This is a request for an ADAMHA Research Scientist Development Award (RSDA). 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 development proliferation and survival. 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. 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 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 immunopurified IGF-l receptor preparations. These studies will be extended to the effect of ethanol on IGF-1 mediated proliferation and survival of neuronal cells in primary cultures and of established glioma cell lines. The results will highlight the mechanisms by which ethanol interferes with the IGF system, and the consequent disruption of cell proliferation, and may provide a basis for more extensive studies of protective measures.
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