Role of Slc25a32 and Its Interaction with Lrp6 in the Etiology of Neural Tube Defects

Slc25a32 的作用及其与 Lrp6 的相互作用在神经管缺陷病因学中的作用

• 批准号: 10355528
• 负责人: RICHARD H. FINNELL
• 金额: $ 57.92万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-03-10 至 2025-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10355528
• 关键词: Biochemical; Biological Assay; CRISPR/Cas technology; Carbon; Cell Line; Cell physiology; Cells; Characteristics; Complex; Congenital Abnormality; Cyst; Cytoplasm; Developing Countries; Development; Embryo; Environmental Risk Factor; Etiology; Failure; Folic Acid; Frequencies; Genes; Genetic; Genetic Screening; Genotype; Glycine; Health Policy; Human; In Vitro; Incidence; Inherited; Intervention; Investigation; Knock-in; Knock-in Mouse; Knock-out; Knockout Mice; Knowledge; Luciferases; Mammals; Measures; Mediating; Metabolism; Mitochondria; Molecular; Mus; Mutant Strains Mice; Mutation; Neural Tube Closure; Neural Tube Defects; Neuroepithelial; Pathway interactions; Play; Population; Prevalence; Process; Proteins; Publishing; Regulation; Reporter; Reporting; Research; Research Project Grants; Resistance; Respiration; Risk; Role; SLC19A1 gene; Serine; Serum; Signal Pathway; Signal Transduction; Structural Congenital Anomalies; Testing; Tetrahydrofolates; Transgenic Mice; Variant; WNT Signaling Pathway; Wild Type Mouse; Work; base; beta catenin; cohort; design; folic acid supplementation; fortification; gene network; genetic variant; in vivo; in vivo evaluation; insight; malformation; metabolic profile; mouse model; mutant; mutant mouse model; neurodevelopment; novel; prevent; programs; receptor; response; uptake

ABSTRACT Neural tube defects (NTDs) are the second most common type of structural birth defects in humans, resulting from the failure of neural tube closure (NTC) during neurulation. The etiology of NTDs are known to be multi- factorial, including interacting genetic and environmental factors. There are multiple developmentally-related signaling pathways involved as NTC proceeds spatially and temporally. The identification of specific genetic variants that contribute significantly to the etiology of NTDs, and the characterization of their underlying molecular and cellular mechanisms leading to failed NTC has progressed slowly over the last several decades. What is important to recognize is that NTDs stand out as a preventable birth defect. Research spanning decades demonstrates that maternal periconceptional supplementation with folic acid can reduce the risk of NTDs by 30% to 70%. Yet not all NTDs are folate responsive. Currently between 30-50% of all NTDs are not preventable by folic acid supplementation. The proposed research project is based on our recently published folic acid non- responsive Slc25a32 null mouse model, and its interaction with a folic acid responsive Wnt co-receptor, Lrp6 mutant mouse model. The studies are designed to help elucidate the underlying mechanisms characteristic of folic acid resistant NTDs, and to test our hypothesis that these folate resistant NTDs may be prevented by interventions with downstream folate metabolites, such as formate. It was recently determined that formate could rescue folic acid-resistant NTD mice, suggesting that mitochondrial one carbon metabolism might be compromised in the non-folate responsive NTD population. Despite almost 40 years of intensive study, we still do not fully understand the molecular, cellular and biochemical mechanisms that underlie the folate-dependent process of NTC. This gap in our knowledge hinders our ability to make informed health policy decisions about folate fortification and to identify novel treatments to prevent folate-resistant NTDs.

摘要 神经管缺陷（NTD）是人类第二种最常见的结构性出生缺陷， 在神经形成期间神经管闭合（NTC）失败。NTD的病因学已知是多种- 因子，包括相互作用的遗传和环境因素。有多种与发育有关的 参与的信号通路的NTC进行空间和时间。特异性遗传物质的鉴定 对NTD的病因学有重要贡献的变异，以及它们的潜在分子特征， 导致NTC失效的细胞机制在过去几十年中进展缓慢。是什么 重要的是要认识到NTD是一种可预防的出生缺陷。数十年的研究 表明母亲围产期补充叶酸可将NTD的风险降低30% 到70%。然而，并非所有NTD都对叶酸有反应。目前，30-50%的NTD无法通过以下方法预防： 叶酸补充剂拟议的研究项目是基于我们最近发表的叶酸非- 响应性Slc 25 a32缺失小鼠模型及其与叶酸响应性Wnt共受体Lrp 6的相互作用 突变小鼠模型。这些研究旨在帮助阐明 叶酸耐药NTDs，并测试我们的假设，这些叶酸耐药NTDs可以预防， 与下游叶酸代谢物，如甲酸的干预。最近确定甲酸盐可以 拯救叶酸抗性NTD小鼠，这表明线粒体一碳代谢可能是 在非叶酸应答NTD人群中受损。尽管近40年的深入研究，我们仍然 并不完全了解叶酸依赖性的分子，细胞和生化机制 NTC的过程。我们知识上的这一差距阻碍了我们做出明智的卫生政策决定的能力， 叶酸强化，并确定新的治疗方法，以防止叶酸耐药NTD。