The impact of hiPSC-derived microglia in human brain development in health and disease

hiPSC 衍生的小胶质细胞对健康和疾病中人脑发育的影响

• 批准号: 10279492
• 负责人: Alysson R. Muotri
• 金额: $ 44.29万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-08-01 至 2026-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10279492
• 关键词: ASD patient; Affect; Appearance; Biological Models; Brain; Cells; Complex; Data; Development; Disease; Environmental Impact; Environmental Risk Factor; Epigenetic Process; Experimental Models; Exposure to; Gene Expression; Genes; Genetic; Genetic Predisposition to Disease; Genetic Transcription; Goals; Health; Human; Impairment; Invaded; Measures; Microglia; Modeling; Modification; Molecular; Mutation; Nerve Degeneration; Neuraxis; Neurodevelopmental Disorder; Neurons; Organoids; Patients; Phagocytosis; Phenotype; Physiological; Physiology; Play; Population; Process; Risk Factors; Role; Synapses; Testing; Time; XCL1 gene; autism spectrum disorder; autistic; base; brain cell; cell type; experimental study; fetal; first responder; genetic variant; high risk; induced pluripotent stem cell; mutant; nervous system disorder; neural network; neurodevelopment; neuron development; new therapeutic target; risk variant; single-cell RNA sequencing; synaptic pruning; synaptogenesis

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.

抽象的 该项目的主要目标是确定人类小胶质细胞在建立 健康和自闭症条件下发育过程中的早期神经网络。虽然确切原因 自闭症谱系障碍（ASD）尚不清楚，表观遗传、遗传和环境因素都在起作用。 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可以 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特征可能会影响 神经元发育。鉴于小胶质细胞起源于外周并随后侵入大脑，因此它们是最重要的 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类型 环境因素赋予它们作为大脑看门人的作用。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铺平道路 在此过程中神经发育和人类小胶质细胞的作用导致了新发现 针对包括 ASD 在内的广泛神经系统疾病的治疗靶点和有效疗法。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 建立以及高风险 ASD 表观遗传基因是否可以改变其功能及其在人类 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： 确定健康的人类小胶质细胞对健康的大脑皮质类器官 (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，以及目标 3：环境 ASD 风险因素与潜在遗传倾向相结合的影响： 两次打击假设。在这里，我们将测试 ASD 相关环境因素对 ASD 的孤立效应和累加效应 小胶质细胞的功能及其对 BCO 生理学的影响。