HMGB1 and Traumatic Brain Injury

描述(申请人提供)：创伤性脑损伤(TBI)是一种破坏性的神经损伤，每年困扰100多万人，包括大量年轻人和军事人员。脑水肿与颅脑损伤后颅内压升高和不良的临床预后有关，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认识上的差距导致缺乏对脑外伤患者有效的临床治疗方法。本实验室最近的工作表明，急性神经元坏死刺激高迁移率族蛋白1(HMGB1)的被动释放，进而导致神经胶质细胞肿胀和脑水肿。具体目标1将确定单个NMDA受体亚单位的激活是否会增加实验性脑损伤后的神经元损伤和脑水肿。NR2A和NR2B基因敲除小鼠的加入将确定单独的NR2亚单位是否有助于HMGB1的释放、脑肿胀和使用头部创伤后的神经学结果。特异性目标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。具体目标3将确定HMGB1是否可以代表一种新的生物标记物来预测人类脑创伤后脑水肿的发展。神经创伤患者脑脊液(CSF)和血清中HMGB1水平的测定将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信号参与脑损伤后脑水肿和颅内压升高的新的可能性。这些研究的结果可能支持针对这一途径的新疗法的未来发展，以限制脑创伤后的神经损伤。 公共卫生相关性：创伤性脑损伤(TBI)是一种严重的医疗状况，导致许多美国人住院并致残，给社会带来巨大的经济负担。目前的药物治疗不能有效地控制脑肿胀，部分原因是缺乏对脑外伤后脑水肿发展的机制了解。在细胞水平上对这些机制的更好理解可能有助于发现新的治疗方法，从而显著降低患者死亡率并改善患者预后。目前的应用将评估继发于谷氨酸兴奋性毒性的神经元坏死作为脑外伤后细胞水肿发展的一个原因的潜在作用。

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.