Gene regulatory networks influencing neuron-microglia interactions in fetal brain development.

影响胎儿大脑发育中神经元-小胶质细胞相互作用的基因调控网络。

• 批准号: 10425902
• 负责人: Claudia Z Han
• 金额: $ 11.48万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-04-01 至 2024-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10425902
• 关键词: Adopted; Affect; Anti-Inflammatory Agents; Apoptosis; Apoptotic; Automobile Driving; Award; Behavior; Behavioral; Biological Models; Brain; Brain Pathology; CRISPR/Cas technology; Cell Communication; Cells; Cerebrum; Chromatin; Coculture Techniques; Communication; Communities; DNA Binding; Data; Data Collection; Development; Disease; Electrophysiology (science); Embryo; Ensure; Environment; Epigenetic Process; Exposure to; Fetal Development; First Pregnancy Trimester; Functional disorder; Genes; Goals; Grant; Health; Heterogeneity; Homeostasis; Human; Human Characteristics; Immune; Inflammation; Inflammatory; Inflammatory Response; Knowledge; Lead; Ligands; Maintenance; Mediating; Mentors; Microglia; Modeling; Molecular; Morphology; Mus; Neurodevelopmental Disorder; Neuroglia; Neurologic; Neurons; Organoids; Outcome; Pathogenesis; Phase; Phenotype; Process; Publications; Publishing; Receptor Signaling; Research; Research Personnel; Risk; Risk Factors; Second Pregnancy Trimester; Series; Signal Transduction; Specimen; Stimulus; Synapses; System; Technology; Testing; Therapeutic Intervention; Time; Tissues; Training; Transducers; Up-Regulation; analytical method; brain cell; brain circuitry; cell type; clinically relevant; critical period; epigenome; experience; fetal; gene regulatory network; genome editing; human fetal brain tissue; immune activation; improved; induced pluripotent stem cell; macrophage; migration; mouse development; mouse model; nerve stem cell; neural circuit; neural network; neurodevelopment; neurogenesis; neuronal circuitry; neurotrophic factor; neurotropic; notch protein; pleiotropism; postnatal; prenatal; programs; receptor; relating to nervous system; response; therapeutic target; tool; transcription factor

Project Summary/Abstract The prenatal period is a sensitive and critical time for brain development characterized by waves of neurogenesis, neuronal migration, and formation of neural networks. In the first and second trimester, microglia are the dominant immune cells of the brain and participate in a variety of processes essential to brain development, including secreting neurotropic factors and engulfing apoptotic neural progenitor cells. Fetal microglia dysfunction can lead to aberrant cortical lamination, resulting in an increased risk of brain pathology. We have identified numerous ligand-receptor pairs involved in microglia-to-cortex and cortex-to-microglia signaling predicted to contribute to human fetal microglia function and fetal brain development. We observe concordant expression of these ligand-receptors pairs in cerebral organoids (COs) and induced pluripotent stem cell-derived microglia with our human fetal data. COs can model early human brain development, but current models lack the immune component of the brain. Our data suggest that induced pluripotent stem cell-derived microglia co- cultured with COs (oMGs) capture significant phenotypic characteristics of human fetal microglia. Thus, a systematic analysis of neural maturation following integration of microglia into COs is the first step in using this model system to interrogate the molecular mechanisms underlying how neuron-microglia interactions establish early brain circuitry. This proposal aims to use COs and oMGs to assess how brain environment signals and corresponding transcription factors contribute to fetal microglia behavior and microglial interaction with neurons in early fetal development. In Aim 1, completed in the K99 phase, I will test the hypothesis that integration of microglia into COs results in enhanced neural maturation. Additionally, I will test how perturbation of homeostatic brain environment signaling in microglia results in microglia dysfunction and altered neuronal subpopulations. In Aim 2, I will identify transcription factor networks underlying human and mouse microglia behavior throughout development, at homeostasis and after an inflammatory insult. The goal for Aim 2 is to uncover species- conserved mechanisms in microglia responses to inflammation for improved therapeutic targeting and murine modeling and to discover potential human-specific risk factors for disease. Additionally, I will test the hypothesis that microglial developmental transcriptional factors are re-wired following an inflammatory insult, leading to long- lasting changes in microglia behavior and disruption of brain circuitry. Studies in Aim 2 will be completed in the independent phase. My long-term goal is to elucidate the epigenetic mechanisms underlying neuronal-microglia communication in health and disease as an independent investigator. I have assembled a diverse group of highly skilled mentors who will ensure that I receive extensive training in neurodevelopment and assessment of neural circuits. My training will be further enhanced by the unique scientific environment of the UCSD research community, which is geared towards the development and usage of cutting-edge technology and analytic methods to assess cellular heterogeneity and dynamic cell-cell interactions in the brain.

项目概要/摘要 产前时期是大脑发育的敏感和关键时期，其特点是神经发生波， 神经元迁移和神经网络的形成。在妊娠早期和中期，小胶质细胞是 大脑的主导免疫细胞并参与大脑发育必需的各种过程， 包括分泌神经营养因子和吞噬凋亡的神经祖细胞。胎儿小胶质细胞 功能障碍可能导致皮质分层异常，从而增加大脑病理的风险。我们有 鉴定了许多参与小胶质细胞到皮质和皮质到小胶质细胞信号传导的配体-受体对 预计有助于人类胎儿小胶质细胞功能和胎儿大脑发育。我们观察到一致 这些配体-受体对在脑类器官（CO）和诱导多能干细胞衍生中的表达 小胶质细胞与我们的人类胎儿数据。 CO可以模拟早期人类大脑发育，但目前的模型缺乏 大脑的免疫部分。我们的数据表明诱导多能干细胞衍生的小胶质细胞共同 用CO (oMG) 培养可捕获人类胎儿小胶质细胞的显着表型特征。因此，一个 对小胶质细胞整合到 CO 后的神经成熟进行系统分析是使用该技术的第一步 模型系统来探究神经元-小胶质细胞相互作用如何建立的分子机制 早期的大脑电路。该提案旨在利用 CO 和 oMG 来评估大脑环境如何发出信号和 相应的转录因子有助于胎儿小胶质细胞的行为以及小胶质细胞与神经元的相互作用 在胎儿发育早期。在 K99 阶段完成的目标 1 中，我将检验以下假设：整合 小胶质细胞转化为 CO 导致神经成熟增强。此外，我将测试稳态的扰动如何 小胶质细胞中的大脑环境信号传导导致小胶质细胞功能障碍和神经元亚群的改变。在 目标 2，我将在整个过程中识别人类和小鼠小胶质细胞行为背后的转录因子网络 发育、稳态和炎症损伤后。目标 2 的目标是发现物种—— 小胶质细胞对炎症反应的保守机制，以改善治疗靶向和小鼠 建模并发现潜在的人类特定疾病危险因素。另外，我将检验假设 小胶质细胞发育转录因子在炎症损伤后重新连接，导致长期 小胶质细胞行为的持久变化和大脑回路的破坏。目标 2 的研究将在 独立相。我的长期目标是阐明神经元小胶质细胞的表观遗传机制 作为独立研究者进行健康和疾病方面的沟通。我组建了一支多元化的高素质团队 熟练的导师将确保我接受神经发育和神经评估方面的广泛培训 电路。加州大学圣地亚哥分校研究的独特科学环境将进一步加强我的培训 社区，致力于尖端技术和分析的开发和使用 评估大脑中细胞异质性和动态细胞间相互作用的方法。