Pathology of traumatic injury to CNS axons

中枢神经系统轴突创伤性损伤的病理学

基本信息

批准号：
7149992
负责人：
KATHRYN E SAATMAN
金额：
$ 20.03万
依托单位：
UNIVERSITY OF KENTUCKY
依托单位国家：
美国
项目类别：
财政年份：
2002
资助国家：
美国
起止时间：
2002-12-15 至 2008-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7149992
关键词：
Acute American Apoptosis Axon Axonal Transport Axotomy Beds Biomechanics Brain Calpain Cell Death Cessation of life Craniocerebral Trauma Cytoskeletal Proteins Cytoskeleton Data Development Diffuse Axonal Injury Disruption Dynein ATPase Elevation Event Genes Goals Growth Human Immunoblotting Impairment Injury Insulin-Like Growth Factor I Interruption Kinesin Label Lead Left Link Localized Measures Mechanics Mediator of activation protein Messenger RNA Microtubule Proteins Microtubules Modeling Mus Natural regeneration Nature Neuraxis Neurologic Neurons Optic Nerve Optic Nerve Injuries Pathologic Pathology Protein Biosynthesis Protein Overexpression Proteins Proteolysis Recovery Relative (related person)Research Personnel Retinal Ganglion Cells Role Severities Somatomedins Stretching Testing Therapeutic Therapeutic Intervention Time Tracer Traumatic Brain Injury Tubulin United States Wallerian Degeneration Work calpain inhibitor caspase-3 central nervous system injury day design disability experience fast axonal transport inhibitor/antagonist injured insight neuron apoptosis neuronal cell body novel therapeutics programs protein degradation repaired research study response retrograde transport tau Proteins therapeutic target

项目摘要

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.

在美国，每年有 200 万人遭受创伤性脑损伤，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。创伤期间轴突的剪切或拉伸脑损伤引发进行性轴突损伤，最终导致轴突切断术和神经元死亡。因为外伤最常导致延迟而不是立即轴索切断术，因此有机会在轴索切除术之前进行治疗干预。阐明创伤性轴突的细胞机制损伤并确定治疗靶点，我们将准确地对小鼠进行动态视神经牵张损伤复制人脑轴突在创伤性损伤期间经历的损伤的生物力学。我们提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突损伤后钙蛋白酶的激活导致微管损伤和轴突损伤除非逆转，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并确定时间与轴索切断术相关的运输障碍过程。在目标 2 中，我们将在通过微管相关蛋白的降解激活钙蛋白酶并中断轴突运输。瞄准 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破坏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 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术后运输障碍通过延迟 RGC 凋亡和上调细胞骨架蛋白合成来减轻轴突损伤。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，因此干预至关重要轴突切除术发生前创伤性轴突损伤的病理级联反应。视神经牵拉损伤模型允许轴突病理学与机械损伤参数或细胞体之间的相关性目前在全脑轴突损伤模型中不可能做出反应。通过利用这些独特的优点，我们希望确定轴突病理学中的关键介质和新的治疗策略在轴突切除术之前有效维持脆弱的神经元并修复轴突损伤。