HEAD INJURY CLINICAL RESEARCH CENTER

由于在大多数长期创伤性脑损伤病例中， 昏迷，我们称这种临床病理状态为弥漫性轴索性 损伤（DAI）。 DAI占严重头部损伤的44%， 三分之一的头部受伤死亡，是最大的原因， 植物人和严重受损的幸存者 此外，轴突损伤 每年在数百万美国人中发生的程度较轻， 脑震荡和局部脑损伤 没有已知的治疗方法 对轴突损伤或DAI有特异性 在我们以前的工作中，我们有 确定轴突损伤主要发生在朗维尔结， 许多轴突在受伤时并没有被切断，而是经历了一个 进行性变性，导致继发性轴突切断后，几个 天 我们认为，更好地了解导致 继发性轴突切断术可能允许治疗干预，以防止其 发生，从而允许轴突修复和恢复功能， 发生. 在本提案中，我们将把这些意见延伸到以下主题： 弥漫性轴索损伤和测试的假设，二次轴切和 创伤性神经元功能障碍是两个因素的产物：钙 在损伤部位的受体介导的损伤和受体介导的损伤的作用 事件 后者可以是轴突损伤的结果， 通过对树突或核周元素的直接损伤。 为了解决这个 假设，我们的目标是1）确定组织学的关系， 轴突损伤和神经递质受体异常的模式， 人类和实验性头部损伤，2）确定钙在 电镜免疫组织化学法测定细胞骨架降解， 评估电压依赖性钙介导的损伤的影响， 钙通道阻滞，抑制钙激活蛋白酶， 减轻钙激活的磷脂酶级联反应，3）测定， 通过单位记录，微离子电渗应用受体激动剂和 拮抗剂和原位杂交的热休克蛋白， 损伤后核周过度兴奋的机制及 轴突损伤的核周改变，4）评估受体 介导的机制影响轴突和神经元的存活， 低阈值钙通道、NMDA或非NMDA拮抗剂，5）开发 轴突损伤和DAI的有生命和无生命模型， 现实的，和6）定义神经保护剂的作用， 导致临床治疗试验。

Because of widespread axonal damage in most cases of prolonged traumatic coma, we have termed this clinical-pathological condition diffuse axonal injury (DAI). DAI comprises 44% of sever head injuries, is responsible for one-third of all head injury deaths, and is the greatest cause of vegetative and severely impaired survivors. In addition, axonal damage occurs to a lesser degree each year in several million Americans who sustain concussion and focal brain injuries. There is no known therapy specific for axonal injury or DAI. In our previous work, we have determined that axonal damage occurs principally at the node of Ranvier and that many axons are not severed at the time of injury, but undergo a progressive degeneration that leads to secondary axotomy after several days. We have held that a better understanding of the events leading the secondary axotomy may allow therapeutic intervention to prevent it from occurring, thereby permitting axonal repair and restitution of function to occur. In this proposal, we will extend these observations on the theme of diffuse Axonal Injury and test the hypothesis that secondary axotomy and traumatic neuronal dysfunction is a product of two factors: calcium mediated damage at the site of injury and the effects of receptor mediated events. The latter can be produced either as a result of axonal damage or by direct damage to dendritic or perikaryal elements. To address this hypothesis, our goals are 1) to define the relationship of histologic patterns of axonal damage and neurotransmitter receptor abnormality in human and experimental head injury, 2) to determine the role of calcium in cytoskeletal degradation by electron microscopic immunohistochemistry and to assess the effect on calcium mediated damage by voltage dependent calcium channel blockade, inhibition of calcium activated proteases and mitigation of the calcium activated phospholipase cascade, 3) to determine, by unit recordings, microiontophoretic application receptor agonists and antagonists and in-situ hybridization of heat shock proteins, the mechanisms of perikaryal overexcitation after injury and the influence of perikaryal changes on axonal damage, 4) to assess the degree that receptor mediated mechanisms affect axonal and neuronal survival by treatment with low threshold calcium channel, NMDA or non-NMDA antagonists, 5) to develop animate and inanimate models of axonal injury and DAI that are clinically realistic, and 6) to define the effects of neuroprotective agents that can lead to clinical treatment trials.