ETHANOL EFFECT ON SIGNALLING PATHWAYS AFFECTING ODC

The proposed research training centers on a study of the molecular effects of ethanol on the developing fetus. Using chick embryos and chick fibroblasts, the effects of ethanol on growth-related signalling pathways will be explored. The downstream target of many mitogenic signalling pathways is ornithine decarboxylase (ODC), the rate-limiting enzyme in polyamine synthesis. Ethanol has been shown to inhibit ODC activity but the molecular mechanisms for this regulation remain unknown. Exogenous insulin and increased intracellular cAMP levels, which can activate protein kinase A (PKA), have been shown to increase ODC activity in chick fibroblasts while protein kinase C (PKC) has been shown to inhibit ODC activity in this same system. Ethanol may act to disrupt the PKA and insulin signalling pathways and/or activate the PKC signalling pathway thus resulting in decreased ODC activity. Ethanol-induced ODC inhibition correlates with growth suppression therefore a disruption of either the PKA or insulin signalling pathways or an upregulation of the PKC signalling pathway, perhaps mediated by increased intracellular Ca2+ levels, could account for some of the growth suppression seen in developing chicks exposed to ethanol. This proposal will investigate the mechanisms by which ethanol inhibits ODC activity. By exploring the insulin, PkA, PKC, and Ca2+ signalling pathways an understanding will be gained of not only the effects of ethanol on these systems but also the cross-talk, if any, which exists between signalling pathways. An understanding of molecular effects caused by ethanol exposure will then lead to a better understanding of fetal alcohol syndrome (FAS) and its devastating consequences.