CASPASE MEDIATED NEURONAL DEATH AFTER HEAD INJURY

Caspase激活是程序性细胞死亡级联反应的第一步，程序性细胞死亡级联反应是一系列严格调控的细胞和分子事件，系统地导致细胞死亡。越来越多的证据表明，在实验模型中，caspase的激活会导致创伤性脑损伤后继发性神经元死亡。重要的是，caspase的药物和分子抑制剂可以减轻啮齿动物脑缺血和创伤性脑损伤后的程序性细胞死亡，尽管报道有限。我们的假设是创伤性脑损伤后caspase的激活导致神经元死亡，抑制caspase的诱导和/或活性可以减少创伤性脑损伤后的继发性神经病理损伤。针对这一假说的具体目的将：1)利用模拟人类严重颅脑损伤的大鼠模型表征Caspase-3的时间、区域、细胞和亚细胞的表达和活性，2)研究细胞色素c和一氧化氮对大鼠和小鼠重型颅脑损伤后caspase上游调控的作用，3)测试几种药物对大鼠重型颅脑损伤后神经病理和功能结局的影响，4)检测其他caspase(Caspase-2和-9)在大鼠重型颅脑损伤后的表达，5)检测目前发现的caspase(Caspase-2-9)在大鼠重型颅脑损伤后的表达，以及5)检测目前发现的caspase(Caspase1-10)在人类重型颅脑损伤后的表达。在美国，创伤性脑损伤是成人和儿童死亡和发病的主要原因。在美国，继发性脑损伤导致成人和儿童的死亡率和发病率。继发性雨水损伤会导致死亡率和发病率，目前只有少数非特异性治疗方法可用。在实验模型和人类中，caspase介导的程序性细胞死亡可能与创伤性脑损伤后继发性神经元死亡有关。旨在减少caspase诱导和/或激活以随后减少继发性神经元死亡的药物治疗策略将在体内创伤性脑损伤模型中进行测试。如果caspase抑制剂在体内减少严重脑损伤后的程序性细胞死亡并改善神经学预后，将为重型脑损伤患者提供一种新的、临床相关的治疗策略。

Caspase activation is the first committed step in the programmed-cell death cascade, a tightly regulated sequence of cellular and molecular events that systematically leads to the death of a cell. Increasing evidence suggests that activation of caspases produces secondary neuronal death after traumatic brain injury in experimental models. Importantly, pharmacologic and molecular inhibitors of the caspases attenuate programmed cell-death after cerebral ischemia and traumatic brain injury in rodents, although reports are limited. Our hypothesis is that activation of caspases after traumatic brain injury contributes to neuronal death and that inhibiting induction and/or activity of caspases reduces secondary neuropathologic injury after traumatic brain injury. Specific aims to address this hypothesis will: 1) characterize the temporal, regional, cellular, and subcellular expression and activity of Caspase-3 using a rat model that mimics severe human traumatic brain injury, 2) examine the upstream regulation the upstream regulation of caspases by cytosolic cytochrome c and nitric oxide after severe traumatic brain injury in rats and mice, 3) test the effects of several pharmacologic caspase inhibitors on neuropathologic and functional outcome after severe traumatic brain injury in rats, 4) examine the expression of other caspases (Caspases-2 and -9) after severe traumatic brain injury in rats, and 5) examine the expression of currently identified caspase (Caspases -2 -9) after severe traumatic brain injury in rats, and 5) examine the expression of currently identified caspases (Caspases 1-10) after severe traumatic brain injury in humans. Traumatic brain injury is a major cause of mortality and morbidity in adults and children in the United States. Secondary brain injury contributes to mortality and morbidity in adults and children in the United States. Secondary rain injury contributes to mortality and morbidity and currently only few, non-specific therapies are available. Caspase-mediated programmed-cell death may contribute to secondary neuronal death after traumatic brain injury in experimental models and in humans as well. Pharmacologic treatment strategies aimed at reducing caspase induction and/or activation to subsequently reduce secondary neuronal death will be tested in models of traumatic brain injury in vivo. If caspase inhibitors reduce programmed-cell death and improve neurologic outcome after severe traumatic brain injury in vivo, a novel, clinically relevant treatment strategy for victims of severe head injury will be available.