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Adhesion G Protein-Coupled Receptors in CNS Development and Regeneration

CNS 发育和再生中的粘附 G 蛋白偶联受体

基本信息

批准号：
10417182
负责人：
Xianhua Piao
金额：
$ 58万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-09-30 至 2026-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10417182
关键词：
ADGR1 gene Actins Adhesions Agonist Attention Axon Bilateral Binding Biology Biotinylation Brain Cell Communication Cell Proliferation Cells Cellular Morphology Cellular biology Coculture Techniques Corpus Callosum Data Defect Demyelinating Diseases Development Disease Expression Profiling F-Actin Failure Family G Protein-Coupled Receptor Signaling G-Protein-Coupled Receptors Genetic Human In Vitro Injury Laminin Ligands Mediating Membrane Microglia Microgyria Modeling Multiple Sclerosis Myelin Myelin Sheath Natural regeneration Nervous System Physiology Nervous system structure Neuraxis Neuroglia Oligodendroglia Optic Nerve Pathway interactions Pattern Pharmacology Play Process Proliferating Proteins Proteomics Publishing Role Shivering Signal Pathway Signal Transduction Slice Testing Work Zebrafish antagonist cellular development design in vivo inhibitor loss of function mutation member mouse model myelination nervous system development nervous system disorder new therapeutic target novel novel therapeutics oligodendrocyte lineage oligodendrocyte precursor polymerization precursor cell progenitor protein expression remyelination repaired single-cell RNA sequencing therapeutic target transglutaminase 2

项目摘要

Myelin is the multilamellar membrane generated by glial cells that insulates, nourishes and protects axons in the vertebrate nervous system. In the central nervous system (CNS), oligodendrocytes (OLs) form the myelin sheath. OL follow an orderly and distinct developmental pattern with stage-specific functions. OL precursor cell (OPC) proliferate. Pre-myelinating OL (pmOL) mediate initial axon ensheathment and myelinating OL (mOL) carry out iterative axon wraps. Our published work demonstrates that G protein-coupled receptor (GPCR) GPR56 regulates OPC proliferation by mediating a tripartite signaling between OPC GPR56, microglia-derived tissue transglutaminase, and matrix protein laminin-111. Intriguingly, single cell RNAseq data reveals that, within the OL lineage, GPR56 is expressed highest at the pmOL stage. Our unpublished data provide tantalizing evidence that (1) pmOL GPR56 is required for F-actin formation; (2) deleting Gpr56specifically in pmOLs results in reduced myelination of the corpus callosum (CC); and (3) pmOLs lacking Gpr56 were unable to form myelin in co-cultured Shiverer cerebellar slices. Taking these data all together, we hypothesize that GPR56 functions in pmOLs to regulate actin organization of the pre-myelinating OL process. This proposal is designed to test this hypothesis, thus establishing novel GPCR signaling pathway in pmOL F-actin polymerization and axon ensheathment. Our data will enhance the understanding of the basic biology of myelination and will potentially reveal a new target for therapeutics to promote repair in the wide spectrum of neurological diseases that implicate myelin damage.

髓磷脂是由神经胶质细胞产生的多层膜，具有隔离、滋养和保护轴突的作用