Two major medical health care issues are inexorably intertwined: a woman's health, and prenatal development of her unborn child. Maternal folate status is one condition that has a profound influence on development of the central nervous system (CNS), and the incidence and recurrence of certain developmental disorders of the CNS (neural tube defects, NTDs). While NTDs are amongst the most common human malformations, the mechanisms by which folate exerts its ameliorative effect on these malformations, or its role in normal morphogenesis of the CNS, is not well understood. Extant data argue for interactions between folate status and developmental pathways controlled by specific transcriptional regulators. This proposal explores the nature of such interactions and consists of five, hypothesis-driven, specific aims linked together in order to present a cohesive picture of the molecular mechanisms by which specific translational coactivators mediate signal transduction in, and contribute to development of, the developing CNS. The overall hypothesis to be tested by the proposed specific aims is that normal CNS development in the mammalian embryo requires folate-mediated activation of a transcriptional complex, functionally dependent on proper expression and integration of specific transcriptional coactivators. Specifically, we propose that not only is proper expression of Folbp and transcriptional coactivators such as CBP, p300, Cited2, Cart1, and AP-2 requisite for CNS formation, but the integration of these molecules into a functional regulon is critical to normal CNS morphogenesis. Investments in research designed to reveal the causes of congenital anomalies such as NT defects provide excellent opportunities to meet Public Health Service requirements that biomedical science must pay social dividends. Experiments proposed in the current application seek to identify genes, genetic variations and molecular pathways associated with susceptibility to NT defects and to understand signaling mechanisms associated with such disorders.NARRATIVE: In the United States, every three minutes a baby is born with a birth defect! While neural tube defects (NTDs) are amongst the most common human malformations, the mechanisms by which folic acid exerts its ameliorative effect on these malformations, or its role in normal development of the neural tube, is not well understood. Studies proposed in the current application should provide a better understanding of prenatal factors influencing the nutritional/health status of pregnant women, and their impact on the health of the developing fetus, particularly as it relates to NTDs.
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