Epigenetic Regulation of CC-(CCL2) and CXC-(CXCL2) Chemokines in the Pathogenesis of Alcoholic Liver Disease
Alcoholic liver disease (ALD) is associated with high morbidity and mortality, and despite being actively investigated there is no FDA approved therapy.
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Overview
Emerging evidence demonstrates that alcohol-induced chemokine up-regulation and hepatic leukocyte infiltration are important factors in the development of ALD. Alcohol-induced alterations in epigenetic mechanisms play a significant role in the development of ALD.
Our preliminary data showed that ethanol increased histone H3 lysine9 (H3K9) acetylation levels at hepatic CCL2 promoter, and that a dietary HDAC inhibitor (tributyrin-a butyrate pro-drug) attenuated alcohol-induced CCL2 and CXCL2 expression, neutrophil infiltration and prevent hepatic inflammation and injury.
This project will determine the molecular mechanisms underlying chronic alcohol-induced chemokine upregulation and will examine the potential of nutrition-based interventions that target HDAC inhibition.
The results of this study will provide critical molecular insights and facilitate the development of therapeutic interventions for ALD.
Hypothesis
Chronic alcohol-induced alterations in hepatic HATs and HDACs drive pathogenic posttranslational modifications of histones and non-histone proteins upregulating CC- and CXC-chemokines expression contributing to liver inflammation and injury.
Principle Investigator
Smita Ghare, PhD
Assistant Professor of Medicine
Division of Gastroenterology, Hepatology & Nutrition
Education
B.Sc. - Wilson College, University of Mumbai
M.Sc. - LTMM College, University of Mumbai
Ph.D. - University of Louisville