Impact of prenatal inflammation on developing human brain

项目摘要 母胎界面是孕期胎儿健康发育的重要环境 和送货。母体营养因子的减少，如母体甲状腺激素或母体 炎症/母体免疫激活(MIA)与神经发育风险增加有关 障碍，如自闭症或早产。然而，到目前为止还没有研究直接评估他们的 对人类发育中的大脑的影响。为了填补这一知识空白，我们建议通过实验研究 利用共培养的脑器官研究炎性因子对人类神经发育的影响 使用小胶质细胞，这是一个模拟人脑发育早期阶段的3D模型。小胶质细胞 是中枢神经系统的免疫细胞，产生于卵黄囊并穿透大脑。 在胚胎发生的关键时期，薄壁组织与突触发生和神经胶质发生相吻合。vt.给出 小胶质细胞是在外围产生的，我们假设小胶质细胞是一个重要的 人类大脑发育的组成部分，很可能是第一种暴露并做出反应的脑细胞 与可能导致产前神经发育障碍的环境因素/毒素有关。 在这里，我们将调查由细菌或病毒感染引起的母体炎症对人类的影响 小胶质细胞以及它如何影响人类发育中的大脑。此外，考虑到一个人可能是 在该人的一生或怀孕期间同时或顺序地暴露于更多的有毒因素， 我们还将通过测试共同接触传染性疾病的影响，来密切复制人类的经历 并研究它们对人类小胶质细胞功能和人类神经发育的协同影响。 目前使用IPSCs的研究样本大小有限，而且样本缺乏多样性 通常来自单一种族/族裔群体的捐赠者。因此，为了有一个更具包容性的方法，在这个 建议，我们将使用来自健康个体(50)的大量样本，代表不同的种族， 种族和性别与美国人口的比例密切相似，这将为 更好地了解人群和特定亚群中的健康差距和干预措施。 最终，我们的目标是更好地了解母体疾病的发病机制。 炎症和更有针对性的治疗，美国的大多数人都可以从中受益。

Project Summary The materno-fetal interface is a crucial environment for a healthy fetal development during pregnancy and delivery. A decrease in maternal trophic factors, such as maternal thyroid hormones or a maternal inflammation/maternal immune activation (MIA) have been linked to an increased risk for neurodevelopmental disorders, such as autism or preterm births. However, there has been no study to date to directly evaluate their impact on human developing brain. To fill this gap of knowledge, we propose to experimentally study the consequences of inflammatory factors on human neurodevelopment using the cerebral organoids co-cultured with microglial cells, a 3D model that mimics the early stages of the human brain development. Microglial cells are immune cells of the central nervous system that are generated in the yolk sac and penetrating the brain parenchyma during a critical time of the embryogenesis coinciding with synaptogenesis and gliogenesis. Given that microglial cells are generated in the periphery, we hypothesized that microglial cells are an important component of the human brain development and most likely the first brain cell type to be exposed and respond to an environmental factor/toxin that can potentially contribute to neurodevelopmental disorders prenatally. Here, we will investigate the impact of maternal inflammation due to bacterial or viral infections on human microglial cells and how that can impact the human developing brain. In addition, given that a person could be exposed to more toxic factors simultaneously or sequentially during that individual’s lifespan or during pregnancy, we will also aim to closely replicate the human experience, by testing the impact of co-exposures to infectious agents and study their synergistic impact on human microglial function and human neurodevelopment. Current studies using iPSCs has been limited sample size and the lack of diversity in the samples that are often derived from donors from a single race/ethnical group. Thus, to have a more inclusive approach, in this proposal, we will use a large cohort of samples from healthy individuals (>50), representative of different races, ethnicities and genders closely mimicking the proportions found in the United States’ population that will provide a better understanding of the health disparities and interventions both in populations and in specific subgroups. Ultimately, our goal is to provide a better understanding of the disease mechanisms involved in maternal inflammation and better targeted therapies from which the majority of the population in the US could benefit from.