Retinoid regulation of hepatic innate immunity.

描述（由申请人提供）：慢性肝病是美国第12大死亡原因，其中酒精性肝病（ALD）和丙型肝炎病毒（HCV）感染分别占44%和37%。值得注意的是，超过一半的HCV感染人群符合酒精中毒的诊断标准。这组特殊的患者表现出肝病快速进展为肝硬化和肝细胞癌。然而，这种协同作用的分子机制知之甚少，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HCV感染的发病机制。乙醇（EtOH）在肝细胞中的代谢主要通过两步氧化分解代谢过程进行，其中乙醇脱氢酶（ADH）和乙醛脱氢酶（ALDH）起核心作用。ADH-ALDH途径还控制类维生素A代谢为其活性代谢物视黄酸（RA）。因此，过量的EtOH消耗会损害RA的产生。新出现的证据表明，RA调节干扰素刺激基因（ISG）的表达，这些基因在细胞间抗病毒先天免疫中发挥核心作用。因此，肝内类维生素A稳态是 对抑制HCV至关重要。在健康的肝脏中储存大部分的全身类维生素A（维生素A），并负责全身分布。ALD中静止HSC向肌成纤维细胞的转化导致类维生素A储存的耗尽。这些观察结果使我们假设：1）（维生素A）肝星状细胞（HSC）EtOH-类维生素A代谢竞争和2）HSC衍生的类维生素A的丧失都会损害肝细胞中的ISGs表达，从而允许HCV的稳健复制。为了验证这些假设，我们提出了以下目标：（Aim 1）确定EtOH-类维生素A代谢竞争对肝细胞抗病毒先天免疫的影响;（Aim 2）确定HSC衍生的类维生素A对HCV先天防御程序的调节作用。本申请的最终目标是确定类维生素A对抗病毒先天免疫的关键作用，并提供更好地理解ALD-HCV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.