Molecular and Genetic Analysis of Adhesion Gpcrs in Myelinating Glial Cell Development

髓鞘胶质细胞发育中粘附 GPCR 的分子和遗传分析

基本信息

批准号：
9732883
负责人：
Kelly R Monk
金额：
$ 10.34万
依托单位：
OREGON HEALTH & SCIENCE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-07-01 至 2021-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9732883
关键词：
ADGR1 gene Action Potentials Address Adhesions Adult Agonist Alleles Axon Binding Biology C-terminal Cell Adhesion Cell surface Cyclic AMP Data Demyelinations Development Disease Drug Targeting Ensure Excision Extracellular Matrix Proteins Foundations Future G-Protein-Coupled Receptors Genetic Goals Health Homeostasis Human Injury Laminin Lead Learning Ligands Maintenance Mediating Molecular Molecular Analysis Morbidity - disease rate Mus Myelin Myelin Sheath N-terminal Nerve Nervous System Physiology Nervous system structure Neuroglia Neurons Pain Paralysed Peptides Peripheral Nervous System Peripheral Nervous System Diseases Pharmaceutical Preparations Phenotype Process Progress Reports Publications Radial Schwann Cells Series Signal Pathway Signal Transduction Site Sorting - Cell Movement Symptoms Testing Therapeutic Transmembrane Domain Travel Zebrafish experimental study extracellular genetic analysis glial cell development human disease in vivo injured member mouse model mutant myelination nervous system development nervous system disorder neurological recovery neuron loss novel prevent programs public health relevance receptor receptor function remyelination repaired therapeutic target therapy development transcription activator-like effector nucleases

项目摘要

DESCRIPTION (provided by applicant): Myelin is a layer of insulation that covers neuronal axon projections in the vertebrate nervous system. In the peripheral nervous system (PNS), Schwann cells (SCs) radially sort axons into a 1:1 relationship and then iteratively wrap axonal segments to form myelin. Myelin ensures that nerve impulses travel quickly and efficiently, ultimately allowing for the entire nervous system to function properly. Disruptions to the myelin sheath in disease (e.g., numerous peripheral neuropathies) or after injury lead to devastating symptoms, and significant morbidity. Moreover, myelin damage can lead to permanent neuron loss. Currently, no treatments exist to prevent demyelination or to hasten remyelination, and there is therefore a pressing need to develop therapies that address these issues. To this end, we must learn more about the mechanisms that govern SC development and myelination. We previously discovered that the adhesion G protein-coupled receptor (aGPCR) Gpr126 is essential for SC radial sorting and myelination, although the mechanisms by which Gpr126 controls these processes are only beginning to be understood. GPCRs are excellent drug targets, representing at least one-third of all approved drugs; thus, aGPCRs are extremely attractive therapeutic targets to stimulate remyelination in humans with myelin disease or injury. Interestingly, we have recently determined that Gpr56, an aGPCR related to Gpr126 is also required during SC radial sorting in development and myelin maintenance in adulthood. In addition to Gpr126 and Gpr56, we have determined that four other aGPCRs are expressed in SCs, though their functions are unknown. In this proposal, we seek to define the aGPCR-mediated SC developmental program. We will: (1) Determine how Gpr126 controls radial sorting; (2) Define the autonomy, downstream signaling, and ligands of Gpr56 in SCs; (3) Test if the four novel SC-expressed aGPCRs are required for PNS development, myelination, and/or myelin maintenance. These experiments will greatly strengthen our understanding of SC and aGPCR biology and may lay the foundation for future therapeutics that stimulate myelin repair in humans.

描述（由适用提供）：髓磷脂是涵盖脊椎动物神经系统中神经元轴突项目的绝缘层。在周围神经系统（PNS）中，雪旺细胞（SCS）从根本上将轴突分为1：1关系，然后迭代地包裹轴突段形成髓磷脂。髓磷脂可确保神经冲动快速有效地行进，最终使整个神经系统正常运行。疾病中髓鞘的干扰（例如，许多周围神经病）或受伤后导致灾难性的症状和明显的发病率。此外，髓磷脂损伤可能导致永久性神经丧失。目前，尚无治疗方法来防止脱髓鞘或加快透明度，因此有必要开发解决这些问题的疗法。为此，我们必须了解有关控制SC发展和髓鞘的机制的更多信息。我们以前发现，粘附G蛋白偶联受体（AGPCR）GPR126对于SC径向分选和髓鞘化至关重要，尽管GPR126控制这些过程的机制才开始被理解。 GPCR是出色的药物靶标，占所有批准药物的至少三分之一；因此，AGPCR是极具吸引力的治疗靶标，可以刺激患有髓鞘疾病或损伤的人的再髓。有趣的是，我们最近确定GPR56在开发过程中还需要与GPR126相关的AGPCR，并且成年后的髓磷脂维持。除GPR126和GPR56外，我们已经确定了其他四个AGPCR在SC中表达，尽管它们的功能尚不清楚。在此提案中，我们试图定义AGPCR介导的SC开发计划。我们将：（1）确定GPR126如何控制径向排序；（2）在SCS中定义GPR56的自主性，下游信号和配体；（3）测试PNS开发，髓磷脂和/或髓磷脂维护是否需要四个新型SC表达的AGPCR。这些实验将极大地增强我们对SC和AGPCR生物学的理解，并可能为未来的疗法奠定基础，从而刺激人类的髓磷脂修复。