The Impact of hiPSC-Derived Microglia in Human Brain Development in Health and Disease

摘要 这个项目的主要目标是确定人小胶质细胞在建立 早期神经网络在健康和自闭症条件下的发育过程。虽然真正的原因是 自闭症谱系障碍(ASD)仍不清楚，表观遗传、遗传和环境因素在起作用。 鉴于ASD是一种复杂的多因素疾病，表观遗传修饰已被证明 控制小胶质细胞的表型/可塑性，我们假设小胶质细胞的表观遗传特征可能影响 神经元发育。鉴于小胶质细胞起源于外周，后来侵入大脑，它们是最 可能是第一种暴露于环境因素或至少受到环境因素影响的脑细胞 环境因素，因为它们是大脑的守门人。因此，更好地理解 基因、环境或两者的协同影响，将为更好地理解人类铺平道路 神经发育和人类小胶质细胞在这一过程中的作用导致了新的发现 治疗目标和有效治疗范围广泛的神经疾病，包括自闭症。因此， 通过这个项目，我们的目标是确定人类小胶质细胞是否以及如何干扰神经网络。 高危ASD表观遗传基因的建立及其是否能改变其功能和作用 神经发育。根据我们的初步数据，我们提出以下具体目标：目标1： 确定健康人小胶质细胞对健康大脑皮质有机体(BCO)的作用，目标2： 测量携带ASD突变的小胶质细胞对BCO发育和功能的影响，并目的 3：环境自闭症风险因素与潜在遗传易感性的影响： 两次命中假说。在这里，我们将测试ASD相关环境因素对 小胶质细胞的功能及其对BCO生理的影响。

Abstract The main goal of this project is to determine the contribution of human microglia in the establishment of early neural networks during development in healthy and autistic conditions. Although the exact cause of Autism Spectrum Disorders (ASD) remains unclear, epigenetic, genetic and environmental factors are at play. Given that ASD is a complex multifactorial disorder and that epigenetic modifications have been shown to control microglial phenotypes/plasticity, we hypothesized that microglial epigenetic signature might influence neuronal development. Given that microglia originate in the periphery and later invade the brain, they are most likely the first brain cell type to be exposed to an environmental factor or at least be impacted by the environmental factor given their role as gate keepers of the brain. Therefore, a better understanding of the genetic, environmental or a synergistic impact of both, will pave the way to a better understanding of human neurodevelopment and human microglial roles during this process yielding to the discovery of novel therapeutic targets and efficient therapies for a broad range of neurological disorders including ASD. Thus, with this project, we aim to establish whether and how human microglia interfere with neural network establishment and if high-risk ASD epigenetic genes could alter their function and their role during human neurodevelopment. Based on our preliminary data we propose the following specific aims are: Aim 1: Determine the role of healthy human microglia on healthy brain cortical organoids (BCO), Aim 2: Measure the impact of microglia carrying ASD mutations on BCO development and function, and Aim 3: Impact of environmental ASD-risk factors in combination with underlying genetic predisposition: the two-hit hypothesis. Here we will test the isolated and additive effect of ASD-related environmental factors on the function of microglia and its impact on BCO physiology.