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

 描述（由申请人提供）：酒精性肝病（ALD）是全球肝硬化和肝功能衰竭的主要原因。然而，目前对ALD的治疗非常有限，并且通常在最严重的疾病病例中仅提供适度的生存益处。我们缺乏针对ALD的特异性和有效的治疗方法是由于对酒精性肝损伤启动和进展为肝硬化的机制的认识存在差距。因此，这些机制的研究是至关重要的新的治疗方法，以改善ALD相关的发病率和死亡率的发展。最近，酒精暴露被发现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器官，因此驻留和迁移的免疫细胞都被触发以启动破坏性炎症反应，包括诱导称为TH17细胞的特定细胞亚群。肠屏障功能障碍导致肝脏炎症是研究酒精性肝损伤的新机制。具体地，本申请寻求解决 酒精如何破坏肠道屏障完整性的保护作用以及肝脏免疫功能如何 通过这种中断触发响应。紧密连接（TJs）是维持肠屏障完整性的主要结构，然而在ALD研究中仅研究了少数紧密连接蛋白组分。连接粘附分子-A（JAM-A）被认为是肠对高分子量物质的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，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强。在这个建议中，我们将采用生物化学，分子，组织学和免疫学技术来测试的假设，慢性酒精暴露破坏JAM-A功能，和JAM-A表达的全球损失将导致更严重的TH 17细胞介导的肝损伤ALD。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JAM-A全面缺乏引起的肠道屏障功能先天性缺陷对ALD中肝脏TH17反应的影响。该项目的长期目标将是充分表征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中肝脏适应性免疫反应的分子机制。总之，这项工作将作为一个框架，以更好地了解人类ALD的病理生理学，并在未来开发更安全，更有效的疗法。

 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.