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

• 批准号: 10454296
• 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
• 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/10454296
• 关键词: Alexander Disease; Animal Behavior; Astrocytes; Axon; Biological Assay; Blood Vessels; Brain; Cell physiology; Cells; Cellular biology; Data; Defect; Development; Drosophila genus; Endoderm; Environment; Enzymes; Epilepsy; Exhibits; Foundations; Functional disorder; G-Protein-Coupled Receptors; GTP-Binding Protein alpha Subunits, Gs; 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; Neuraxis; 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; Synapses; Vertebrates; Work; Zebrafish; autism spectrum disorder; base; brain cell; brain health; cell growth; cell motility; cell type; extracellular; fly; 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

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.

摘要 星形胶质细胞是人脑中含量最丰富的胶质细胞类型，对中枢神经系统至关重要。 (CNS)发展和功能。成熟的星形胶质细胞是异常精细的细胞，具有错综复杂的 分枝形态。它们众多的细微细胞突起与突触、神经细胞 中枢神经系统中的小体、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 发挥多种功能以支持和增强神经元活动，维持中枢神经系统的动态平衡，并调节 电路。强调星形胶质细胞正常发育的重要性，星形胶质细胞生长缺陷或丧失 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，星形胶质细胞如何发展其复杂的形态仍然知之甚少。 联想和调节神经回路功能。 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，靶向其 突触的过程，并利用这些细胞-细胞接触来调节大脑功能。我们最近表演了一场 在果蝇中进行基因筛查，以确定星形胶质细胞发育的新调节因素，并发现了一个新的基因， 被困于内胚层1(Tre1)，这是星形胶质细胞形态发生所必需的。我们发现失去Tre1会导致 严重降低了体内星形胶质细胞的复杂性，导致突触神经纤维的渗透减少。Tre1 编码一个在中枢神经系统中未知功能的G蛋白偶联受体(GPCR)。此提案将使用 果蝇和斑马鱼可用的分子遗传工具与新工具的协同组合 我们已经产生并在体内成像：确定Tre1如何调节星形胶质细胞的形态发生、功能、 和果蝇的动物行为(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Tre1的进化保守性(目标3)。我们的工作将 为调节星形胶质细胞体内发育和功能的机制提供了令人兴奋的新见解 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。