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：
10449399
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/10449399
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，称为雪旺细胞的特殊神经胶质细胞形成髓磷脂鞘，这是快速动作电位传播以及神经元健康和生存所必需的。这髓磷脂在正常神经系统功能中的重要性也许可以通过髓磷脂的损失和在诸如脱髓鞘性周围神经病等疾病中观察到的轴突束髓鞘再生效率低下。髓磷脂的这种破坏会导致永久性神经元损失、严重疼痛和发病，并最终导致麻痹。目前，尚无治疗方法可以预防脱髓鞘或增强髓鞘再生，部分原因是我们对髓鞘形成的遗传和分子控制的不完全理解。为了确定髓鞘神经胶质细胞发育的新调节因子，我们之前进行了大规模的正向研究斑马鱼的遗传筛选。通过这个筛选，我们在胞质分裂专用子（dock1）中发现了新的突变体之前表明，这些全局突变体在径向排序和减少方面表现出严重缺陷发育过程中 PNS 中的髓鞘形成。此外，我们的初步分析表明， Dock1 在成年斑马鱼损伤后的神经修复中的作用。 Dock1 编码高度保守的非典型鸟嘌呤核苷酸交换因子，可以激活小Rho GTPase Rac1。迄今为止，Dock1 功能没有任何作用尽管 Rac1 是雪旺细胞发育的已知调节因子，但在雪旺细胞中的作用已被描述。这里，我们建议使用斑马鱼和小鼠模型来剖析 Dock1 控制 PNS 的机制开发和修复。我们的目标是定义 Dock1 在雪旺细胞中的功能（目标 1），揭示通路 Dock1 功能的上游和下游（目标 2），并测试 Dock1 是否需要髓磷脂维持或修复哺乳动物 PNS 神经损伤后（目标 3）。这些实验将共同定义基本的轴突-雪旺细胞在发育、损伤和修复过程中相互作用的潜在机制，可以奠定为治疗人类神经病和周围神经损伤的新疗法奠定了基础。