The deleterious effects of alcohol are primarily mediated by its metabolic by-products. Ethanol metabolism by microsomal and mitochondrial systems generates reactive oxygen and nitrogen species, and is associated with diminished glutathione and antioxidant enzymatic activity, all of which promote oxidative stress. In addition, the accumulation of ethanol-derived aldehydes and hydroxyethyl radicals serves to modify critical biological functions by forming adducts with proteins and DNA. The availability of animal models in which ethanol metabolism or antioxidant mechanisms are genetically modified facilitates investigation of the role these enzymes and oxidative stress play in diseases associated with ethanol consumption. The goals of this application are to: A) maintain and develop unique transgenic knockouts that can be made available to the larger research community for the investigation of the pathogenesis of alcohol abuse and the mechanisms underlying the deleterious effects of alcohol, and B) offer metabolomics and tissue imaging mass spectrometry (IMS) expertise to facilitate investigation of the biochemical consequences of alcohol exposure and pathogenesis. Our overarching aim is to provide valuable transgenic animal models and metabolomics resources to the larger research community that will greatly enhance our understanding of the mechanisms underlying alcohol-induced disease and the pathophysiological effects of acute and chronic alcohol consumption. It is anticipated that our metabolomic platforms will offer state-of-the-art techniques to dissect the molecular mechanisms of alcohol-induced tissue injury. Such knowledge will facilitate the development of more effective treatments of alcohol abuse.
Alcohol-induced toxicity is associated with the deleterious effects of its by-products and oxidative stress resulting from ethanol metabolism. The goals of this application are to: (a) maintain and expand/generate animal models with genetic defects in alcohol metabolizing enzymes and in glutathione synthesizing enzymes that will continue to be available to the research community, and b) offer investigators the opportunity to employ metabolomics analysis and/or tissue mass spectrometry imaging in their research efforts relating to investigation of the mechanisms by which alcohol elicits deleterious pathophysiological effects.
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