Folate-p53 Interactions in Neural Tube Defects

摘要： 神经管缺陷(Ntds)是一种有害的先天缺陷，会导致突出和暴露神经。 当神经管不能关闭时，胚胎发育过程中的组织。叶酸缺乏表现出很高的 与NTDS的发展有关，70%的NTDS对叶酸有反应。然而，这种机制 这一救援效果如何仍有待阐明。抑癌蛋白P53在肿瘤中起重要作用 发展。体外研究表明，P53和叶酸1碳代谢之间存在相互作用。 特别是从头合成胸腺嘧啶(DTMP)的生物合成途径。斯托弗实验室已经证明 DTMP生物合成途径的损伤最终导致NTDS的增加。上一首 研究表明，从头合成DTMP受损导致尿嘧啶在DNA和 基因组不稳定性和另一篇论文表明尿嘧啶在DNA中的积累导致P53介导 细胞凋亡。汇编这些信息，提出了叶酸缺乏性NTDS的发展机制 已经开发出来，并将进行检查。具体地说，这项建议旨在研究P53在叶酸中的作用 以及它如何影响基因组的不稳定性和NTD的发病率。 该提案的第一部分将确定叶酸缺乏对老年人NTDS发病率的影响 P53缺失以及P53缺失的NTD是否对叶酸有反应。这些结果将说明在体内 神经管畸形发生过程中P53与叶酸一碳代谢的相互作用在这 目的：对胚胎进行NTDS表型鉴定。提案的第二部分将确定叶酸的效果 在基因组不稳定方面，缺乏症会导致P53基因缺失。这个问题将由以下人员回答 用生物标记物γH_2AX测定dTMP的合成、dna中的尿嘧啶和dna损伤。这 提案将揭示P53和叶酸缺乏之间的相互作用与从头开始的胸腺酸 合成，DNA中的尿嘧啶，以及基因组的不稳定性。最重要的是，这个项目可能会阐明 叶酸缺乏母体胚胎基因组不稳定性和NTDS的发生机制 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.