This is a resubmitted revised application for renewal of an ongoing project relating to the consequences of exposure to ethanol during nervous system development. The proposed studies are designed to test two major hypotheses: That a primary target of ethanol during nervous system development is proliferating cells, and that ethanol-induced changes in proliferation of neuronal and glial cells or precursors result from disruption of actions of growth factors. The proposed studies will use primarily in vitro analyses to examine the interactions of ethanol and several growth factors which have been shown to affect cellular proliferation. These factors include the mitogens basic fibroblast growth factor (bFGF), platelet-derived growth factor (PDGF), and the anti-mitogen transforming growth factor beta-1(TGF-beta1). The cellular populations to be used to assay the interactions of ethanol with these substances will be C6 astrocytoma cells, primary cortical astrocyte cultures, and B104 neuroblastoma cells. A wide variety of procedures will be applied to these studies, ranging from quantitative molecular techniques to neuroanatomical analyses. Specific experiments will determine the influence of ethanol exposure on expression and secretion of growth factors; effects of ethanol on the expression of specific growth factor receptors; the influences on these growth factors on regulation of cell proliferation and cell cycle kinetics; the effects of ethanol on binding characteristics of growth factor receptors; ethanol influences on growth factor and growth factor receptor MAP kinase activity and expression; and a developmental analysis of growth factor and growth factor receptor expression in vivo. These studies are designed to examine many levels at which ethanol may act, including ligands, receptors, receptor-mediated signal transduction, secretion, transcription and translation.
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