Fetal Brain-Placental Immune Activation in Maternal Obesity

母亲肥胖中胎儿脑胎盘免疫激活

基本信息

批准号：
10229462
负责人：
Andrea Goldberg Edlow
金额：
$ 39.46万
依托单位：
MASSACHUSETTS GENERAL HOSPITAL
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：
2019-09-01 至 2023-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10229462
关键词：
Ablation Adaptor Signaling Protein Adolescent Adult Children Affect Age Anti-Inflammatory Agents Antigens Anxiety Attention deficit hyperactivity disorder Behavior Biological Body mass index Brain Cells Child Chronic Cognitive deficits Data Development Embryo Encephalitis Enzyme-Linked Immunosorbent Assay Evaluation Female Fetus Flow Cytometry Frequencies Hippocampus (Brain)Human Immune Immune signaling Individual Inflammation Inflammatory Intervention Knowledge Lead Learning Learning Disabilities Life Link Lipopolysaccharides Longevity Maternal Exposure Mathematics Mediating Mental Depression Microglia Morbidity - disease rate Mus Myelogenous Neurocognitive Deficit Obese Mice Obesity Pathogenesis Placenta Play Population Pre-Clinical Model Pregnancy Reading Reporting Risk Role Saline Secondary to Sentinel Sex Differences Signal Transduction Testing Therapeutic Thinness Tissues Toll-like receptors Transgenic Mice United States Woman Yolk Sac autism spectrum disorder brain cell cell type cytokine density diet-induced obesity epidemiology study experimental study fetal immune activation immune function immunoreactivity in utero innovation macrophage male maternal obesity mother nutrition mouse model neonate neurodevelopment novel obese mothers offspring programs reproductive response sex sexual dimorphism single-cell RNA sequencing transcriptome

项目摘要

PROJECT SUMMARY In the United States, one in three women of reproductive age is obese. In large epidemiologic studies, maternal obesity is associated with cognitive deficits in children, including reduced and low IQ (<70), and lower reading and math scores. Underlying mechanisms remain unclear. What is known is that maternal obesity is a state of chronic low-level immune activation, and both placental and brain inflammation have been reported in fetuses and offspring of obese women. Microglia, the resident immune cells of the brain, have been implicated in the pathogenesis of many of the neurodevelopmental morbidities noted with increased frequency in offspring of obese women. Despite this, there is a gap in knowledge about if/how placental inflammation affects fetal brain development in the setting of maternal obesity. We have demonstrated sex-specific fetal brain transcriptomes in the setting of maternal obesity, with dysregulated immune and inflammatory signaling highlighted as key effects of maternal obesity on both the male and female embryonic brain. We subsequently demonstrated a significant and sexually dimorphic effect of maternal obesity on microglial antigen (Iba-1) density in the embryonic hippocampus, and hippocampal learning deficits in obesity-exposed offspring, with male offspring more significantly affected. These data support the hypothesis that aberrant brain immune activation in embryonic life is one mechanism underlying enduring cognitive deficits. Inappropriate fetal microglial priming may therefore have lifelong neurodevelopmental consequences, but direct evaluation of microglial function in a living human fetus or neonate is impossible. Fortunately, placental macrophages (Hofbauer cells) and microglia have a common origin in the fetal yolk sac. Yolk-sac-derived macrophages comprise the permanent pool of brain microglia throughout an individual’s lifetime. Therefore, placental Hofbauer cells represent a potentially novel biologic sentinel that may mirror microglial immunoreactivity. Here, we seek to test the following hypotheses: (1a) maternal obesity will prime both Hofbauer cells and fetal brain microglia to overrespond to an immune challenge (1b) Maternal obesity will induce key alterations in the fetal microglial single cell transcriptome which will be recapitulated in the Hofbauer cell transcriptome (2) Selective ablation of pro-inflammatory macrophage signaling in the fetal brain and placenta using an innovative transgenic mouse will rescue maternal obesity-associated hippocampal learning deficits. The proposed experiments will fill a knowledge gap by ascertaining whether increased pro-inflammatory macrophage signaling in the placenta and fetal brain is a mechanism underlying offspring hippocampal learning deficits in maternal obesity. Demonstrating a causal link between fetal placental and brain macrophage-mediated inflammation and neurodevelopmental morbidity has potential therapeutic applications. If Hofbauer cells can serve as a more accessible cell type that provides information about the behavior of fetal brain microglia, there may be broader implications for assessing offspring risk in the setting of maternal exposures beyond obesity.

项目摘要在美国，三分之一的生殖年龄妇女肥胖。在大型流行病学研究中，母亲肥胖与儿童的认知定义有关，包括减少和低智商（<70）和较低的阅读和数学分数。潜在机制尚不清楚。众所周知，物物肥胖是胎儿已经报道了慢性低水平免疫反应以及胎盘感染和肥胖妇女的后代。小胶质细胞是大脑的常驻免疫球，已在许多神经发育的发病机理在后代的频率增加中指出肥胖的妇女。尽管如此，关于是否/下部炎症如何影响胎儿大脑仍然存在差距在孕产妇肥胖的情况下发展。我们已经证明了性别特异性的胎儿脑转录组孕产妇物体的设置，免疫和炎症信号失调为关键作用男性和雌性胚胎大脑上的孕产妇肥胖症。随后，我们证明了重要的母体肥胖对胚胎中小胶质细胞抗原（IBA-1）密度的性二态效应海马和海马学习在肥胖暴露后代定义，男性后代更多受到重大影响。这些数据支持胚胎生命中异常大脑免疫激活的假设是一种持久认知缺陷的基础机制。因此在活的人类胎儿或新生儿中评估小胶质功能是不可能的。幸运的是，胎盘巨噬细胞（Hofbauer细胞）和小胶质细胞在胎儿蛋黄囊中具有共同的起源。蛋黄 - 衍生的巨噬细胞包括整个人的一生中永久的脑小胶质细胞池。所以，胎盘霍夫鲍尔细胞代表了一种潜在的新型生物哨兵，可能会镜像小胶质免疫反应性。在这里，我们试图检验以下假设：（1a）孕产妇肥胖将倍增霍夫鲍尔细胞和胎儿脑小胶质细胞过度应对免疫挑战（1B）孕产妇肥胖症将诱发关键胎儿小胶质细胞转录组的改变，该转录组将在Hofbauer细胞中概括转录组（2）选择性消融胎儿脑和plopeta中促疾病的巨噬细胞信号传导使用创新的转基因小鼠将挽救与生物肥胖相关的海马学习缺陷。提出的实验将通过确定增加促炎性来填补知识差距 plapeta和胎儿大脑中的巨噬细胞信号传导是海马学习的基础机制在孕产妇肥胖症中确定。展示胎儿斑点和脑巨噬细胞介导的因果关系炎症和神经发育发病率具有潜在的治疗应用。如果霍夫鲍尔细胞可以充当一种更容易获得的细胞类型，可提供有关胎儿脑小胶质细胞行为的信息在肥胖以外的孕产妇暴露期间，评估后代风险可能是更广泛的影响。