The Molecular Architecture of Axons in Health and Disease

健康和疾病中轴突的分子结构

• 批准号: 10616551
• 负责人: MATTHEW N RASBAND
• 金额: $ 95.96万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-05-17 至 2029-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10616551
• 关键词: Action Potentials; Ankyrins; Architecture; Axon; Cytoskeletal Proteins; Cytoskeleton; Disease; Dissection; Electrophysiology (science); Genetic; Health; Image; Impairment; Injury; Ion Channel; Knockout Mice; Maintenance; Methods; Modernization; Molecular; Natural regeneration; Nervous System; Nervous System Physiology; Neurons; Proteins; Proteomics; Ranvier' s Nodes; Research; Signal Transduction; Spectrin; Structure; Therapeutic; conditional knockout; design; experimental study; gain of function; loss of function; mouse model; preservation; repaired

Project Summary Action potential initiation and propagation in myelinated axons requires high densities of ion channels clustered at axon initial segments (AIS), nodes of Ranvier, and a robust axonal cytoskeleton to help axons resist mechanicial injury. AIS also function to maintain neuronal polarity and regulate the distinction between axonal and somatodendritic domains. Unfortunately, disruption of these domains and the cytoskeleton during disease or after injury dramatically impairs nervous system function. Furthermore, the molecular mechanisms that control the assembly, function, and maintenance of AIS, nodes, and axonal cytoskeleton remain poorly understood. Since any therapeutic approach aimed at nervous system repair or regeneration must include the reassembly or preservation of axons, AIS and nodes of Ranvier, a detailed mechanistic understanding of their structure, mechanisms of assembly, and composition is urgently needed. To this end we developed proteomic approaches to perform a molecular dissection of AIS and nodes of Ranvier; these experiments will yield AIS and node 'interactomes.' To determine the functions of identified proteins we will perform rigorous gain and loss of function studies using modern molecular, imaging, genetic, and electrophysiological methods. Building on our previous research accomplishments and our discovery that mechanisms of node assembly converge on ankyrin and spectrin cytoskeletons, we will also determine the functions of these enigmatic, yet essential, cytoskeletal proteins using conditional knockout mouse models that we have developed. Together, we expect these studies to reveal key molecular mechanisms responsible for the assembly, maintenance, and function of axons. These discoveries may reveal targets and mechanisms that can be used for therapies to repair or preserve axon function.

项目摘要 髓鞘轴突中的动作潜在启动和传播需要高密度的离子通道 聚集在轴突初始片段（AIS），兰维尔的节点和强大的轴突细胞骨架上，以帮助轴突 抵抗机械损伤。 AI还起到维持神经元极性并调节区别的功能 轴突和躯体根系域。不幸的是，这些域和细胞骨架的破坏 疾病或受伤后极大地损害神经系统功能。此外，分子机制 控制AIS，节点和轴突细胞骨架的组装，功能和维护 理解。由于任何针对神经系统修复或再生的治疗方法都必须包括 重新组装或保存轴突，AIS和Ranvier节点，对其的详细机械理解 迫切需要结构，组装机制和组成。为此，我们开发了蛋白质组学 对Ranvier的AIS和淋巴结进行分子解剖的方法；这些实验将产生AIS 和节点“互动”。为了确定已识别蛋白的功能，我们将执行严格的增益和 使用现代分子，成像，遗传和电生理方法的功能研究丧失。建筑 关于我们以前的研究成就以及我们发现节点组件的机制会融合 Ankyrin和Spectrin细胞骨架，我们还将确定这些神秘但必不可少的功能 使用我们已经开发的条件基因敲除小鼠模型的细胞骨架蛋白。我们期望在一起 这些研究揭示了负责组装，维护和功能的关键分子机制 轴突。这些发现可能会揭示可用于修复疗法的目标和机制 保留轴突功能。

项目成果

Pleiotropic Ankyrins: Scaffolds for Ion Channels and Transporters.

多效性锚蛋白：离子通道和转运蛋白的支架。

• DOI: 10.1080/19336950.2022.2120467
• 发表时间: 2022-12
• 期刊: CHANNELS
• 影响因子: 3.3
• 作者: Stevens, Sharon R.;Rasband, Matthew N.
• 通讯作者: Rasband, Matthew N.

Axon Initial Segments Are Required for Efficient Motor Neuron Axon Regeneration and Functional Recovery of Synapses.

轴突初始段是有效运动神经元轴突再生和突触功能恢复所必需的。

• DOI: 10.1523/jneurosci.1261-22.2022
• 发表时间: 2022
• 期刊: The Journal of neuroscience : the official journal of the Society for Neuroscience
• 作者: Teliska,LindsayH;DallaCosta,Irene;Sert,Ozlem;Twiss,JefferyL;Rasband,MatthewN
• 通讯作者: Rasband,MatthewN

Antibody-directed extracellular proximity biotinylation reveals Contactin-1 regulates axo-axonic innervation of axon initial segments.

• DOI: 10.1101/2023.03.06.531378
• 发表时间: 2023-03-06
• 期刊: bioRxiv
• 作者: Ogawa，Yuki;Lim，Brian C.;Rasband，Matthew N.
• 通讯作者: Rasband，Matthew N.

Antibody-directed extracellular proximity biotinylation reveals that Contactin-1 regulates axo-axonic innervation of axon initial segments.

• DOI: 10.1038/s41467-023-42273-8
• 发表时间: 2023-10-26
• 期刊: NATURE COMMUNICATIONS
• 影响因子: 16.6
• 作者: Ogawa, Yuki;Lim, Brian C;George, Shanu;Oses-Prieto, Juan A;Rasband, Joshua M;Eshed-Eisenbach, Yael;Hamdan, Hamdan;Nair, Supna;Boato, Francesco;Peles, Elior;Burlingame, Alma L;Van Aelst, Linda;Rasband, Matthew N
• 通讯作者: Rasband, Matthew N