权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

MOLECULAR AND GENETIC ANALYSIS OF GPR126 IN PERIPHERAL NERVE.

周围神经中 GPR126 的分子和遗传分析。

基本信息

批准号：
8462712
负责人：
Kelly R Monk
金额：
$ 32.09万
依托单位：
WASHINGTON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-05-01 至 2016-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8462712
关键词：
Address Adhesions Adult Axon Biochemical Cell Adhesion Molecules Cell Culture Techniques Cell Differentiation process Cell Proliferation Cell-Matrix Junction Cells Cyclic AMP Cyclic AMP Receptors Cyclic AMP-Responsive DNA-Binding Protein Data Demyelinations Development Disease Drug Targeting Embryo Ensure Foundations Future G Protein-Coupled Receptor Signaling G-Protein-Coupled Receptors Gap Junctions Genetic Transcription Goals Heterotrimeric GTP-Binding Proteins Homeostasis Human In Vitro Injury Knockout Mice Lead Learning Ligands Maintenance Mammals Membrane Molecular Molecular Analysis Morbidity - disease rate Multiple Sclerosis Mus Mutant Strains Mice Myelin Myelin Sheath Natural regeneration Nerve Nervous System Physiology Nervous system structure Neurons Nuclear Paralysed Pathway interactions Patients Perinatal Peripheral Nerves Peripheral Nervous System Peripheral Nervous System Diseases Pharmaceutical Preparations Phenotype Protein Kinase Proteins Recovery Reporting Role Schwann Cells Seminal Signal Pathway Signal Transduction Spinal cord injury Staging Symptoms Testing Therapeutic Time Tissues Transgenic Mice Transmembrane Domain Travel Work Zebrafish base cell type extracellular falls fascinate genetic analysis human GPRC5C protein in vivo injured mutant myelination nerve injury nervous system development nervous system disorder neuron loss prevent receptor remyelination repaired research study small molecule therapeutic target therapy development

项目摘要

DESCRIPTION (provided by applicant): Myelin is a layer of insulation that covers neuronal projections called axons in the vertebrate nervous system. In the peripheral nervous system, specialized cells called Schwann cells spiral themselves around axons to form the myelin sheath. 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 (like multiple sclerosis or peripheral neuropathy) or after injury (like spinal cord trauma) lead to devastating symptoms, significant morbidity, and myelin loss can lead to permanent neuron loss, and ultimately, paralysis. 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 myelination, myelin maintenance, and remyelination. We discovered that the orphan G protein-coupled receptor, Gpr126, is an essential component of the incompletely understood axon-Schwann cell signaling nexus that controls myelination. In Gpr126 mutant mice, Schwann cells associate with axons, but fail to spiral their membranes to generate the myelin sheath. G protein-coupled receptors are excellent drug targets, representing at least one-third of all approved drugs; thus, Gpr126 represents an extremely attractive potential target to stimulate remyelination in humans with myelin disease or injury. We therefore propose to dissect the mechanisms by which Gpr126 controls myelination and to determine if Gpr126 is required for myelin homeostasis or remyelination after injury. These studies encompass our broad goals to define the mechanisms that form, maintain, and regenerate myelinated axons in the vertebrate nervous system. In the first aim, we will define the signaling pathway downstream of Gpr126 activation by performing biochemical analyses on Gpr126 mutant tissue and cells. In the second aim, we will test the hypothesis that Gpr126 is required autonomously in Schwann cells for myelination. We will employ conditional mouse mutants to delete Gpr126 specifically in Schwann cells or in neurons, and we will perform immunohistochemical and ultrastructural analyses to determine the consequences of cell type specific loss. In this aim, we will also define the developmental window of Gpr126 requirement by temporally deleting Gpr126 in developing embryonic and perinatal transgenic mice. In the third aim, we will define the roles of Gpr126 in adult peripheral nerve. Specifically, we will determine if Gpr126 is required for myelin maintenance, demyelination, and/or remyelination after nerve injury by temporally deleting Gpr126 in mature nerve and in injured mature nerve. Together, these experiments will define the mechanisms by which Gpr126 controls myelination, will elucidate if Gpr126 is required for remyelination in adult nerve, and may lay the foundation for future therapeutics that stimulate myelin repair in humans.

描述（由申请人提供）：髓磷脂是覆盖脊椎动物神经系统中称为轴突的神经元突起的绝缘层。在周围神经系统中，称为许旺细胞的特殊细胞围绕轴突螺旋状形成髓鞘。髓鞘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（如多发性硬化症或周围神经病变）或损伤（如脊髓创伤）后髓鞘的破坏会导致破坏性症状，严重的发病率，髓鞘丢失会导致永久性神经元丢失，最终导致瘫痪。目前，没有治疗方法可以预防脱髓鞘或加速髓鞘再生，因此迫切需要开发解决这些问题的疗法。为此，我们必须更多地了解髓鞘形成、髓鞘维持和髓鞘再生的机制。我们发现，孤儿G蛋白偶联受体，Gpr 126，是一个不完全理解的轴突雪旺细胞信号联系，控制髓鞘形成的重要组成部分。在Gpr 126突变小鼠中，雪旺细胞与轴突结合，但不能螺旋它们的膜以产生髓鞘。G蛋白偶联受体是极好的药物靶点，占所有批准药物的至少三分之一;因此，Gpr 126代表了一个非常有吸引力的潜在靶点，可以刺激患有髓鞘疾病或损伤的人类的髓鞘再生。因此，我们建议剖析Gpr 126控制髓鞘形成的机制，并确定Gpr 126是否需要髓鞘稳态或损伤后髓鞘再生。这些研究涵盖了我们的广泛目标，以确定在脊椎动物神经系统中形成，维持和再生有髓鞘轴突的机制。在第一个目标中，我们将通过对Gpr 126突变组织和细胞进行生化分析来确定Gpr 126激活下游的信号通路。在第二个目标，我们将测试的假设，Gpr 126所需的自主施万细胞髓鞘。我们将采用条件小鼠突变体删除Gpr 126特异性雪旺细胞或神经元，我们将进行免疫组织化学和超微结构分析，以确定细胞类型特异性损失的后果。在这个目标中，我们还将通过在发育中的胚胎和围产期转基因小鼠中暂时缺失Gpr 126来定义Gpr 126需求的发育窗口。在第三个目标中，我们将确定Gpr 126在成人外周血中的作用，神经。具体来说，我们将确定是否需要Gpr 126髓鞘的维护，脱髓鞘，和/或神经损伤后的髓鞘再生暂时删除Gpr 126在成熟的神经和受伤的成熟神经。总之，这些实验将确定Gpr 126控制髓鞘形成的机制，将阐明Gpr 126是否是成人神经髓鞘再生所必需的，并可能为未来刺激人类髓鞘修复的治疗奠定基础。