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

脊髓损伤后，大脑中的神经细胞和脊髓中的神经细胞之间的连接丢失，无法再生长。在脊髓损伤患者中，这会导致永久性残疾，包括损伤平面以下的瘫痪，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)的再生有两个主要障碍。首先，中枢神经系统神经细胞不会启动轴突蓬勃再生所需的机制。其次，神经细胞必须将生长所需的成分输送到神经纤维的顶端，神经纤维的尖端可能相当远，因为轴突可以从细胞体延伸很长一段路。许多中枢神经系统神经细胞在损伤后不能将生长蛋白运输到轴突中。这些蛋白质对于通过脊柱损伤的敌对地形的神经纤维再生是必不可少的。在AxonRepair中，我们的目标是通过以下方式促进脊髓中的轴突再生：1.激活神经纤维延伸所需的基因程序；2.克服促进生长蛋白进入受损轴突的运输障碍。为了实现目标1，我们的方法利用了我们联盟收集的关于周围神经细胞强大的再生能力的技术诀窍。外周神经细胞确实能够成功再生，因为它们有一种“开关”，可以启动一种强大的再生机制，而且它们不会将生长相关的分子排除在轴突之外。我们已经确定了这种开关的关键分子成分，并旨在利用这些成分来激活脊髓损伤后神经元的再生程序。以前的尝试主要集中在单个分子上，这些分子可以被认为是开关的单独部分。在AxonRepair中，我们正在尝试一种新的策略，我们同时针对开关的多个协作元件。许多成熟的中枢神经系统神经元在其细胞体和轴突之间的过渡区有一个特殊的结构，作为促进再生蛋白运输的分子屏障。最近人们认识到，这种分子屏障在轴突再生失败中起着重要作用：损伤后，轴突再生所需的某些蛋白质(如整合素)被排除在神经纤维之外。因此，AxonRepair的目标2是“溶解”运输屏障，允许必要的促再生蛋白运输到受损的轴突。在AxonRepair完成时，我们预计已经开发出一种干预策略，以促进长脊髓轴索损伤后强大的轴突再生和功能恢复。在AxonRepair的背景下获得的结果将为脊髓损伤的潜在治疗策略提供基础。

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.