Retinoid regulation of hepatic innate immunity.

描述(申请人提供)：慢性肝病是美国第12大死因，其中酒精性肝病(ALD)和丙型肝炎病毒(丙型肝炎)感染分别占44%和37%。值得注意的是，超过一半的丙型肝炎病毒感染者符合酒精中毒的诊断标准。这组特殊的患者表现出肝脏疾病迅速发展为肝硬变和肝细胞癌。然而，这种协同作用的分子机制尚不清楚，因此缺乏有效的管理策略。这项拟议的研究旨在了解过量饮酒如何增强慢性丙型肝炎病毒感染的发病机制。乙醇在肝细胞中的代谢主要经历两步氧化分解代谢过程，其中乙醇脱氢酶(ADH)和乙醛脱氢酶(ALDH)起核心作用。ADH-ALDH途径还调控类维甲酸向其活性代谢产物维甲酸(RA)的代谢。因此，过量的乙醇消耗会损害RA的产生。新的证据表明，RA调节干扰素刺激基因(ISGs)的表达，而ISGs在细胞间抗病毒先天免疫中发挥核心作用。因此，肝内维甲酸动态平衡是 对抑制丙型肝炎病毒至关重要。在健康的肝脏中，大部分储存在全身的维甲酸(Vitamn A)，并负责全身分布。在ALD中，静止的HSCs转化为肌成纤维细胞会导致维甲酸储备的耗尽。这些观察结果使我们推测，1)(维生素A)肝星状细胞(HSC)乙醇-维甲酸代谢竞争和2)HSC来源的维甲酸丢失都会损害肝细胞中ISGs的表达，从而允许丙型肝炎病毒的强劲复制。为了验证这些假说，我们提出了以下目标：(AIM1)定义乙醇-维甲酸代谢竞争对肝细胞抗病毒天然免疫的影响；(AIM2)定义HSC衍生的维甲酸在调节抗丙型肝炎病毒天然防御计划中的作用。这项应用的最终目的是确定维甲酸在抗病毒天然免疫中的关键作用，并更好地了解ALD-丙型肝炎病毒协同作用的发病机制。

DESCRIPTION (provided by applicant): Chronic liver diseases is the 12th leading cause of death in the US, in which alcoholic liver disease (ALD) and Hepatitis C Virus (HCV) infection account for 44% and 37%, respectively. Of note, more than half of the HCV infected population meets the diagnostic criteria of alcoholism. This particular group of patients exhibits rapid progression of liver disease to cirrhosis and hepatocellular carcinoma. However, the molecular mechanisms of this synergism are poorly understood and therefore effective management strategies are lacking. This proposed research is designed to understand how excessive alcohol consumption enhances the pathogenesis of chronic HCV infection. Ethanol (EtOH) metabolism in hepatocytes mainly employs two steps of the oxidative catabolic process in which alcohol dehydrogenase (ADH) and aldehyde dehydrogenase (ALDH) play central roles. The ADH-ALDH pathway also governs metabolism of retinoid to its active metabolite, Retinoic Acid (RA). Therefore, excessive EtOH consumption impairs the production of RA. Emerging evidence suggests that RA regulates the expression of Interferon Stimulated Genes (ISGs), which play a central role in intercellular antiviral innate immunity. Thus, intrahepatic retinoid homeostasis is critical for HCV suppression. in the healthy liver store the majority of total body retinoid (Vitamn A) and are responsible for systemic distribution. The transformation of quiescent HSCs to myofibroblasts in ALD results in depletion of retinoid stores. These observations lead us to hypothesize that both 1) (Vitamin A) Hepatic Stellate Cells (HSC) EtOH-retinoid metabolic competition and 2) Loss of HSC derived retinoid impairs ISGs expression in hepatocytes, thereby allowing robust replication of HCV. In order to test these hypotheses, we propose the following aims; (Aim1) Define the impact of EtOH-retinoid metabolic competition on hepatocyte antiviral innate immunity and (Aim2) Define the role of HSC derived retinoid on regulation of the innate defense program against HCV. The ultimate goal of this application is to define the critical role of retinoid on antiviral innate immunity and provide a better understanding of the pathogenesis of ALD-HCV synergism.