Neural tube defects (NTDs) are common human congenital anomalies whose etiologies remain largely unknown. One of the most promising clues to the causes of NTDs is that women who use vitamins containing folic acid in early pregnancy are at reduced risk for NTD-affected pregnancies. However, the underlying mechanisms by which folic acid reduces risks are unknown. Also unknown is why a substantial proportion of women who take folic acid continue to have NTD-affected pregnancies. This research proposes an extensive NTD gene and risk factor discovery program which focus on etiologies of NTDs by: 1) studying new genetic polymorphisms related to the folate pathway; 2) exploring dietary intake of important nutritional factors such as choline and glycemic index, controlling for folate intake; 3) measuring specific nutrients and antibodies in midpregnancy sera from women who deliver fetuses/infants with NTDs compared to those who do not; and 4) exploring three unique mouse models pertaining to impaired folate transport to identify new target genes that can be applied to our human studies. This multidisciplinary and integrated 5- year research program will use four large population-based epidemiologic datasets containing data on 1559 infants or fetuses with NTDs and 3353 nonmalformed control infants in combination with state-of-the-art laboratory genotyping methods of human DNA, and will capitalize on unique genetic mouse models to further inform epidemiologic direction. The research program has four collaborating institutions, the California Birth Defects Monitoring Program, the Institute of Biosciences and Technology at Texas A&M University, University of Nijmegen, and Children's Hospital Oakland Research Institute. The research capitalizes on the investigators' collective expertise in molecular and nutritional epidemiology, clinical, molecular, and murine genetics, and teratology. This research program will enhance scientific understanding of the genetic and nutritional causes of NTDs. Because NTDs result in substantial morbidity as well as high emotional and economic costs, further scientific understanding leading to possible prevention would greatly benefit society. ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
7R01NS050249-05
Application #
7877247
Study Section
Developmental Brain Disorders Study Section (DBD)
Program Officer
Riddle, Robert D
Project Start
2005-09-01
Project End
2010-11-30
Budget Start
2009-03-01
Budget End
2009-11-30
Support Year
5
Fiscal Year
2008
Total Cost
$103,362
Indirect Cost
Name
Stanford University
Department
Pediatrics
Type
Schools of Medicine
DUNS #
009214214
City
Stanford
State
CA
Country
United States
Zip Code
94305
Lupo, Philip J; Mitchell, Laura E; Canfield, Mark A et al. (2014) Maternal-fetal metabolic gene-gene interactions and risk of neural tube defects. Mol Genet Metab 111:46-51
Lei, Yunping; Zhu, Huiping; Duhon, Cody et al. (2013) Mutations in planar cell polarity gene SCRIB are associated with spina bifida. PLoS One 8:e69262
Wallingford, John B; Niswander, Lee A; Shaw, Gary M et al. (2013) The continuing challenge of understanding, preventing, and treating neural tube defects. Science 339:1222002
Yang, Wei; Carmichael, Suzan L; Tinker, Sarah C et al. (2012) Association between weight gain during pregnancy and neural tube defects and gastroschisis in offspring. Birth Defects Res A Clin Mol Teratol 94:1019-25
Carmichael, Suzan L; Yang, Wei; Feldkamp, Marcia Lynn et al. (2012) Reduced risks of neural tube defects and orofacial clefts with higher diet quality. Arch Pediatr Adolesc Med 166:121-6
Cabrera, Robert M; Finnell, Richard H; Zhu, Huiping et al. (2012) Transcriptional analyses of two mouse models of spina bifida. Birth Defects Res A Clin Mol Teratol 94:782-9
Lupo, Philip J; Canfield, Mark A; Chapa, Claudia et al. (2012) Diabetes and obesity-related genes and the risk of neural tube defects in the national birth defects prevention study. Am J Epidemiol 176:1101-9
Lupo, Philip J; Chapa, Claudia; Nousome, Darryl et al. (2012) A GCH1 haplotype and risk of neural tube defects in the National Birth Defects Prevention Study. Mol Genet Metab 107:592-5
Etheredge, Analee J; Finnell, Richard H; Carmichael, Suzan L et al. (2012) Maternal and infant gene-folate interactions and the risk of neural tube defects. Am J Med Genet A 158A:2439-46
Chandler, Angela L; Hobbs, Charlotte A; Mosley, Bridget S et al. (2012) Neural tube defects and maternal intake of micronutrients related to one-carbon metabolism or antioxidant activity. Birth Defects Res A Clin Mol Teratol 94:864-74

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