CASPASE MEDIATED NEURONAL DEATH AFTER HEAD INJURY

半胱天冬酶激活是程序性细胞死亡级联反应中的第一个关键步骤，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，半胱天冬酶的激活导致创伤性脑损伤后继发性神经元死亡。重要的是，半胱天冬酶的药理学和分子抑制剂减弱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，创伤性脑损伤后半胱天冬酶的激活有助于神经元死亡，抑制半胱天冬酶的诱导和/或活性减少创伤性脑损伤后继发性神经病理损伤。解决这一假设的具体目标是：1）使用模拟严重的人类创伤性脑损伤的大鼠模型表征胱天蛋白酶-3的时间、区域、细胞和亚细胞表达和活性，2）在大鼠和小鼠中检查严重创伤性脑损伤后通过胞质细胞色素c和一氧化氮的胱天蛋白酶的上游调节，3）检测几种药物半胱氨酸蛋白酶抑制剂对大鼠重型创伤性脑损伤后神经病理和功能结局的影响，4）检测其他半胱氨酸蛋白酶的表达，（胱天蛋白酶-2和-9）在大鼠严重创伤性脑损伤后，和5）检测目前鉴定的caspase的表达（Caspases-2 - 9）在大鼠严重创伤性脑损伤后，和5）检测目前鉴定的半胱天冬酶（半胱天冬酶1-10）在人类严重创伤性脑损伤后的表达。创伤性脑损伤是美国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。半胱天冬酶介导的程序性细胞死亡可能导致实验模型和人类创伤性脑损伤后继发性神经元死亡。将在体内创伤性脑损伤模型中测试旨在减少半胱天冬酶诱导和/或活化以随后减少继发性神经元死亡的药理学治疗策略。如果半胱天冬酶抑制剂减少程序性细胞死亡，改善严重创伤性脑损伤后的神经功能的结果在体内，一个新的，临床相关的治疗策略，严重的头部损伤的受害者将是可用的。

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.