Iron Deficiency and Neural Tube Defects

描述（由申请人提供）：神经管缺陷（NTDs）包括脊柱裂、无脑畸形和无前脑畸形是人类最常见的结构性出生缺陷。人们对这些被忽视热带病的原因知之甚少，但很明显，环境和遗传因素都有影响。在预防脊柱裂和无脑畸形方面取得了重大进展，人们认识到，通过孕期补充叶酸可以显著降低这些ntd的发病率。有趣的是，当叶酸和复合维生素一起服用时，发病率可以进一步降低；然而，复合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营养素之一。铁在细胞代谢中起着重要作用，是所有生物发育和生长所必需的。缺铁是育龄妇女和怀孕期间最常见的营养缺陷之一。此外，膳食铁摄入量低与NTD风险增加有关；然而，更明确的证据表明，铁是必要的神经管关闭一直缺乏。我们产生了一种新的小鼠突变体flatiron (ffe)，其编码铁转运蛋白（Fpn1）的基因发生了半形突变，该基因是铁从母体运输到胎儿所必需的。我们对等位基因系列和条件Fpn1突变体的分析表明，包括脊柱裂、畸形和HPE在内的NTDs是由于向胚胎输送的铁减少而发生的。本文提出的实验将验证我们的新假设，即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铁与叶酸结合在预防被忽视热带病中的作用的第一个证据，并阐明缺乏这种重要营养素导致出生缺陷的机制途径。这些研究将为预防被忽视热带病提供新的简单和廉价的治疗方法，从而对人类健康产生重大影响，并将提供必要的初步数据，以便开始调查缺铁是否是人类被忽视热带病的一个重要促成因素，以及是否可以通过补充铁来预防被忽视热带病。

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.