Chemical and genetic screens for modulators of nervous system development and myelination

描述(申请人提供)：在脊椎动物神经系统中，髓鞘胶质细胞完成了一项壮观的壮举，反复将其膜包裹在轴突周围，形成髓鞘。髓鞘允许神经冲动的快速传播，而制造髓鞘的神经胶质细胞对神经元的健康和生存也是必不可少的。髓鞘的重要性在髓鞘被破坏的疾病中得到强调，包括多发性硬化症、脑白质营养不良和许多周围神经病。到目前为止，在疾病或损伤中还没有阻止脱髓鞘或刺激重新髓鞘形成的治疗策略。作为一种脊椎动物模式生物，斑马鱼既可以接受化学筛选，也可以接受遗传筛选，它代表了剖析髓鞘形成的分子机制的理想系统。在先前的正向遗传学筛查中，我们发现G蛋白偶联受体(GPCR)GPR126对于周围神经系统的髓鞘形成是必不可少的，尽管GPR126的作用机制尚不完全清楚。作为一种GPCR，GPR126是一种很好的潜在的刺激髓鞘再生的治疗靶点。为此，我们将在一个低形的GPR126突变体中使用化学和遗传筛选来确定GPR126在神经胶质发育和髓鞘形成中的介导途径，该突变体在外周神经系统中产生水平降低的髓鞘。(1)我们将进行大规模的化合物文库筛选，以发现可以增强或抑制亚型GPR126突变表型的小分子。(2)我们将对2,000个基因组进行正向遗传增强/抑制筛选，以确定GPR126的遗传修饰因子。总之，这些实验将确定GPR126介导髓鞘形成的机制。关键的是，这些筛查还可以发现新的化学物质和基因，这些化学物质和基因独立于GPR126调控胶质细胞的发育和髓鞘形成。这些筛选将增强我们对控制神经系统发育的机制的理解，并可能为促进人类神经系统修复的新疗法指明方向。

DESCRIPTION (provided by applicant): In the vertebrate nervous system, myelinating glia performs the spectacular feat of iteratively wrapping their membrane around axons to form the myelin sheath. Myelin allows for rapid nerve impulse propagation, and the glial cells that make myelin are also essential for neuronal health and survival. The importance of myelin is underscored in diseases in which it is disrupted, including multiple sclerosis, leukodystrophies, and numerous peripheral neuropathies. To date, no therapeutic strategies exist to halt demyelination or stimulate remyelination in disease or injury. As a vertebrate model organism that is amenable to both chemical and genetic screens, zebrafish represent the ideal system with which to dissect the molecular mechanisms that govern myelination. In a previous forward genetic screen, we discovered that the G protein-coupled receptor (GPCR) Gpr126 is essential for myelination in the peripheral nervous system, although the mechanisms by which Gpr126 functions are not completely understood. As a GPCR, Gpr126 represents an excellent potential therapeutic target to stimulate remyelination. To this end, we will define Gpr126-mediated pathways in glial development and myelination using both chemical and genetic screens in a hypomorphic gpr126 mutant, which generates reduced levels of myelin in the peripheral nervous system. (1) We will perform large-scale compound library screens to discover small molecules that can enhance or suppress the hypomorphic gpr126 mutant phenotype. (2) We will perform a forward genetic enhancer/suppressor screen of 2,000 genomes to define genetic modifiers of gpr126. Together, these experiments will define the mechanisms by which Gpr126 mediates myelination. Critically, these screens can also uncover new chemicals and genes that regulate glial cell development and myelination independently of Gpr126. These screens will enhance our understanding of the mechanisms that govern nervous system development and may point the way to novel therapeutics to promote nervous system repair in humans.