MECHANISMS & TREATMENT OF PROGRESSIVE DAMAGE AFTER TBI

几个使用局灶性和弥漫性创伤性脑损伤（TBI）模型的实验室报告了组织病理学损伤的进行性，这种损伤可以在啮齿动物模型中持续长达一年。有证据表明，人类头部外伤后会出现进行性损伤。本研究首次提出的初步数据为中度液体冲击脑损伤后的慢性白质病理提供了定量数据。拟议研究的总体目标是评估中度和重度脑外伤对创伤后长期脆弱性模式的重要性。在具体目标1中，将评估灰质和白质病理的区域模式及其相关的神经行为改变。组织病理学技术以及磁共振成像（MRI）策略将用于评估进行性损伤的时间和区域模式，以便将这些变化与行为结果联系起来。在特异性目标2中，轴突损伤、脱髓鞘、细胞萎缩和细胞死亡的免疫细胞化学标志物将用于评估细胞损伤进展。为了开始确定渐进性白质损伤的病理机制，我们将在区域和时间上评估长期灌注不足和异常蛋白聚集在这些结构变化中的作用。最后，针对兴奋毒性过程和异常蛋白聚集的治疗策略将被评估以减少进展性萎缩的进展。我们认为，这些实验对于了解进行性损伤的发病机制以及制定促进TBI后功能恢复的治疗策略是必要的。已建立的动物模型和行为学、MRI、免疫细胞化学、放射自显影和分子技术将被利用。

Several laboratories using focal and diffuse models of traumatic brain injury (TBI) have reported the progressive nature of histopathological damage that can continue in rodent models up to one year. Evidence for progressive damage has previously been reported in humans following head trauma. Preliminary data in this application presented for the first time provides quantitative data for chronic white matter pathology following moderate fluid-percussion brain injury. The overall goal of the proposed studies is to assess the importance of moderate and severe TBI on long-term vulnerability patterns after trauma. In Specific Aim 1, regional patterns of gray and white matter pathology and their associated neurobehavioral alterations will be assessed. Histopathological techniques along with magnetic resonance imaging (MRI) strategies will be used to assess temporal and regional patterns of progressive damage in order to correlate these changes with behavioral outcomes. In Specific Aim 2, immunocytochemical markers of axonal damage, demyelination, cell atrophy, and cell death will be utilized to assess cellular injury progression. To begin to determine the pathomechanisms underlying progressive white matter injury, the role of prolonged hypoperfusion and abnormal protein aggregation on these structural changes will be regionally and temporally assessed. Finally, therapeutic strategies targeting excitotoxic processes as well as abnormal protein aggregation will be evaluated to reduce progression of advancing atrophy. It is felt that these experiments are necessary to understand the pathogenesis of progressive injury as well as to develop therapeutic strategies to promote recovery of function following TBI. Established animal models and behavioral, MRI, immunocytochemical, autoradiography, and molecular techniques will be utilized.