Folate-p53 Interactions in Neural Tube Defects

叶酸-p53 在神经管缺陷中的相互作用

• 批准号: 9761864
• 负责人: Erica Rose Lachenauer
• 金额: $ 1.83万
• 依托单位: CORNELL UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-01 至 2020-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9761864
• 关键词: Affect; Anabolism; Apoptosis; Biological Markers; Brain; Carbon; Cell Cycle Arrest; Congenital Abnormality; DNA; DNA Damage; DNA Double Strand Break; DNA Methylation; DNA biosynthesis; DNA-Directed DNA Polymerase; Development; Diet; Embryo; Embryonic Development; Enzymes; Etiology; Exhibits; Folic Acid; Folic Acid Deficiency; Gamma-H2AX; Gene Dosage; Genomic Instability; Impairment; In Vitro; Incidence; Laboratories; Lead; Measures; Mediating; Metabolism; Mus; Nerve Tissue; Neural Tube Defects; Neural Tube Development; Neural tube; Nuclear; Paper; Paralysed; Pathway interactions; Penetrance; Phenotype; Play; Pregnancy; Protein p53; Purines; Role; Spinal Cord; Supplementation; TP53 gene; Tumor Suppressor Proteins; Uracil; Vitamin B Complex; base; folic acid supplementation; in vivo; nutrition related genetics; prevent; thymidylate; Affect; Anabolism; Apoptosis; Biological Markers; Brain; Carbon; Cell Cycle Arrest; Congenital Abnormality; DNA; DNA Damage; DNA Double Strand Break; DNA Methylation; DNA biosynthesis; DNA-Directed DNA Polymerase; Development; Diet; Embryo; Embryonic Development; Enzymes; Etiology; Exhibits; Folic Acid; Folic Acid Deficiency; Gamma-H2AX; Gene Dosage; Genomic Instability; Impairment; In Vitro; Incidence; Laboratories; Lead; Measures; Mediating; Metabolism; Mus; Nerve Tissue; Neural Tube Defects; Neural Tube Development; Neural tube; Nuclear; Paper; Paralysed; Pathway interactions; Penetrance; Phenotype; Play; Pregnancy; Protein p53; Purines; Role; Spinal Cord; Supplementation; TP53 gene; Tumor Suppressor Proteins; Uracil; Vitamin B Complex; base; folic acid supplementation; in vivo; nutrition related genetics; prevent; thymidylate

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.

抽象的： 神经管缺陷（NTD）是有害的先天缺陷，导致神经的疝气和暴露 当神经管无法关闭时，胚胎发生过程中的组织。叶酸缺乏表现出很高的 与NTD的发展和所有NTD的70％的相关性是叶酸的反应。但是，机制 这种救援效应仍有待阐明。肿瘤抑制蛋白p53在 发展。体外研究表明，p53和叶酸一种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。斯托弗实验室已经证明 从头DTMP生物合成途径中的损害最终导致NTD的增加。以前的 研究表明，从头DTMP生物合成受损会导致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 凋亡。汇编此信息，叶酸不足NTD的发展的拟议机制具有 已开发并将检查。具体而言，该建议旨在研究p53在叶酸中的作用 缺乏及其如何影响基因组不稳定性和NTD发病率。 提案的第一部分将确定叶酸缺乏对NTD事件的影响 缺乏p53以及p53 null NTD是否具有叶酸反应。这些结果将说明体内 p53和叶酸之间的相互作用在神经管缺陷的发展中。在这个 目的，将对NTD进行表型。提案的第二部分将确定叶酸的效果 在基因组不稳定性方面，p53无效胚胎的缺陷具有。这个问题将由 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 提案将揭示p53和叶酸缺乏的相互作用。 合成，DNA中的尿嘧啶和基因组不稳定性。最重要的是，该项目可能会阐明可能 基因组不稳定性发展的机制和Mater叶酸默认的胚胎中NTD的机制 饮食。