Organization and Maintenance of Axonal Domains

轴突域的组织和维护

• 批准号: 8061771
• 负责人: Courtney Lynn Thaxton
• 金额: $ 5.3万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-02-01 至 2013-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8061771
• 关键词: Ablation; Adult; Ankyrins; Axon; Biochemical; Biogenesis; Biological; Cell Adhesion Molecules; Cell membrane; Cells; Cessation of life; Cytoskeletal Proteins; Cytoskeleton; Demyelinating Diseases; Development; Disease Progression; Evaluation; Future; Generations; Genetic; Individual; Ion Channel; Knock-out; Knockout Mice; Lead; Light; Long-Term Effects; Maintenance; Methods; Multiple Sclerosis; Mus; Muscle fasciculation; Myelin; Nerve; Nervous System Physiology; Nervous system structure; Neurites; Neuroglia; Neurons; Nodal; Pathology; Physiological; Protein Isoforms; Ranvier' s Nodes; Relative (related person); Role; Septate; Sodium; Sodium Channel; Techniques; axonal degeneration; comparative; expiration; in vivo; insight; myelination; neurofascin; neurofilament; postnatal; prevent; recombinase; restoration; segregation; therapeutic development; voltage

DESCRIPTION (provided by applicant): Enrichment of voltage-gated sodium channels to nodes of Ranvier is vital for the proper conductance of the nerve impulse in a saltatory manner. While myelination and the interaction of glia with axons facilitates the segregation of ion channels within specific subcellular axonal domains, the exact mechanisms governing the formation, organization and maintenance of the node are elusive. Recently, a group of cell adhesions molecules, known as Neurofascins (Nfasc), have been implicated in the coordination and stabilization of axonal domains. Two major isoforms have been characterized and are shown to be spatio-temporally regulated during development. NfascNF155 (NF155) is expressed specifically in glia within the paranodal myelin loops, while NfascNF186 (NF186), is enriched at the nodes of Ranvier and expressed specifically in neurons. Genetic ablation of Nfasc in mice resulted in the absolute disorganization of axonal domains (the node, paranode, and juxtaparanode), loss of both isoforms, and death at postnatal day 7, which has significantly hindered the examination of the individual roles of each isoform in nodal development, coordination, and stabilization. In this proposal, we seek to use a combination of genetic, cell biological, physiological and biochemical methods to determine the specific role of NF186 in nodal formation and the role of Nfascs during long-term axonal domain organization, axonal integrity and axonal function. Our specific aims are to: 1. Determine the role of NF86 during nodal biogenesis and development. 2. Determine the role of NF186 in the long-term maintenance and stabilization of axonal domains. 3. Determine whether loss of neurofascins in adults results in axonal degeneration. PUBLIC HEALTH RELEVANCE: The recent implication of Neurofascins in disease progression and pathology in demyelinating diseases, such as multiple sclerosis, has brought considerable focus towards the elucidation of their functions during axonal domain organization, axonal stability and axonal function. The studies proposed here will help to provide considerable insight into the individual and collective functions of Neurofascins to nodal formation and stabilization, as well as overall axonal domain organization and stability. It is likely that these studies will contribute towards the future development of therapeutic strategies that will allow for the treatment of afflicted individuals, through the restoration of the intimate relationship between axons and glia.

描述（由申请人提供）：富集朗飞结点的电压门控钠通道对于神经脉冲以跳跃方式的正确传导至关重要。虽然髓鞘形成以及神经胶质细胞与轴突的相互作用促进了特定亚细胞轴突域内离子通道的分离，但控制节点形成、组织和维持的确切机制尚不清楚。最近，一组称为神经成束蛋白（Nfasc）的细胞粘附分子与轴突域的协调和稳定有关。两种主要亚型已被表征，并显示在发育过程中受到时空调节。 NfascNF155 (NF155) 在节旁髓磷脂环内的神经胶质细胞中特异性表达，而 NfascNF186 (NF186) 在 Ranvier 节点富集并在神经元中特异性表达。小鼠 Nfasc 的基因消融导致轴突结构域（节点、旁节点和近旁节点）的绝对解体、两种亚型的丢失以及出生后第 7 天的死亡，这显着阻碍了对每种亚型在节点发育、协调和稳定中的个体作用的检查。在本提案中，我们寻求结合遗传、细胞生物学、生理学和生化方法来确定 NF186 在节点形成中的具体作用以及 Nfascs 在长期轴突结构域组织、轴突完整性和轴突功能中的作用。我们的具体目标是： 1. 确定 NF86 在节点生物发生和发育过程中的作用。 2.确定NF186在轴突结构域的长期维持和稳定中的作用。 3. 确定成人神经成束蛋白的缺失是否会导致轴突变性。 公共健康相关性：最近神经成束素在脱髓鞘疾病（如多发性硬化症）的疾病进展和病理学中的影响，引起了人们对阐明其在轴突结构域组织、轴突稳定性和轴突功能中的功能的关注。这里提出的研究将有助于深入了解神经成束蛋白对节点形成和稳定以及整体轴突域组织和稳定性的个体和集体功能。这些研究很可能有助于未来治疗策略的发展，通过恢复轴突和神经胶质细胞之间的密切关系来治疗患病个体。