Role of three novel CAMs in myelinating glia

三种新型 CAM 在髓鞘神经胶质细胞中的作用

• 批准号: 7341070
• 负责人: ELIOR PELES
• 金额: $ 14.21万
• 依托单位: WEIZMANN INSTITUTE OF SCIENCE
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-12-01 至 2009-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7341070
• 关键词: Actin-Binding Protein; Action Potentials; Adaptor Signaling Protein; Ankyrins; Antibodies; Axon; Binding; Biochemical; Biological Assay; Cell Adhesion Molecules; Cells; Coculture Techniques; Collaborations; Communication; Demyelinating Diseases; Development; Disruption; Electron Microscopy; Exons; Extracellular Domain; Fiber; Future; G Actin; Gene Expression; Gene Targeting; Generations; Genes; Immunofluorescence Immunologic; Immunofluorescence Microscopy; Immunoglobulins; In Vitro; Ion Channel; Knockout Mice; Localized; Maintenance; Measurement; Mediating; Membrane; Molecular; Mus; Mutant Strains Mice; Myelin; Nerve; Neuroglia; Neurons; Nodal; Oligodendroglia; Peptide Signal Sequences; Personal Satisfaction; Physiological; Play; Process; Proteins; RNA Interference; Ranvier' s Nodes; Research; Research Personnel; Research Proposals; Role; Schwann Cells; Spectrin; Structure; System; base; cDNA Library; cellular microvillus; contactin; contactins; design; embryonic stem cell; expression cloning; gastrointestinal microvillus; homologous recombination; in vivo; insight; molecular assembly/self assembly; myelination; neurofascin; nodal protein; novel; programs; protein distribution; protein expression; protein function; receptor; research study

DESCRIPTION (provided by applicant): The interaction between myelinating glial cells and their underlying axons organize the axonal membrane at and around the nodes of Ranvier into distinct domains, each of which contains a unique set of ion channels, cell adhesion molecules and cytoplasmic adaptor proteins. This local differentiation of the axon is essential for the fast and efficient propagation of action potentials and its disruption results in pathophysiological changes often seen in demyelinating diseases. This research proposal sets out to identify the molecular mechanisms by which myelinating Schwann cells (SC) regulate the establishment of the nodes of Ranvier. We have recently identified three novel glial cell adhesion molecules (glial CAMs), Gliomedin, CDO and Zig1 that are localized at the SC microvilli which contact the nodes of Ranvier. Furthermore, we have found that Gliomedin is the long sought-after glial receptor for NrCAM and neurofascin, two cell adhesion molecules that are associated with Na+ channels at the nodal axolemma. We propose to determine whether axon-glial contact mediated by these glial CAMs controls the clustering of Na+ channels along the axonal membrane. First, the distribution of these proteins during development will be examined and correlated with the molecular assembly of the nodes. Secondly, we will determine their role in myelination and the formation of the nodes of Ranvier using an in vitro myelination system, as well as by analyzing mice in which Gliomedin, CDO or Zig1 have been eliminated by gene targeting. Finally, a combined biochemical and molecular approach will be taken to reveal the molecular interactions mediated by these glial CAMs at the nodes. Our studies will yield important insight into the yet elusive mechanisms of axon-glial communication and the coordinated differentiation of axons and myelin-forming cells, which allows myelinated fibers to maximize their conduction velocity. A better understanding of these mechanisms may help to design future therapeutical strategies for demyelinating disorders.

描述（由申请人提供）：髓鞘形成神经胶质细胞与其下方轴突之间的相互作用将朗维尔结处及其周围的轴突膜组织成不同的结构域，每个结构域包含一组独特的离子通道、细胞粘附分子和细胞质衔接蛋白。轴突的这种局部分化对于动作电位的快速和有效传播是必不可少的，并且其破坏导致脱髓鞘疾病中常见的病理生理变化。这项研究计划旨在确定髓鞘化雪旺细胞（SC）调节朗维尔结建立的分子机制。我们最近发现了三种新的胶质细胞粘附分子（胶质细胞CAM），Gliomedin，CDO和Zig 1，它们位于SC微绒毛接触的节点Ranvier。此外，我们已经发现，Gliomedin是NrCAM和neurofascin的长期追求的神经胶质受体，这两种细胞粘附分子与节点轴膜处的Na+通道相关。 我们建议确定是否轴突-胶质细胞接触介导的这些胶质细胞CAM控制集群的Na+通道沿着轴突膜。首先，这些蛋白质在发育过程中的分布将被检查，并与节点的分子组装相关。其次，我们将使用体外髓鞘形成系统以及通过分析其中Gliomedin、CDO或Zig 1已通过基因靶向消除的小鼠来确定它们在髓鞘形成和Ranvier节点形成中的作用。最后，一个生物化学和分子生物学相结合的方法将被用来揭示这些胶质细胞CAM在节点介导的分子相互作用。我们的研究将产生重要的洞察力，但难以捉摸的机制轴突神经胶质细胞的通信和协调分化的轴突和髓鞘形成细胞，这使得有髓纤维，以最大限度地提高其传导速度。更好地了解这些机制可能有助于设计未来的脱髓鞘疾病的治疗策略。