HMGB1 and Traumatic Brain Injury

HMGB1 和创伤性脑损伤

基本信息

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
项目类别：
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

项目摘要

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.

项目概要创伤性脑损伤 (TBI) 是一种毁灭性的神经损伤，影响超过 1 每年数百万人，其中包括大量年轻人和军人人员。脑水肿与颅内压增高有关 (ICP) 和 TBI 后临床结果不佳，尽管细胞这一过程背后的机制仍然未知。这个差距在对脑水肿形成的了解导致临床上缺乏 TBI 患者的有效治疗方法。我们实验室的最新工作表明急性神经元坏死刺激高的被动释放迁移族盒蛋白 1 (HMGB1)，进而诱导神经胶质细胞肿胀并脑水肿。具体目标 1 将确定是否激活个人 NMDA 受体亚基增加神经元损伤和脑水肿实验性创伤性脑损伤。 NR2A 和 NR2B 敲除小鼠的掺入将确定单个 NR2 亚基是否有助于 HMGB1 释放，大脑头部外伤后的肿胀和神经系统结果。具体目标 2 将确定 Toll 样受体 4 (TLR4) 是否介导亲 HMGB1 的炎症和脑水肿促进作用。的能力 HMGB1 刺激星形细胞水通道 AQP4 也将得到解决在 TLR4 突变小鼠中。具体目标 3 将决定 HMGB1 是否可以代表预测脑水肿发展的新型生物标志物人类头部外伤后。测量 HMGB1 水平神经外伤患者的脑脊液（CSF）和血清将相关伴有急性神经元损伤和神经系统结果。共同提出的研究将调查 HMGB1-TLR4 信号传导的新可能性导致脑水肿的发展和颅内压升高创伤性脑损伤。这些研究结果可能支持小说的未来发展针对该途径的治疗可限制以下神经损伤头部外伤。

项目成果

期刊论文数量（19）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

The Histone Deacetylase Inhibitor Suberoylanilide Hydroxamic Acid (SAHA) Confers Acute Neuroprotection After Intracerebral Hemorrhage in Mice.

组蛋白脱乙酰酶抑制剂辛二酰苯胺异羟肟酸 (SAHA) 可在小鼠脑出血后提供急性神经保护作用。

DOI：
发表时间：
2016-04
期刊：
影响因子：
6.9
作者：
Sukumari;Alleyne Jr, Cargill H;Dhandapani, Krishnan M
通讯作者：
Dhandapani, Krishnan M

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

远程缺血后处理通过 AMPK 依赖性免疫调节促进血肿消退。

DOI：
发表时间：
2018-10-01
期刊：
影响因子：
0
作者：
Vaibhav, Kumar;Braun, Molly;Khan, Mohammad Badruzzaman;Fatima, Sumbul;Saad, Nancy;Shankar, Adarsh;Khan, Zenab T;Harris, Ruth B S;Yang, Qiuhua;Huo, Yuqing;Arbab, Ali S;Giri, Shailendra;Alleyne Jr, Cargill H;Vender, John R;Hess, David C;Baban
通讯作者：
Baban

TNF-alpha receptor antagonist, R-7050, improves neurological outcomes following intracerebral hemorrhage in mice.

TNF-α 受体拮抗剂 R-7050 可改善小鼠脑出血后的神经系统结果。

DOI：
发表时间：
2013-05-10
期刊：
影响因子：
2.5
作者：
King, Melanie D;Alleyne Jr, Cargill H;Dhandapani, Krishnan M
通讯作者：
Dhandapani, Krishnan M

Overexpression of Nrf2 attenuates Carmustine-induced cytotoxicity in U87MG human glioma cells.

Nrf2 的过度表达可减弱卡莫司汀诱导的 U87MG 人神经胶质瘤细胞的细胞毒性。

DOI：
发表时间：
2015-03-13
期刊：
影响因子：
3.8
作者：
Sukumari;Prasad, Niyathi;Alleyne, Cargill H;Vender, John R;Dhandapani, Krishnan M
通讯作者：
Dhandapani, Krishnan M

Selective activation of cannabinoid receptor-2 reduces neuroinflammation after traumatic brain injury via alternative macrophage polarization.

选择性激活大麻素受体 2 通过替代巨噬细胞极化减少创伤性脑损伤后的神经炎症。

DOI：
发表时间：
2018-02
期刊：
影响因子：
0
作者：
Braun, Molly;Khan, Zenab T;Khan, Mohammad B;Kumar, Manish;Ward, Ayobami;Achyut, Bhagelu R;Arbab, Ali S;Hess, David C;Hoda, Md Nasrul;Baban, Babak;Dhandapani, Krishnan M;Vaibhav, Kumar
通讯作者：
Vaibhav, Kumar