Neuromodulation of maternal immune adaptations in pregnancy

项目摘要 怀孕依赖于母体免疫系统的微调适应，以建立和维持免疫耐受 半同种异体胎儿，这似乎是不平衡的妇女经历并发症，如早产。 在妊娠期以外，中枢神经系统可以通过交感神经调节全身免疫 然而，它在妊娠期间调节母体免疫系统适应中的作用仍然未知。 了解整个怀孕期间免疫调节的决定因素是提高早期风险的先决条件 病理性妊娠的评估和治疗。该研究项目旨在研究 大脑、怀孕和免疫系统。最先进的免疫学（质谱细胞术）和神经科学 （离散神经元回路的神经调节）方法将结合起来，全面研究神经免疫 调节人类足月妊娠和早产以及小鼠妊娠模型。具体来说，我们假设 过度活跃的交感神经（肾上腺素能）紧张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建议的第一个目的是监测响应情况， 先天性促炎单核细胞对肾上腺素能信号的反应（使用单细胞高维质谱细胞术）， 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）。 这一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， 继续我之前在过去100天的健康分娩前血浆签名和免疫组学的深入分析， 怀孕，准确预测分娩的开始。在目标2中，为了理解脑-妊娠通信， 机械水平，神经科学方法（纤维光度学和化学遗传学）将在 Luis de Lecea实验室，他是尖端神经调节技术的先驱。在这里，我将操纵离散神经元 已知抑制或增强外周免疫的小鼠妊娠晚期， 目是监测它们与外周单核细胞反应性的联系。反过来，纤维光度法也可以追踪怀孕- 这些神经群体的活动的特定改变。在第三个也是最后一个目标3中，我将确定单核细胞是否 对交感神经信号的反应在整个早产与足月妊娠中是不同的， 每个妊娠三个月，使用高维单细胞质量细胞计数。机器学习方法将是 用于训练用于早产与足月样本分类的模型。在独立R 00阶段，我设想应用 从免疫学和神经科学的技术来了解怀孕生物学和病理学从中枢神经系统 系统视角总之，这一系列拟议中的研究将回答新兴大脑领域的基本问题- 外周免疫串扰，并阐明未充分研究的妊娠神经免疫调节机制，而 这对我的职业发展和学术独立的过渡有很大的帮助。

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.