The proposed plan is designed to secure advanced training for my career development and allow me to become an independent investigator in a dynamic alcohol research environment. These career goals constitute steps in my more comprehensive plan to one day apply for a tenure track position, further solidify my research program and complete my transition to independent research status. To meet the career development goals, a systematic plan has been developed which include course work, workshops, interaction with my mentors and consultant, attending professional meetings, seminars and conferences, research training and grant application writing. The proposed research project is designed to increase our understanding of the molecular mechanisms underlying alcohol-induced dysmorphogenesis. It follows up on our previous identification of selected regions of the brain, otic, and optic primordia as targets of ethanol induced apoptosis and subsequent birth defects. Using in situ hybridization, we will test the hypothesis that abnormal expression of patterning genes occurs in the embryonic brain, eye and inner ear shortly after ethanol exposure; changes that presage subsequent dysmorphogenesis. Analyses of temporally and regionally-specific alterations in patterning genes and apoptosis will be conducted utilizing an acute ethanol exposure paradigm, whole embryo culture, and laser confocal imaging. Recognizing that ethanol exposure can interfere with retinoid metabolism and that retinoic acid regulates gene expression, we will also examine the hypothesis that diminishing retinoic acid-dependent gene signaling underlies ethanol's teratogenicity. For this work, we will compare gene expression patterns and patterns of apoptosis in the developing brain, eye and inner ear of retinoid-deficient (BMS493-treated) and ethanol-exposed mouse embryos and test retinoic acid's ameliorative potential. Additionally, because complex adaptive responses almost certainly are multigenic, we will identify and classify gene networks and pathways that mediate critical events in the ethanol-exposed developing brain using microarray-based analysis. Specifically, the gene networks and pathways that underlie the ethanol's concentration-dependent effects in the embryonic mouse brain will be identified and compared. This study is expected to provide important new data relative to molecular mechanisms of alcohol-related birth defects.
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