Sex Differences in Fetal Brain-Placental Immune Programming in Maternal Obesity

母亲肥胖中胎儿脑胎盘免疫编程的性别差异

• 批准号: 10093233
• 负责人: Andrea Goldberg Edlow
• 金额: $ 16.84万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-01 至 2022-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10093233
• 关键词: Ablation; Administrative Supplement; Age; Anxiety; Attention deficit hyperactivity disorder; Attentional deficit; Behavior; Biological; Biological Assay; Brain; Cells; Child; Cognitive deficits; Disease; Dopamine; Eating; Eating Disorders; Embryo; Encephalitis; Evaluation; Female; Fetus; Flow Cytometry; Funding; Gene Expression; Gene Expression Profile; Genes; Goals; Hippocampus (Brain); Human; Hyperactive behavior; Immune; Immunity; Inflammation; Inflammatory; Knowledge; Lead; Learning; Link; Maternal Exposure; Mediating; Mental Depression; Microglia; Modeling; Molecular Profiling; Morbidity - disease rate; Mus; Neuroimmune; Obesity; Outcome; Pathogenesis; Pathway interactions; Placenta; Play; Population; Precision therapeutics; Pregnancy; Prosencephalon; Reporting; Rewards; Risk; Role; Sampling; Sex Bias; Sex Differences; Signal Pathway; Signal Transduction; Testing; Thinness; Tissues; Toll-like receptors; Training; Transgenic Mice; United States; Weight; Woman; Yolk Sac; autism spectrum disorder; base; brain cell; cell type; density; design; epidemiology study; experimental study; fetal; immune activation; immunoreactivity; in utero; insight; macrophage; male; maternal obesity; mother nutrition; mouse model; neonate; neurodevelopment; neuroinflammation; novel; obese mothers; offspring; parent grant; personalized intervention; potential biomarker; pre-clinical; prevent; programs; reproductive; sex; single-cell RNA sequencing; targeted treatment; transcriptome

PROJECT SUMMARY In the United States, one in three women of reproductive age is obese. In epidemiologic studies, maternal obesity is associated with neurodevelopmental morbidity in children, including cognitive deficits, autism spectrum disorder, anxiety and depression, disordered eating, and attention deficit hyperactivity disorder. Many of these disorders have a sex bias, and aberrant brain immune activation (microglial priming, or “trained immunity”), has been implicated in their pathogenesis. While direct evaluation of microglial function in a living human fetus or neonate is impossible, resident placental macrophages (Hofbauer cells) and microglia have a common origin in the fetal yolk sac. “Fetal Brain-Placental Immune Activation in Maternal Obesity” is a pre-clinical R01 that tests the hypothesis that maternal obesity-associated inflammatory priming of fetal brain microglia and placental Hofbauer cells is a targetable mechanism underlying offspring cognitive deficits. A key translational aspect of the funded project is the use of single-cell RNA sequencing (scRNA-Seq) to determine whether Hofbauer cells represent a novel biologic surrogate for microglial immunoreactivity in the setting of maternal obesity. In 2019, we were funded to complete the following specific aims: Aim 1a: Determine whether maternal obesity primes fetal brain and placental resident macrophages to overrespond to an immune challenge. Aim 1b: Evaluate whether Hofbauer cells can serve as a biologic surrogate for brain microglial priming, using scRNA-Seq and flow cytometry. Aim 2: Determine if targeted ablation of pro-inflammatory signaling in fetal resident tissue macrophages (including microglia and placental Hofbauer cells) rescues hippocampal learning deficits in offspring, using a novel Cx3cr1-CreBT:MyD88f/f transgenic mouse. Both sexes are evaluated in all experiments, except the scRNA-Seq in Aim 1b. We have completed initial sequencing for 16 male brain and placental macrophage samples from obese and lean dams. We have demonstrated novel gene programs and cell states that define male microglia and Hofbauer cells in the context of maternal obesity. This administrative supplement proposal aims to expand the scRNA-Seq experiments in Aim 1b of the parent grant to include female fetal microglia and placental macrophages. This will allow us to test whether maternal obesity induces sex-specific alterations in fetal microglial and Hofbauer cell programs, and whether Hofbauer cell subsets can serve as a biologic surrogate for fetal brain microglial priming in the setting of maternal obesity. Determination of how fetal sex impacts microglial and placental macrophage gene programs and cell states will generate key insights into how obesity-associated brain and placental immune activation influences sex-specific neurodevelopmental outcomes. If Hofbauer cells can serve as a more accessible cell type that provides information about brain microglial function in maternal obesity, there may be broader implications for assaying the impact of other maternal exposures on fetal brain immune activation. Understanding sex differences in fetal brain and placental immune programming in maternal obesity is critical to designing precision therapies.

