FETAL ALCOHOL SYNDROME: GENETIC STUDIES IN ZEBRAFISH

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This application is being submitted for consideration as a small grant (R03). I am a new investigator planning to expand my research focus to include the area of ethanol-induced birth defects. The long-range goal of this project is to elucidate the molecular mechanisms by which ethanol perturbs embryonic and fetal development and to identify genes that play a role in the sensitivity to ethanol-induced teratogenesis. Fetal Alcohol Syndrome (FAS) is a constellation of congenital anomalies seen in some newborns exposed to alcohol through maternal consumption and is characterized by prenatal and postnatal failure to thrive, central nervous system disorders, and a distinctive set of patterning defects that affect the cardiovascular system, facial structures and limbs. Data from twin studies and animal models argue strongly for a robust genetic component to FAS. Our hypothesis is that mutations in single genes influence one's resistance to ethanol-induced teratogenesis. The zebrafish vertebrate model system has proven to be very powerful for the purpose of identifying genes that play a role in specific physiological events. The specific aims of this proposal are to: [1] Analyze the non-lethal teratogenic effects of ethanol in selected zebrafish strains, and [2] Map and isolate the genomic region(s) containing the gene(s) responsible for the differential sensitivity of zebrafish strains to the embryolethal effects of ethanol exposure. Comparing sensitive and resistant zebrafish strains will elucidate the genetic and molecular mechanisms behind the sensitivity of vertebrate embryos to alcohol toxicity, and may apply directly to alcohol sensitivity in humans. The final products of the project described herein will be a thorough characterization of the nonlethal teratogenic effects of ethanol exposure in zebrafish that are characteristic of FAS, and the identification of several large genomic clones containing candidate genes that influence the sensitivity of zebrafish to the effects of ethanol exposure.