Iron Deficiency and Neural Tube Defects

描述(由申请人提供)：神经管缺陷(NTD)包括脊柱裂、无脑和无前脑畸形，是人类最常见的结构性出生缺陷。人们对这些NTDS的原因知之甚少，但很明显，这既有环境因素，也有遗传因素。在预防脊柱裂和无脑畸形方面的一个重大进展来自于意识到这些NTDS的发生率可以通过妊娠周补充叶酸显着降低。有趣的是，当叶酸与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不可少的其他营养物质(S)仍不清楚。我们最近的数据表明，铁是神经管关闭所必需的，这表明铁可能是这些重要营养物质之一。铁在细胞新陈代谢中起着重要作用，是所有生物体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乏症之一。此外，饮食中铁摄入量低与NTD风险增加有关；然而，缺乏更明确的证据表明铁是关闭神经管所必需的。我们产生了一种新的小鼠突变Flatiron(FFE)，其编码铁蛋白(Fpn1)的基因发生了亚型突变，Fpn1是铁从母亲转移到胎儿所必需的。我们对一系列等位基因和条件Fpn1突变体的分析表明，包括脊柱裂、脑外畸形和HPE在内的NTDS的发生是由于向胚胎输送的铁减少。这里提出的实验将调查我们的新假设，即铁是神经管发育所必需的营养物质。这些研究的总体目标是提供铁和脂肪酸联合使用预防NTDS的第一个证据，并阐明这种重要营养物质缺乏导致出生缺陷的机制。这些研究将通过提供新的、简单和廉价的治疗方法来预防NTDS，从而显著影响人类健康，并将提供必要的初步数据，以便开始研究缺铁是否是人类NTDS的一个重要因素，以及是否可以通过补充铁来预防NTDS。

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.