Mechanisms of Liver Injury by Hepatitis C and Alcohol

丙型肝炎和酒精损伤肝的机制

• 批准号: 7928541
• 负责人: STEVEN A WEINMAN
• 金额: $ 12.97万
• 依托单位: UNIVERSITY OF KANSAS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-20 至 2012-03-09
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7928541
• 关键词: Alcohol consumption; Alcoholic Liver Diseases; Alcohols; American; Antioxidants; Antiviral Therapy; Binding; Calcium; Cell Death; Cells; Chronic; Cirrhosis; Complex; Core Protein; Disease Progression; Electron Transport; Equilibrium; Hepatic; Hepatitis C; Hepatitis C virus; Hepatocyte; Homeostasis; Immune; Infection; Injury; Liver; Liver Failure; Liver diseases; Measures; Mitochondria; Mitochondrial Proteins; Modification; Mus; Oxidants; Oxidative Stress; Pathogenesis; Patients; Play; Primary carcinoma of the liver cells; Process; Production; Protein Binding; Proteomics; Reactive Oxygen Species; Replicon; Role; Testing; Transgenic Mice; Transgenic Organisms; United States; Viral; Viral Proteins; Virus; alcohol effect; base; cohort; feeding; hepatitis C virus nucleocapsid protein; human SOD2 protein; liver function; novel; novel strategies; overexpression; prevent; protein function; protein protein interaction; response

DESCRIPTION (provided by applicant): Hepatitis C virus infects approximately 3 million Americans and is the most common cause of cirrhosis, liver failure and hepatocellular carcinoma in the United States. Current therapies benefit less than half of those infected and new approaches to eradicate the virus and slow progression of the disease are needed. Patients who consume alcohol have a particularly rapid state of disease progression and markedly reduced response to antiviral therapy. Measures to slow disease progression in this cohort would have enormous potential benefit. The mechanism of liver pathogenesis of Hepatitis C is poorly understood and involves an immune process, direct viral effects, and the hepatic response. Multiple studies have demonstrated that hepatic oxidative stress is more prominent in Hepatitis C than other chronic liver diseases. Recent studies have shown that HCV viral proteins stimulate reactive oxygen species production and exacerbate the hepatic effects of alcohol. The HCV core protein itself directly associates with mitochondria, inhibits electron transport, and increases mitochondrial ROS production. Synergistic effects of HCV and alcohol on mitochondrial function may therefore contribute importantly to disease progression. This proposal will evaluate the hypothesis that HCV core protein binds specifically to mitochondrial targets causing alterations in mitochondrial protein function either directly via protein-protein interactions, or indirectly via changes in mitochondrial calcium homeostasis. Mitochondrial injury is a primary mechanism responsible for HCV-alcohol synergy and increasing mitochondrial antioxidant capacity can prevent some of these effects. This hypothesis will be tested by the following specific aims: 1. To determine if direct core-protein mitochondria interactions are responsible for mitochondrial functional changes. 2. To determine the proteomic mechanisms of HCV-induced complex I inhibition. 3. To determine whether mitochondrial calcium accumulation contributes to for core-induced changes in mitochondrial function. 4. To determine the role of mitochondrial oxidant-antioxidant balance in HCV protein and alcohol induced liver injury. These aims will be achieved by specifically altering core protein targeting, measuring mitochondrial electron transport, determining the state oxidative derivitization of mitochondrial proteins, measuring mitochondrial calcium homeostasis, and examining the effects of novel antioxidants and overexpressed mitochondrial superoxide dismutase on mitochondrial function in alcohol fed HCV transgenic mice.

描述(申请人提供)：丙型肝炎病毒感染约300万美国人，是美国最常见的肝硬变、肝功能衰竭和肝细胞癌的原因。目前的治疗方法使不到一半的感染者受益，需要新的方法来根除病毒和减缓疾病的进展。饮酒的患者病情进展特别快，对抗病毒治疗的反应明显降低。在这组人群中减缓疾病进展的措施将产生巨大的潜在好处。丙型肝炎的肝脏发病机制尚不清楚，涉及免疫过程、病毒的直接作用和肝脏反应。多项研究表明，与其他慢性肝病相比，丙型肝炎患者的肝脏氧化应激更为突出。最近的研究表明，丙型肝炎病毒蛋白刺激活性氧的产生，并加剧酒精对肝脏的影响。丙型肝炎病毒核心蛋白本身直接与线粒体结合，抑制电子传递，增加线粒体ROS的产生。因此，丙型肝炎病毒和酒精对线粒体功能的协同作用可能在疾病进展中起重要作用。该提案将评估一种假设，即丙型肝炎病毒核心蛋白与线粒体靶标特异结合，直接通过蛋白质-蛋白质相互作用引起线粒体蛋白质功能的改变，或通过改变线粒体钙稳态间接引起线粒体蛋白质功能的改变。线粒体损伤是导致丙型肝炎病毒-酒精协同作用的主要机制，提高线粒体的抗氧化能力可以阻止其中的一些影响。这一假说将通过以下具体目标来验证：1.确定线粒体核心-蛋白质直接相互作用是否导致线粒体功能变化。2.确定丙型肝炎病毒诱导的复合体I抑制的蛋白质组学机制。3.确定线粒体钙蓄积是否参与核心诱导的线粒体功能改变。4.探讨线粒体氧化-抗氧化平衡在丙型肝炎病毒蛋白和酒精性肝损伤中的作用。这些目标将通过特定的改变核心蛋白靶向，测量线粒体电子传递，确定线粒体蛋白的氧化衍生化状态，测量线粒体钙稳态，以及检测新型抗氧化剂和过表达的线粒体超氧化物歧化酶对酒精喂养的丙型肝炎转基因小鼠线粒体功能的影响来实现。