ETHANOL EFFECT ON SIGNALLING PATHWAYS AFFECTING ODC

Project: Research project

Project Details

Description

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.
StatusFinished
Effective start/end date3/1/952/29/96

Funding

  • National Institute on Alcohol Abuse and Alcoholism

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