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; 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中的贡献 在健康和自闭症状况下发展过程中的早期神经网络。虽然确切的原因是 自闭症谱系障碍（ASD）仍然不清楚，表观遗传，遗传和环境因素正在发挥作用。 鉴于ASD是一种复杂的多因素障碍，并且表观遗传修饰已被证明是 控制小胶质表型/可塑性，我们假设小胶质细胞表观遗传学特征可能会影响 神经元发展。鉴于小胶质细胞起源于外围，后来侵入大脑，它们是最多的 可能是第一种脑细胞类型暴露于环境因素，或者至少受到影响 环境因素鉴于它们是大脑守门员的作用。因此，更好地理解 两者的遗传，环境或协同影响，将为人们更好地理解人类铺平道路 在此过程中，神经发育和人类小胶质细胞的作用赋予了新颖的发现 包括ASD在内的广泛神经系统疾病的治疗靶标和有效疗法。因此， 通过这个项目，我们旨在确定人类小胶质细胞是否干扰神经网络 建立和高风险的ASD表观遗传基因可以改变其功能和在人类中的作用 神经发育。根据我们的初步数据，我们提出以下具体目的是：目标1： 确定健康人类小胶质细胞对健康脑皮质器官（BCO）的作用，AIM 2： 测量携带ASD突变对BCO开发和功能的小胶质细胞的影响，并瞄准 3：环境ASD风险因素与潜在的遗传易感性的影响： 两次打击的假设。在这里，我们将测试与ASD相关环境因素的孤立和加性效应 小胶质细胞的功能及其对BCO生理的影响。