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（由申请人提供）：髓磷脂是一层绝缘层，覆盖脊椎动物神经系统中的神经轴突投射。在周围神经系统 (PNS) 中，雪旺细胞 (SC) 将轴突按 1:1 关系放射状分类，然后迭代地排列。包裹轴突节段形成髓磷脂，确保神经冲动快速有效地传播，最终使整个神经系统正常运作。疾病中（例如，许多周围神经病）或损伤后的髓鞘损伤会导致严重的症状，而且，髓磷脂损伤可导致永久性神经丧失，目前尚无治疗方法可以预防脱髓鞘或加速髓鞘再生。为此，我们迫切需要开发解决这些问题的疗法，我们必须更多地了解控制 SC 发育和髓鞘形成的机制。 (aGPCR) Gpr126 对于 SC 径向分选和髓鞘形成至关重要，尽管 Gpr126 控制这些过程的机制才刚刚开始被了解，GPCR 是优秀的药物靶点，因此，aGPCR 至少占所有批准药物的三分之一；刺激患有髓鞘疾病或损伤的人类的髓鞘再生的极具吸引力的治疗靶点意味着，我们最近确定在 SC 过程中也需要 Gpr56，一种与 Gpr126 相关的 aGPCR。除了 Gpr126 和 Gpr56 之外，我们还确定了 SC 中表达的其他四种 aGPCR，尽管它们的功能尚不清楚。在本提案中，我们试图定义 aGPCR 介导的 SC 发育程序。我们将： (1) 确定 Gpr126 如何控制径向排序； (2) 定义 SC 中 Gpr56 的自主性、下游信号传导和配体；如果这四种新型 SC 表达的 aGPCR 是 PNS 发育、髓鞘形成和/或髓磷脂维持所必需的，那么这些实验将极大地加强我们对 SC 和 aGPCR 生物学的理解，并可能为未来刺激人类髓磷脂修复的疗法奠定基础。