Pathology of traumatic injury to CNS axons

在美国，创伤性脑损伤每年折磨着200万人，其中许多人患有持续性脑损伤。 弥漫性轴索损伤导致的神经功能障碍。在创伤过程中轴突的剪切或拉伸 脑损伤引发进行性轴突损伤，最终导致轴突切断和神经元死亡。因为 创伤性损伤最常引起延迟而不是立即的轴突切断， 在轴突切断术之前进行治疗干预。阐明创伤性轴突损伤的细胞机制 损伤和确定治疗靶点，我们将在小鼠中进行动态视神经牵张损伤， 在创伤性损伤期间复制人脑中轴突所经历的损伤的生物力学。我们 我建议使用这个已建立的中枢神经系统轴突损伤模型来验证我们的工作假设 创伤性轴突损伤后钙蛋白酶的激活导致微管损伤和轴突损伤， 这一转运，除非逆转，否则将导致轴突切断和神经元凋亡。在目标1中，我们将评估 顺行和逆行快速轴突运输作为损伤严重程度的函数， 与轴突切断术相关的运输损伤过程。在目标2中，我们将在以下方面建立一种机制联系： 钙蛋白酶激活和通过微管相关蛋白降解中断轴突运输。在Aim中 3，我们将测试我们的假设，即视神经轴突中轴突运输的长期中断导致 视网膜神经节细胞（RGCs）凋亡。在目标4中，我们将使用IGF-1过表达小鼠和外源性 IGF-1治疗以确定IGF-1水平升高是否可以逆转治疗后的转运障碍 通过延迟RGC凋亡和上调细胞骨架蛋白合成来损伤轴突。因为 中枢神经系统轴突的再生仍然是一个难以捉摸的目标，重要的是干预神经系统轴突的再生。 病理级联的创伤性轴突损伤轴突切开术发生之前。视神经牵张损伤模型 允许轴突病理与机械损伤参数或细胞体之间的相关性 这是目前在全脑轴突损伤模型中不可能实现的。通过利用这些独特的 优势，我们希望确定轴突病理学中的关键介质和新的治疗策略， 有效地维持脆弱的神经元并在轴突切断之前修复轴突损伤。

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.