HMGB1 and Traumatic Brain Injury

描述（由申请人提供）：创伤性脑损伤（TBI）是一种毁灭性的神经损伤，每年有超过100万人受到影响，其中包括大量的年轻人和军人。脑水肿与颅内压升高（ICP）和较差的临床预后相关，尽管这一过程背后的细胞机制尚不清楚。这种对脑水肿形成的理解上的差距导致缺乏临床有效的治疗TBI患者的方法。我们实验室最近的研究表明，急性神经元坏死刺激高迁移率群盒蛋白1 （HMGB1）的被动释放，从而诱导神经胶质肿胀和脑水肿。特异性目的1将确定单个NMDA受体亚单位的激活是否会增加实验性TBI后的神经元损伤和脑水肿。NR2A和NR2B敲除小鼠的结合将确定单个NR2亚基是否有助于HMGB1的释放、脑肿胀和脑外伤后的神经预后。特异性Aim 2将确定toll样受体-4 （TLR4）是否介导HMGB1的促炎和脑水肿作用。HMGB1刺激星形细胞水通道AQP4的能力也将在TLR4突变小鼠中得到解决。特异性Aim 3将确定HMGB1是否可以作为一种新的生物标志物来预测人类头部创伤后脑水肿的发展。神经外伤患者脑脊液（CSF）和血清中HMGB1水平的测定与急性神经元损伤和神经预后相关。总之，拟议的研究将探讨HMGB1-TLR4信号参与脑外伤后脑水肿发展和颅内压增加的新可能性。这些研究的结果可能支持未来针对这一途径的新疗法的发展，以限制头部创伤后的神经损伤。

DESCRIPTION (provided by applicant): 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 following 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. PUBLIC HEALTH RELEVANCE: Traumatic brain injury (TBI) is a serious medical condition that hospitalizes and disables many Americans, placing a large economic burden on society. Current medical therapies do not effectively control brain swelling, in part, due to a lack of mechanistic understanding regarding the development of cerebral edema following TBI. An improved understanding of these mechanisms at the cellular levels may aid in the discovery of novel therapeutics, which could substantially reduce patient mortality and improve patient outcome. The present application will assess the potential role of neuronal necrosis, secondary to glutamate excitotoxicity, as a causative factor in the development of cellular edema following TBI.