The central theme and overall objective of this program is to determine the biological mechanisms whereby folic acid insufficiency and hyperhomocysteinemia may contribute to abnormal development of the heart. This program project is designed to provide maximum focus upon this theme, and to optimize scientific and intellectual synergy among members of the research team. Discovery of the cellular mechanisms that provide this protection is the objective of the research program proposed here. Two hypotheses will be tested: Hyperhomocysteinemia that results from folic acid insufficiency may induce abnormal development of the conotruncal region of the heart, as well as other neural crest and neural tube derivatives, by inhibiting the function of N-methyl-D-aspartate receptors (NMDA). Folate insufficiency also may induce abnormal development by a direct effect upon the growth and differentiation of neural crest and neural tube cells directly, for example, by limiting the availability of methyl groups for gene methylation. A principle objective of this research program is to sort out the biological effects of low folate from those of hyperhomocysteinemia; and to determine how these two mechanisms may interact. It is inferred that they converge upon processes that are especially critical to the cardiac neural crest, other regions of the neural crest, and the neural tube. Project 1 will examine the teratogenic interaction of homocysteine with other NMDA antagonists, and will determine the degree to which embryos can be rescued by NMDA activation. Project 2 will investigate the impact of impaired folate binding and transport on the development of the heart, as well as other neural crest and neural tube derivatives, using transgenic mouse embryos models made for this purpose. Project 3 will concentrate upon the relative roles of hyperhomocysteinemia and the NMDA on the one hand, and folate insufficiency on the other, as they impact on neural crest cell migration and differentiation. Project 4 will test the elements of each of these hypotheses in a population-based study.
| 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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