Mechanisms of Axon-Schwann cell interactions

轴突-雪旺细胞相互作用的机制

基本信息

批准号：
10316940
负责人：
Kelly R Monk
金额：
$ 38.5万
依托单位：
OREGON HEALTH & SCIENCE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-07-15 至 2026-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10316940
关键词：
Action Potentials Adult Axon Biological Cell Communication Cells Cellular Morphology Cellular biology Cytokinesis Data Defect Demyelinations Development Disease ERBB2 gene Exhibits Foundations Genetic Genetic Screening Guanine Nucleotide Exchange Factors Health Human Impairment Injury Lead Link Lipids Maintenance Mammals Membrane Molecular Morbidity - disease rate Multiple Sclerosis Mutant Strains Mice Mutation Myelin Myelin Sheath Natural regeneration Nervous System Physiology Nervous system structure Neuroglia Neurons Neuropathy Pain Paralysed Pathway interactions Peripheral Nerves Peripheral Nervous System Peripheral Nervous System Diseases Phagocytosis Pharmacology Phenotype Play Process Radial Receptor Protein-Tyrosine Kinases Resolution Role Schwann Cells Signal Pathway Signal Transduction Sorting - Cell Movement Testing Time Work Zebrafish axon regeneration axonal degeneration cell type experimental study genetic approach glial cell development in vivo imaging injured injury and repair insight mouse model mutant myelination nerve injury nerve repair nervous system development nervous system disorder neurological recovery neuron loss novel therapeutics peripheral nerve damage prevent remyelination repaired rho GTP-Binding Proteins

项目摘要

In the vertebrate peripheral nervous system (PNS), specialized glial cells called Schwann cells form the myelin sheath, which is required for fast action potential propagation as well as neuronal health and survival. The importance of myelin in normal nervous system function is perhaps best underscored by myelin loss and inefficient remyelination of axon tracts observed in diseases such as demyelinating peripheral neuropathies. Such disruptions of myelin can lead to permanent neuron loss, significant pain and morbidity, and ultimately paralysis. Currently, no treatments exist to prevent demyelination or to enhance remyelination, in part because of our incomplete understanding of the genetic and molecular control of myelination. To identify new regulators of myelinating glial cell development, we previously performed a large-scale forward genetic screen in zebrafish. Through this screen, we identified new mutants in dedicator of cytokinesis (dock1) and previously showed that these global mutants exhibit severe defects in radial sorting and reduced myelination in the PNS during development. Moreover, our preliminary analyses suggest a critical function for Dock1 in nerve repair following injury in adult zebrafish. Dock1 encodes a highly conserved atypical guanine nucleotide exchange factor that can activate the small Rho GTPase Rac1. To date, no role for Dock1 function in Schwann cells has been described, although Rac1 is a known regulator of Schwann cell development. Here, we propose to use zebrafish and mouse models to dissect the mechanisms by which Dock1 controls PNS development and repair. We aim to define the function of Dock1 in Schwann cells (Aim 1), uncover pathways up- and downstream of Dock1 function (Aim 2), and test if Dock1 is required for myelin maintenance or repair following nerve injury in the mammalian PNS (Aim 3). Together, these experiments will define fundamental mechanisms underlying axon-Schwann cell interactions in development, injury, and repair and can lay the foundation for new therapies to treat human neuropathies and peripheral nerve damage.

在脊椎动物周围神经系统（PNS）中，称为schwann细胞的专门神经胶质细胞形成髓磷脂鞘，这是快速动作潜力传播以及神经元健康和生存所必需的。这髓鞘在正常神经系统功能中的重要性可能是髓鞘损失和在诸如脱髓鞘神经病等疾病中观察到的轴突区域的效率低下。髓鞘的这种干扰会导致永久性神经元丧失，明显的疼痛和发病率，并最终导致麻痹。目前，尚无治疗方法来防止脱髓鞘或增强透明式，部分原因是我们对髓鞘形成的遗传和分子控制不完全理解。为了识别髓神经胶质细胞发育的新调节剂，我们以前进行了大规模前进斑马鱼中的遗传屏幕。通过此屏幕，我们在细胞因子的奉献者（DOCK1）中确定了新的突变体（DOCK1）以前表明，这些全局突变体在径向分类中表现出严重的缺陷和减少开发过程中PNS的髓鞘化。此外，我们的初步分析提出了一个关键功能成年斑马鱼受伤后神经修复中的DOCK1。 DOCK1编码高度保守的非典型鸟嘌呤可以激活小的Rho GTPase Rac1的核苷酸交换因子。迄今为止，dock1功能没有角色尽管Rac1是Schwann细胞发育的已知调节剂，但已经描述了Schwann细胞中。这里，我们建议使用斑马鱼和鼠标模型来剖析Dock1控制PNS的机制开发和维修。我们旨在定义schwann细胞中Dock1的功能（AIM 1），发现途径 Dock1功能的上下和下游（AIM 2），并测试髓磷脂维护或维修是否需要DOCK1 哺乳动物PNS神经损伤后（AIM 3）。这些实验将共同定义基本轴突 - 切恩细胞相互作用的开发，伤害和修复的机制，可以放置治疗人类神经病和周围神经损伤的新疗法的基础。