Neuroglial interactions at the node of Ranvier

Ranvier 结的神经胶质细胞相互作用

• 批准号: 8687750
• 负责人: MATTHEW N RASBAND
• 金额: $ 38.73万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-09-30 至 2016-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8687750
• 关键词: Ablation; Actins; Action Potentials; Adult; Afferent Neurons; Ankyrins; Axon; Binding; Biological Preservation; Cell Adhesion Molecules; Conflict (Psychology); Cre-LoxP; Cytoskeleton; Development; Diffusion; Disease; Extracellular Matrix; Funding; Genetic Models; Injury; Ion Channel; Lateral; Link; Maintenance; Mediating; Membrane Proteins; Methods; Molecular; Multiple Sclerosis; Mus; Natural regeneration; Nervous System Physiology; Nervous system structure; Neuroglia; Neurons; Nodal; Peripheral; Play; Potassium Channel; Proteins; Proteomics; Ranvier' s Nodes; Recruitment Activity; Reporting; Retinal Ganglion Cells; Role; Site; Spectrin; Spinal cord injury; Syndrome; Technology; Testing; Therapeutic; cell type; discount; intravitreal injection; mouse model; mutant mouse model; nervous system disorder; protein expression; repaired; scaffold

DESCRIPTION (provided by applicant): Ion channel clustering in myelinated axons is essential for proper nervous system function. Ion channels are clustered at nodes of Ranvier through neuron-glia interactions. However, the mechanisms responsible for channel clustering remain poorly understood. Recent studies suggest that multiple mechanisms may contribute to node formation. Among these, the axonal submembranous cytoskeleton comprised of ankyrins and spectrins has been proposed to be key components. In particular, nodes of Ranvier themselves are enriched with ankyrinG (ankG) and ?IV spectrin; ankG is thought to bind directly to the Na+ and K+ channels, and then link to the actin cytoskeleton through ?IV spectrin. At paranodes, both ankyrinB and ?II spectrin are clustered, although their functions at paranodes remain unknown. Paranodes are also thought to function as a paranodal diffusion barrier and a second mechanism to mediate ion channel clustering at nodes, although the mechanisms responsible for this barrier function remain unknown. Furthermore, a major impediment to elucidating the function of paranodes is the relatively few proteins that have been identified at this site. In this proposal we will seek to determine the function of the nodal and paranodal cytoskeletons in node of Ranvier assembly and maintenance. We will do this using three new mouse models that utilize Cre-Lox technology to control the temporal and spatial (cell-type specific) expression of ankG, ankB, and ?II spectrin. We will silence expression of these proteins in peripheral sensory neurons, in retinal ganglion cells, and in myelinating glia during both development and in adults. Finally, we will use proteomic methods to identify new paranodal proteins, and then seek to determine their functions.

描述（由申请人提供）：有髓轴突中的离子通道聚集对于正常的神经系统功能至关重要。离子通道通过神经元-胶质细胞相互作用聚集在郎飞叶节点。然而，对通道聚类的机制仍然知之甚少。最近的研究表明多种机制可能有助于节点的形成。其中，由锚蛋白和血影蛋白组成的轴突膜下细胞骨架被认为是关键成分。特别是，Ranvier 的节点本身富含锚蛋白 (ankG) 和 ?IV 血影蛋白； ankG 被认为直接与 Na+ 和 K+ 通道结合，然后通过 ?IV 血影蛋白与肌动蛋白细胞骨架连接。在副节点，ankyrinB 和 ?II 血影蛋白都聚集在一起，尽管它们在副节点的功能仍然未知。旁节点也被认为充当旁节点扩散屏障和介导节点处离子通道聚集的第二种机制，尽管负责这种屏障功能的机制仍然未知。此外，阐明副节点功能的一个主要障碍是在该位点鉴定的蛋白质相对较少。在本提案中，我们将寻求确定朗飞节组装和维护中节点和节旁细胞骨架的功能。我们将使用三种新的小鼠模型来实现这一点，这些模型利用 Cre-Lox 技术来控制 ankG、ankB 和 ?II 血影蛋白的时间和空间（细胞类型特异性）表达。我们将在发育期间和成人中沉默这些蛋白质在外周感觉神经元、视网膜神经节细胞和髓鞘神经胶质细胞中的表达。最后，我们将使用蛋白质组学方法来鉴定新的旁节蛋白，然后寻求确定它们的功能。