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）是人类中第二大常见的结构性先天缺陷类型，导致神经管闭合（NTC）在神经过程中的失败。已知NTD的病因是多的阶乘，包括相互作用的遗传和环境因素。有多个与发展有关的随着NTC的空间和时间进行涉及的信号通路。特定遗传的鉴定对NTD的病因产生显着贡献的变体及其潜在分子的表征在过去的几十年中，导致NTC失败的细胞机制逐渐发展。是什么重要的是要认识到NTD是可预防的先天缺陷。数十年来的研究证明用叶酸补充母亲的周围感受可以将NTD的风险降低30％至70％。但是，并非所有NTD都是叶酸的反应。目前无法预防所有NTD的30-50％补充叶酸。拟议的研究项目基于我们最近发表的叶酸非 - 响应迅速的SLC25A32无效小鼠模型，以及与叶酸响应wnt wnt共受体LRP6的相互作用突变小鼠模型。研究旨在帮助阐明的基本机制的特征抗叶酸的NTD，并检验我们的假设，即可能会阻止这些叶酸抗性NTD 与下游叶酸代谢产物（例如甲状酸盐）的干预措施。最近确定甲酸盐可以拯救抗叶酸的NTD小鼠，表明线粒体一碳代谢可能是在非叶酸响应式NTD种群中受到损害。尽管进行了将近40年的深入研究，但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的过程。我们知识的这一差距阻碍了我们做出明智的健康政策决策的能力叶酸强化并确定新的治疗方法以防止抗叶酸的NTD。