Clinical and experimental evidence suggests that periconceptual folate supplementation reduces the risk for contruncal heart defects (CHD). This protective effect afforded by folic acid is unlikely to be the result of ameliorating a simple maternal folate deficiency. The data also argues against a folic acid deficiency inducing CHDs by limiting the availability of nucleic acids or disrupted transmethylation of genes in the developing embryo. It is likely that complex nutrient-gene interactions regulates the sensitivity of developing embryos to the induction of , or protection from, CHDs. The objective of this research program is to test critical hypotheses involving the regulation of intracellular folate and homocysteine concentrations on conotruncal cardiac development. Project 2 will test the hypothesis that cardiac defects may result from a direct effect of folate insufficiency on embryonic cells and will permit a comparison between these direct effects, and the secondary effects of increased homocysteine concentration. We intend to examine on morphological, molecular and physiological/cellular levels, those developmental processes which are compromised by either the absence of sufficient available folate molecules, or by exposure to elevated concentrations of homocysteine. We also intend to identify those processes that benefit from maternal folate supplementation. Specifically, we will examine the interaction between maternal folate intake and sensitive embryonic genotypes utilizing unique transgenic knockout mouse models in which the folate receptor (Folbp1) and/or the reduced folate carrier (RFC) have been inactivated. The impact of maternal folate and vitamin supplementation on the developmental morphology of the conotruncus in the various embryonic genotypes, as well as Folbp1 and RFC protein expression/distribution, neural crest cell migration and apoptosis patterns, and regulation of downstream gene expression will be assessed. The development of these model systems should greatly improve our understanding of comparable events occurring in humans.
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