HCV CORE PROTEIN AND HEPATOCYTE GROWTH REGULATION

丙型肝炎病毒（HCV）经常引起长期和持续的感染，肝细胞癌（HCC）和HCV感染之间的关联已被注意到。 理解病毒发病机制的分子基础是深入了解HCV相关疾病进展的主要挑战。肝损伤的发病机制可能与病毒和免疫介导的因素有关。 HCV核心蛋白具有多种理化和生物学活性。 核心蛋白表现出体外RNA和核糖体结合活性，核质定位，对细胞和无关病毒启动子的调节作用，并与异质核核糖核蛋白K和胞质尾的α-光敏素-β受体相互作用。 此外，核心蛋白在某些条件下抑制程序性细胞死亡（凋亡），对原代啮齿动物细胞具有转化潜力，并在转基因小鼠中诱导肝细胞癌。 这些有趣的特性表明，核心蛋白可能在细胞生长失调中发挥关键作用，从而有助于持续感染期间病毒介导的发病机制。 该初步研究计划旨在（1）确定HCV核心基因表达在正常人肝细胞生长中的作用，（2）绘制负责人肝细胞生长调节的核心蛋白结构域。 这项初步研究的结果将是非常翔实的丙型肝炎病毒核心蛋白在其自然宿主的功能作用的表征。转化原代人肝细胞的能力将提供一个模型来详细研究核心基因和相关辅因子，因为它们与体外多阶段肝癌发生事件有关。 本研究的长期目标是了解HCV核心蛋白介导的发病机制，并设计有效的干预策略，在人类HCV相关疾病。

Hepatitis C virus (HCV) often causes a prolonged and persistent infection, and an association between hepatocellular carcinoma (HCC) and HCV infection has been noted. Understanding the molecular basis of viral pathogenesis is a major challenge in the effort to gain insight into HCV associated disease progression. The pathogenesis of liver damage is likely to be related to both viral and immune mediated factors. HCV core protein displays numerous physicochemical and biological activities. The core protein exhibits in vitro RNA and ribosome binding activities, nucleocytoplasmic localization, a regulatory role on cellular and unrelated viral promoters, and interacts with heterogeneous nuclear ribonucleoprotein K and the cytoplasmic tail of the lymphotoxin-beta receptor. Furthermore, the core protein inhibits programmed cell death (apoptosis) under certain conditions, has a transforming potential on primary rodent cells, and induces hepatocellular carcinoma in transgenic mice. These interesting properties suggest the hypothesis that the core protein may play a critical role in cell growth deregulation, and thus contribute to virus mediated pathogenesis during persistent infection. This pilot research proposal is designed to (1) determine the role of HCV core gene expression in normal human hepatocyte growth and (2) map the core protein domain responsible for human hepatocyte growth regulation. The results from this pilot study will be extremely informative in the characterization of the functional role of HCV core protein in its natural host. The capacity to transform primary human hepatocytes will provide a model to examine in detail the core gene and associated cofactors as they relate to multistage hepatocarcinogenicevents in vitro. The long term goal of this study is to understand the molecular mechanism of HCV core protein mediated pathogenesis and to design effective strategies for intervention of HCV related disease in humans.