Folate metabolism is required for the synthesis of nucleotides (purines and dTMP) and S- adenosylmethionine (AdoMet). Disruption of folate metabolism affects AdoMet and dTMP syntheses and thereby influences AdoMet-dependent methylation reactions and uracil content in DNA. Both DNA uracil and methylation affect DNA stability, and chromatin methylation regulates the expression of many genes. It is not known if the associations between disruptions in folate metabolism and pathologies (including certain cancers, cardiovascular disease) and developmental anomalies (including neural tube defects (NTDs)) result from altered AdoMet synthesis and/or dTMP synthesis. Recently, we demonstrated that the enzyme cytoplasmic serine hydroxymethyltransferase (cSHMT) is a metabolic switch that regulates the flux of folate-activated one-carbon units between the dTMP and AdoMet biosynthetic pathways. Reduced expression of cSHMT, as observed in both cSHMT+/- and cSHMT-/- mice, induces embryonic NTDs, sensitizes the animals to colon cancer, affects uracil content in DNA and increases the AdoMet/AdoHcy ratio. This is the only mouse model to exhibit NTDs as a result of the disruption of a folate-dependent enzyme, and thereby enables elucidation of the mechanisms underlying folate-responsive NTDs. CSHMT is expressed in tissues known to be associated with folate-related pathologies/developmental anomalies including NTDs. The expression and activity of cSHMT is dynamically regulated by several nutrients and therefore the cSHMT has the potential to contribute to the etiology of folate-related pathologies and may be a target for prevention through diet. The contributions of diet, embryonic and maternal cSHMT genotype to NTD occurrence will be determined, and the metabolic role of cSHMT in NTD etiology will be elucidated.
The specific aims are: 1) to determine the gene-nutrient interactions that increase risk for NTDs in mice deficient in cSHMT. 2) to determine the metabolic defect associated with neural tube closure defects. 3) to elucidate the contribution of cSHMT SUMOylation to NTD frequency. 4) to determine if cSHMT and MTHFR interact to increase risk for folate-responsive NTDs. The principle hypotheses to be tested are that: 1) cSHMT expression contributes to folate-responsive NTD risk by altering folate metabolism. 2) impairments in cSHMT SUMOylation affect dTMP and AdoMet synthesis and risk for NTDs. 3) the cSHMT and MTHFR genes interact to increase risk for folate-responsive NTDs. The long-term goals of this project is to determine the mechanisms underlying neural tube closure defects and the role of cSHMT in NTD prevention. Folate-related pathologies, including certain cancers, and developmental defects, including neural tube defects, are common and complex disorders involving gene nutrient interactions but the underlying mechanisms are not established. Folate-fortification of the US food supply was implemented to reduce incidence of birth defects, yet concerns remain regarding the effects of folate fortification on cancer incidence. The studies outlined in this proposal will investigate the mechanisms of folate-related birth defects and role of folate and other dietary components in preventing these defects in the first mouse model of folate-related birth defects resulting from disrupted folate metabolism.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Project (R01)
Project #
5R01HD059120-05
Application #
8298622
Study Section
Special Emphasis Panel (ZRG1-EMNR-G (02))
Program Officer
Henken, Deborah B
Project Start
2008-09-25
Project End
2014-06-30
Budget Start
2012-07-01
Budget End
2014-06-30
Support Year
5
Fiscal Year
2012
Total Cost
$311,018
Indirect Cost
$109,058
Name
Cornell University
Department
Nutrition
Type
Schools of Earth Sciences/Natur
DUNS #
872612445
City
Ithaca
State
NY
Country
United States
Zip Code
14850
Field, Martha S; Stover, Patrick J (2017) Safety of folic acid. Ann N Y Acad Sci :
Stover, Patrick J; Berry, Robert J; Field, Martha S (2016) Time to Think About Nutrient Needs in Chronic Disease. JAMA Intern Med 176:1451-1452
Field, Martha S; Kamynina, Elena; Stover, Patrick J (2016) MTHFD1 regulates nuclear de novo thymidylate biosynthesis and genome stability. Biochimie 126:27-30
Field, Martha S; Kamynina, Elena; Watkins, David et al. (2015) Human mutations in methylenetetrahydrofolate dehydrogenase 1 impair nuclear de novo thymidylate biosynthesis. Proc Natl Acad Sci U S A 112:400-5
Stover, Patrick J; MacFarlane, Amanda J; Field, Martha S (2015) Bringing clarity to the role of MTHFR variants in neural tube defect prevention. Am J Clin Nutr 101:1111-2
Finkelstein, Julia L; Layden, Alexander J; Stover, Patrick J (2015) Vitamin B-12 and Perinatal Health. Adv Nutr 6:552-63
Field, Martha S; Kamynina, Elena; Watkins, David et al. (2015) New insights into the metabolic and nutritional determinants of severe combined immunodeficiency. Rare Dis 3:e1112479
Martiniova, Lucia; Field, Martha S; Finkelstein, Julia L et al. (2015) Maternal dietary uridine causes, and deoxyuridine prevents, neural tube closure defects in a mouse model of folate-responsive neural tube defects. Am J Clin Nutr 101:860-9
Field, Martha S; Kamynina, Elena; Agunloye, Olufunmilayo C et al. (2014) Nuclear enrichment of folate cofactors and methylenetetrahydrofolate dehydrogenase 1 (MTHFD1) protect de novo thymidylate biosynthesis during folate deficiency. J Biol Chem 289:29642-50
Scotti, Marco; Stella, Lorenzo; Shearer, Emily J et al. (2013) Modeling cellular compartmentation in one-carbon metabolism. Wiley Interdiscip Rev Syst Biol Med 5:343-65

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