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

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。中心假设是ALD产生氧化应激，其增强肿瘤坏死因子（TNF）的细胞毒性，肿瘤坏死因子是肝脏疾病的主要致病介质。我们以前已经表明，HCV核心蛋白结合到TNF受体的胞质结构域，并使细胞对TNF诱导的细胞溶解敏感。这些因素一起可能导致这些患者肝脏疾病的严重程度增加。在这个项目中，我们将建立表达CYP4502E1酶和HCV核心蛋白的细胞系，CYP4502E1酶与ALD中的氧化损伤有关。将检测这些细胞系对乙醇和TNF的细胞毒性反应，以检查其可能的协同效应。

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.