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

 描述（由申请人提供）：髓磷脂是覆盖脊椎动物神经系统中神经元轴突投射的绝缘层。在外周神经系统（PNS）中，雪旺细胞（SC）放射状地将轴突分类为1：1的关系，然后迭代地包裹轴突节段以形成髓鞘。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。疾病中髓鞘的破坏（例如，许多周围神经病）或损伤后导致破坏性症状和显著的发病率。此外，髓鞘损伤可导致永久性神经元损失。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SC发育和髓鞘形成的机制。我们以前发现，粘附G蛋白偶联受体（aGPCR）Gpr 126是至关重要的SC径向分选和髓鞘，虽然Gpr 126控制这些过程的机制才刚刚开始被理解。GPCR是出色的药物靶点，至少占所有批准药物的三分之一;因此，aGPCR是刺激患有髓鞘疾病或损伤的人类髓鞘再生的极具吸引力的治疗靶点。有趣的是，我们最近已经确定，Gpr 56，一个与Gpr 126相关的aGPCR也需要在SC径向分选在发展和髓鞘维持在成年期。除了Gpr 126和Gpr 56之外，我们已经确定了其他四种aGPCR在SC中表达，尽管它们的功能尚不清楚。在这个提议中，我们试图定义aGPCR介导的SC发育程序。我们将：（1）确定Gpr 126如何控制径向分选;（2）定义SC中Gpr 56的自主性、下游信号传导和配体;（3）测试PNS发育、髓鞘形成和/或髓鞘维持是否需要四种新的SC表达的aGPCR。这些实验将大大加强我们对SC和aGPCR生物学的理解，并可能为未来刺激人类髓鞘修复的治疗奠定基础。

 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.