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

描述（由申请人提供）：在脊椎动物神经系统中，髓鞘形成神经胶质细胞执行迭代地将其膜包裹在轴突周围以形成髓鞘的壮观壮举。髓鞘允许快速神经冲动传播，并且制造髓鞘的神经胶质细胞对于神经元的健康和存活也是必不可少的。髓磷脂的重要性在其被破坏的疾病中被强调，包括多发性硬化症、脑白质营养不良和许多周围神经病。迄今为止，还没有治疗策略来阻止疾病或损伤中的脱髓鞘或刺激髓鞘再生。作为一种脊椎动物模式生物，是服从化学和遗传筛选，斑马鱼代表了理想的系统，与解剖的分子机制，管理髓鞘。 在以前的正向遗传筛选中，我们发现G蛋白偶联受体（GPCR）Gpr 126对周围神经系统的髓鞘形成至关重要，尽管Gpr 126的功能机制尚未完全了解。作为GPCR，Gpr 126代表了刺激髓鞘再生的极好的潜在治疗靶点。为此，我们将定义Gpr 126介导的神经胶质细胞发育和髓鞘形成的途径，使用化学和遗传筛选在一个亚型gpr 126突变体，它产生的髓鞘在周围神经系统中的水平降低。(1)我们将进行大规模的化合物库筛选，以发现可以增强或抑制亚纯型gpr 126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子/抑制子筛选，以确定gpr 126的遗传修饰因子。总之，这些实验将确定Gpr 126介导髓鞘形成的机制。重要的是，这些筛选还可以发现独立于Gpr 126调节神经胶质细胞发育和髓鞘形成的新化学物质和基因。这些屏幕将增强我们对神经系统发育机制的理解，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.