EXCEED THE SPACE PROVIDED. Over the past several years, we have pursued the hypothesis that signal transduction pathways coupled to activation of acetylcholine muscarinic receptors may represent a relevant target for the developmental neurotoxicity of ethanol. Initially, we provided evidence of a strong association between disruption of muscarinic receptor second messenger systems and ethanol-induced microencephaly. As proliferation of glial cells is a major event occurring during the brain growth spurt, a period most sensitive to ethanol-induced microencephaly, we formulated the hypothesis that acetylcholine may act as a mitogen in astrocytes and that disruption of acetylcholine-driven glial cell proliferation may play a primary role in the developmental neurotoxicity of ethanol, and may provide a link between the observed inhibition of muscarinic receptor function and the ensuing microencephaly. The general aim of this proposal remains that of investigating the cellular and molecular mechanisms underlying the developmental neurotoxicity of alcohol, and specifically the mechanisms involved in its ability to inhibit muscarinic receptor-induced astroglial cell proliferation.
The specific aims are: 1. To investigate the mechanisms by which ethanol affects the activation of phospholipase D and the formation of phosphatidic acid by muscarinic agonists in astroglial cells. 2. To investigate the effects of ethanol on protein kinase C and its role in the mitogenic effect of muscarinic agonists. 3. To investigate the effect of ethanol on two down-stream effectors of PKC , p70S6 kinase and NF-KB, and their role in carbachol-induced proliferation of astroglial cells. Altogether, these studies will add important information on the mechanisms by which ethanol inhibits muscarinic receptor-induced proliferation of astroglial cells, which would be relevant for its neurotoxic effects in the developing brain. PERFORMANCE SITE ========================================Section End===========================================
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