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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.

总结