Regulation of node of Ranvier formation and maintenance by astrocytes

星形胶质细胞对郎飞叶结形成和维持的调节

基本信息

批准号：
10472506
负责人：
Cody Lee Call
金额：
$ 6.72万
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：
2021-08-01 至 2024-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10472506
关键词：
Action Potentials Adhesions Area Astrocytes Axon Behavior Biology CRISPR screen Cell Adhesion Molecules Cell Communication Cells Cellular biology Cerebral cortex Communication Complex Confocal Microscopy Cuprizone Cytoplasm Demyelinating Diseases Demyelinations Development Disease Environment Equilibrium Extracellular Matrix Failure Foundations Future Generations Genes Genetic Genetic Screening Image Ion Channel Ions Knock-out Knowledge Laboratories Lead Length Light Literature Maintenance Membrane Molecular Morphology Multiple Sclerosis Mus Myelin Myelin Sheath Natural regeneration Nervous System Physiology Nervous system structure Neuraxis Neuroglia Neurons Nodal Nutrient Oligodendroglia Optics Outcome Pathologic Pathway interactions Pattern Persons Physiology Positioning Attribute Process Property Protease Inhibitor Publishing Ranvier&apos s Nodes Recording of previous events Recovery of Function Regulation Research Research Personnel Role Serpins Shapes Speed Spinal Cord Structural Protein Structure Surface Synapses Thick Thinness Time Training Transgenic Organisms Work Zebrafish adhesion process cell type density experience experimental study flexibility in vivo in vivo imaging in vivo monitoring interest member mouse model multiple sclerosis treatment mutant myelination neurofascin neuronal circuitry novel offspring oligodendrocyte lineage oligodendrocyte precursor preservation prevent regeneration potential remyelination reverse genetics tool training opportunity

项目摘要

Proper nervous system function depends on interactions between neurons and non-neuronal glial cells. These neuron-glia relationships can be highly specific, such as the myelination of axons by oligodendrocytes. At the junctions between adjacent myelin sheaths, the nodes of Ranvier, complex structural components adhere the sheath to the axon membrane and constrain high densities of Na channels at the node in order to allow rapid saltatory conduction. Astrocytes, another glial cell, produce highly-ramified morphologies that effectively fill the space between all other cells to distribute nutrients and balance ion concentrations to provide an environment for neuronal communication. Nearly every node of Ranvier is covered by perinodal astrocyte processes (PAPs). While the neuron-oligodendrocyte interactions necessary for node of Ranvier structure and function have been extensively studied, the role of astrocytes at nodes and their interactions with oligodendrocytes' myelin sheaths are almost entirely unknown. While PAPs likely help maintain ion concentrations necessary for action potential generation, PAPs may serve additional functional and structural roles that could alter nodal size and excitability and even myelin sheath thickness. However, it remains unknown when astrocytes insert processes at the node and whether astrocytes contribute to the initial spacing of nodes during myelination onset, a factor that considerably shapes the speed and timing of action potential propagation. In addition to a potential role in establishing the pattern of myelination during development, PAPs may also contribute to the accuracy of remyelination. Following demyelination in diseases such as multiple sclerosis (MS), node of Ranvier ion channels and structural protein organization is disrupted, leading to action potential failure. However, some nodes of Ranvier are maintained throughout demyelination or reformed prior to remyelination, serving both as potential guideposts for newly generated myelin sheaths and maintaining action potential propagation in the absence of myelin. Enhancing this outcome would significantly impact functional recovery following a demyelinating attack in people with MS. In this proposal, essential astrocyte-oligodendrocyte interactions during node of Ranvier formation and the required astrocytic genetic factors will be identified. The unparalleled optical properties and genetic tools of the developing zebrafish will be used to visualize astrocyte process dynamics in vivo as myelin sheaths and nodes are created during development, and when they are disrupted during myelin sheath remodeling. Finally, critical genes governing these dynamics will be disrupted in astrocytes in a mouse model of MS to determine the extent to which these factors regulate node of Ranvier maintenance during remyelination. These experiments, lab environment, and additional training opportunities outlined in this proposal will present a phenomenal training experience that will enhance my technical skillset, further develop my knowledge of glial cell biology, and allow me to carve out a research area to lead as an independent investigator with my own laboratory.

正常的神经系统功能取决于神经元和非神经元胶质细胞之间的相互作用。这些神经元-神经胶质细胞的关系可以是高度特异性的，例如少突胶质细胞的轴突髓鞘化。在相邻髓鞘之间的连接处，朗飞结，复杂的结构成分将髓鞘粘附到轴突膜上，并限制结点处高密度的 Na 通道，以允许快速跳跃传导。星形胶质细胞是另一种神经胶质细胞，产生高度分支的形态，有效地填充所有其他细胞之间的空间，以分配营养物质并平衡离子浓度，从而为神经元交流提供环境。几乎每个朗飞结都被节周星形胶质细胞突起（PAP）覆盖。虽然朗飞结节结构和功能所必需的神经元-少突胶质细胞相互作用已被广泛研究，但星形胶质细胞在结节中的作用及其与少突胶质细胞髓鞘的相互作用几乎完全未知。虽然 PAP 可能有助于维持动作电位产生所需的离子浓度，但 PAP 可能发挥额外的功能和结构作用，可能改变节点大小和兴奋性，甚至髓鞘厚度。然而，目前尚不清楚星形胶质细胞何时在节点处插入突起，以及星形胶质细胞是否有助于髓鞘形成过程中节点的初始间距，这是一个在很大程度上影响动作电位传播速度和时间的因素。除了在发育过程中确定髓鞘形成模式方面发挥潜在作用外，PAP 还可能有助于髓鞘再生的准确性。多发性硬化症 (MS) 等疾病发生脱髓鞘后，朗飞离子通道节点和结构蛋白组织被破坏，导致动作电位衰竭。然而，朗飞叶的一些节点在整个脱髓鞘过程中保持不变或在髓鞘再生之前重新形成，既充当新生成髓鞘的潜在路标，又在缺乏髓鞘的情况下维持动作电位传播。增强这一结果将显着影响多发性硬化症患者脱髓鞘发作后的功能恢复。在该提案中，将确定朗飞节形成过程中重要的星形胶质细胞-少突胶质细胞相互作用以及所需的星形胶质细胞遗传因素。发育中的斑马鱼无与伦比的光学特性和遗传工具将用于可视化体内星形胶质细胞的过程动态，因为髓鞘和节点在发育过程中产生，以及它们在髓鞘重塑过程中被破坏。最后，在多发性硬化症小鼠模型的星形胶质细胞中，控制这些动态的关键基因将被破坏，以确定这些因素在髓鞘再生过程中调节郎飞叶维持节点的程度。本提案中概述的这些实验、实验室环境和额外的培训机会将带来非凡的培训体验，这将增强我的技术技能，进一步发展我的神经胶质细胞生物学知识，并让我能够开辟一个研究领域，作为独立的领导者调查员和我自己的实验室。