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

Emory University, Atlanta GA

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Abstract

? 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.