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

摘要 该项目的主要目标是确定人类小胶质细胞在建立 在健康和自闭症条件下发育的早期神经网络。虽然确切的原因 自闭症谱系障碍（ASD）仍然不清楚，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，并且表观遗传修饰已被证明是 控制小胶质细胞表型/可塑性，我们假设小胶质细胞表观遗传标记可能影响 神经元发育鉴于小胶质细胞起源于外周，后来侵入大脑，它们是最常见的。 可能是暴露于环境因素或至少受到环境因素影响的第一种脑细胞类型。 环境因素，因为它们是大脑的看门人。因此，更好地了解 遗传、环境或两者的协同影响，将为更好地了解人类 神经发育和人类小胶质细胞在这一过程中的作用产生了新的发现， 治疗靶点和有效疗法，用于广泛的神经系统疾病，包括ASD。因此，在本发明中， 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。 建立和高风险ASD表观遗传基因是否可以改变其功能和在人类发育过程中的作用 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脑皮质类器官（BCO）的作用，目的2： 测量携带ASD突变的小胶质细胞对BCO发育和功能的影响， 3：环境ASD风险因素与潜在遗传易感性的结合： 两次打击假说在这里，我们将测试与ASD相关的环境因素的孤立和累加效应， 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.