Molecular pathways regulating astrocyte morphogenesis and function

调节星形胶质细胞形态发生和功能的分子途径

基本信息

批准号：
10645162
负责人：
Marc R Freeman
金额：
$ 49.07万
依托单位：
OREGON HEALTH & SCIENCE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-08-01 至 2026-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10645162
关键词：
Alexander Disease Animal Behavior Astrocytes Axon Biological Assay Blood Vessels Brain Cell physiology Cells Cellular biology Central Nervous System Data Defect Development Drosophila genus Endoderm Environment Enzymes Epilepsy Exhibits Foundations Functional disorder G-Protein-Coupled Receptors Genes Genetic Genetic Models Genetic Screening Germ Cells Goals Growth Homeostasis Homologous Gene Human Image Individual Infiltration Light Lipids Maintenance Membrane Molecular Molecular Genetics Morphogenesis Morphology Mus Mutation Neuroglia Neurologic Neurons Neuropil Neurotransmitters Nutrient Organism Orthologous Gene Pathway interactions Phenocopy Physiology Process Protein phosphatase RNA Interference RNA interference screen Regulation Role Signal Pathway Signal Transduction Signaling Molecule Specific qualifier value Synapses Vertebrates Visualization Work Zebrafish autism spectrum disorder brain cell brain health cell growth cell motility cell type comparison control extracellular fly gene conservation genetic approach human disease in vivo in vivo imaging insight ionic balance knock-down lipid phosphate phosphatase live cell imaging mutant nervous system development nervous system disorder neural circuit neuronal cell body novel synaptogenesis tool wasting

项目摘要

SUMMARY Astrocytes are the most abundant glial cell type in the human brain and are critical for central nervous system (CNS) development and function. Mature astrocytes are unusually elaborate cells, with an intricate and ramified morphology. Their numerous fine cellular processes interact closely with synapses, neuronal cell bodies, axons, blood vessels, and other glial cells throughout the CNS. Through these interactions, astrocytes fulfil diverse functions to support and enhance neuronal activity, maintain CNS homeostasis, and modulate circuits. Underscoring the importance of proper astrocyte development, defects in astrocyte growth or loss of astrocyte complexity are implicated in many neurological diseases, including Alexander's disease, autism, and epilepsy. However, it remains poorly understood how astrocytes develop their intricate morphological associations and regulate neural circuit function. Our long-terms goals are to understand how astrocyte acquire their remarkable morphology, target their processes to synapses, and use these cell-cell contacts to modulate brain function. We recently performed a genetic screen in Drosophila to identify new regulators of astrocyte development, and uncovered a novel gene, Trapped in endoderm 1 (Tre1), as required for astrocyte morphogenesis. We find that loss of Tre1 leads to severely reduced astrocyte complexity in vivo, resulting in decreased infiltration of the synaptic neuropil. Tre1 encodes a G protein-coupled receptor (GPCR) with no known function in the CNS. This proposal will use a synergistic combination of molecular-genetic tools available in Drosophila and zebrafish along with new tools we have generated and in vivo imaging to: determine how Tre1 regulates astrocyte morphogenesis, function, and animal behavior in Drosophila (Aim 1); elucidate signaling pathways upstream and downstream of Tre1 activation (Aims 1+2); and define the evolutionary conservation of Tre1 in vertebrates (Aim 3). Our work will provide exciting new insights into the mechanisms regulating astrocyte development and function in vivo and lay the foundation for understanding astrocyte growth and dysfunction in human disease.

概括星形胶质细胞是人脑中最丰富的神经胶质细胞类型，对中枢神经系统至关重要（中枢神经系统）的发育和功能。成熟的星形胶质细胞是异常复杂的细胞，具有复杂且分枝形态。它们众多的精细细胞过程与突触、神经元细胞密切相互作用整个中枢神经系统的身体、轴突、血管和其他神经胶质细胞。通过这些相互作用，星形胶质细胞履行多种功能，支持和增强神经元活动、维持中枢神经系统稳态和调节电路。强调星形胶质细胞正常发育、星形胶质细胞生长缺陷或星形胶质细胞丧失的重要性星形胶质细胞的复杂性与许多神经系统疾病有关，包括亚历山大病、自闭症和癫痫。然而，人们对星形胶质细胞如何发展其复杂的形态仍知之甚少。关联并调节神经回路功能。我们的长期目标是了解星形胶质细胞如何获得其非凡的形态，瞄准其过程到突触，并利用这些细胞与细胞的接触来调节大脑功能。我们最近进行了一次在果蝇中进行遗传筛选，以确定星形胶质细胞发育的新调节因子，并发现了一个新基因，被困在内胚层 1 (Tre1) 中，这是星形胶质细胞形态发生所需的。我们发现 Tre1 的缺失会导致体内星形胶质细胞的复杂性严重降低，导致突触神经纤维的浸润减少。特雷1 编码 G 蛋白偶联受体 (GPCR)，其在中枢神经系统中的功能尚不清楚。该提案将使用果蝇和斑马鱼可用的分子遗传工具与新工具的协同组合我们已经生成了体内成像来：确定 Tre1 如何调节星形胶质细胞的形态发生、功能、果蝇的动物行为（目标 1）；阐明 Tre1 上游和下游的信号通路激活（目标 1+2）；并定义脊椎动物中 Tre1 的进化保守性（目标 3）。我们的工作将为体内调节星形胶质细胞发育和功能的机制提供令人兴奋的新见解为了解人类疾病中星形胶质细胞的生长和功能障碍奠定基础。