR I, TNFR II, lymphotoxin-beta receptor (LTbetaR) and Fas. These receptors are important components of the cellular immune defense mechanism and are involved in cellular apoptosis. Thus, the interaction between the HCV core protein and these receptors can potentially disrupt cellular defense, accounting for viral persistent infection. Alternatively, these interactions could sensitize hepatocytes to TNFs, leading to hepatitis. These findings thus provide new avenues for studying HCV persistency and pathogenesis. In this project, four specific aims are planned: 1. To characterize the biochemical properties of these interactions. 2. To study the biological effects of these interactions, including the effects of HCV core on the cellular responses to TNFs and the signal transduction of these receptors. 3. To use primary hepatocytes derived from HCV(+) livers to examine the possible effects of cytokines or hormones on HCV replication. 4. To characterize the molecules other than TNFRs detected in the yeast two-hybrid system, which may interact with the HCV core protein. These projects are expected to reveal the potential role of the core protein in HCV persistency and pathogenesis, and may contribute to the establishment of an in vitro culture system for HCV. These two goals are the major theme of this Hepatitis C Cooperative Research Center. Our proposed projects represent new directions for the research in these areas. They also form the basis for Project II (HCV core transgenic mice) and Project IV (tumor necrosis factors receptors, lymphocyte and HCV therapy.)