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

• 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
• 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' 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

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，例如少突胶质细胞对轴突的髓鞘形成。在相邻髓鞘之间的连接处，朗维尔结，复杂的结构成分将鞘粘附到轴突膜上，并在节点处限制高密度的Na通道，以允许快速跳跃传导。星形胶质细胞，另一种神经胶质细胞，产生高度分枝的形态，有效地填充所有其他细胞之间的空间，以分配营养物质和平衡离子浓度，为神经元通信提供环境。几乎所有的Ranvier淋巴结都被结周星形胶质细胞突起（PAP）所覆盖。虽然神经元-少突胶质细胞之间的相互作用对于朗维尔结的结构和功能来说是必要的，但是星形胶质细胞在节点处的作用以及它们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可能具有额外的功能和结构作用，可以改变结节大小和兴奋性，甚至髓鞘厚度。然而，它仍然是未知的，当星形胶质细胞插入过程中的节点和星形胶质细胞是否有助于初始间距的节点在髓鞘形成发作，一个因素，大大形状的速度和时间的动作电位传播。除了在发育过程中建立髓鞘形成模式的潜在作用外，PAP还可能有助于髓鞘再生的准确性。在诸如多发性硬化症（MS）的疾病中的脱髓鞘之后，朗维尔离子通道和结构蛋白组织的节点被破坏，导致动作电位衰竭。然而，在整个脱髓鞘过程中保持朗维尔节的一些节点或在髓鞘再生之前进行重组，作为新生成的髓鞘的潜在路标，并在没有髓鞘的情况下保持动作电位传播。增强这一结果将显着影响MS患者脱髓鞘攻击后的功能恢复。在该提案中，将确定Ranvier节点形成过程中必要的星形胶质细胞-少突胶质细胞相互作用和所需的星形胶质细胞遗传因子。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，以及当它们在髓鞘重塑过程中被破坏时。最后，在MS小鼠模型中的星形胶质细胞中，将破坏控制这些动力学的关键基因，以确定这些因素在髓鞘再生过程中调节Ranvier节点维持的程度。这些实验，实验室环境，以及本提案中概述的额外培训机会将提供一个惊人的培训经验，这将提高我的技术技能，进一步发展我的神经胶质细胞生物学知识，并允许我开拓一个研究领域，作为独立的研究者领导我自己的实验室。