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

• 批准号: 9145803
• 负责人: Xianhua Piao
• 金额: $ 39.25万
• 依托单位: BOSTON CHILDREN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-09-30 至 2019-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9145803
• 关键词: ADGR1 gene; Adhesions; Affect; Alleles; 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; Health; 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; Play; Property; Proteomics; RNA Splicing; Role; Signal Transduction; Stem cells; Testing; Tissues; Toxin; Transgenic Mice; Transglutaminases; Up-Regulation; Validation; Variant; Work; astrocyte progenitor; brain malformation; cell type; design; glial cell development; in vivo; myelination; nervous system development; nervous system disorder; new therapeutic target; novel; oligodendrocyte lineage; oligodendrocyte precursor; precursor cell; prevent; receptor; remyelination; repaired; therapeutic target; white matter

 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、髓鞘形成和髓鞘修复的分子机制知之甚少。髓磷脂在许多神经系统疾病中受到破坏，因此更好地了解 OL 生物学具有重要的临床意义。本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。 GPR56 突变会导致一种毁灭性的人类大脑畸形，称为双侧额顶多小脑回 (BFPP)，其中大脑的正常皮质褶皱被许多小回所取代。 BFPP 患者除了大脑皮层形成不良外，白质也受到不利影响。 BFPP 大脑的 MRI 图像揭示了表明髓鞘形成缺陷的信号变化。此外，我们的初步研究表明：1）GPR56在少突胶质祖细胞（OPC）和未成熟的OL中表达； 2）Gpr56的破坏导致小鼠中枢神经系统髓磷脂缺陷； 3) CNS 中存在一种新的 GPR56 推定配体。综上所述，我们的数据支持这样的假设：GPR56 是中枢神经系统髓鞘形成的一个以前未被认识到的调节因子。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。我们的工作可能会增强对髓鞘形成基本生物学的理解，并有可能揭示促进髓鞘疾病修复的新治疗靶点。