Mechanisms of CNS node of Ranvier formation

CNS结Ranvier形成的机制

• 批准号: 8652840
• 负责人: MATTHEW N RASBAND
• 金额: $ 33.21万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-05-01 至 2015-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8652840
• 关键词: Action Potentials; Affect; Axon; Binding; Biological; Cell Adhesion Molecules; Cells; Complex; Cytoskeleton; Data; Demyelinating Diseases; Demyelinations; Development; Diffusion; Disease; Extracellular Matrix; Functional disorder; Gated Ion Channel; Genetic; Goals; Health; Hippocampus (Brain); Human; Injury; Ion Channel; Knock-out; Knockout Mice; Lateral; Maintenance; Membrane Proteins; Methods; Modeling; Molecular; Multiple Sclerosis; Mus; Myelin; Myelin Sheath; NRCAM gene; Nervous system structure; Neuraxis; Neuroglia; Neurons; Nodal; Oligodendroglia; Peripheral Nervous System; Proteins; Ranvier' s Nodes; Role; Schwann Cells; Spinal Ganglia; Spinal cord injury; Testing; Therapeutic; Work; density; gain of function; genetic analysis; innovation; interest; loss of function; myelination; nodal protein; research study; scaffold; voltage

PROJECT SUMMARY Rapid and efficient propagation of action potentials in the mammalian nervous system requires both myelination and the high-density clustering of voltage-gated ion channels at gaps in the myelin sheath called nodes of Ranvier. Although many demyelinating diseases and injuries cause disruption of nodes and nervous system dysfunction, the mechanisms that are responsible for ion channel clustering at central nervous system (CNS) nodes of Ranvier remain unknown. We propose that three distinct cellular and molecular interactions contribute to CNS node formation and maintenance: 1) interactions between axonal cell adhesion molecules and a unique CNS nodal extracellular matrix, 2) interactions between axons and myelinating glia at paranodal junctions set up a membrane protein diffusion barrier to restrict the lateral mobility of nodal proteins, and 3) interactions between nodal membrane proteins and nodal cytoskeletal scaffolds maintain high density clusters of ion channels. Thus, multiple, overlapping mechanisms may exist in the CNS to facilitate ion channel clustering at nodes of Ranvier. In this project we will undertake both cell biological and genetic methods to determine the mechanisms underlying CNS node of Ranvier formation. We will focus on the extrinsic, glial-derived interactions that are necessary for CNS node formation. In the first aim we will elucidate the molecular interactions between nodal cell adhesion molecules and CNS nodal ECM proteins. We will determine if soluble ECM proteins are sufficient to induce clustering of nodal proteins in purified neuronal cultures. In the second aim we will perform genetic analyses of single, double, and triple knockout mice lacking extracellular matrix molecules, paranodal junctions, and/or cytoskeletal interactions to uncover the existence of, and requirement for, each overlapping mechanism.

项目概要 哺乳动物神经中动作电位的快速有效传播 系统需要髓鞘形成和电压门控离子的高密度聚集 髓鞘间隙中的通道称为朗飞结。虽然很多 脱髓鞘疾病和损伤导致节点和神经系统破坏 功能障碍，负责中枢离子通道聚集的机制 朗飞的神经系统（CNS）节点仍然未知。我们建议三 不同的细胞和分子相互作用有助于中枢神经系统节点的形成和 维护：1）轴突细胞粘附分子和独特的 CNS 节点细胞外基质，2) 轴突和髓鞘神经胶质细胞之间的相互作用 结旁连接建立膜蛋白扩散屏障以限制横向 节点蛋白的流动性，以及 3) 节点膜蛋白和 节点细胞骨架支架维持高密度离子通道簇。因此， CNS 中可能存在多种重叠机制以促进离子通道 在 Ranvier 节点处聚类。在这个项目中，我们将进行细胞生物学和 遗传方法确定朗飞中枢神经系统结的潜在机制 形成。我们将重点关注神经胶质细胞衍生的外在相互作用，这是必要的 CNS节点形成。在第一个目标中，我们将阐明分子相互作用 结细胞粘附分子和 CNS 结 ECM 蛋白之间的关系。我们将 确定可溶性 ECM 蛋白是否足以诱导节点蛋白聚集 纯化的神经元培养物。在第二个目标中，我们将对单个、 缺乏细胞外基质分子的双重和三重敲除小鼠，节点旁 连接和/或细胞骨架相互作用以揭示其存在和要求 对于每个重叠机制。