HCV CORE PROTEIN AND HEPATOCYTE GROWTH REGULATION

丙型肝炎病毒(丙型肝炎病毒)通常导致长期和持续的感染，肝细胞癌(肝细胞癌)和丙型肝炎病毒感染之间的关系已经被注意到。了解病毒发病的分子基础是深入了解丙型肝炎病毒相关疾病进展的主要挑战。肝损伤的发病机制可能既与病毒因素有关，也与免疫因素有关。丙型肝炎病毒核心蛋白具有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和淋巴毒素-β受体的细胞质尾巴相互作用。此外，该核心蛋白在一定条件下可抑制细胞程序性死亡，对原代啮齿动物细胞具有转化潜能，并可诱导转基因小鼠发生肝细胞癌。这些有趣的特性表明，核心蛋白可能在细胞生长放松调控中发挥关键作用，从而在持续感染过程中参与病毒介导的致病机制。这项先导性研究的目的是(1)确定丙型肝炎病毒核心基因表达在人正常肝细胞生长中的作用；(2)定位负责调节人肝细胞生长的核心蛋白结构域。这项初步研究的结果将为描述丙型肝炎病毒核心蛋白在其自然宿主中的功能作用提供极大的信息。转化原代人肝细胞的能力将提供一个详细研究核心基因和相关辅助因子的模型，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丙型肝炎病毒核心蛋白介导的致病机制，为人类丙型肝炎病毒相关疾病的干预设计有效的策略。

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.