Gene-Nutrient Interactions in Neural Tube Defects

描述（由申请人提供）：合成核苷酸（嘌呤和dTMP）和S-腺苷蛋氨酸（AdoMet）需要叶酸代谢。叶酸代谢的破坏影响AdoMet和dTMP的合成，从而影响AdoMet依赖的甲基化反应和DNA中尿嘧啶的含量。DNA尿嘧啶和甲基化都影响DNA的稳定性，染色质甲基化调节许多基因的表达。目前尚不清楚叶酸代谢紊乱与病理（包括某些癌症、心血管疾病）和发育异常（包括神经管缺陷（NTDs））之间的关联是否源于AdoMet合成和/或dTMP合成的改变。最近，我们证明了胞浆丝氨酸羟甲基转移酶（cSHMT）是一种代谢开关，调节dTMP和AdoMet生物合成途径之间叶酸活化的碳单元的通量。在cSHMT和cSHMT-/-小鼠中观察到，cSHMT的表达降低，诱导胚胎NTDs，使动物对结肠癌敏感，影响DNA中尿嘧啶含量，增加AdoMet/AdoHcy比值。这是唯一一种由于叶酸依赖酶的破坏而表现出NTDs的小鼠模型，从而能够阐明叶酸反应性NTDs的机制。CSHMT在已知与叶酸相关病理/发育异常（包括NTDs）相关的组织中表达。cSHMT的表达和活性受到多种营养物质的动态调节，因此cSHMT可能与叶酸相关病理的病因有关，并可能成为通过饮食预防的目标。研究将确定饮食、胚胎和母体cSHMT基因型对NTD发生的贡献，并阐明cSHMT在NTD病因学中的代谢作用。具体目的是：1)确定cSHMT缺乏小鼠中增加NTDs风险的基因-营养素相互作用。2)确定神经管闭合缺陷相关的代谢缺陷。3)阐明cSHMT summoylation对NTD频率的贡献。4)确定cSHMT和MTHFR是否相互作用增加叶酸反应性NTDs的风险。待验证的主要假设是：1)cSHMT表达通过改变叶酸代谢而增加叶酸反应性NTD风险。2) cSHMT summoylation的损伤影响dTMP和AdoMet的合成和NTDs的风险。3) cSHMT和MTHFR基因相互作用增加叶酸反应性NTDs的风险。公共卫生相关性：该项目的长期目标是确定神经管闭合缺陷的潜在机制和cSHMT在NTD预防中的作用。叶酸相关的病理，包括某些癌症和发育缺陷，包括神经管缺陷，是涉及基因营养相互作用的常见和复杂的疾病，但潜在的机制尚未确定。美国食品供应中的叶酸强化是为了减少出生缺陷的发生率，但人们仍然担心叶酸强化对癌症发病率的影响。本研究将探讨叶酸相关出生缺陷的机制，以及叶酸和其他饮食成分在预防叶酸代谢紊乱导致的叶酸相关出生缺陷的第一个小鼠模型中的作用。

DESCRIPTION (provided by applicant): 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. PUBLIC HEALTH RELEVANCE: 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.