Iron physiology and pathology in pregnancy

项目摘要 怀孕期间充足的铁供应对胎儿发育和孕产妇健康至关重要。缺铁性 其最常见的表现是贫血，在怀孕期间非常普遍， 母亲和胎儿认识到缺铁的有害影响导致了普遍的政策， 在包括美国在内的许多国家，铁的补充。然而，在发达国家， 女人是铁充足的比缺铁的。在这种情况下，不加选择地补充铁可能不仅 不必要，但甚至可能具有与增加氧化应激或潜在不良反应相关的有害影响。 与炎症的相互作用。尽管它的重要性，很少有人知道的基本生理铁调节 在怀孕期间，或者在复杂的怀孕中它是如何改变的。 具体目标1。我们将明确母亲和胎儿hepcidin在调节铁稳态的作用， 怀孕我们在小鼠模型中的初步数据表明，母体铁调节激素铁调素必须 在怀孕期间受到抑制，以确保胎盘转移有足够的铁可用性， 是铁调素抑制活性的重要来源。我们将确定孕产妇死亡的机制， 铁调素在健康妊娠中受到抑制;并确定母体铁调素水平是否 不适当地增加人类发炎怀孕，以促进产妇铁限制。 具体目标2。我们的初步数据表明，在母体铁缺乏或过量，胎盘铁， 调节转运蛋白以确保维持胎盘铁稳态。针对产妇 在小鼠和人类的铁缺乏症中，这种机制以牺牲 为胎儿提供足够的铁，我们称之为“自私胎盘”。这具有重要 对了解胎儿缺铁的发病机制的影响。我们将确定监管电路 以及妊娠期自私胎盘反应的生物学相关性。 具体目标3。我们在小鼠模型中的初步数据表明， 妊娠期间母体铁过量和母体炎症，靶向胎盘内皮，以及 导致胎儿畸形和胚胎死亡。我们将通过关注 对母体炎症和妊娠激素，以及胎盘和胎儿炎症，氧化应激， 和细胞死亡途径。 我们的建议将回答有关母亲和胎儿铁调节的病理生理学的基本问题 孕期从长远来看，它有可能改变我们在治疗过程中管理铁紊乱的方法。 怀孕

PROJECT SUMMARY Adequate iron availability during pregnancy is essential for fetal development and maternal health. Iron deficiency and its most common manifestation, anemia, are highly prevalent during pregnancy and can have adverse effects on the mother and the fetus. Recognition of detrimental effects of iron deficiency has led to the policy of universal iron supplementation in many countries including the US. However, in developed countries, more pregnant women are iron-replete than iron-deficient. Indiscriminate iron supplementation in this setting may be not only unnecessary, but may even have harmful effects related to increased oxidative stress or potential adverse interaction with inflammation. Despite its importance, little is known about the basic physiology of iron regulation during pregnancy, or how it is altered in complicated pregnancies. Specific Aim 1. We will define the role of maternal and fetal hepcidin in regulating iron homeostasis during pregnancy. Our preliminary data in mouse models indicate that maternal iron-regulatory hormone hepcidin must be suppressed during pregnancy to ensure sufficient iron availability for placental transfer, and that trophoblast is an important source of the hepcidin-suppressive activity. We will identify the mechanism(s) by which maternal hepcidin is suppressed in healthy pregnancy; and determine whether maternal hepcidin levels are inappropriately increased in human inflamed pregnancies to promote maternal iron restriction. Specific Aim 2. Our preliminary data show that during maternal iron deficiency or excess, placental iron transporters are regulated to ensure the maintenance of placental iron homeostasis. In response to maternal iron deficiency in both mice and humans, this mechanism sequesters iron in the placenta at the expense of providing adequate iron to the fetus, a phenomenon we termed the “selfish placenta”. This has important implications for understanding the pathogenesis of fetal iron deficiency. We will define the regulatory circuitries and biological relevance of the selfish placental response in pregnancy. Specific Aim 3. Our preliminary data in mouse models demonstrate a dramatic adverse interaction between maternal iron excess and maternal inflammation during pregnancy, targeting placental endothelium, and resulting in fetal malformations and embryonic lethality. We will define the underlying mechanisms by focusing on maternal inflammation and pregnancy hormones, as well as placental and fetal inflammation, oxidative stress, and cell death pathways. Our proposal will answer fundamental questions about the pathophysiology of maternal and fetal iron regulation during pregnancy. Long-term, it has the potential to change our approaches to managing iron disorders during pregnancy.