Mechanisms of mitochondrial folate metabolism in neural tube closure

线粒体叶酸代谢在神经管闭合中的机制

• 批准号: 8397881
• 负责人: Jessica E. Momb
• 金额: $ 5.22万
• 依托单位: UNIVERSITY OF TEXAS AT AUSTIN
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-01 至 2015-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8397881
• 关键词: Adverse effects; Anabolism; Biochemical; Biological Assay; Carbon; Cell Proliferation; Cereals; Congenital Abnormality; Congenital Heart Defects; Cytoplasm; Defect; Dependence; Development; Dietary Intervention; Dietary Supplementation; Embryo; Embryonic Development; Ensure; Enzymes; Etiology; Exhibits; Female of child bearing age; Folate; Folic Acid; Folic Acid Deficiency; Formates; Foundations; Gene Expression; Genes; Genetic; Genotype; Glycine; Goals; Health Policy; Human; Incidence; Knock-out; Knockout Mice; Knowledge; Lead; Life; Link; Metabolic; Metabolism; Mission; Mitochondria; Modeling; Mus; Neural Tube Closure; Neural Tube Defects; Neural Tube Development; Nutritional; Outcome; Pathway interactions; Penetrance; Phenotype; Population; Predisposition; Prevalence; Prevention; Process; Production; Public Health; Purines; Research; Risk; Safety; Supplementation; Testing; Therapeutic Intervention; Variant; Work; dietary requirement; disease diagnosis; disease phenotype; embryonic stem cell; enzyme activity; enzyme pathway; folic acid metabolism; fortification; human disease; innovation; insight; methyl group; mouse model; prevent; programs; purine; thymidylate

DESCRIPTION (provided by applicant): Neural tube defects (NTDs), among the most common birth defects in humans, are believed to have multifactorial causes. One of the strongest links to modifying NTD susceptibility is to maternal folic acid status. However, the biochemical mechanisms that underlie these folate-dependent processes are not understood. This gap in our knowledge hinders our ability to make informed health policy decisions about folic acid fortification and prevention of NTDs and other human diseases, both congenital and those occurring later in life. My long term goal is to understand the mechanisms by which folic acid supports normal neural tube development, and how altered folate metabolism leads to the development of NTDs. The objective of this proposal is to identify the mechanism(s) by which loss of a specific folate-dependent enzyme (mitochondrial MTHFD1L) leads to NTDs. My central hypothesis is that the NTDs observed in the Mthfd1l nullizygous mouse are caused by defects in mitochondrial folate-dependent one-carbon (1C) metabolism, which supplies 1C units for essential processes such as de novo purine, thymidylate, glycine, and methyl group biosynthesis. The rationale for this research is that the Mthfd1l mouse model provides a unique opportunity to discover the specific metabolic mechanism(s) that underlie the folate dependence of normal neural tube development. More importantly, a better mechanistic understanding is likely to lead to new and innovative approaches to folate fortification or other therapeutic interventions in the effort to reduce or prevent NTDs in humans. I will test my central hypothesis, and thereby accomplish the objective of this proposal, through one Specific Aim: Identify the biochemical defects responsible for neural tube defects in Mthfd1l nullizygous embryos. Under this aim, I will use biochemical assays to analyze the folate-dependent metabolic processes in normal (+/+), heterozygous (+/-), and nullizygous (-/-) embryos and in embryonic stem (ES) cells derived from the three Mthfd1l genotypes. The expected outcome of this aim is the identification of specific metabolic mechanisms responsible for the NTDs observed in Mthfd1l nullizygous embryos. The research proposed in this application is innovative, in my opinion, because it focuses on a new mouse NTD model (Mthfd1l knockout) that closely replicates the human NTD phenotype, and does not require additional nutritional intervention to express the disease phenotype. Moreover, a common variant of human Mthfd1l has been shown to be associated with increased risk of NTDs in some populations. This contribution is significant because identification of specific metabolic mechanisms will fundamentally advance understanding of folate-responsive NTDs, and will provide much needed new insight into non-folate-responsive NTDs as well. This detailed mechanistic information will be essential as we evaluate the efficacy and safety of the current folic acid fortification program in reducing the prevalence of human NTDs. PUBLIC HEALTH RELEVANCE: The proposed research is relevant to public health because while we know that dietary supplementation with folic acid reduces the incidence of neural tube defects; the mechanism behind this protection is very poorly understood. Understanding the link between this gene and development of neural tube defects will provide a mechanistic link between these devastating birth defects and folate metabolism. Thus, the proposed research is relevant to NIH's mission of increasing our understanding of life processes to lay the foundation for advances in disease diagnosis, treatment and prevention.

描述（由申请人提供）：神经管缺陷（NTD）是人类最常见的出生缺陷之一，被认为具有多因素原因。改变NTD易感性的最强联系之一是母体叶酸状态。然而，这些叶酸依赖性过程的生化机制尚不清楚。我们知识上的这一差距阻碍了我们就叶酸强化和预防NTD和其他人类疾病（包括先天性和晚年发生的疾病）做出明智的卫生政策决定的能力。我的长期目标是了解叶酸支持正常神经管发育的机制，以及叶酸代谢的改变如何导致NTD的发展。本提案的目的是确定特定叶酸依赖性酶（线粒体MTHFD1L）缺失导致NTD的机制。我的中心假设是，在Mthfd1l缺失型小鼠中观察到的NTDs是由线粒体叶酸依赖性一碳（1C）代谢缺陷引起的，该代谢为嘌呤、胸苷酸、甘氨酸和甲基生物合成等基本过程提供1C单位。这项研究的基本原理是，Mthfd1l小鼠模型提供了一个独特的机会来发现正常神经管发育依赖叶酸的特定代谢机制。更重要的是，更好的机制理解可能会导致新的和创新的方法来强化叶酸或其他治疗干预措施，以减少或预防人类NTD。我将检验我的中心假设， 从而通过一个特定目的实现本发明的目的：鉴定导致Mthfd11缺失合型胚胎中神经管缺陷的生物化学缺陷。在此目标下，我将使用生化分析，以分析叶酸依赖的代谢过程中正常（+/+），杂合（+/-），和nullized（-/-）胚胎和胚胎干（ES）细胞来自三个Mthfd1l基因型。这一目标的预期结果是鉴定负责在Mthfd1l失合子胚胎中观察到的NTD的特定代谢机制。在我看来，这项申请中提出的研究是创新的，因为它关注的是一种新的小鼠NTD模型（Mthfd1l敲除），该模型密切复制了人类NTD表型，并且不需要额外的营养干预来表达疾病表型。此外，人类Mthfd1l的一种常见变异已被证明与某些人群中NTD风险增加相关。这一贡献是重要的，因为确定特定的代谢机制将从根本上推进对叶酸反应性NTD的理解，并将提供急需的新的见解，以及非叶酸反应性NTD。这些详细的机制信息将是必不可少的，因为我们评估的有效性和安全性，目前的叶酸强化计划，在减少人类NTD的患病率。 公共卫生相关性：拟议的研究与公共卫生有关，因为虽然我们知道膳食补充叶酸可以降低神经管缺陷的发生率，但这种保护背后的机制却知之甚少。了解这个基因和神经管缺陷的发展之间的联系将提供这些破坏性的出生缺陷和叶酸代谢之间的机制联系。因此，拟议的研究与NIH的使命有关，即增加我们对生命过程的理解，为疾病诊断、治疗和预防的进步奠定基础。