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)是全球范围内导致肝硬变和肝功能衰竭的主要原因。然而，目前ALD的治疗方法非常有限，通常只在最严重的病例中提供适度的生存益处。我们缺乏对酒精性肝病的特效治疗，这是由于人们对酒精性肝损伤引发和发展为肝硬变的机制认识不足所致。因此，对这些机制的研究对于开发新的治疗方法以改善ALD相关的发病率和死亡率至关重要。最近，人们发现酒精暴露会破坏肠道屏障的完整性，导致细菌毒素泄漏到血液中。由于肝脏是第一个遇到这种毒素的猩猩，驻留和迁徙的免疫细胞都会被触发，以启动破坏性的炎症反应，包括诱导一种被称为TH17细胞的特定细胞亚群。导致肝脏炎症的肠屏障功能障碍是研究酒精性肝损伤的新机制。具体地说，该应用程序试图解决 酒精如何破坏肠道屏障完整性的保护作用以及肝脏如何免疫 响应是通过这种干扰来触发的。紧密连接(TJ)是维持肠道屏障完整性的主要结构，但在ALD研究中仅对少数紧密连接蛋白成分进行了研究。连接黏附分子-A(JAM-A)被认为是肠道对高分子物质通透性的主要调节因子。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，JAM-A基因缺失的小鼠具有先天性肠道完整性受损，并显示出对这种疾病的易感性增加。NASH是一种与ALD有许多共同特征的疾病。在这个方案中，我们将使用生化、分子、组织学和免疫学技术来检验这一假说，即慢性酒精暴露扰乱了JAM-A的功能，JAM-A表达的全面丧失将导致更严重的TH17细胞介导的ALD肝损伤。拟议研究的具体目的是(1)确定慢性酒精暴露在改变肠道JAM-A功能中的作用；(2)阐明由于JAM-A全球缺陷导致的先天性肠道屏障功能缺陷对ALD患者肝脏TH17反应的影响。该项目的长期目标将是全面描述乙醇破坏肠屏障完整性的分子靶点，并阐明肠屏障功能调节ALD肝脏适应性免疫反应的分子机制。综上所述，这项工作将成为更好地了解人类ALD病理生理学的框架，并有助于未来更安全、更有效的治疗方法的开发。