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The primary objective of this application is to determine the impact of chronic ethanol feeding on the regulation of insulin-like growth factors (IGF). Both IGF-1 (which is dependent of plasma levels of growth hormone) and IGF-2 ( which is less growth hormone dependent) have potent effects on protein synthesis in many tissues and appear to have a regulatory role in both wound healing and the maintenance of immune competence. Previous research from our laboratory indicates that chronic ethanol induces unique changes in the endocrine system which are not detectable using acute ethanol administration. Specifically, we have observed a decrease in plasma IGF-1 after chronic ethanol feeding and proposed that at least part of the decreases in protein synthesis resulting from chronic ethanol are mediated by a decline in serum concentrations of this hormone. Our working hypothesis is that the chronic ethanol-induced decrease in protein synthesis is the result of two factors: 1) an inhibition of IGF-1 gene expression in liver; and 2) an inhibition of specific neuroendocrine compensatory mechanisms which further exacerbate the reduced IGF-1 concentrations. The studies described in this proposal will test this hypothesis directly by: 1) Implementing a chronic ethanol feeding regimen using intragastric cannulation to serve as a model system for the effects of ethanol on the neuroendocrine system. This methodology will alleviate many of the limitations of other ethanol feeding regimens and will be used to reassess the effects of ethanol on tissue protein synthesis, plasma IGF- 1 and growth hormone secretory dynamics; 2) Testing the hypothesis that the ethanol-induced decline in plasma IGF-1 concentrations is the result of a decrease in IGF-1 gene expression using both dot-blot and in situ hybridization technology. Secondary hypotheses will test whether there is alternative processing of the primary transcript of IGF-1 mRNA and whether other tissues that express the IGF-1 gene are sensitive to the effects of ethanol; 3) Testing the hypothesis that chronic ethanol feeding inhibits growth hormone gene expression. Secondary hypotheses will test whether these changes are related to alterations in somatostatin and/or growth hormone releasing factor gene expression; 4) Assessing the effects of chronic ethanol on IGF-2 concentrations and gene expression. We believe that we are in a unique position to continue a comprehensive analysis of neuroendocrine-endocrine regulation of protein synthesis at the molecular level using a model system for ethanol administration. The results of these studies should provide valuable data which closely correlate with endocrine changes which occur in the human population in response to chronic ethanol consumption.
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