MECHANISMS OF LIVER INJURY BY HEPATITIS C AND ALCOHOL

丙型肝炎是美国最常见的慢性肝病， 据估计，有400万至500万人感染。这种疾病的特点是 肝脏炎症和进行性纤维化导致最终发展 高达20%-30%的人患有肝硬变和/或肝细胞癌 个人。饮酒大大增加了病情的严重性和快速性 但酒精/丙型肝炎病毒协同作用的机制尚不清楚。 新的治疗方法的发展一直受到有限的 现有的实验模型和系统，以及对 涉及致病机制。这项研究的长期目标是 鉴定一种表达丙型肝炎病毒蛋白的转基因小鼠模型 并利用这一模型来确定氧化应激和 线粒体功能障碍在酒精肝毒性增加中的作用 治疗慢性丙型肝炎的具体目标是：1.研究其发病机制和 丙型肝炎病毒蛋白诱导的ROS产生刺激的后果。这些 实验将使用细胞培养表达系统来确定效果 丙型肝炎病毒核心蛋白对基础和肿瘤坏死因子诱导的ROS产生的影响 ROS异常的来源。核心诱导的ROS变化对细胞的影响 生存及其通过抗氧化剂和核因子-xb激活的修饰将是 下定决心。丙型肝炎病毒蛋白表达诱导的基因表达变化 细胞系将使用核糖核酸酶保护分析进行测量。2.确定 丙型肝炎病毒蛋白表达在酒精性肝损伤中的作用慢性 对正常小鼠和非转基因小鼠进行酒精喂养，肝脏 组织学与氧化性损伤的比较。酒精引起的肝脏基因改变 表达将使用DNA微阵列进行测量。3.评价抗氧化剂 基于修改丙型肝炎病毒/酒精诱导的细胞和肝脏损伤的方法。 乙醇喂养的转基因动物和细胞培养系统将用于 确定改善丙型肝炎病毒/酒精诱导的肝损伤的可能性 抗氧化剂和抗肿瘤坏死因子抗体。成功完成这些研究 将导致开发一种研究丙型肝炎病毒诱导的新模型 肝损伤--对氧化应激在丙型肝炎病毒/酒精中作用的新认识 诱导性肝损伤及潜在治疗方法的初步评价 这种疾病的治疗方法。

Hepatitis C is the most common form of chronic liver disease in the U.S. with an estimated 4-5 million people infected. The disease is characterized by hepatic inflammation and progressive fibrosis leading to eventual development of cirrhosis and/or hepatocellular carcinoma in as many as 20-30% of individuals. Alcohol consumption greatly increases the severity and rapidity of disease progression but the mechanism of alcohol/HCV synergy is unknown. Development of new therapeutic approaches has been hampered by the limited experimental models systems available and a lack of understanding of the pathogenic mechanisms involved. The long-term objective of this study is to characterize a transgenic mouse model which expresses HCV proteins in the liver and to use this model to determine the role of oxidative stress and mitochondrial dysfunction in producing the increased liver toxicity of alcohol in chronic hepatitis C. The specific aims are 1. To examine the mechanisms and consequences of HCV protein-induced stimulation of ROS production. These experiments will use cell culture expression systems to determine the effects of HCV core protein on basal and TNF-induced ROS production and examine the source of abnormal ROS. The consequences of core-induced ROS changes to cell survival and its modification by antioxidants and NF-XB activation will be determined. Changes in gene expression induced by HCV protein expression in cell lines will be measured using RNase protection assays. 2. To determine the effects of HCV protein expression on ethanol-induced liver injury. Chronic alcohol feeding of normal and a-ansgenic mice will be performed and liver histology and oxidant injury compared. Alcohol induced changes in liver gene expression will be measured using DNA microarrays. 3. To evaluate antioxidant based approaches to modify HCV/alcohol-induced cell and liver injury. Ethanol-fed transgenic animals and cell culture systems will be used to determine the potential to modify HCV/alcohol -induced liver injury with antioxidants and anti-TNF antibodies. Successful completion of these studies will result in the development of a new model for the study of HCV-induced liver injury, new insight into the role of oxidative stress in HCV/alcohol induced liver injury, and a preliminary evaluation of potential therapeutic modalities for this disease.