HMGB1 and Traumatic Brain Injury

HMGB1 和创伤性脑损伤

• 批准号: 8525465
• 负责人: KRISHNAN M. DHANDAPANI
• 金额: $ 30.41万
• 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 2015-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8525465
• 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; 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; receptor; toll-like receptor 4; transcription factor; water channel; young adult

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.

项目摘要 创伤性脑损伤（TBI）是一种毁灭性的神经损伤 每年有百万人，包括大量的年轻人和军队 人员。脑水肿与颅内压增加有关 （ICP）TBI之后的临床结局不佳，尽管细胞 该过程的基础机制仍然未知。这个差距 对脑水肿形成的理解有助于缺乏临床 TBI患者的有效治疗。我们实验室的最近工作 证明急性神经元坏死刺激了高的被动释放 迁移率组盒蛋白1（HMGB1），进而引起神经胶质肿胀和 大脑水肿。具体目标1将确定是否激活个体 NMDA受体亚基增加神经元损伤和脑水肿 实验性TBI。 NR2A和NR2B敲除小鼠的结合将 确定单个NR2亚基是否有助于HMGB1释放，大脑 肿胀和神经系统结局，使用以下头部创伤。具体目标 2将确定Toll样受体-4（TLR4）是否介导了pro- 炎症和脑水肿促进HMGB1的作用。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。特定目标3将确定HMGB1是否可以 代表一种新的生物标志物来预测脑水肿的发展 在人类中造成头部创伤。测量HMGB1水平 脑脊液（CSF）和神经瘤患者的血清将相关 急性神经元损伤和神经系统损伤。一起，提议 研究将研究HMGB1-TLR4信号传导的新颖可能性 有助于大脑水肿的发展和ICP增加 TBI。这些研究的结果可能支持新颖的未来发展 针对这种途径的治疗剂，以限制神经系统损伤 头部创伤。

项目成果

Attenuation of hematoma size and neurological injury with curcumin following intracerebral hemorrhage in mice.

• DOI: 10.3171/2011.2.jns10784
• 发表时间: 2011-07
• 期刊: Journal of neurosurgery
• 影响因子: 4.1
• 作者: King MD;McCracken DJ;Wade FM;Meiler SE;Alleyne CH Jr;Dhandapani KM
• 通讯作者: Dhandapani KM

High mobility group box protein-1 promotes cerebral edema after traumatic brain injury via activation of toll-like receptor 4.

• DOI: 10.1002/glia.22581
• 发表时间: 2014-01
• 期刊: Glia
• 影响因子: 6.2
• 作者: Laird MD;Shields JS;Sukumari-Ramesh S;Kimbler DE;Fessler RD;Shakir B;Youssef P;Yanasak N;Vender JR;Dhandapani KM
• 通讯作者: Dhandapani KM

Curcumin attenuates cerebral edema following traumatic brain injury in mice: a possible role for aquaporin-4?

• DOI: 10.1111/j.1471-4159.2010.06630.x
• 发表时间: 2010-05
• 期刊: Journal of neurochemistry
• 影响因子: 4.7
• 作者: Laird MD;Sukumari-Ramesh S;Swift AE;Meiler SE;Vender JR;Dhandapani KM
• 通讯作者: Dhandapani KM

Remote ischemic post-conditioning promotes hematoma resolution via AMPK-dependent immune regulation.

• DOI: 10.1084/jem.20171905
• 发表时间: 2018-10-01
• 期刊: The Journal of experimental medicine
• 作者: Vaibhav K;Braun M;Khan MB;Fatima S;Saad N;Shankar A;Khan ZT;Harris RBS;Yang Q;Huo Y;Arbab AS;Giri S;Alleyne CH Jr;Vender JR;Hess DC;Baban B;Hoda MN;Dhandapani KM
• 通讯作者: Dhandapani KM

Necrostatin-1 reduces neurovascular injury after intracerebral hemorrhage.

• DOI: 10.1155/2014/495817
• 发表时间: 2014
• 期刊: International journal of cell biology
• 作者: King MD;Whitaker-Lea WA;Campbell JM;Alleyne CH Jr;Dhandapani KM
• 通讯作者: Dhandapani KM