HCV CORE PROTEIN AND HEPATOCYTE GROWTH REGULATION

丙型肝炎病毒（HCV）经常引起长期和持续性感染，肝细胞癌（HCC）和HCV感染之间的关联已被注意到。了解病毒发病机制的分子基础是了解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核心蛋白表现出多种物理化学和生物活性。核心蛋白在体外表现出RNA和核糖体结合活性，核胞质定位，对细胞和不相关的病毒启动子起调节作用，并与异质核核糖核蛋白K和淋巴毒素β受体的细胞质尾部相互作用。此外，该核心蛋白在一定条件下抑制细胞程序性死亡（凋亡），对啮齿动物原代细胞具有转化潜能，并在转基因小鼠中诱导肝细胞癌。这些有趣的特性提出了一种假设，即核心蛋白可能在细胞生长失调中发挥关键作用，从而在持续感染期间促进病毒介导的发病机制。该试点研究计划旨在：(1)确定HCV核心基因表达在正常人类肝细胞生长中的作用；(2)绘制负责人类肝细胞生长调控的核心蛋白结构域。这项初步研究的结果将为HCV核心蛋白在其天然宿主中的功能作用的表征提供极其丰富的信息。转化原代人肝细胞的能力将为详细检查核心基因和相关辅助因子提供一个模型，因为它们与体外多阶段肝癌事件有关。本研究的长期目标是了解HCV核心蛋白介导的发病机制，设计有效的HCV相关疾病的干预策略。

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.