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

• 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
• 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

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.

怀孕期间充足的铁供应对于胎儿发育和孕产妇健康至关重要。缺铁及其最常见的表现是贫血，在怀孕期间非常普遍，会对母亲和胎儿产生不利影响。怀孕期间的全身性母体炎症也很常见，要么由感染（细菌、病毒、寄生虫）引起，要么伴随肥胖、糖尿病和自身免疫性疾病等慢性疾病。与炎症妊娠相关的不良后果包括自然流产、早产、宫内生长受限、胎儿死亡、后代严重发育异常和自闭症行为。我们对小鼠的初步研究表明，母体缺铁和炎症之间存在令人惊讶的协同不利相互作用，导致胚胎毒性，而单独使用任何一种情况都未观察到这种相互作用。与铁状态正常的母鼠相比，在注射脂多糖引起的急性母体炎症的情况下，缺铁的母鼠胚胎异常的频率明显更高。我们的目标是确定这种协同作用的潜在机制： 目标 1. 确定缺铁对母体、胎盘和胚胎炎症的影响。利用我们的脂多糖引发炎症的小鼠模型，我们将检查怀孕期间缺铁是否会增强促炎症反应或改变母亲、胎盘和胚胎中的免疫细胞普查。目标 2. 表征 TNF 受体 1 的铁依赖性调节基于人类和小鼠胎盘 TNFR1 和 TFR1 之间的强相关性，我们假设细胞铁状态调节 TNFR1 水平。我们将定义响应缺铁而增加 TNFR1 的特定胎盘细胞类型，并检查调节 TNFR1 的候选机制。 。目标 3. 确定 TNF 通路在体内不良协同作用中的作用——我们的初步数据表明 TNFα-TNFR 通路在介导缺铁炎症妊娠的不良后果中。我们将使用内皮细胞或滋养层特异性 TNFR1 缺陷的小鼠来确定 TNF 通路是否是急性炎症模型中不利协同作用所必需的。目标 4. 确定缺铁对胎盘细胞转录组的影响。我们将通过对经 LPS 处理的缺铁和铁充足妊娠的小鼠胎盘进行无偏单细胞 RNAseq 来补充我们的候选驱动方法，以详细了解铁缺乏如何改变胎盘细胞群及其响应炎症的转录活性。我们的提案分析了缺铁与炎症之间的一种新的相互作用。考虑到孕妇中这种疾病组合的高患病率，该主题具有突出的转化重要性，我们的研究可以帮助解释常见的不良后果。从长远来看，我们的研究结果有可能影响妊娠期铁和炎症性疾病的治疗。