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: 10592426
• 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/10592426
• 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; Cell Death; 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; Gene Expression Regulation; Goals; Grant; Health; Heterogeneity; Homeostasis; Human; Human Characteristics; Immune; Inflammation; Inflammatory; Inflammatory Response; Knowledge; Ligands; Macrophage; Maintenance; Mediating; Mentors; Microglia; Modeling; Molecular; Morphology; Mus; Neurodevelopmental Disorder; Neuroglia; 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; human fetal brain tissue; immune activation; improved; induced pluripotent stem cell; migration; mouse development; mouse model; nerve stem cell; nervous system disorder; neural; neural circuit; neural network; neurodevelopment; neurogenesis; neuronal circuitry; neuropathology; neurotransmission; neurotrophic factor; neurotropic; notch protein; pleiotropism; postnatal; prenatal; receptor; response; skills; synaptic pruning; 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.

项目摘要/摘要 产前期是脑发育的敏感和关键时期，其特征是神经发生波， 神经元迁移和神经网络的形成。在第一和第二学期，小胶质细胞是 大脑的主要免疫细胞并参与大脑发育必不可少的各种过程 包括分泌神经性因素和吞噬凋亡神经祖细胞。胎儿小胶质细胞 功能障碍会导致异常的皮质层压，从而增加患脑病理的风险。我们有 鉴定了许多参与小胶质细胞和皮质至微神经的配体受体对 预计有助于人类胎儿小胶质细胞功能和胎儿脑发育。我们观察到一致 这些配体受体的表达在大脑器官（COS）和诱导多能干细胞衍生的表达 与我们的人类胎儿数据的小胶质细胞。 cos可以建模早期的人脑发育，但是当前的模型缺乏 大脑的免疫成分。我们的数据表明，诱导多能干细胞衍生的小胶质细胞共胶质 用COS（OMG）培养的人类小胶质细胞捕获了显着的表型特征。因此， 将小胶质细胞整合到COS之后的神经成熟的系统分析是使用此步骤的第一步 询问神经元 - 神经元相互作用的分子机制的模型系统 早期脑电路。该建议旨在使用COS和OMG评估大脑环境信号和 相应的转录因子有助于胎儿小胶质细胞行为和与神经元的小胶质细胞相互作用 在早期胎儿发育中。在AIM 1（在K99阶段完成）中，我将检验以下假设。 小胶质细胞进入COS导致神经成熟增强。此外，我将测试稳态的扰动 小胶质细胞中的大脑环境信号传导会导致小胶质细胞功能障碍和神经元亚群的改变。在 AIM 2，我将确定整个人类和小鼠小胶质细胞行为的转录因子网络 发育，稳态和炎症性侮辱之后。目标2的目标是发现物种 - 小胶质细胞对炎症的保守机制，以改善治疗靶向和鼠 建模并发现潜在的人类特异性疾病因素。此外，我将检验假设 炎症性侮辱后，小胶质细胞发育转录因素被重新连接，导致长期 小胶质细胞行为的持久变化和脑电路的破坏。 AIM 2的研究将在 独立阶段。我的长期目标是阐明神经元 - 神经元的表观遗传机制 作为独立研究者的健康和疾病的沟通。我聚集了一群高度 熟练的导师将确保我接受神经发育和评估的广泛培训 电路。 UCSD研究的独特科学环境将进一步增强我的培训 社区，旨在开发和使用尖端技术和分析 评估大脑中细胞异质性和动态细胞相互作用的方法。