项目摘要 在美国，三分之一的育龄妇女肥胖。在流行病学研究中， 与儿童的神经发育发病率有关，包括认知缺陷、自闭症谱系 障碍、焦虑和抑郁、饮食失调和注意力缺陷多动障碍。许多这些 疾病有性别偏见，异常的大脑免疫激活（小胶质细胞启动，或“训练免疫”）， 与其发病机制有关。虽然直接评估活的人类胎儿或 新生儿是不可能的，常驻胎盘巨噬细胞（霍夫鲍尔细胞）和小胶质细胞有一个共同的起源， 胎儿卵黄囊“母亲肥胖症中胎儿大脑-胎盘免疫激活”是一项临床前R 01， 假设母体肥胖相关的胎儿脑小胶质细胞和胎盘炎性启动 Hofbauer细胞是后代认知缺陷的靶向机制。一个关键的翻译方面， 该资助项目是使用单细胞RNA测序（scRNA-Seq）来确定霍夫鲍尔细胞是否 代表了一种新的生物替代小胶质细胞免疫反应性的母亲肥胖的设置。在2019年， 我们获得资助，以完成以下具体目标：目标1a：确定母亲肥胖是否引发 胎儿大脑和胎盘驻留的巨噬细胞对免疫挑战反应过度。目标1b：评估 Hofbauer细胞是否可以作为脑小胶质细胞启动的生物替代物，使用scRNA-Seq和flow 细胞仪目的2：确定是否在胎儿驻留组织中靶向消融促炎信号传导 巨噬细胞（包括小胶质细胞和胎盘Hofbauer细胞）挽救海马学习缺陷， 后代，使用新型Cx 3cr 1-CreBT：MyD 88 f/f转基因小鼠。在所有实验中评估两性， 除了目标1b中的scRNA-Seq。我们已经完成了16个男性大脑和胎盘的初步测序 来自肥胖和瘦的母鼠的巨噬细胞样品。我们已经展示了新的基因程序和细胞状态 在母体肥胖的背景下定义男性小胶质细胞和霍夫鲍尔细胞。 本行政补充提案旨在扩大母公司目标1b中的scRNA-Seq实验 准许包括雌性胎儿小胶质细胞和胎盘巨噬细胞。这将使我们能够测试是否产妇 肥胖诱导胎儿小胶质细胞和Hofbauer细胞程序的性别特异性改变， 细胞亚群可以作为母体肥胖情况下胎儿脑小胶质细胞启动的生物学替代物。 确定胎儿性别如何影响小胶质细胞和胎盘巨噬细胞基因程序和细胞状态将 产生关键的见解，如何肥胖相关的大脑和胎盘免疫激活影响性别特异性 神经发育结果。如果霍夫鲍尔细胞可以作为一种更容易接近的细胞类型， 关于母亲肥胖的脑小胶质细胞功能的信息，可能对测定 其他母体暴露对胎儿脑免疫激活的影响。了解胎儿的性别差异 母亲肥胖症中的大脑和胎盘免疫编程对于设计精确疗法至关重要。