This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The project, as initially proposed, involves using a molecular genetic approach to focus mechanistically on alterations in developmental events leading to malformations of the inner ear subsequent to prenatal alcohol exposure (Fetal Alcohol Syndrome; FAS). Epidemiological evidence suggests that approximately 30% of children affected with FAS experience sensorineural hearing loss, yet the underlying mechanisms are largely unknown. It was hypothesized that malformations of the inner ear/cochlea following in utero alcohol exposure resulted from a decrease in endogenous retinoic acid biosynthesis due to competition between alcohol and retinol for alcohol dehydrogenase enzyme pathways. This hypothesis was substantiated by in vitro experiments using an F9 cell line with a RARE-lacZ construct, in which a decrease in ?-galactosidase staining (positive for activation of the retinoic acid response element (RARE)) was demonstrated as increasing concentrations of ethanol were added to the media. Ethanol administration to pregnant dams of the inbred SWV murine strain resulted in offspring with multiple birth defects, including exencephaly, midfacial hypoplasia, cleft lip/palate, heart defects, and caudal regression, all of which were prevented when the mice were fed a diet rich in vitamin A. The impact of ethanol exposure on inner ear morphology was examined in both murine and chick embryo models. However, the teratogenic effects of maternal alcohol exposure were recognized to be very pleiotropic, and the project has re-focused on a single gene/pathway involved in a neurosensory system. The new proposal will investigate genetic/biochemical pathways regulated by microphthalmia-associated transcription factor (Mitf) in development of the retinal pigment epithelium (RPE) and in the stria vascularis of the inner ear. This will include the function of Mift in cell fate determination in the RPE and stria, its response to endothelial growth factors, and its role in modulating oxidative stress.
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