Adverse Interaction Between Iron Deficiency and Inflammation in Pregnancy

妊娠期缺铁与炎症之间的不良相互作用

基本信息

批准号：
10303471
负责人：
Elizabeta Nemeth
金额：
$ 23.4万
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：
2021
资助国家：
美国
起止时间：
2021-08-21 至 2023-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10303471
关键词：
Acute Adverse effects Affect Anemia Apoptosis Area Autoimmune Diseases Cells Cellular Metabolic Process Censuses Child Chronic Complement Country Data Developing Countries Development Diabetes Mellitus Disease Embryo Endothelial Cells Endothelium Erythrocytes Fetal Death Fetal Development Fetal Growth Retardation Fetus Foundations Frequencies Genetic Transcription Health Homeostasis Human Immune Infection Inflammation Inflammatory Inflammatory Response Injections Investigation Iron Iron deficiency anemia Knockout Mice Low Birth Weight Infant Maternal Health Maternal Mortality Mediating Messenger RNA Modeling Molecular Mothers Mus Neurodevelopmental Problem Obesity Pathway interactions Phenotype Placenta Population Post-Translational Protein Processing Pregnancy Pregnant Women Premature Birth Premature Labor Prevalence Protein Biosynthesis Proteins Regulation Reporting Research Resources Role Severities Spontaneous abortion TFRC gene TNF gene Trace metal Tumor Necrosis Factor Receptor Viral Woman adverse outcome adverse pregnancy outcome autistic behaviour base cell type cytokine embryo tissue fetal in vitro Model in vivo insight iron deficiency maternal morbidity maternal risk mouse model novel offspring oxygen transport pregnancy disorder programs receptor response single-cell RNA sequencing synergism transcriptome translational impact trophoblast uptake

项目摘要

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. Systemic maternal inflammation during pregnancy is also quite common, and either results from infections (bacterial, viral, parasitic), or accompanies chronic conditions including obesity, diabetes, and autoimmune diseases. Adverse outcomes associated with inflamed pregnancies include spontaneous abortion, preterm labor, intrauterine growth restriction, fetal death, gross developmental abnormalities and autistic behaviors in offspring. Our preliminary studies in mice demonstrated a surprising synergistic adverse interaction between maternal iron deficiency and inflammation that led to embryotoxicity which was not observed with either condition alone. Compared to dams with normal iron status, those that were iron-deficient had significantly higher frequency of embryo abnormalities in the setting of acute maternal inflammation caused by LPS injection. We aim to define the underlying mechanisms of this synergy: Aim 1. Determine the effect of iron deficiency on maternal, placental and embryo inflammation. Using our mouse models of LPS-triggered inflammation, we will examine whether iron deficiency in pregnancy enhances pro-inflammatory response or alters immune cell census in the mother, placenta and embryo. Aim 2. Characterize the iron-dependent regulation of TNF receptor 1 Based on the strong correlation between placental TNFR1 and TFR1 in both humans and mice, we hypothesize that cellular iron status regulates TNFR1 levels. We will define the specific placental cell type that increases TNFR1 in response to iron deficiency, and examine candidate mechanisms regulating TNFR1. . Aim 3. Determine the role of the TNF pathway in adverse synergy in vivo—Our preliminary data implicated TNFα-TNFR pathway in mediating adverse outcomes in iron-deficient inflamed pregnancies. We will use mice with endothelial- or trophoblast-specific deficiency of TNFR1 to determine whether the TNF pathway is required for the adverse synergy in the model of acute inflammation. Aim 4. Define the effect of iron deficiency on placental cellular transcriptome. We will complement our candidate-driven approaches with an unbiased single-cell RNAseq on mouse placentas from iron-deficient and iron-replete pregnancies treated with LPS to gain detailed insight into how iron deficiency alters placental cell populations as well as their transcriptional activity in response to inflammation. Our proposal analyzes a novel interaction between iron deficiency and inflammation. Considering the high global prevalence of this combination of disorders in pregnant women, the subject has outstanding translational importance, and our studies could help explain commonly observed adverse outcomes. Long-term, our findings have the potential to influence the management of iron and inflammatory disorders of pregnancy.

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。铁缺乏症及其最常见的表现，贫血，在怀孕期间高度普遍，可能对母亲和胎儿产生不利影响。怀孕期间的全身性造物感染也很常见，要么是由感染（细菌，病毒，寄生虫）引起的，要么涉及慢性病，包括肥胖，糖尿病和自身免疫性疾病。与发炎的怀孕有关的不良后果包括发育堕胎，早产，内在的生长限制，胎儿死亡，大量发育异常和后代的加速行为。我们在小鼠中的初步研究表明，产妇铁缺乏症和炎症之间存在令人惊讶的协同不良相互作用，这导致了胚胎毒性，仅在任何一种情况下都没有观察到胚胎。与铁状态正常的大坝相比，在LPS注射引起的急性母体注射的情况下，胚胎异常的频率明显更高。我们旨在定义这种协同作用的基本机制：目标1。确定铁缺乏对物物，斑点和胚胎注射的影响。使用我们的LPS触发注射的小鼠模型，我们将检查妊娠中的铁缺乏症是否可以增强炎症反应或改变母亲，胎盘和胚胎的免疫细胞普查。 AIM 2。根据人类和小鼠的lopenal TNFR1和TFR1之间的强相关性来表征TNF受体1的铁依赖性调节，我们假设细胞铁状态调节TNFR1水平。我们将定义特定的斑点细胞类型，该细胞类型会因铁缺乏而增加TNFR1，并检查调查TNFR1的候选机制。。 AIM 3。确定TNF途径在体内不良协同中的作用 - 我们实施的TNFα-TNFR途径在介导铁缺陷型发炎妊娠中的不良后果中实现的初步数据。我们将使用TNFR1的内皮细胞或滋养细胞特异性缺乏的小鼠来确定急性炎症模型中不良协同作用是否需要TNF途径。 AIM 4。定义铁缺乏对位置细胞转录组的影响。我们将通过通过LPS治疗的铁缺陷和铁恢复妊娠的小鼠斑点上的无偏见的单细胞rnaseq来完成我们的候选驱动方法，以详细了解铁缺乏症如何改变斑点细胞群体以及如何改变其转录活性，以应对炎症。我们的建议分析了铁缺乏和感染之间的新型相互作用。考虑到这种孕妇这种疾病组合的全球性较高，该受试者具有出色的翻译重要性，我们的研究可以帮助解释通常观察到的不良后果。长期，我们的发现有可能影响妊娠的铁和炎症性疾病的治疗。