Alcoholism is associated with profound alterations in cell growth and proliferation. The most serious manifestation of disrupted cell growth is the fetal alcohol syndrome, although altered cell growth may also play a significant role in the development of anemia, cirrhosis, and the general catabolic state associated with alcoholism. The activation of insulin- like growth factor 1 (IGF-1) receptor by its ligands IGF-1 and IGF-2 plays a critical role in cellular proliferation and survival, and central nervous system development. It has been demonstrated that ethanol, at physiologically tolerated levels, markedly reduces the autophosphorylation of the IGF-1 receptor by its ligands, and effectively inhibits IGF-1- mediated cell proliferation and protection from apoptosis. It is now proposed to investigate the respective roles of the IGF-1 receptor and its ligands in the inhibition of cellular proliferation by ethanol. The model system of mouse fibroblasts will be used initially since these cells are exquisitely IGF-growth regulated, and offer the opportunity to genetically manipulate the cells to study the various functional components of the IGF signalling pathway. The in vitro effect of ethanol on IGF and IGF-1 receptor mRNA expression will be studied. The mechanism of ethanol action on the IGF-1 receptor will be analyzed in purified plasma membranes and purified IGF-1 receptor preparations. The effect of ethanol on the ability of IGF-1 and its receptor to prevent apoptosis will be studied. These studies will be extended to the effect of ethanol on IGF-1-mediated proliferation and survival of neuroglial cells in primary cultures and of established glioma cell lines. Lastly, the expression of IGF ligands and receptors in the central nervous system of fetal rats, chronically intoxicated with ethanol, will be determined. The results will highlight the mechanisms by which ethanol interferes with the IGF system, and the consequent disruption of cell proliferation and possibly CANS development, and may provide a basis for more extensive studies of protective measures.
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