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：
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
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/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

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，对于中枢神经系统至关重要（CNS）开发和功能。成熟的星形胶质细胞是异常复杂的细胞，具有复杂的和分支形态。它们的许多细胞过程与突触，神经元细胞紧密相互作用整个中枢神经系统中的身体，轴突，血管和其他神经胶质细胞。通过这些相互作用，星形胶质细胞履行各种功能，以支持和增强神经元活动，保持CNS稳态并调节电路。强调适当的星形胶质细胞发展的重要性，星形胶质细胞增长的缺陷或丧失星形胶质细胞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。但是，它仍然不太了解星形胶质细胞如何发展其复杂的形态学关联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，以目标为目标突触的过程，并使用这些细胞电池触点调节大脑功能。我们最近进行了果蝇中的遗传筛选以鉴定星形胶质细胞发育的新调节剂，并发现了一个新型基因，如星形胶质细胞形态发生所必需的内胚层1（TRE1）。我们发现Tre1的损失导致体内严重降低了星形胶质细胞的复杂性，导致突触神经纤维浸润降低。 TRE1 编码G蛋白偶联受体（GPCR），在中枢神经系统中没有已知功能。该建议将使用果蝇和斑马鱼可用的分子遗传工具的协同组合以及新工具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形态发生，功能，果蝇中的动物行为（AIM 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的进化保护（AIM 3）。我们的工作将对调节体内星形胶质细胞开发和功能的机制提供令人兴奋的新见解奠定理解人类疾病中星形胶质细胞生长和功能障碍的基础。