Chronic ethanol consumption contributes to long-term liver damage, resulting in the initiation and progression of alcoholic liver disease. Unfortunately, the current prognosis for end-stage alcoholic liver disease is poor and often untreatable, largely because the pathogenic mechanisms are not well understood. This research proposal by two early stage investigators puts forward the hypothesis that alcohol metabolism induces changes in mitochondrial protein acetylation, and other newly discovered post-translational modifications including propionylation and succinylation, all resulting in mitochondrial dysfunction. To test this hypothesis, we propose complete proteomic mapping studies, full metabolic characterization, and a series of innovative in vivo mouse physiology experiments with novel murine models, which will lead to a deeper understanding of the role of mitochondria protein acylation during alcohol metabolism. The work performed by our lab will focus specifically on the metabolic characterization, and the in vivo mouse physiology experiments, whereas the work performed by Dr. Fritz will focus on the proteomic mapping studies, as well as in vivo mouse physiology experiments. During the past few years, we have collaborated extensively to map the mitochondrial protein acetylome, and begin to understand the role of acetylation on mitochondrial function during alcohol metabolism. Our preliminary data shows that in addition to changes in acetylation, propionylation and succinylation change in response to alcohol metabolism. Thus, identifying the full repertoire of post- translational modifications and understanding their influence on mitochondrial metabolism are key to understanding the progression of alcoholic liver disease and potential strategies for intervention and treatment.
In the United States, approximately 14 million people meet the diagnostic criteria for alcoholism, two million are estimated to have alcoholic liver disease, and 14,000 die of cirrhotic liver failure annually. This research proposal addresses a novel mechanism for the pathogenesis of alcoholic liver disease.
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