Mechanisms of Liver Injury by Hepatitis C and Alcohol

丙型肝炎和酒精损伤肝的机制

基本信息

批准号：
7293750
负责人：
STEVEN A WEINMAN
金额：
$ 4.89万
依托单位：
UNIVERSITY OF TEXAS MED BR GALVESTON
依托单位国家：
美国
项目类别：
财政年份：
2000
资助国家：
美国
起止时间：
2000-09-27 至 2010-08-31
项目状态：
已结题

项目摘要

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（由申请人提供）：丙型肝炎病毒感染了大约 300 万美国人，是美国肝硬化、肝衰竭和肝细胞癌的最常见原因。目前的疗法使不到一半的感染者受益，需要新的方法来根除病毒并减缓疾病的进展。饮酒的患者的疾病进展特别快，并且对抗病毒治疗的反应显着降低。减缓该人群疾病进展的措施将带来巨大的潜在益处。丙型肝炎的肝脏发病机制尚不清楚，它涉及免疫过程、直接病毒效应和肝脏反应。多项研究表明，丙型肝炎中的肝脏氧化应激比其他慢性肝病更为突出。最近的研究表明，HCV 病毒蛋白会刺激活性氧的产生并加剧酒精对肝脏的影响。 HCV核心蛋白本身直接与线粒体结合，抑制电子传递，并增加线粒体ROS的产生。因此，HCV 和酒精对线粒体功能的协同作用可能对疾病进展发挥重要作用。该提案将评估以下假设：HCV 核心蛋白与线粒体靶标特异性结合，直接通过蛋白质-蛋白质相互作用或通过线粒体钙稳态的变化间接导致线粒体蛋白质功能的改变。线粒体损伤是 HCV-酒精协同作用的主要机制，增加线粒体抗氧化能力可以防止其中一些影响。该假设将通过以下具体目标进行检验： 1. 确定直接核心蛋白线粒体相互作用是否导致线粒体功能变化。 2. 确定HCV诱导的复合物I抑制的蛋白质组学机制。 3. 确定线粒体钙积累是否有助于核心诱导的线粒体功能变化。 4. 确定线粒体氧化-抗氧化平衡在HCV蛋白和酒精引起的肝损伤中的作用。这些目标将通过专门改变核心蛋白靶向、测量线粒体电子传递、确定线粒体蛋白的氧化衍生状态、测量线粒体钙稳态以及检查新型抗氧化剂和过度表达的线粒体超氧化物歧化酶对酒精喂养的 HCV 中线粒体功能的影响来实现转基因小鼠。