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Retinoid regulation of hepatic innate immunity.

类视黄醇对肝脏先天免疫的调节。

基本信息

批准号：
8914476
负责人：
Takeshi Saito
金额：
$ 19.01万
依托单位：
UNIVERSITY OF SOUTHERN CALIFORNIA
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-08-20 至 2017-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8914476
关键词：
Accounting Address Alcohol dehydrogenase Alcoholic Liver Diseases Alcoholism Antiviral Agents Biochemical Genetics CYP2E1 gene Catabolic Process Catabolism Cause of Death Chronic Hepatitis C Cirrhosis Clinical Consumption Diagnostic Disease Progression Disease model Enzymes Ethanol Exhibits Future Gene Expression Genes Genetic Transcription Goals Health Heavy Drinking Hepatic Hepatic Stellate Cell Hepatitis C Hepatitis C virus Hepatocyte Homeostasis Human Immune Immunity Impairment In Vitro Integration Host Factors Interferons Investigation Lead Life Cycle Stages Lipids Liver Liver diseases Mediating Metabolic Metabolic Pathway Metabolism Molecular Mus Myofibroblast Natural Immunity Pathogenesis Pathway interactions Patients Play Population Primary carcinoma of the liver cells Production Public Health Regulation Research Retinoids Role Severities Staging Testing Therapeutic Tretinoin United States Viral Virus Diseases Virus Replication Vitamin A adaptive immunity aldehyde dehydrogenases base chronic liver disease design genetic approach improved in vivo insight intrahepatic meetings novel programs stable cell line synergism

项目摘要

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.

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，半数以上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病迅速发展为肝硬化和肝细胞癌。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HCV感染的发病机制。乙醇（EtOH）在肝细胞内的代谢主要包括两个氧化分解代谢过程，其中乙醇脱氢酶（ADH）和醛脱氢酶（ALDH）起核心作用。ADH-ALDH途径还控制类维甲酸向其活性代谢物维甲酸（RA）的代谢。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（ISGs）的表达，ISGs在细胞间抗病毒先天免疫中发挥核心作用。因此，肝内类视黄醇稳态是