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（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（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，人们对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丙型肝炎病毒感染的发病机制。肝细胞中的乙醇（EtOH）代谢主要采用氧化分解代谢过程的两个步骤，其中乙醇脱氢酶（ADH）和乙醛脱氢酶（ALDH）起核心作用。 ADH-ALDH 途径还控制类视黄醇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。新的证据表明，RA 调节干扰素刺激基因 (ISG) 的表达，该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稳态是对于抑制 HCV 至关重要。健康肝脏中储存着大部分全身类维生素A（维生素A）并负责全身分布。 ALD 中静止的 HSC 转化为肌成纤维细胞会导致类视黄醇储备的耗尽。这些观察结果使我们假设 1)（维生素 A）肝星状细胞 (HSC) EtOH-类视黄醇代谢竞争和 2) HSC 衍生的类视黄醇的损失会损害肝细胞中的 ISG 表达，从而使 HCV 能够稳健复制。为了检验这些假设，我们提出以下目标；（目标 1）定义 EtOH-类视黄醇代谢竞争对肝细胞抗病毒先天免疫的影响，（目标 2）定义 HSC 衍生的类视黄醇在调节 HCV 先天防御程序中的作用。该应用的最终目标是明确类视黄醇在抗病毒先天免疫中的关键作用，并更好地了解 ALD-HCV 协同作用的发病机制。