PILOT--HCV AND ALCOHOL SENSITIZEHEPATOCYTES FOR TNF-A MEDIATED CYTOTOXICITY

试点——HCV 和酒精使肝细胞对 TNF-A 介导的细胞毒性敏感

• 批准号: 6299209
• 负责人: m lai
• 金额: $ 20.56万
• 依托单位: UNIVERSITY OF SOUTHERN CALIFORNIA
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-01-01 至 2000-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6299209
• 关键词: alcoholic hepatitis; cell line; chemosensitizing agent; cytotoxicity; drug interactions; ethanol; hepatitis C virus; technology /technique development; tissue /cell culture; toxin metabolism; tumor necrosis factor alpha

The long-range goal of this project is to define the molecular mechanism by which the presence of alcoholic liver disease (ALD) increases the severity of the hepatitis C virus (HCV) infection or vice versa. The central hypothesis is that ALD produces oxidative stress, which enhances the cytotoxicity of tumor necrosis factor (TNF), a primary pathogenic mediator of liver diseases. We have previously shown that HCV core protein binds to the cytoplasmic domain of TNF receptor and sensitizes cells to TNF-induced cytolysis These factors together may count for the increased severity of the liver disease in these patients. In this project, we will establish cell lines expressing both CYP4502E1 enzyme, which is implicated in oxidative injury in ALD, and HCV core proteins. These cell lines will be tested for their cytotoxic responses to ethanol and TNF to examine their possible synergistic effects.

该项目的长期目标是确定酒精性肝病 (ALD) 的存在增加丙型肝炎病毒 (HCV) 感染严重程度的分子机制，反之亦然。核心假设是 ALD 会产生氧化应激，从而增强肿瘤坏死因子 (TNF) 的细胞毒性，而肿瘤坏死因子是肝脏疾病的主要致病介质。我们之前已经表明，HCV 核心蛋白与 TNF 受体的细胞质结构域结合，并使细胞对 TNF 诱导的细胞溶解敏感。这些因素共同可能导致这些患者的肝病严重程度增加。在这个项目中，我们将建立表达 CYP4502E1 酶（与 ALD 氧化损伤有关）和 HCV 核心蛋白的细胞系。将测试这些细胞系对乙醇和 TNF 的细胞毒性反应，以检查它们可能的协同效应。