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

 描述(申请人提供)：髓鞘是一层绝缘层，覆盖了脊椎动物神经系统中的神经元轴突投射。在周围神经系统(PNS)中，雪旺细胞(SCs)将轴突放射状排列成1：1的关系，然后反复包裹轴突片段形成髓鞘。髓鞘确保神经冲动快速有效地传播，最终允许整个神经系统正常运作。在疾病中(例如，许多周围神经病)或在受伤后，髓鞘的破坏会导致毁灭性的症状和显著的发病率。此外，髓鞘损伤可能导致永久性神经元丢失。目前，还没有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治疗方法。为此，我们必须更多地了解支配干细胞发育和髓鞘形成的机制。我们以前发现粘附性G蛋白偶联受体(AGPCR)GPR126对SC径向分选和髓鞘形成是必不可少的，尽管GPR126控制这些过程的机制才刚刚开始了解。GPCRs是很好的药物靶点，至少占所有已批准药物的三分之一；因此，aGPCRs是非常有吸引力的治疗靶点，可以刺激患有髓鞘疾病或损伤的人类重新髓鞘形成。有趣的是，我们最近确定了GPR56，这是一个与GPR126相关的aGPCR，在SC径向分选发育和成年后髓鞘维持过程中也是必需的。除了GPR126和GPR56，我们已经确定了另外四个aGPCR在SCs中表达，尽管它们的功能尚不清楚。在这项提案中，我们试图定义aGPCR介导的SC发展计划。我们将：(1)确定GPR126如何控制径向分选；(2)定义GPR56在SCs中的自主性、下游信号和配体；(3)测试四个新的SC表达的aGPCRs是否对PNS的发育、髓鞘形成和/或髓鞘维持是必需的。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鞘修复的疗法奠定基础。

 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.