Spinal cord repair: releasing the neuron-intrinsic brake on axon regeneration

脊髓修复：释放神经元对轴突再生的内在制动

• 批准号: MR/R004544/1
• 负责人: James Fawcett
• 金额: $ 30.07万
• 依托单位: University of Cambridge
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2017
• 资助国家: 英国
• 起止时间: 2017 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FR004544%2F1
• 关键词: Spinal; cord; repair; releasing; neuron

After Spinal Cord Injury, the connections between nerve cells in the brain and in the spinal cord are lost and fail to grow back. In patients with SCI this results in permanent disability, including paralysis below the level of the injury, and loss of sensory, bladder and sexual function.There are two major obstacles to the regeneration of nerve fibers (referred to as axons) of central nervous system (CNS) neurons. First, CNS nerve cells do not switch on the necessary machinery for vigorous regrowth of axons. Second, a nerve cell has to deliver the necessary components for growth to the tip of the nerve fibre, which may be quite far as the axon can extend a long way from the cell body. Many CNS nerve cells fail to transport growth proteins into their axons after injury. These proteins are essential for nerve fiber regeneration through the hostile terrain of a spinal lesion. In AxonRepair we aim to promote axon regeneration in the spinal cord by 1. Activating the gene program required for nerve fiber extension, and by 2. Overcoming the transport block of growth-promoting proteins into injured axons.To achieve aim 1 our approach takes advantage of know-how collected by our consortium on the powerful regenerative abilities of peripheral nerve cells. Peripheral nerve cells do regenerate successfully because they have a kind of 'switch' which turns on a robust regenerative machinery, and because they do not exclude growth-related molecules from their axons. We have identified key molecular components of this switch and aim to use these to activate the regeneration program in neurons after a spinal cord lesion. Previous attempts to do this have focused on individual molecules, which can be considered individual parts of the switch. In AxonRepair we are attempting a novel strategy where we target multiple collaborating elements of the switch at the same time.Many mature CNS neurons have a specialized structure at the transition zone between their cell body and their axon that acts as a molecular barrier for transport of pro-regenerative proteins. It has recently been recognized that this molecular barrier plays a major role in the failure of axon regeneration: following an injury certain proteins (e.g. integrins) required for axon regeneration are excluded from the nerve fibers. Aim 2 of AxonRepair is therefore to "dissolve" the transport barrier allowing transport of essential pro-regenerative proteins into injured axons.At the completion of AxonRepair we expect to have developed an intervention strategy to promote robust axon regeneration and functional recovery after injury to long spinal cord axon tracts. The results obtained in the context of AxonRepair will provide the basis for a potential therapeutic strategy for SCI.

脊髓损伤后，大脑和脊髓中神经细胞之间的连接丢失，无法重新生长。在SCI患者中，这会导致永久性残疾，包括损伤水平以下的瘫痪，以及感觉、膀胱和性功能的丧失。中枢神经系统（CNS）神经元的神经纤维（称为轴突）再生有两个主要障碍。首先，中枢神经系统的神经细胞不能启动轴突再生的必要机制。其次，神经细胞必须将生长所需的成分输送到神经纤维的尖端，这可能相当远，因为轴突可以从细胞体延伸很长一段路。许多CNS神经细胞在损伤后不能将生长蛋白运输到它们的轴突中。这些蛋白质对于神经纤维通过脊髓损伤的不利地形的再生是必不可少的。在AxonRepair中，我们的目标是通过1.激活神经纤维延伸所需的基因程序，并通过2.克服生长促进蛋白进入受损轴突的转运障碍。为了实现目标1，我们的方法利用了我们联盟收集的关于外周神经细胞强大再生能力的专有技术。外周神经细胞确实能成功再生，因为它们有一种“开关”，可以打开一个强大的再生机制，而且它们不会将与生长相关的分子从轴突中排除。我们已经确定了这种开关的关键分子成分，并旨在使用这些来激活脊髓损伤后神经元的再生程序。以前的尝试都集中在单个分子上，这些分子可以被认为是开关的单个部分。在AxonRepair中，我们正在尝试一种新的策略，我们同时靶向开关的多个协作元件。许多成熟的CNS神经元在其细胞体和轴突之间的过渡区具有专门的结构，作为促再生蛋白运输的分子屏障。最近已经认识到，这种分子屏障在轴突再生的失败中起主要作用：在损伤后，轴突再生所需的某些蛋白质（例如整合素）被从神经纤维中排除。AxonRepair的第二个目标是“溶解”运输屏障，将重要的促再生蛋白运输到受损的轴突中。在AxonRepair完成后，我们期望开发出一种干预策略，以促进长脊髓轴突束损伤后的强大轴突再生和功能恢复。在AxonRepair的背景下获得的结果将为SCI的潜在治疗策略提供基础。

项目成果

Dorsal Root Ganglion Injection and Dorsal Root Crush Injury as a Model for Sensory Axon Regeneration.

• DOI: 10.3791/55535
• 发表时间: 2017-05
• 期刊: Journal of visualized experiments : JoVE
• 作者: Menghon Cheah;J. Fawcett;Melissa R. Andrews

PI 3-kinase delta enhances axonal PIP3 to support axon regeneration in the adult CNS

PI 3-激酶 delta 增强轴突 PIP3 以支持成人中枢神经系统的轴突再生

• DOI: 10.1101/787994
• 发表时间: 2019
• 作者: Barber A

Integrin-Driven Axon Regeneration in the Spinal Cord Activates a Distinctive CNS Regeneration Program.

• DOI: 10.1523/jneurosci.2076-22.2023
• 发表时间: 2023-06-28
• 期刊: JOURNAL OF NEUROSCIENCE
• 影响因子: 5.3
• 作者: Cheah, Menghon;Cheng, Yuyan;Petrova, Veselina;Cimpean, Anda;Jendelova, Pavla;Swarup, Vivek;Woolf, Clifford J.;Geschwind, Daniel H.;Fawcett, James W.
• 通讯作者: Fawcett, James W.