Neuromodulation of maternal immune adaptations in pregnancy

项目总结 怀孕依赖于母体免疫系统的微调适应来建立和维持免疫耐受。 对于半异基因胎儿，这在经历并发症的妇女中似乎是不平衡的，例如早产。 在怀孕环境之外，中枢神经系统可以通过交感神经调节系统免疫。 虽然它在调节孕期母体免疫系统适应方面的作用尚不清楚。 了解孕期免疫调节的决定因素是增加早期风险的先决条件。 病理性妊娠的评估和治疗。这项研究项目提出的目标是 大脑、怀孕和免疫系统。最新免疫学(质量细胞学)和神经科学 (离散神经回路的神经调节)方法将结合起来全面研究神经免疫 人类足月妊娠、早产妊娠和小鼠妊娠模型的调节。具体地说，我们假设 过度活跃的交感神经(肾上腺素能)可增强全身促炎单核细胞反应，从而有助于 早产儿的胎儿耐受性受损。这项提案的第一个目标是监测响应情况 先天促炎单核细胞对肾上腺素能信号的作用(使用单细胞高维质量细胞术)，以及 神经系统相关蛋白质组(例如，肾上腺素能分析物，Brice Gaudilliere实验室)贯穿人类妊娠晚期。 这个目标是基于我目前在人类妊娠免疫学和多参数方法方面的专业知识，以及一个 继续我先前对健康人最后100天产前血浆标志物和免疫学的深入分析 怀孕，它准确地预测了分娩的开始。在目标2中，了解大脑与怀孕之间的沟通 机械层面，神经科学方法(纤维光度和化学遗传学)将在监督下使用 路易斯·德·莱西亚实验室，他是尖端神经调节技术的先驱。在这里，我将操控离散神经 已知的抑制或增强外周免疫的种群，在妊娠晚期，与 目的是监测它们与外周血单核细胞反应性之间的联系。反过来，光纤光度技术将跟踪怀孕- 这些神经群体活动的特定变化。在第三个也是最终目标3中，我将确定单核细胞 通过分析在早产和足月妊娠中采集的母血，对交感信号的反应在早产和足月妊娠期间有所不同 妊娠每三个月，采用高维单细胞质量细胞术。机器学习方法将是 用于训练先行术语与术语样本分类的模型。在独立的R00阶段，我设想应用 从中枢神经了解妊娠生物学和病理学的免疫学和神经科学技术 系统视角。总之，这组拟议的研究将回答新生的大脑领域的基本问题-- 外周免疫串扰，并阐明妊娠期间神经免疫调节的未被研究的机制，而 对我的职业发展和向独立的学业过渡有很大的帮助。

PROJECT SUMMARY Pregnancy relies on finely-tuned adaptations of the maternal immune system to establish and maintain immune-tolerance to the semi-allogeneic fetus, which appear to be imbalanced in women experiencing complications, such as preterm birth. Outside the pregnancy context, the central nervous system can modulate systemic immunity via the sympathetic nervous system, while its role in modulating maternal immune system adaptations during pregnancy remains unknown. Understanding the determinants of immune regulation throughout pregnancy is a prerequisite to advance the early risk assessment and treatment of pathological pregnancies. This research project proposes to target the interaction between the brain, pregnancy, and the immune system. State-of-the-art immunology (mass cytometry) and neuroscience (neuromodulation of discrete neuronal circuitry) approaches will be combined to comprehensively investigate neuroimmune regulation of human term and preterm pregnancies and mouse models of pregnancy. Specifically, we hypothesize that a hyperactive sympathetic (adrenergic) tone enhances systemic pro-inflammatory monocyte responses, thereby contributing to a compromised fetal tolerance in preterm pregnancies. The first aim of this proposal will monitor the responsiveness innate pro-inflammatory monocytes to adrenergic signals (using single-cell high-dimensional mass cytometry), and the nervous-system associated proteome (e.g., adrenergic analytes, Brice Gaudilliere lab) throughout the human third trimester. This aim is based on my current expertise in human pregnancy immunology and multi-parameter approaches, and a continuation of my prior in-depth analyses of the pre-labor plasma signature and immunome in the last 100 days of healthy pregnancy, which accurately predict the onset of labor. In aim 2, to understand brain-pregnancy communication on a mechanistic level, neuroscience approaches (fiber photometry and chemogenetics) will be used under supervision of the Luis de Lecea lab, who pioneered cutting-edge neuro-modulatory techniques. Here, I will manipulate discrete neural populations, known to either suppress or enhance peripheral immunity, throughout late gestation in mouse pregnancies with the aim to monitor their link to peripheral monocyte responsiveness. Reciprocally, fiber photometry will track pregnancy- specific alterations in activity of these neural populations. In the third and final aim 3, I will determine whether monocyte responses to sympathetic signals differ throughout preterm vs. term pregnancies by analyzing maternal blood collected in each trimester of pregnancy, using high-dimensional single-cell mass cytometry. Machine learning approaches will be utilized to train a model for preterm vs. term sample classification. In the independent R00 phase, I envision to apply techniques from immunology and neuroscience to understand pregnancy biology and pathology from a central nervous system perspective. Together, the set of proposed studies will answer fundamental questions in the nascent field of brain- peripheral immunity cross-talk, and elucidate understudied mechanism of neuroimmunomodulation in pregnancy, while significantly aiding in my career development and academic transition to independence.