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

神经系统发育和髓鞘形成调节剂的化学和遗传筛选

• 批准号: 9644758
• 负责人: Kelly R Monk
• 金额: $ 15.4万
• 依托单位: OREGON HEALTH & SCIENCE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-01-01 至 2019-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9644758
• 关键词: Chemical; genetic; screens; modulators; nervous

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.

描述（由申请人提供）：在脊椎动物神经系统中，髓质神经胶质在迭代地将膜缠绕在轴突周围的壮观壮举中，形成髓磷脂鞘。髓磷脂可快速脉冲传播，使髓磷脂的神经胶质细胞对于神经元健康和生存也是必不可少的。髓磷脂的重要性在破坏的疾病中强调，包括多发性硬化症，白细胞营养不良和许多周围神经病。迄今为止，尚无治疗策略来阻止脱髓鞘或刺激疾病或损伤的再髓。作为一种适合化学和遗传筛查的脊椎动物模型生物，斑马鱼代表了剖析控制髓鞘化的分子机制的理想系统。 在先前的正向遗传筛选中，我们发现G蛋白偶联受体（GPCR）GPR126对于周围神经系统中的髓鞘化至关重要，尽管尚未完全了解GPR126功能的机制。作为GPCR，GPR126代表了刺激再生的极好潜在治疗靶标。为此，我们将使用化学和遗传筛选在肌张力型和遗传筛选中定义GPR126介导的途径，在肌肌GPR126突变体中同时使用化学和遗传筛选，从而在外周神经系统中产生髓磷脂水平降低。 （1）我们将执行大规模的复合库筛选，以发现可以增强或抑制型GPR126突变体表型的小分子。 （2）我们将执行2,000个基因组的正向遗传增强子/抑制筛选，以定义GPR126的遗传修饰剂。这些实验将共同定义GPR126介导髓鞘的机制。至关重要的是，这些筛选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，这些化学物质和基因调节神经胶质细胞的发育和髓鞘形成。这些筛查将增强我们对控制神经系统发展的机制的理解，并可能指向新的治疗剂以促进人类神经系统修复的道路。