Iron physiology and pathology in pregnancy

妊娠期铁的生理学和病理学

• 批准号: 10457812
• 负责人: Elizabeta Nemeth
• 金额: $ 40.69万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-06-11 至 2024-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10457812
• 关键词: Address; Adverse effects; Affect; Anemia; Area; Binding Proteins; Biological; Cell Death; Cellular Metabolic Process; Child; Country; Data; Developed Countries; Development; Diet; Educational workshop; Embryo; Endocrine; Endothelium; Ensure; Erythrocytes; Ferritin; Fetal Development; Fetal Growth Retardation; Fetus; Foundations; Functional disorder; Gestational Diabetes; Health; Homeostasis; Hormonal; Hormones; Human; Infection; Inflammation; Investigation; Iron; Iron Metabolism Disorders; Iron Overload; Iron Regulatory Protein 1; Link; Long-Term Effects; Maintenance; Malnutrition; Maternal Health; Maternal and Child Health; Mediating; Molecular; Mothers; Mus; Oxidative Stress; Pathogenesis; Pathology; Pathway interactions; Physiological; Physiology; Placenta; Policies; Pregnancy; Pregnant Women; Premature Birth; Prevention; Regulation; Research Priority; Risk; Role; Sampling; Science; Source; Supplementation; Trace metal; United States National Institutes of Health; adverse outcome; adverse pregnancy outcome; design; epidemiology study; fetal; healthy pregnancy; hepcidin; improved; iron deficiency; iron supplementation; malformation; metal transporting protein 1; mouse model; oxygen transport; placental transfer; pregnancy disorder; preservation; response; screening; success; trophoblast

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.

项目摘要 怀孕期间足够的铁可用性对于胎儿发育和孕产妇健康至关重要。铁缺乏 它最常见的表现，贫血，在怀孕期间高度普遍，可能对 母亲和胎儿。意识到铁缺乏症的有害影响已导致普遍的政策 包括美国在内的许多国家补充铁。但是，在发达国家，更多的怀孕 妇女比铁缺乏的是铁的恢复。在这种情况下，不加区分的铁补充剂不仅可能是 不必要的，但甚至可能具有与氧化应激增加或潜在不利有关的有害影响 与炎症的相互作用。尽管重要性，但对铁调节的基本生理知之甚少 在怀孕期间，或在复杂的怀孕中如何改变。 具体目标1。我们将定义母体和胎儿肝素在调节铁稳态中的作用 怀孕。我们在鼠标模型中的初步数据表明，材料铁调节马酮肝素必须 在怀孕期间被抑制以确保足够的铁可用性用于胎盘转移，并确保滋养细胞 是肝素抑制活性的重要来源。我们将确定孕产妇的机制 肝素在健康妊娠中受到抑制；并确定母体肝素水平是否是 人类发炎的怀孕不适用于促进材料铁的限制。 具体目标2。我们的初步数据表明，在含铁缺乏或超过斑点铁期间 对转运蛋白进行调节，以确保维持位置铁稳态。响应母亲 小鼠和人类的铁缺乏症，这种机制以牺牲零食为代价 为胎儿提供足够的铁，这是我们称为“自私胎盘”的现象。这很重要 了解胎儿铁缺乏的发病机理的意义。我们将定义监管圈 和自私的妊娠反应的生物学相关性。 特定目的3。我们在鼠标模型中的初步数据证明了在 孕妇在怀孕期间超过产妇的感染，靶向斑点内皮和 导致胎儿畸形和胚胎致死性。我们将通过聚焦来定义基本机制 关于孕产妇感染和妊娠恐怖，以及斑点和胎儿感染，氧化应激， 和细胞死亡途径。 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 怀孕期间。长期，它有可能改变我们在管理铁疾病期间的方法 怀孕。