HMGB1 and Traumatic Brain Injury

HMGB1 和创伤性脑损伤

• 批准号: 7792899
• 负责人: KRISHNAN M. DHANDAPANI
• 金额: $ 32.16万
• 依托单位: AUGUSTA UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-01 至 2014-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7792899
• 关键词: Acute; Acute Brain Injuries; Address; American; Astrocytes; Biological Markers; Brain; Brain Edema; Cause of Death; Cerebral Edema; Cerebral Ischemia; Cerebrospinal Fluid; Clinical; Clinical Management; Coma; Craniocerebral Trauma; Data; Development; Economic Burden; Edema; Etiology; Event; Extracellular Space; Future; Genetic; Glutamate Receptor; Glutamates; Goals; HMGB Proteins; HMGB1 Protein; Human; Incidence; Individual; Inflammation; Inflammatory; Interleukin-1 Receptors; Intracranial Hypertension; Intracranial Pressure; Knockout Mice; Laboratories; Lesion; Ligands; Liquid substance; Measurement; Measures; Mediating; Medical; Membrane Proteins; Military Personnel; Molecular; Mus; Mutant Strains Mice; N-Methyl-D-Aspartate Receptors; NMDA receptor A1; Natural Immunity; Necrosis; Nervous System Trauma; Neurological outcome; Neuronal Injury; Neurons; Outcome; Pathway interactions; Patients; Process; Rodent; Role; Scanning; Secondary to; Sensorimotor functions; Serum; Signal Transduction; Societies; Swelling; Therapeutic; Time; Toll-like receptors; Traumatic Brain Injury; Work; X-Ray Computed Tomography; aquaporin 4; base; cell type; cellular development; clinically relevant; disability; excitotoxicity; extracellular; improved; inhibitor/antagonist; insight; mortality; neuroinflammation; new therapeutic target; novel; novel therapeutics; outcome forecast; public health relevance; receptor; toll-like receptor 4; transcription factor; water channel; young adult

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.

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，每年遭受超过100万人的影响，包括大量的年轻人和军事人员。脑水肿与TBI后的颅内压（ICP）升高（ICP）和临床结果差有关，尽管该过程的细胞机制仍然未知。理解脑水肿形成的差距有助于缺乏针对TBI患者的临床有效疗法。我们的实验室最近的工作表明，急性神经元坏死刺激了高迁移率组盒蛋白1（HMGB1）的被动释放，这又诱导了神经胶质肿胀和脑水肿。特定的目标1将确定实验性TBI后单个NMDA受体亚基的激活是否会增加神经元损伤和脑水肿。 NR2A和NR2B敲除小鼠的掺入将确定单个NR2亚基是否有助于使用以下头部创伤有助于HMGB1释放，脑溶胀和神经系统肿瘤结果。具体目标2将确定Toll样受体-4（TLR4）是否介导HMGB1的促炎性和脑水肿促进作用。 HMGB1刺激星形细胞水通道AQP4的能力也将在TLR4突变小鼠中解决。具体目标3将确定HMGB1是否可以代表一种新型生物标志物，以预测人类头部创伤后脑水肿的发展。脑脊液（CSF）内HMGB1水平的测量和神经肿瘤患者的血清将与急性神经元损伤和神经系统结局相关。共同提出的研究将研究HMGB1-TLR4信号传导有助于大脑水肿的发展和ICP增加的新颖可能性。这些研究的结果可能支持针对这种限制头部外伤后神经损伤的新型治疗剂的未来发展。 公共卫生相关性：创伤性脑损伤（TBI）是一种严重的医疗状况，可住院并禁用许多美国人，给社会带来巨大的经济负担。当前的医疗疗法不能有效地控制脑肿胀，部分原因是对TBI后脑水肿的发展缺乏机械理解。对细胞水平上这些机制的了解可以有助于发现新型治疗剂，从而大大降低患者死亡率并改善患者的预后。本应用将评估神经元坏死的潜在作用，即谷氨酸兴奋性毒性，作为TBI后细胞水肿发展的病因。