Identifying genetic modifiers of alcohol induced birth effects

Univ Of North Carolina Chapel Hill, Chapel Hill NC

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Abstract

Abstract: The objective of the proposed research is to identify genetic factors that modify sensitivity to prenatal alcohol exposure-induced birth defects, with the long-term goals of informing clinical practice, and ultimately reducing the incidence and severity of Fetal Alcohol Spectrum Disorders (FASD). This objective will be met by applying an innovative approach that includes utilization of high-throughput transcriptome sequencing (RNA-Seq), genetically modified mice, and the developing mammalian limb as a readily examined target tissue whose molecular signaling pathways and vulnerability to alcohol teratogenesis are well documented. This research proposal is founded on 1) strong evidence that at early developmental stages, alcohol-induced postaxial limb deficiencies occur as a result of a primary interference with developmental events that are upstream of antero-posterior (AP) limb patterning, 2) recognition that AP patterning is dependent upon signaling through the Sonic hedgehog (Shh) pathway, 3) illustration that genetically-based reduction in Shh signaling results in increased vulnerability to alcohol-induced birth defects, and 4) the hypothesis that haploinsufficiency of additional genes, both up-and downstream of Shh, will impart enhanced sensitivity to alcohol teratogenesis. The latter will be tested with experiments that employ a well-established FASD mouse model and will address the following Specific Aims: Aim 1 is to define gene expression differences between control and alcohol-exposed C57Bl/6J mouse embryos at the time of initial forelimb bud outgrowth and concurrent with peak sensitivity to alcohol teratogenesis; Aim 2 is to define gene expression differences between control and alcohol-exposed C57Bl/6J mouse forelimb buds at times concurrent with a later developmental epoch, the establishment of AP patterning; and the Aim 3 studies will identify the significance of specific genes that are modified following alcohol exposure by comparing pertinent genetically engineered mice relative to their sensitivity to alcohol?s teratogenicity. The proposed studies will be conducted by NCCU faculty and trainees under the mentorship of UNC?s Bowles Center for Alcohol Studies researchers. In addition to expanding our understanding of genetic susceptibilities to alcohol?s teratogenicity, this research project will foster state of the art research by budding minority scientists and will provide the foundation for important FASD studies to be addressed in future grant applications/research.