Research Component 5 - Sulik 'Pathogenesis and Mechanisms of Ethanol-lnduced Teratogenicity'The goal of the proposed investigations is to make new discoveries regarding the pathology, pathogenesis,and mechanisms underlying early gestational (human first trimester equivalent) ethanol-induced craniofacialand central nervous system (CNS) defects and to extend these findings to Fetal Alcohol Spectrum Disorder(FASD) prevention strategies. To this end, we propose to utilize a mouse FASD model to meet 3 SpecificAims. For the first Aim, we will employ a unique platform of high resolution Magnetic Resonance Imagingand Diffusion Tensor Imaging to provide high- throughput dysmorphology screening and subsequentdiscovery of ethanol-induced CNS and associated craniofacial dysmorphology. This methodology promisesto provide an efficient means of comprehensively identifying patterns of ethanol-induced form and volumechanges. The results of this work are expected to highlight the damaging effect of first trimester ethanolexposure, inform human clinical research and identify new FASD diagnostic indicators. Studies for Aim 2 willbe informed by the results of the imaging analyses, and will explore developmental cascades of cell andtissue changes that underlie the observed ethanol-induced CNS dysmorphology. Based on preliminarystudies, initial emphasis will be placed on testing the hypothesis that ethanol insult early in the human firsttrimester equivalent diminishes populations of cortical and hippocampal interneurons; an effect that isassociated with insult to a source of their progenitor populations, the ganglionic eminences. Experiments forAim 3 are based on our previous findings and those of others that implicate oxidative damage and NF-kBactivation as a mechanism underlying ethanol's insult to early embryos. To extend this work, we propose totest the hypothesis that the teratogenic response of embryos' to ethanol involves reactive oxygen species(ROS)-mediated activation of NF-kB. Experiments to this end will include analyses of ethanol's induction ofboth upstream and downstream NF-kB-related signals and examination of ethanol-exposed NF-kB reporterembryos. Additionally, using high-throughput imaging techniques as for Aim 1, we will test the hypothesisthat maternal dietary antioxidant treatment will diminish the incidence and severity of ethanol-induced CNSdysmorphology. The results of the work for the third Aim are expected to provide a strong foundation forantioxidant supplementation as a practical human FASD-reduction approach.
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