Folate-p53 Interactions in Neural Tube Defects

摘要： 神经管缺陷（NTD）是一种有害的出生缺陷，可导致脑疝和神经暴露。 在胚胎发育过程中当神经管不能闭合时的组织。叶酸缺乏显示出高 叶酸与NTD的发展有关，70%的NTD是叶酸反应性的。然而，机制 这一拯救作用仍有待阐明。抑癌蛋白p53在肿瘤的发生发展中起着重要的作用。 发展体外研究证实了p53和叶酸一碳代谢之间的相互作用， 特别是从头胸苷酸（dTMP）生物合成途径。秸秆实验室已经证明 从头dTMP生物合成途径的损伤最终导致NTD的增加。先前 研究表明，dTMP从头生物合成受损导致尿嘧啶在DNA中积累， 基因组不稳定性，另一篇论文表明DNA中尿嘧啶的积累导致p53介导的 凋亡根据这些信息，叶酸缺乏NTD的形成机制已被提出， 已经制定并将进行审查。具体来说，这项提议旨在研究p53在叶酸代谢中的作用。 缺陷以及它如何影响基因组不稳定性和NTD发病率。 该提案的第一部分将确定叶酸缺乏对NTD发病率的影响， p53缺失和p53无效NTD是否是叶酸应答性的。这些结果将说明在体内 p53和叶酸一碳代谢在神经管缺陷发生中的相互作用在这 目的是对胚胎进行NTD表型分析。该提案的第二部分将确定叶酸的效果 缺陷在p53缺失胚胎中具有基因组不稳定性。这个问题将由以下人员回答： 用生物标志物γH2AX测量从头dTMP合成、DNA中的尿嘧啶和DNA损伤。这 一项提案将揭示p53和叶酸缺乏之间的相互作用， 合成、DNA中的尿嘧啶和基因组不稳定性。最重要的是，这个项目可能会阐明一个可能的 母体叶酸缺乏胚胎中基因组不稳定性和NTDs发生的机制 节食。

Abstract: Neural tube defects (NTDs) are deleterious birth defects that result in herniation and exposure of nervous tissue during embryogenesis when the neural tube fails to close. Folate deficiency has shown a high association to the development of NTDs and 70% of all NTDs are folate responsive. However, the mechanism of this rescue effect remains to be elucidated. The tumor suppressor protein p53 plays an important role in development. Studies in vitro demonstrate interactions between p53 and folate one carbon metabolism, specifically the de novo thymidylate (dTMP) biosynthesis pathway. The Stover laboratory has demonstrated that impairments in the de novo dTMP biosynthesis pathway ultimately leads to an increase in NTDs. Previous studies have demonstrated impaired de novo dTMP biosynthesis leads to uracil accumulation in DNA and genomic instability and another paper has shown that uracil accumulation in DNA leads to p53-mediated apoptosis. Compiling this information, a proposed mechanism of the development of folate deficient NTDs has been developed and will be examined. Specifically, this proposal aims to investigate the role of p53 in folate deficiency and how it may affect genomic instability and NTD incidence. The first part of the proposal will determine the effect folate deficiency has on the incidence of NTDs in the absence of p53 and whether p53 null NTDs are folate responsive. These results will illustrate the in vivo interaction between p53 and folate one carbon metabolism in the development of neural tube defects. In this aim, embryos will be phenotyped for NTDs. The second part of the proposal will determine the effect folate deficiency has in p53 null embryos in terms of genomic instability. This question will be answered by measuring de novo dTMP synthesis, uracil in DNA, and DNA damage with the biomarker γH2AX. This proposal will uncover the interaction between p53 and folate deficiency in regards to de novo thymidylate synthesis, uracil in DNA, and genomic instability. Most importantly, this project may elucidate a possible mechanism for the development of genomic instability and NTDs in embryos from maternal folate deficient diets.