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：
9349611
负责人：
Xianhua Piao
金额：
$ 38.72万
依托单位：
BOSTON CHILDREN'S HOSPITAL
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 2018-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9349611
关键词：
ADGR1 gene Adhesions Affect Alleles Alpha Cell Antithymoglobulin Astrocytes Axon Bilateral Binding Biochemical Biological Biology Biotinylation Brain Caliber Cell Cycle Cells Cerebral cortex Cerebrum Clinical Communication Corpus Callosum Cuprizone Data Defect Demyelinating Diseases Demyelinations Development Disease Exons Extracellular Matrix Extracellular Matrix Proteins Family Family member G-Protein-Coupled Receptors Genetic Human Image Injury Knock-out Knockout Mice Lesion Ligands Magnetic Resonance Imaging Mediating Membrane Microgyria Modeling Molecular Multiple Sclerosis Mus Mutation Myelin Myelin Sheath Natural regeneration Nervous System Physiology Nervous system structure Neuraxis Neuroglia Oligodendroglia Patients Phenotype Platelet-Derived Growth Factor alpha Receptor Play Property Proteomics RNA Splicing Role Signal Transduction Stem cells Systems Development Testing Tissues Transgenic Mice Transglutaminases Up-Regulation Validation Variant Work alpha Toxin brain malformation cell type design glial cell development in vivo myelination nervous system disorder new therapeutic target novel oligodendrocyte lineage oligodendrocyte precursor oligodendrocyte progenitor precursor cell premature prevent public health relevance receptor remyelination repaired therapeutic target white matter

项目摘要

DESCRIPTION (provided by applicant): Myelin is the multilayered membrane generated by glial cells that insulates and protects axons in the vertebrate nervous system. In the central nervous system (CNS), oligodendrocytes (OLs) form the myelin sheath. The molecular mechanisms that govern oligodendrocyte development, myelination, and myelin repair are poorly understood; myelin is disrupted in many neurological diseases, and so a better understanding of OL biology has important clinical implications. The object of this proposal is to study how the adhesion G protein- coupled receptor GPR56 regulates OL development, myelination, and myelin repair. Mutations in GPR56 cause a devastating human brain malformation called bilateral frontoparietal polymicrogyria (BFPP), in which the normal cortical folds of the cerebrum are replaced by numerous small gyri. In addition to the poor formation of the cerebral cortex, white matter is also adversely affected in BFPP patients. MRI images of BFPP brains reveal signal changes indicating myelination defects. Furthermore, our preliminary studies demonstrate that: 1) GPR56 is expressed in oligodendrocyte progenitor cells (OPCs) and immature OLs; 2) disruption of Gpr56 leads to CNS myelin defects in mice; and 3) there is a novel putative ligand of GPR56 in CNS. Taken together, our data support the hypothesis that GPR56 is a previously unappreciated regulator of myelination in the CNS. This proposal is designed to test this hypothesis, thus establishing novel regulators of glial cell development and myelination. Our work is likely to enhance the understanding of the basic biology of myelination and will potentially reveal a new target for therapeutics to promote repair in myelin disease.

描述（由申请人提供）：髓磷脂是由神经胶质细胞产生的多层膜，可隔离和保护脊椎动物神经系统中的轴突。在中枢神经系统（CNS）中，少突胶质细胞（OL）形成髓鞘。人们对少突胶质细胞发育、髓鞘形成和髓磷脂修复知之甚少；髓磷脂在许多神经系统疾病中受到破坏，因此需要更好地了解OL 生物学具有重要的临床意义，该提案的目的是研究粘附 G 蛋白偶联受体 GPR56 如何调节 OL 发育、髓鞘形成和髓鞘修复。，其中大脑的正常皮质褶皱被许多小回所取代。除了大脑皮层的形成不良之外，白质也受到不利影响。此外，我们的初步研究表明：1) GPR56 在少突胶质细胞祖细胞 (OPC) 和未成熟的 OL 中表达；2) Gpr56 的破坏导致中枢神经系统髓鞘缺陷。小鼠中；3) CNS 中存在一种新的 GPR56 假定配体综上所述，我们的数据支持 GPR56 的假设。是以前未被认识的中枢神经系统髓鞘形成的调节因子，该提案旨在检验这一假设，从而建立神经胶质细胞发育和髓鞘形成的新调节因子，并有可能增强对髓鞘形成基本生物学的理解。促进髓磷脂疾病修复的新治疗目标。