Proposed studies in this renewal application are directed at investigating the molecular pathophysiology of alcohol-induced end organ disease, especially as it relates to non-oxidative ethanol metabolism in extra-hepatic organs. Fatty acid ethyl ester synthases, discovered in myocardium in the laboratory of the principal investigator in 1981, catalyze the formation of fatty acid ethyl esters from ethanol. These lipids accumulate in human organs most commonly damaged by alcohol abuse, their rates of synthesis are greatest in these organs and they cause impairment of mitochondrial function, a hallmark of alcohol-induced end organ damage. Since many organs such as heart and pancreas lack oxidative metabolism of alcohol, this pathway may provide a crucial link between ethanol ingestion and genetic vulnerabilities found in alcohol-induced end-organ diseases, such as pancreatitis and cardiomyopathy. Proposed studies will focus on the biochemical characterization of the human pancreatic minor fatty acid ethyl ester synthase because the enzyme is now known to be present in the greatest amount in pancreas (Science 231:497, 1986) and because the minor synthase accounts for the majority of synthase activity. Its four molecular forms (200, 100, 67 and 52 kDa) will be all purified to homogeneity, characterized and protein sequences determined in part to allow use of recombinant DNA techniques. These will be employed to detect restriction fragment length polymorphisms, clone the synthases and provide chromosomal localization of their genes. The results directly relate to establishing molecular links in the pathophysiology of alcohol-induced end organ damage at the genetic level.
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