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)增加丙型肝炎病毒(丙型肝炎病毒)感染严重程度或反之亦然的分子机制。中心假设是ALD产生氧化应激，从而增强肿瘤坏死因子(TNF)的细胞毒性，肿瘤坏死因子是肝脏疾病的主要致病介质。我们以前已经证明，丙型肝炎病毒核心蛋白结合到肿瘤坏死因子受体的胞浆区域，并使细胞对肿瘤坏死因子诱导的细胞溶解敏感，这些因素共同作用可能是这些患者肝脏疾病加重的原因。在这个项目中，我们将建立同时表达与ALD氧化损伤有关的CYP4502E1酶和丙型肝炎病毒核心蛋白的细胞系。这些细胞株将被测试它们对乙醇和肿瘤坏死因子的细胞毒性反应，以检查它们可能的协同效应。

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.