Abstract

Supplemental folic acid is associated with significant decreases in conotruncal, orofacial, and neural tube defects. The amino acid homocysteine increases with folate deficiency, and elevated homocysteine per se appears to be a risk factor for these defects. Our recent studies have led to the hypothesis that homocysteine may perturb neural crest and neural tube development by acting as an antagonist for the N-methyl-D-aspartate glutamate receptor (NMDAR). Indeed, some of the best known risk factors for neural crest and neural tube abnormalities also are NMDAR antagonist. The present proposal will test the hypothesis that homocysteine induces conotruncal and related defects by acting as an NMDAR antagonist. Both the chicken and the mouse embryo models will be employed in these experiments. There are three aims of this proposal:
Aim 1, to test the hypotheses that NMDAR agonists will rescue homocysteine-treated embryos, and conversely, that exogenous NMDAR antagonists will interact synergistically with homocysteine to exacerbate the disruption of normal development.
Aim 2, to test the hypothesis that homocysteine and exogenous NMDAR antagonists disrupt the expression of key genes during hypothesis that homocysteine and exogenous NMDAR antagonists disrupt the expression of key genes during neural crest migration and neural tube closure.
Aim 2, to determine the effect of homocysteine and exogenous NMDAR antagonists on neural crest cell functions. This proposal offers the first unifying hypothesis regarding a mechanism for a set of important risk factors for abnormal development that includes therapeutic and recreational drugs, environmental contaminants, and low folate. A common mechanism of actions would show that these factors may interact in previous unsuspected ways. This proposal will begin to explore the role of gene/environment interactions in the induction of these abnormalities. Although folate supplements will result in fewer abnormalities, the most effective and comprehensive prevention strategies will come through a thorough understanding of the mechanisms that underlie abnormal development..

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL055940-07
Application #
6530687
Study Section
Cardiovascular and Pulmonary Research A Study Section (CVA)
Program Officer
Ershow, Abby
Project Start
1995-09-30
Project End
2004-02-29
Budget Start
2002-03-01
Budget End
2003-02-28
Support Year
7
Fiscal Year
2002
Total Cost
$341,002
Indirect Cost

  Institution

Name
University of Nebraska Medical Center
Department
Genetics
Type
Schools of Medicine
DUNS #
City
Omaha
State
NE
Country
United States
Zip Code
68198

  Publications

Latacha, Kimberly S; Rosenquist, Thomas H (2005) Homocysteine inhibits extra-embryonic vascular development in the avian embryo. Dev Dyn 234:323-31
Volcik, Kelly A; Zhu, Huiping; Finnell, Richard H et al. (2004) Evaluation of the jumonji gene and risk for spina bifida and congenital heart defects. Am J Med Genet A 126A:215-7
Brauer, P R; Tierney, B J (2004) Consequences of elevated homocysteine during embryonic development and possible modes of action. Curr Pharm Des 10:2719-32
Tierney, Brent J; Ho, Trang; Reedy, Mark V et al. (2004) Homocysteine inhibits cardiac neural crest cell formation and morphogenesis in vivo. Dev Dyn 229:63-73
Zhu, Huiping; Junker, Wade M; Finnell, Richard H et al. (2003) Lack of association between ZIC2 and ZIC3 genes and the risk of neural tube defects (NTDs) in Hispanic populations. Am J Med Genet A 116A:414-5
Volcik, Kelly A; Shaw, Gary M; Zhu, Huiping et al. (2003) Risk factors for neural tube defects: associations between uncoupling protein 2 polymorphisms and spina bifida. Birth Defects Res A Clin Mol Teratol 67:158-61
Brauer, Philip R; Rosenquist, Thomas H (2002) Effect of elevated homocysteine on cardiac neural crest migration in vitro. Dev Dyn 224:222-30
Rosenquist, T H; Finnell, R H (2001) Genes, folate and homocysteine in embryonic development. Proc Nutr Soc 60:53-61
Eudy, J D; Spiegelstein, O; Barber, R C et al. (2000) Identification and characterization of the human and mouse SLC19A3 gene: a novel member of the reduced folate family of micronutrient transporter genes. Mol Genet Metab 71:581-90
Rosenquist, T H; Schneider, A M; Monogham, D T (1999) N-methyl-D-aspartate receptor agonists modulate homocysteine-induced developmental abnormalities. FASEB J 13:1523-31

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