Iron Deficiency and Neural Tube Defects

缺铁和神经管缺陷

• 批准号: 8739302
• 负责人: Irene E Zohn
• 金额: $ 20.9万
• 依托单位: CHILDREN'S RESEARCH INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-21 至 2016-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8739302
• 关键词: Acids; Affect; Anencephaly; Clinical Trials; Conceptions; Congenital Abnormality; Data; Defect; Diet; Dietary Iron; Effectiveness; Embryo; Embryonic Development; Exencephalies; Female; Female of child bearing age; Fetus; Folate; Folic Acid; Genes; Genetic; Genetic Predisposition to Disease; Genetic screening method; Goals; Growth and Development function; Health; Holoprosencephaly; Human; Incidence; Intake; Iron; LDL-Receptor Related Protein 2; Laboratories; Metabolism; Molecular; Mothers; Multivitamin; Mus; Mutant Strains Mice; Mutation; Neural Tube Closure; Neural Tube Defects; Neural Tube Development; Nutrient; Nutritional; Organism; Outcome; Pathway interactions; Patients; Pattern; Penetrance; Phenotype; Play; Population; Pregnancy; Prevalence; Prevention; Prosencephalon; Protocols documentation; Publishing; Research; Resistance; Retrospective Studies; Risk; Role; Series; Severities; Signal Transduction; Spinal Dysraphism; Structural Congenital Anomalies; Supplementation; Testing; Time; United States; base; bone morphogenic protein; chordin; clinical practice; cost; dietary supplements; feeding; innovation; iron deficiency; iron supplementation; metal transporting protein 1; mouse model; mutant; novel; prevent; public health relevance; research study

DESCRIPTION (provided by applicant): Neural tube defects (NTDs) including spina bifida, anencephaly and holoprosencephaly are some of the most common structural birth defects observed in humans. The causes of these NTDs are poorly understood, but it is clear that there are both environmental and genetic components. A major advancement in the prevention of spina bifida and anencephaly came with the realization that the incidence of these NTDs can be significantly reduced by periconceptional folic acid supplementation. Intriguingly, incidence can be reduced even further when folic acid is taken along with a multivitamin; however, the essential other nutrient(s) in multivitamin supplements remain unknown. Our recent data indicate that iron is necessary for neural tube closure suggesting that iron may be one of these important nutrients. Iron plays fundamental roles in cellular metabolism and is required for development and growth of all organisms. Iron deficiency is one of the most common nutritional deficits in women of childbearing age and during pregnancy. Furthermore, low dietary iron intake has been associated with increased NTD risk; however, more definitive evidence that iron is necessary for neural tube closure has been lacking. We generated a novel mouse mutant flatiron (ffe) with a hypomorphic mutation in the gene encoding Ferroportin (Fpn1) essential for transport of iron from the mother to the fetus. Our analysis of an allelic series and conditional Fpn1 mutants demonstrate that NTDs including spina bifida, exencephaly and HPE develop due to reduced iron delivered to the embryo. Experiments proposed here will investigate our novel hypothesis that iron is an essential nutrient needed for neural tube development. The overall goal of these studies is to provide the first evidence of the utility of iron in combination with flic acid in the prevention of NTDs and to elucidate the mechanistic pathways by which deficiency of this important nutrient leads to birth defects. These studies will significantly impact human health by providing new simple and inexpensive treatments to prevent NTDs and will provide necessary preliminary data needed to begin to investigate whether iron deficiency is an important contributing factor in human NTDs and if NTDs can be prevented by iron supplementation.

描述（由申请人提供）：神经管缺陷（NTD）包括脊柱裂、无脑畸形和前脑无裂畸形，是人类最常见的结构性出生缺陷。这些NTD的原因知之甚少，但很明显，有环境和遗传因素。在预防脊柱裂和无脑畸形方面的一个重大进展是认识到这些NTD的发生率可以通过围受孕期补充叶酸来显着降低。有趣的是，当叶酸与多种维生素一起沿着服用时，发病率甚至可以进一步降低;然而，多种维生素补充剂中必需的其他营养素仍然未知。我们最近的数据表明，铁是神经管闭合所必需的，这表明铁可能是这些重要的营养素之一。铁在细胞代谢中起着重要作用，是所有生物体发育和生长所必需的。铁缺乏症是育龄妇女和怀孕期间最常见的营养缺陷之一。此外，低膳食铁摄入量与NTD风险增加有关;然而，缺乏铁对神经管闭合所必需的更明确的证据。我们产生了一种新的小鼠突变体flatiron（ffe）的基因编码的铁转运蛋白（Fpn 1）的运输铁从母亲到胎儿是必不可少的亚型突变。我们的等位基因系列和条件Fpn 1突变体的分析表明，NTDs，包括脊柱裂，露脑和HPE的发展，由于减少铁交付给胚胎。这里提出的实验将调查我们的新假设，铁是神经管发育所需的必需营养素。这些研究的总体目标是提供第一个证据，证明铁与叶酸联合用于预防NTD，并阐明这种重要营养素缺乏导致出生缺陷的机制途径。这些研究将通过提供新的简单和廉价的治疗方法来预防NTD，并将提供必要的初步数据，开始调查缺铁是否是人类NTD的重要影响因素，以及是否可以通过补充铁来预防NTD。