Iron physiology and pathology in pregnancy

妊娠期铁的生理学和病理学

基本信息

批准号：
10649598
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
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-06-11 至 2025-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10649598
关键词：
Address Adverse effects Affect Anemia Area Binding Proteins Biological Cell Death Cell physiology 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 Iron deficiency anemia Link Long-Term Effects Maintenance Malnutrition Maternal Health Maternal and Child Health Mediating Metabolism Molecular Mothers Mus Oxidative Stress Pathogenesis Pathology Pathway interactions Physiological Physiology Placenta Policies Pregnancy Pregnancy Complications Pregnant Women Premature Birth Prevention Regulation Research Priority Risk Role Sampling Science Shapes Source Supplementation Trace metal United States National Institutes of Health absorption 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

项目摘要

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.

项目概要怀孕期间充足的铁供应对于胎儿发育和孕产妇健康至关重要。其最常见的表现是贫血，在怀孕期间非常普遍，会对胎儿产生不利影响对母亲和胎儿缺铁造成的痛苦的认识导致了普遍的政策。包括美国在内的许多国家都补充铁剂，但在发达国家，怀孕的情况较多。女性铁质充足，而不是缺铁。不必要的，但甚至可能产生与氧化应激增加或潜在不利影响相关的有害影响尽管它很重要，但人们对铁调节的基本生理学知之甚少。怀孕期间，或者怀孕是多么复杂。具体目标 1. 我们将定义母体和胎儿铁调素在调节铁稳态中的作用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，以确保有足够的铁用于胎盘移植，并且滋养层是铁调素抑制活性的重要来源，我们将确定母体的机制。健康妊娠时铁调素受到抑制；并确定母体铁调素水平是否正常人类炎症妊娠中不当增加铁含量以促进母体铁限制。具体目标 2. 我们的初步数据表明，在母亲铁缺乏或过量期间，胎盘铁调节转运蛋白以确保维持胎盘铁稳态以响应母体。小鼠和人类都缺乏铁，这种机制将铁隔离在胎盘中，但以牺牲铁为代价。为胎儿提供足够的铁，这种现象我们称之为“自私胎盘”，这一点很重要。对理解胎儿缺铁发病机制的影响我们将定义调节电路。以及怀孕期间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，怀孕期间母体铁过剩和母体炎症，针对胎盘内皮，以及导致胎儿畸形和胚胎致死的潜在机制。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。我们的提案将回答有关母体和胎儿铁调节的病理生理学的基本问题从长远来看，它有可能改变我们在怀孕期间处理铁失调的方法。怀孕。

项目成果

期刊论文数量（28）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Effects of maternal iron status on placental and fetal iron homeostasis.

母体铁状态对胎盘和胎儿铁稳态的影响。

DOI：
10.1172/jci127341
发表时间：
2019-12-17
期刊：
The Journal of clinical investigation
影响因子：
0
作者：
Veena Sangkhae;Allison L. Fisher;Shirley Wong;M. D. Koenig;L. Tussing;Alison Chu;M. Lelić;T. Ganz;E. Nemeth
通讯作者：
E. Nemeth

Clinical Immunoassay for Human Hepcidin Predicts Iron Deficiency in First-Time Blood Donors.

人铁调素的临床免疫测定可预测首次献血者的铁缺乏症。

DOI：
发表时间：
2020-09-01
期刊：
影响因子：
0
作者：
Gutschow, Patrick;Han, Huiling;Olbina, Gordana;Westerman, Keith;Nemeth, Elizabeta;Ganz, Tomas;Copeland, Karen;Westerman, Mark;Ostland, Vaughn
通讯作者：
Ostland, Vaughn

Lung Iron Overload Does Not Exacerbate the Fibrotic Response to Bleomycin in a Mouse Model of Pulmonary Fibrosis.

肺铁过载不会加剧肺纤维化小鼠模型对博莱霉素的纤维化反应。

DOI：
发表时间：
2020
期刊：
影响因子：
6.4
作者：
Zhang, Vida;Nemeth, Elizabeta;Kim, Airie
通讯作者：
Kim, Airie

Placental iron transport: The mechanism and regulatory circuits.

胎盘铁转运：机制和调节回路。

DOI：
10.1016/j.freeradbiomed.2018.07.001
发表时间：
2019-03
期刊：
Free radical biology & medicine
影响因子：
7.4
作者：
Sangkhae V;Nemeth E
通讯作者：
Nemeth E

Fetal and amniotic fluid iron homeostasis in healthy and complicated murine, macaque, and human pregnancy.

健康和复杂的小鼠、猕猴和人类妊娠中胎儿和羊水铁稳态。

DOI：
发表时间：
2020
期刊：
影响因子：
8
作者：
Fisher, Allison L;Sangkhae, Veena;Presicce, Pietro;Chougnet, Claire A;Jobe, Alan H;Kallapur, Suhas G;Tabbah, Sammy;Buhimschi, Catalin S;Buhimschi, Irina A;Ganz, Tomas;Nemeth, Elizabeta
通讯作者：
Nemeth, Elizabeta