Mechanisms of Liver Disease Progression by Hepatitis C Virus

丙型肝炎病毒导致肝病进展的机制

• 批准号: 8299564
• 负责人: Ranjit Ray
• 金额: $ 31.44万
• 依托单位: SAINT LOUIS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-08-01 至 2014-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8299564
• 关键词: Address; Affect; Applications Grants; Cell Culture Techniques; Chronic Hepatitis C; Complementary DNA; Core Protein; Cytokine Activation; Data; Diabetes Mellitus; Disease Progression; Epidemiologic Studies; Extracellular Matrix; Genes; Goals; Health; Hepatic Fibrogenesis; Hepatic Stellate Cell; Hepatitis C; Hepatitis C virus; Hepatocyte; Human; Infection; Inflammatory; Insulin Resistance; Insulin Resistance Pathway; Insulin Signaling Pathway; Interleukin-6; Knowledge; Kupffer Cells; Lead; Length; Liver; Liver Fibrosis; Liver diseases; Mediating; Mediator of activation protein; Metabolic; Molecular; Non-Insulin-Dependent Diabetes Mellitus; Pathologic; Pathway interactions; Patients; Phosphorylation; Polyproteins; Prevalence; Replicon; Research Proposals; Role; Serine; Steatohepatitis; Transgenic Mice; Viral Proteins; base; cellular targeting; cytokine; fibrogenesis; follow-up; forkhead protein; hepatitis C virus nucleocapsid protein; insulin receptor serine kinase; insulin signaling; liver function; novel therapeutic intervention; prevent; protein function; stellate cell; therapeutic target; virus core

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.

描述（由申请人提供）：丙型肝炎病毒（HCV）通常会导致人类持续感染，这可能导致进行性肝脏疾病。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介导的肝脏疾病进展背后的潜在机制。我们是第一批发现许多与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蛋白协同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空白。HCV诱导肝细胞胰岛素抵抗和肝纤维化。我们在本次资助申请中的重点是研究HCV诱导胰岛素抵抗和纤维形成的潜在机制，作为我们在本次申请中提供的初步数据的后续研究。目前的研究计划包括补充但独立的目标来解决我们的假设。Aim 1将研究HCV核心蛋白磷酸化IRS的机制，Aim 2将研究HCV核心蛋白诱导代谢调节因子的功能相关性，Aim 3将评估HCV核心蛋白在肝纤维化中的作用。研究还将使用全长cDNA、复制子或培养HCV的细胞进行，以提供HCV核心蛋白在其他HCV蛋白背景下功能的分子基础。了解HCV介导的疾病进展中涉及的分子决定因素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）经常引起持续感染和进行性肝病。我们计划了解参与HCV介导的肝脏疾病进展的分子决定因素，这将为新的治疗方法开辟道路。