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

基本信息

批准号：
10577749
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
项目类别：
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/10577749
关键词：
Biochemical Biological Assay CRISPR/Cas technology Carbon Cell Line Cell physiology Cells Characteristics Complex Conceptions Congenital Abnormality Cyst Cytoplasm Developing Countries Development Embryo Environmental Risk Factor Etiology Failure Folic Acid Formates Frequencies Genes Genetic Genetic Screening Genotype Glycine Health Policy Heterozygote 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 Risk Reduction Role SLC19A1 gene Serine Serum Signal Pathway Signal Transduction Structural Congenital Anomalies Testing Tetrahydrofolates Transgenic Mice Variant WNT Signaling Pathway Wild Type Mouse Work 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

项目摘要

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.

抽象的神经管缺陷（NTD）是人类第二常见的结构性出生缺陷类型，导致神经管闭合（NTC）在神经形成过程中失败。 NTD 的病因学已知有多种：因子，包括相互作用的遗传和环境因素。存在多种与发育相关的 NTC 在空间和时间上进行时涉及的信号通路。特定基因的鉴定对 NTD 病因学及其潜在分子特征有显着影响的变异体导致 NTC 失败的细胞机制在过去几十年中进展缓慢。什么是需要认识到的重要一点是，被忽视的热带疾病是一种可以预防的出生缺陷。研究跨越数十年研究表明，母亲围孕期补充叶酸可将 NTD 风险降低 30% 至 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：补充叶酸。拟议的研究项目基于我们最近发表的叶酸非响应性 Slc25a32 无效小鼠模型及其与叶酸响应性 Wnt 共受体 Lrp6 的相互作用突变小鼠模型。这些研究旨在帮助阐明潜在的机制特征叶酸抗性 NTD，并检验我们的假设，即这些叶酸抗性 NTD 可以通过以下方法预防：对下游叶酸代谢物（例如甲酸）的干预。最近确定甲酸盐可以拯救叶酸抗性 NTD 小鼠，表明线粒体一碳代谢可能是在非叶酸反应性 NTD 人群中受到损害。尽管经过近 40 年的深入研究，我们仍然不完全了解叶酸依赖性的分子、细胞和生化机制 NTC过程。我们的知识差距阻碍了我们做出明智的卫生政策决策的能力叶酸强化并确定预防叶酸抗性 NTD 的新疗法。