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.
| Lie, Octavian V; Bennett, Gregory D; Rosenquist, Thomas H (2010) The N-methyl-d-aspartate receptor in heart development: a gene knockdown model using siRNA. Reprod Toxicol 29:32-41 |
| Rosenquist, Thomas H; Chaudoin, Tammy; Finnell, Richard H et al. (2010) High-affinity folate receptor in cardiac neural crest migration: a gene knockdown model using siRNA. Dev Dyn 239:1136-44 |
| Cabrera, Robert M; Shaw, Gary M; Ballard, Johnathan L et al. (2008) Autoantibodies to folate receptor during pregnancy and neural tube defect risk. J Reprod Immunol 79:85-92 |
| Gelineau-van Waes, Janee; Maddox, Joyce R; Smith, Lynette M et al. (2008) Microarray analysis of E9.5 reduced folate carrier (RFC1;Slc19a1) knockout embryos reveals altered expression of genes in the cubilin-megalin multiligand endocytic receptor complex. BMC Genomics 9:156 |
| Gelineau-van Waes, Janee; Heller, Steven; Bauer, Linda K et al. (2008) Embryonic development in the reduced folate carrier knockout mouse is modulated by maternal folate supplementation. Birth Defects Res A Clin Mol Teratol 82:494-507 |
| Finnell, Richard H; Shaw, Gary M; Lammer, Edward J et al. (2008) Gene-nutrient interactions: importance of folic acid and vitamin B12 during early embryogenesis. Food Nutr Bull 29:S86-98;discussion S99-100 |
| Zhu, Huiping; Wlodarczyk, Bogdan J; Scott, Melissa et al. (2007) Cardiovascular abnormalities in Folr1 knockout mice and folate rescue. Birth Defects Res A Clin Mol Teratol 79:257-68 |
| Chevrier, Cecile; Perret, Claire; Bahuau, Michel et al. (2007) Fetal and maternal MTHFR C677T genotype, maternal folate intake and the risk of nonsyndromic oral clefts. Am J Med Genet A 143:248-57 |
| Rosenquist, Thomas H; Finnell, Richard H (2007) Another key role for the cardiac neural crest in heart development. Am J Physiol Heart Circ Physiol 292:H1225-6 |
| Chen, Brian H; Carmichael, Suzan L; Shaw, Gary M et al. (2007) Association between 49 infant gene polymorphisms and preterm delivery. Am J Med Genet A 143A:1990-6 |
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