HMGB1 and Traumatic Brain Injury

项目摘要 创伤性脑损伤（TBI）是一种毁灭性的神经损伤， 每年有100万人，其中包括大量的年轻人和军人。 人员的脑水肿与颅内压增高有关 (ICP)和TBI后的不良临床结果，尽管细胞 这一过程的基本机制仍不清楚。的这一缺陷 对脑水肿形成的理解有助于缺乏临床- 对TBI患者的有效治疗。我们实验室最近的工作 表明急性神经元坏死刺激高浓度的 迁移率族蛋白1（HMGB 1），这反过来又诱导神经胶质肿胀， 脑水肿具体目标1将确定是否激活个人 NMDA受体亚单位增加神经元损伤和脑水肿 实验性脑外伤NR 2A和NR 2B基因敲除小鼠的掺入将使NR 2A和NR 2B基因敲除小鼠的免疫应答增加。 确定单个NR 2亚基是否有助于HMGB 1的释放， 肿胀和神经学结果。具体目标 2将确定Toll样受体-4（TLR 4）是否介导促凋亡， HMGB 1的炎症和脑水肿促进作用。的能力 HMGB 1刺激星形胶质细胞水通道，AQP 4，也将得到解决 在TLR 4突变小鼠中。具体目标3将确定HMGB 1是否可能 代表了一种新的生物标志物来预测脑水肿的发展 人类头部创伤后死亡HMGB 1水平的测量 脑外伤患者的脑脊液（CSF）和血清将相关 伴有急性神经元损伤和神经学结果。在一起，拟议的 研究将探讨HMGB 1-TLR 4信号转导的新可能性， 导致脑水肿的发展和颅内压升高， 创伤性脑损伤这些研究结果可能会支持未来的发展小说 针对该途径的治疗以限制以下神经损伤： 头部外伤

Project Summary Traumatic brain injury (TBI) is a devastating neurological injury afflicting over 1 million people annually, including a large number of young adults and military personnel. Cerebral edema is associated with increased intracranial pressure (ICP) and a poor clinical outcome following TBI, although the cellular mechanisms underlying this process remain unknown. This gap in the understanding of cerebral edema formation contributes to the lack of clinically- effective therapeutics for TBI patients. Recent work by our laboratory demonstrates that acute neuronal necrosis stimulates the passive release of high mobility group box protein 1 (HMGB1), which in turn induces glial swelling and cerebral edema. Specific Aim 1 will establish whether activation of individual NMDA receptor subunits increase neuronal injury and cerebral edema following experimental TBI. The incorporation of NR2A and NR2B knockout mice will determine whether individual NR2 subunits contribute to HMGB1 release, brain swelling, and neurological outcome using following head trauma. Specific Aim 2 will determine whether toll-like receptor-4 (TLR4) mediates the pro- inflammatory and cerebral edema promoting effects of HMGB1. The ability of HMGB1 to stimulate the astrocytic water channel, AQP4, will also be addressed in TLR4 mutant mice. Specific Aim 3 will determine whether HMGB1 may represent a novel biomarker to predict the development of cerebral edema folowing head trauma in humans. Measurement of HMGB1 levels within the cerebrospinal fluid (CSF) and serum of neurotrauma patients will be correlated with acute neuronal injury and neurological outcome. Together, the proposed studies will investigate the novel possibility that HMGB1-TLR4 signaling contributes to the development of cerebral edema and increased ICP following TBI. The results of these studies may support the future development of novel therapeutics directed against this pathway to limit neurological injury following head trauma.