Iron physiology and pathology in pregnancy

项目总结 孕期充足的铁供应对胎儿发育和产妇健康至关重要。缺铁 其最常见的表现是贫血，在怀孕期间非常普遍，并可能对 母亲和胎儿。认识到缺铁的有害影响导致了全民健身的政策 包括美国在内的许多国家的铁质补充剂。然而，在发达国家，更多的孕妇 女性铁质充足，而不是缺铁。在这种情况下不分青红皂白地补充铁可能不仅 不必要的，但甚至可能有与增加氧化应激有关的有害影响或潜在的不利影响 与炎症相互作用。尽管它很重要，但人们对铁调节的基本生理学知之甚少。 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.我们将确定母体和胎儿海普西丁在调节铁稳态中的作用 怀孕了。我们在小鼠模型中的初步数据表明，母体铁调节激素海普西丁必须 在怀孕期间被抑制，以确保胎盘转移有足够的铁供应，滋养细胞 是海普西丁抑制活性的重要来源。我们将确定(S)母体通过什么机制 在健康妊娠中，海普西丁被抑制；并确定母亲的海普西丁水平是否 在人类发炎的妊娠中不适当地增加以促进母亲的铁限制。 具体目标2.我们的初步数据显示，在母亲铁缺乏或过剩期间，胎盘铁 转运蛋白被调节以确保胎盘铁稳态的维持。为了回应母体 在小鼠和人类缺铁的情况下，这种机制将铁隔离在胎盘中，代价是 为胎儿提供足够的铁，我们称之为“自私的胎盘”。这一点很重要 对了解胎儿铁缺乏发病机制的启示。我们将定义调节电路 以及孕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显示， 母体铁过量和妊娠期母体炎症，以胎盘内皮为靶点，以及 导致胎儿畸形和胚胎死亡。我们将通过集中精力定义潜在的机制 关于母体炎症和妊娠激素，以及胎盘和胎儿炎症，氧化应激， 以及细胞死亡途径。 我们的建议将回答有关母体和胎儿铁调节的病理生理学的基本问题。 在怀孕期间。从长远来看，它有可能改变我们在 怀孕了。

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.