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）：髓鞘轴突中的离子通道聚类对于适当的神经系统功能至关重要。通过神经元相互作用将离子通道聚集在兰维尔的节点上。但是，导致渠道聚类的机制仍然很少理解。最近的研究表明，多种机制可能有助于淋巴结形成。其中，已经提出由脚踝和光谱蛋白组成的轴突膜细胞骨架是关键成分。特别是，Ranvier本身的节点充满了Ankyring（Ankg）和？IV Spectrin； ANKG被认为直接与Na+和K+通道结合，然后通过？IV谱链接到肌动蛋白细胞骨架。在paranodes，Ankyrinb和？ii光谱都聚集，尽管它们在副词的功能仍然未知。偏言也被认为是偏言式扩散屏障，也是介导节点处离子通道聚类的第二种机制，尽管负责此屏障功能的机制仍然未知。此外，阐明偏anod虫功能的主要障碍是在该部位鉴定的相对较少的蛋白质。在此提案中，我们将寻求确定兰维尔组装和维护节点中淋巴结和偏an的细胞骨架的功能。我们将使用三种使用CRE-Lox技术来控制ANKG，ANKB和？II Spectrin的时间和空间（细胞类型特异性）表达的新小鼠模型来执行此操作。我们将使这些蛋白质在周围感觉神经元，视网膜神经节细胞以及发育过程中的髓质神经胶质中的表达保持沉默。最后，我们将使用蛋白质组学方法来识别新的偏anodal蛋白，然后寻求确定其功能。