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.

神经系统的正常功能依赖于神经元和非神经元神经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形成。在相邻髓鞘之间的交界处，Ranvier的结节，复杂的结构成分将鞘附着在轴突膜上，并限制结点上高密度的Na通道，以便允许快速跳跃传导。星形胶质细胞是另一种神经胶质细胞，它能产生高度分叉的形态，有效地填充所有其他细胞之间的空间，从而分配营养物质并平衡离子浓度，为神经元交流提供环境。几乎每个兰维尔结节都被结周星形细胞突起(PAPs)所覆盖。虽然兰维尔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，可能改变结节的大小和兴奋性，甚至改变髓鞘厚度。然而，星形胶质细胞何时在结节插入突起，以及星形胶质细胞是否在髓鞘形成开始时对结节的初始间距做出贡献，这一因素在很大程度上决定了动作电位传播的速度和时间，目前尚不清楚。除了在建立发育过程中髓鞘形成模式方面的潜在作用外，PAPs还可能有助于重新髓鞘形成的准确性。随着多发性硬化症(MS)等疾病的脱髓鞘，Ranvier离子通道结点和结构蛋白组织被破坏，导致动作电位失效。然而，Ranvier的一些结节在脱髓鞘过程中保持不变，或者在重新髓鞘形成之前重新形成，既可以作为新生成的髓鞘的潜在指标杆，也可以在没有髓鞘的情况下维持动作电位的传播。加强这一结果将显著影响多发性硬化症患者脱髓鞘发作后的功能恢复。在这项建议中，将确定兰维尔结节期间星形胶质细胞-少突胶质细胞的基本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被用来在体内可视化星形胶质细胞过程动态，当髓鞘和节点在发育过程中被创建时，以及当它们在髓鞘重塑过程中被破坏时。最后，在多发性硬化症的小鼠模型中，控制这些动态的关键基因将被打乱，以确定这些因素在多大程度上调节重新髓鞘形成过程中兰维尔结节的维持。这些实验、实验室环境和本提案中概述的其他培训机会将提供一种非凡的培训经验，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，并允许我开辟一个研究领域，作为一名独立研究员领导我自己的实验室。