HMGB1 and Traumatic Brain Injury

项目摘要 创伤性脑损伤是一种破坏性的神经损伤，其病死率超过1%。 每年有数百万人，包括大量的年轻人和军人 人事部。脑水肿与颅内压升高有关 (颅内压)和较差的临床结果，尽管细胞 这一过程背后的机制仍不清楚。这一差距在 对脑水肿形成的了解有助于临床上缺乏... 对脑外伤患者有效的治疗方法。我们实验室最近的工作 表明急性神经元坏死刺激了高密度脂蛋白的被动释放 迁移率组盒蛋白1(HMGB1)，进而诱导胶质细胞肿胀和 脑水肿。具体目标1将确定个人是否被激活 NMDA受体亚基增加神经元损伤和脑水肿 实验性脑外伤。NR2A和NR2B基因敲除小鼠的加入将 确定单个NR2亚基是否对HMGB1的释放有贡献 头部创伤后的肿胀和神经学结果。特定目标 2将确定Toll样受体-4(TLR4)是否介导 HMGB1促进炎症和脑水肿的作用。的能力 HMGB1刺激星形细胞水通道，AQP4，也将被解决 在TLR4突变小鼠中。具体目标3将确定HMGB1是否可以 代表一种新的预测脑水肿发展的生物标志物 人类的头部创伤。体内HMGB1水平的测量 神经创伤患者脑脊液与血清的相关性研究 有急性神经元损伤和神经学后果。总而言之，建议的 研究将调查HMGB1-TLR4信号的新可能性 导致脑水肿和术后颅内压升高 TBI。这些研究的结果可能会为小说的未来发展提供支持 针对这一途径的治疗方法以限制以下神经损伤 头部创伤。

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.