The proposed project explores the possible physiological implications for liver regeneration of the interactions of ethanol with growth factor- induced signal transduction processes. Ethanol has been reported to inhibit liver regeneration after partial hepatectomy in vivo and there is evidence that ethanol interferes with growth factor-induced DNA synthesis in vitro. Also, liver regeneration is deficient in chronically ethanol-fed rats. Previous studies from several laboratories, including our own, have identified multiple mechanisms by which ethanol interferes with signal transduction processes activated by growth factors and cytokines. These include effects of acute or chronic ethanol exposure on growth factor receptor tyrosine kinase activity, activation of phospholipases C and D, with consequent chances in cytosolic [Ca2+], diacylglycerol and phosphatidic acid levels, and changes in the activity of trimeric G proteins. However, the conditions under which these or other effects of ethanol occur, the impact they might have on the sequence of events associated with liver regeneration, and the alterations in these processes after long-term ethanol exposure remain unclear. We intend to characterize these ethanol-mediated effects, focussing in particular on the early signal transduction events activated by epidermal growth factor and hepatocyte growth factor, i.e., the receptor tyrosine kinase and the activation of specific target proteins that are activated by, or associate with the growth factor receptors, namely phospholipases C and D,phosphatidylinositol-3 kinase, and proteins that initiate activation of the Ras/MAP kinase sequence.The role of the Gi proteins in the activation of phospholipase C-gamma mediated by growth factors and its involvement in the growth factor-induced cytoskeletal changes will also be investigated. The interactions of ethanol with growth factor-mediated signal transduction processes will be correlated with its effect on growth factor-stimulated DNA synthesis. The studies on isolated hepatocytes will be complemented by an analysis of effects of ethanol on second messenger patterns associated with liver regeneration after partial hepatectomy. The effects of long-term ethanol exposure on the response to growth factors will be studied both in vivo, after chronic ethanol feeding of the animals, and after prolonged ethanol exposure in vitro, using cultured hepatocytes. These studies are expected to expand our understanding of the mechanisms by which ethanol affects the early signal transduction events that mediate the actions of growth factors on liver parenchymal cells which are important in the control of liver regeneration.
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