Pathology of traumatic injury to CNS axons

在美国，每年有200万人遭受创伤性脑损伤的折磨，其中许多人持续遭受 弥漫性轴索损伤所致的神经功能障碍。外伤性轴突的剪切或伸展 脑损伤引起进行性轴突损伤，最终导致轴突切断和神经元死亡。因为 创伤性损伤最常导致延迟而不是立即的轴突切断术，机会是存在的 在轴突切断术前进行治疗干预。阐明创伤性轴突的细胞机制 确定损伤和治疗靶点，我们将对小鼠进行动态视神经牵拉损伤，准确 复制创伤性损伤期间人脑轴突所经历的损伤的生物力学。我们 建议使用这个已建立的中枢神经系统轴突损伤模型来检验我们的工作假设 创伤性轴索损伤后钙痛的激活导致微管损伤和轴突损伤 运输，除非逆转，将导致轴突切断和神经元凋亡。在目标1中，我们将评估 轴突顺行和逆行快速运输作为损伤严重程度的函数并确定时间 与轴突切断相关的运输障碍的病程。在目标2中，我们将在 通过微管相关蛋白的降解激活和中断轴突运输。在AIM 3，我们将检验我们的假设，即视神经轴突中轴突运输的长期中断会导致 视网膜神经节细胞(RGC)的凋亡。在目标4中，我们将使用过量表达IGF-1的小鼠和外源 胰岛素样生长因子-1治疗以确定提高胰岛素样生长因子-1水平是否可以逆转脑损伤后的运输障碍 通过延缓RGC的凋亡和上调细胞骨架蛋白的合成而造成轴突损伤。因为 中枢神经系统轴突的再生仍然是一个难以实现的目标，干预是至关重要的 轴突切断术前创伤性轴索损伤的病理级联。视神经牵拉伤模型的建立 允许轴突病理与机械损伤参数或细胞体相关 这是目前在全脑轴突损伤模型中无法实现的反应。通过利用这些独特的 优势，我们希望确定轴突病理中的关键介质和新的治疗策略 在轴突切断前，有效地维持脆弱的神经元并修复轴突损伤。

Traumatic brain injury afflicts 2 million people each year in the United States, many of whom suffer persistent neurological disability as a result of diffuse axonal injury. Shearing or stretching of axons during traumatic brain injury initiates progressive axonal damage, ultimately leading to axotomy and neuronal death. Because traumatic injury most often causes delayed rather than immediate axotomy, the opportunity exists to intervene therapeutically prior to axotomy. To elucidate the cellular mechanisms underlying traumatic axonal injury and identify therapeutic targets, we will perform dynamic optic nerve stretch injury in mice, accurately replicating the biomechanics of injury experienced by axons in the human brain during traumatic injury. We propose to use this established model of central nervous system axonal injury to test our working hypothesis that activation of calpains after traumatic axonal injury causes microtubule damage and impairment of axonal transport which, unless reversed, will lead to axotomy and neuronal apoptosis. In Aim 1, we will evaluate anterograde and retrograde fast axonal transport as a function of injury severity and establish the time course of transport impairment relative to axotomy. In Aim 2, we will establish a mechanistic link between calpain activation and interruption of axonal transport via degradation of microtubule-related proteins. In Aim 3, we will test our hypothesis that prolonged disruption of axonal transport in optic nerve axons leads to apoptosis of retinal ganglion cells (RGCs). In Aim 4, we will use IGF-1 overexpressing mice and exogenous IGF-1 treatment to determine whether elevation of IGF-1 levels can reverse transport impairment after axonal injury by delaying RGC apoptosis and upregulating cytoskeletal protein synthesis. Because regeneration of central nervous system axons remains an elusive goal, it is vital to intervene in the pathologic cascade of traumatic axonal injury before axotomy occurs. The optic nerve stretch injury model allows correlations between axonal pathology and either mechanical injury parameters or the cell body response that are not currently possible in whole-brain axonal injury models. By exploiting these unique advantages, we hope to identify key mediators in axonal pathology and novel therapeutic strategies to effectively sustain the vulnerable neuron and repair axonal damage prior to axotomy.