A pivotal role for junctional adhesion molecule-A in alcoholic liver injury

连接粘附分子-A在酒精性肝损伤中的关键作用

• 批准号: 9266196
• 负责人: Daniel Michael Chopyk
• 金额: $ 4.9万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-05-01 至 2019-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9266196
• 关键词: Adaptive Immune System; Address; Adoptive Transfer; Alcoholic Liver Diseases; Alcoholism; Alcohols; Automobile Driving; Bacterial Toxins; Biochemical; Blood; Blood Circulation; CD4 Positive T Lymphocytes; California; Cells; Characteristics; Cholesterol; Chronic; Cirrhosis; Complex; Cytology; Data; Defect; Development; Diet; Disease; Epithelial; Ethanol; Fatty acid glycerol esters; Functional disorder; Future; Genetic; Genetic Transcription; Goals; Hepatic; Histologic; Histological Techniques; Human; Immune; Immune response; Immunity; Immunologic Techniques; Impairment; Infiltration; Inflammation; Inflammatory Response; Integral Membrane Protein; Interleukin-17; Interruption; Intestines; Knock-out; Knockout Mice; Knowledge; Laboratories; Leukocytes; Liquid substance; Liver; Liver Failure; Liver diseases; Mediating; Metastatic Neoplasm to the Liver; Methods; Modality; Modeling; Molecular; Molecular Target; Molecular Weight; Morbidity - disease rate; Mus; Pathogenicity; Pathology; Patients; Pattern; Permeability; Phenotype; Phosphorylation; Play; Predisposition; Production; Property; Proteins; Reporting; Research; Role; Scaffolding Protein; Secondary to; Serological; Serum; Severities; Signal Pathway; Signaling Protein; Stream; Structural Protein; Structure; Study models; T cell differentiation; T cell response; T-Lymphocyte; T-Lymphocyte Subsets; Techniques; Testing; Tight Junctions; Toxin; Training; Universities; Work; adaptive immune response; alcohol effect; alcohol exposure; base; cytokine; effective therapy; feeding; improved; in vivo; indexing; insight; junctional adhesion molecule; liver inflammation; liver injury; liver transplantation; mortality; nonalcoholic steatohepatitis; novel therapeutics; occludin; pathogen; prognostic; protective effect; protein expression; public health relevance; response

 DESCRIPTION (provided by applicant): Alcoholic liver disease (ALD) is a leading cause of cirrhosis and liver failure worldwide. However, current treatments for ALD are very limited and generally offer only modest survival benefits in the most severe cases of disease. Our lack of specific and effective treatments for ALD are a result of gaps in knowledge of the mechanisms by which alcoholic liver injury is initiated, and progresses, to cirrhosis. Hence, the study of thee mechanisms is crucial for development of new therapeutics to improve ALD-related morbidity and mortality. Recently, alcohol exposure was found to disrupt intestinal barrier integrity, causing bacterial toxins to leak into the blood stream as a result. Since the liver is the first oran to encounter such toxins, both resident and migratory immune cells are triggered to initiate damaging inflammatory responses, including induction of a particular cellular subset known as TH17 cells. Intestinal barrier dysfunction that leads to liver inflammation is an emerging mechanism in which to study alcoholic liver injury. Specifically, this application seeks to address how alcohol can disrupt the protective effects of intestinal barrier integrity and how liver immune responses are triggered through this disruption. Tight junctions (TJs) are the primary structures that maintain intestinal barrier integrity, however only a few tight junction protein components have been studied in ALD research. Junctional Adhesion Molecule-A (JAM-A) is believed to be a primary regulator of intestinal permeability to high molecular weight substances. Furthermore, data from ongoing studies in the Anania laboratory related to non-alcoholic steatohepatitis (NASH), a disorder that shares many characteristics with ALD, reveal that mice with a genetic deletion of JAM-A have congenitally impaired intestinal integrity and show enhanced susceptibility to this disease. In this proposal, we will employ biochemical, molecular, histological, and immunological techniques to test the hypothesis that chronic alcohol exposure disrupts JAM-A function, and global loss of JAM-A expression will result in more severe TH17-cell-mediated liver injury in ALD. The specific aims of the proposed research are (1) to identify the role of chronic alcohol exposure in altering intestinal JAM-A function; and (2) to elucidate th effects that a congenital deficiency in intestinal barrier function, resulting from a global deficiency in JAM-A, has on liver TH17 responses in ALD. The long-term goals of this project will be to fully characterize the molecular targets of ethanol in disrupting intestinal barrier integrity, and, also, to elucidate the molecular mechanisms whereby intestinal barrier function regulates the liver adaptive immune response in ALD. Taken together, this work will serve as a framework to better understand human ALD pathophysiology and to aid in future development of safer, more effective therapies.

 描述（由申请人提供）：酒精性肝病（ALD）是全世界肝硬化和肝功能衰竭的主要原因，但目前针对 ALD 的治疗方法非常有限，并且在最严重的疾病病例中通常只能提供有限的生存益处。由于对酒精性肝损伤发生和进展为肝硬化的机制了解不足，因此对 ALD 的特异性和有效治疗方法的研究对于开发新的治疗方法至关重要。最近发现，酒精暴露会破坏肠道屏障的完整性，导致细菌毒素渗入血液，因为肝脏是第一个接触此类毒素的器官，无论是驻留的还是迁移的免疫细胞。被触发引发破坏性炎症反应，包括诱导称为 TH17 细胞的特定细胞亚群，导致肝脏炎症，这是研究酒精性肝损伤的新兴机制。 酒精如何破坏肠道屏障完整性的保护作用以及肝脏免疫如何 紧密连接 (TJ) 是维持肠道屏障完整性的主要结构，但 ALD 研究中仅研究了少数紧密连接蛋白成分 (JAM-A)。是肠道对高分子量物质渗透性的主要调节剂。此外，Anania 实验室正在进行的与非酒精性脂肪性肝炎 (NASH) 相关的研究数据显示，NASH 是一种与 ALD 具有许多共同特征的疾病。揭示 JAM-A 基因缺失的小鼠先天性损害肠道完整性，并表现出对这种疾病的易感性增强。在本提案中，我们将采用生化、分子、组织学和免疫学技术来检验慢性酒精暴露破坏 JAM 的假设。 -A 功能和 JAM-A 表达的整体丧失将导致 ALD 中更严重的 TH17 细胞介导的肝损伤。本研究的具体目的是 (1) 确定慢性酒精暴露在改变肠道中的作用。 JAM-A 功能；(2) 阐明由于 JAM-A 整体缺乏而导致的先天性肠道屏障功能缺陷对 ALD 中肝脏 TH17 反应的影响。全面表征乙醇破坏肠道屏障完整性的分子靶标，并阐明肠道屏障功能调节 ALD 中肝脏适应性免疫反应的分子机制。总而言之，这项工作将成为更好的框架。了解人类 ALD 病理生理学并帮助未来开发更安全、更有效的疗法。