EXCEED THE SPACE PROVIDED. ? Ethanol inhibits cell adhesion mediated by the L1 cell adhesion molecule in neural cells and in fibroblasts ransfected with human L1. Because the brains of children with L1 mutations resemble those of children with tal alcohol syndrome, it is possible that inhibition of L1-mediated cell adhesion contributes to the eratogenic effects of ETOH. Structure activity analysis of a series of straight and branch-chain alcohols demonstrates remarkable structural specificity for alcohol inhibition of cell-cell adhesion. Moreover, we have dentified a series of compounds that antagonize the effects of ethanol on L1-mediated cell-cell adhesion, on BMP morphogenesis in cultured neural cells, and on the development of mouse whole embryo cultures. The underlying hypothesis of this proposal is that compounds that antagonize ethanol inhibition of L1-mediated cell-cell adhesion will also prevent ethanol teratogenesis. The proposed research has three specific aims: 1. To identify the structural determinants of alcohols and related compounds that are required for inhibition of cell-cell adhesion in L1-expressing cells and for antagonism of this inhibition; 2. To determine the mechanism(s) by which ethanol inhibits L1 adhesion and induces apoptotic cell death in neurons; 3. To characterize regions of L1 that are necessary for alcohol inhibition and for antagonism of ethanol inhibition; 4. To evaluate selected ethanol antagonists for their ability to prevent the teratogenic effects of ethanol in mouse whole embryo culture and during early embryogenesis in C57BI/J6 mice. Techniques employed in these studies will include mammalian cell transfection, cell-aggregation assays, mutagenesis of the L1 molecule, mousewhole embryo culture, and macroscopic and microscopic analysis of mice exposed to ethanol in utero. These experiments may lead to a better understanding of how ethanol interacts with neura proteins and may reveal mechanisms whereby ethanol causes birth defects. A major goal of the proposed research is to identify compounds that reduce the teratogenic effects of ethanol.
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