The role of Cyp2e1, alcohol and HCV in modulation of hepatocyte homeostasis HCV replication and resistance to interferon

由饮酒和丙型肝炎病毒（HCV）感染引起的肝脏疾病是主要的国家卫生问题。酒精可大大加速HCV引起的肝脏疾病，但酒精、HCV引发的生化事件与导致肝脏疾病的炎症途径之间的关系尚不清楚。初步研究已经确定了一种重要的酒精代谢酶Cyp2e1、丙型肝炎病毒复制、氧化应激和一种强大的肝损伤介质肿瘤坏死因子α之间的联系。此外，我们已经表明，Cyp2e1的酒精代谢导致HCV复制增加，并对干扰素的抗病毒作用产生负面影响。本提案中包含的研究旨在通过试图确定Cyp2e1表达、酒精和HCV复制导致的肝脏疾病的新介质和机制，建立这些令人兴奋的新见解。我们还将研究酒精增强丙型肝炎病毒复制的分子机制。这些研究将有助于制定有利于酒精和丙型肝炎相关肝病的治疗策略。

Liver disease caused by alcohol consumption and hepatitis C virus (HCV) infection are major national health problems. Liver disease caused by HCV is greatly accelerated by alcohol consumption, however, the connection between the biochemical events initiated by alcohol, HCV and inflammatory pathways resulting in liver disease are not well understood. Preliminary studies have identified a link between an important alcohol-metabolising enzyme, Cyp2e1, HCV replication, oxidative stress and a powerful mediator of liver injury called tumour necrosis factor alpha. Furthermore we have shown that alcohol metabolism by Cyp2e1 results in an increase in HCV replication and negatively impacts on the anti-viral action of interferon. The studies contained within this proposal aim to build on these exciting new insights by attempting to identify new mediators and mechanisms of liver disease as a consequence of Cyp2e1 expression, alcohol and HCV replication. We will also examine the molecular mechanisms by which alcohol potentiates HCV replication. These studies will assist in developing therapeutic strategies that will benefit alcohol- and HCV-related liver disease.