Mechanisms of Liver Disease Progression by Hepatitis C Virus

描述（由申请人提供）：丙型肝炎病毒（HCV）经常引起人类持续感染，可能导致进行性肝病。我们假设慢性HCV感染的疾病进展至少部分归因于HCV核心蛋白对宿主细胞基因表达的影响。我们的长期目标是了解HCV介导的肝病进展背后的潜在机制。我们是第一批鉴定出许多与HCV核心蛋白相关的有趣功能的人之一，这些功能可能显著促进疾病进展。然而，我们对核心蛋白单独或与其他HCV蛋白结合发挥这些功能的关键细胞靶点和分子机制的理解存在重大差距。HCV诱导肝细胞胰岛素抵抗和肝纤维化。我们在这项资助申请中的重点是研究HCV诱导的胰岛素抵抗和纤维化的潜在机制，作为我们提供的初步数据的后续行动。目前的研究计划包括补充但独立的目标，以解决我们的假设。目的1探讨HCV核心蛋白磷酸化IRS的机制，目的2探讨HCV核心蛋白诱导代谢调节因子的功能相关性，目的3探讨HCV核心蛋白在肝纤维化中的作用。还将使用全长cDNA、复制子或细胞培养生长的HCV进行研究，以提供HCV核心蛋白功能与其他HCV蛋白相关的分子基础。对HCV介导的疾病进展的分子决定因素的了解将为新的治疗方法开辟道路。公共卫生相关性：丙型肝炎病毒（HCV）经常导致持续感染和进行性肝病。我们计划了解参与HCV介导的肝病进展的分子决定因素，这将为新的治疗方法开辟道路。

DESCRIPTION (provided by applicant): Hepatitis C virus (HCV) often causes persistent infection in humans, which may lead to progressive liver disease. We hypothesize that disease progression from chronic HCV infection is attributed, at least in part, to the effect of HCV core protein on the expression of host cellular genes. Our long term goal is to understand the underlying mechanisms behind HCV mediated liver disease progression. We were among the first to identify many intriguing functions related to HCV core protein, which may significantly contribute to disease progression. However, there are critical gaps in our understanding of the key cellular targets and molecular mechanisms by which core protein exerts these functions alone or in context to other HCV proteins. HCV induces hepatocellular insulin resistance and hepatic fibrogenesis. Our focus in this grant application is to examine the underlying mechanisms of HCV induced insulin resistance and fibrogenesis as a follow up to our preliminary data provided with this application. The current research proposal includes complementary but independent aims to address our hypothesis. Aim 1 will investigate the mechanism of IRS phosphorylation by HCV core protein, Aim 2 will investigate the functional correlates of HCV core protein induced metabolic regulators, and Aim 3 will evaluate the role of HCV core protein in hepatic fibrosis. Studies will also be performed using full-length cDNA, replicon or cell culture grown HCV to provide a molecular basis for HCV core protein functions in context to other HCV proteins. Knowledge on the molecular determinants involved in HCV mediated disease progression will open avenues for novel therapeutic approach. PUBLIC HEALTH RELEVANCE: Hepatitis C virus (HCV) often causes persistent infection and progressive liver disease. We plan to understand the molecular determinants involved in HCV mediated liver disease progression, which will open avenues for novel therapeutic approach.