Abstract

The project proposes to test the hypothesis that abnormal maternal and/or fetal folate receptor increases environmentally-induced neural tube defects (NTD), and that the lack of folate results in abnormal gene expression during critical developmental periods. Arsenate will be used as a model teratogen to induce NTD.
For aim 1, knockout mice have been developed for folate binding protein 1 (FBP-1) and folate binding protein 2 (FBP-2). Animals possessing different FBP status will be examined for NTD and the effect of arsenate will be examined.
In aim 2, fusion protein transgenics animals will be studied. These animals will have FBP-1 and FBP-2 fusions with green fluorescence proteins (different GFPs that give emission spectra) in order to specifically detect the expression of each FBP so that the patterns of expression of each can be determined.
In aim 3, the effect of teratogenic concentrations of arsenate on expression of a number of transcription factor and growth factor genes will be examined. As well, the expression of cell cycle control and DNA repair genes will be examined.
In aim 4, the effect on neural tube closure of supplemental folate treatment on FBP compromised animals will be examined, as will the effect of arsenate.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Project (R01)
Project #
5R01HD035396-04
Application #
6181882
Study Section
Special Emphasis Panel (ZES1-CKS-B (02))
Program Officer
Henken, Deborah B
Project Start
1997-04-01
Project End
2002-03-31
Budget Start
2000-04-01
Budget End
2002-03-31
Support Year
4
Fiscal Year
2000
Total Cost
$220,727
Indirect Cost

  Institution

Name
University of Nebraska Medical Center
Department
Physical Medicine & Rehab
Type
Schools of Medicine
DUNS #
168559177
City
Omaha
State
NE
Country
United States
Zip Code
68198

  Publications

Finnell, Richard H; Waes, Janee Gelineau-van; Eudy, James D et al. (2002) Molecular basis of environmentally induced birth defects. Annu Rev Pharmacol Toxicol 42:181-208
Gefrides, Lisa A; Bennett, Gregory D; Finnell, Richard H (2002) Effects of folate supplementation on the risk of spontaneous and induced neural tube defects in Splotch mice. Teratology 65:63-9
Wlodarczyk, B; Spiegelstein, O; Gelineau-van Waes, J et al. (2001) Arsenic-induced congenital malformations in genetically susceptible folate binding protein-2 knockout mice. Toxicol Appl Pharmacol 177:238-46
Spiegelstein, O; Eudy, J D; Finnell, R H (2000) Identification of two putative novel folate receptor genes in humans and mouse. Gene 258:117-25
Barber, R C; Lammer, E J; Shaw, G M et al. (1999) The role of folate transport and metabolism in neural tube defect risk. Mol Genet Metab 66:1-9
Piedrahita, J A; Oetama, B; Bennett, G D et al. (1999) Mice lacking the folic acid-binding protein Folbp1 are defective in early embryonic development. Nat Genet 23:228-32
Barber, R C; Bennett, G D; Greer, K A et al. (1999) Expression patterns of folate binding proteins one and two in the developing mouse embryo. Mol Genet Metab 66:31-9
Barber, R C; Shaw, G M; Lammer, E J et al. (1998) Lack of association between mutations in the folate receptor-alpha gene and spina bifida. Am J Med Genet 76:310-7