MOLECULAR AND GENETIC ANALYSIS OF GPR126 IN PERIPHERAL NERVE.

周围神经中 GPR126 的分子和遗传分析。

• 批准号: 8343490
• 负责人: Kelly R Monk
• 金额: $ 33.25万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 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/8343490
• 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 Delivery Systems; 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

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. PUBLIC HEALTH RELEVANCE: Lack of robust remyelination represents one of the major barriers to recovery of neurological functions in disease or following injury in many disorders of the nervous system. Here, we propose to determine how Gpr126 controls myelination during development and to elucidate whether Gpr126 is required for myelin maintenance and remyelination in adult nerves. These studies will help to define new strategies to stimulate remyelination in the injured and diseased human nervous system.

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称为轴突的神经元突起。在周围神经系统中，称为雪旺细胞的特殊细胞围绕轴突旋转，形成髓鞘。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（如多发性硬化症或周围神经病）或损伤后（如脊髓创伤）中髓鞘的破坏会导致毁灭性的症状、显着的发病率，而髓鞘的丧失会导致永久性神经元丧失，并最终导致瘫痪。目前，尚无预防脱髓鞘或加速髓鞘再生的治疗方法，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控制髓鞘形成、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 Gpr126 是控制髓鞘形成的轴突-雪旺细胞信号传导连接的重要组成部分，这一连接尚不完全清楚。在 Gpr126 突变小鼠中，雪旺细胞与轴突结合，但无法使其膜螺旋形成髓鞘。 G蛋白偶联受体是极好的药物靶点，至少占所有批准药物的三分之一；因此，Gpr126 代表了一个极具吸引力的潜在靶标，可以刺激患有髓磷脂疾病或损伤的人类的髓鞘再生。因此，我们建议剖析 Gpr126 控制髓鞘形成的机制，并确定损伤后髓鞘稳态或髓鞘再生是否需要 Gpr126。这些研究涵盖了我们的广泛目标，即定义脊椎动物神经系统中形成、维持和再生有髓轴突的机制。 第一个目标是，我们将通过对 Gpr126 突变组织和细胞进行生化分析来定义 Gpr126 激活下游的信号通路。在第二个目标中，我们将检验雪旺细胞髓鞘形成自主需要 Gpr126 的假设。我们将使用条件小鼠突变体来特异性删除雪旺细胞或神经元中的 Gpr126，并且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缺失的后果。为此，我们还将通过在发育胚胎和围产期转基因小鼠中暂时删除 Gpr126 来定义 Gpr126 需求的发育窗口。在第三个目标中，我们将定义 Gpr126 在成人外周血中的作用 神经。具体来说，我们将通过暂时删除成熟神经和受伤的成熟神经中的 Gpr126 来确定神经损伤后髓磷脂维持、脱髓鞘和/或髓鞘再生是否需要 Gpr126。这些实验将共同确定 Gpr126 控制髓鞘形成的机制，阐明成人神经髓鞘再生是否需要 Gpr126，并可能为未来刺激人类髓鞘修复的疗法奠定基础。 公共卫生相关性：缺乏强有力的髓鞘再生是许多神经系统疾病中或损伤后神经功能恢复的主要障碍之一。在这里，我们建议确定 Gpr126 在发育过程中如何控制髓鞘形成，并阐明 Gpr126 是否是成人神经髓鞘维持和髓鞘再生所必需的。这些研究将有助于确定刺激受损和患病人类神经系统髓鞘再生的新策略。