NLRP3 inflammasome and TBI

NLRP3 炎性体和 TBI

基本信息

批准号：
8666092
负责人：
KRISHNAN M. DHANDAPANI
金额：
$ 7.43万
依托单位：
AUGUSTA UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-06-01 至 2016-05-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8666092
关键词：
Acquired Immunodeficiency Syndrome Address American Astrocytes Attenuated Behavioral Biochemical Brain Brain Edema Brain Injuries Caspase-1 Cause of Death Cerebral Edema Cerebrovascular Circulation Clinical Clinical Trials Complication Craniocerebral Trauma Curcumin Demographic Aging Deterioration Development Drug Targeting Economic Burden Edema Event Extracellular Space FDA approved Future Gender Genetic Glyburide Health Hour Human Incidence Individual Inflammation Mediators Inflammatory Injury Interleukin-1 Intracranial Hypertension Knowledge Laboratories Life Liquid substance Measures Mediator of activation protein Medical Modeling Molecular Multiple Sclerosis Mus Nervous System Trauma Neurologic Neurologic Dysfunctions Neurological outcome Outcome Patients Pattern Population Pre-Clinical Model Process Production Public Health Purinoceptor Recruitment Activity Regulation Research Role Secondary to Severities Signal Transduction Societies Spinal cord injury Swelling Testing Therapeutic Therapeutic Intervention Translating Trauma Traumatic Brain Injury aquaporin 4 clinical practice controlled cortical impact disability drug development effective therapy improved inhibitor/antagonist killings malignant breast neoplasm mortality neuroimaging neuroinflammation novel outcome forecast procaspase-1 protein complex public health relevance receptor therapeutic development water channel

项目摘要

DESCRIPTION (provided by applicant): Traumatic brain injury (TBI) is a leading cause of mortality and long-term disability worldwide. Over 1.7 million Americans suffer a TBI annually and up to 2% of the population currently lives with the long-term neurological consequences of a previous TBI, placing a $76.5 billion annual economic burden on society. Preventative measures reduce injury incidence and/or severity, yet one-third of hospitalized TBI patients die from injuries that are secondary to the initial trauma. Cerebral edema is a life-threatening neurological complication that promotes elevated ICP and leads to clinical deterioration in the hours and days after a TBI. Unfortunately, neurosurgical approaches to control elevated ICP are limited and efficacious medical therapies to control cerebral edema are lacking. A critical barrier to improving patient prognoses remains a lack of clinically effective treatment options after TBI. The objective of this proposal is to implicate NLRP3 as a functional mediator of neurovascular injury after TBI. Specific Aim 1 will test the hypothesis that P2X7 promotes NLRP3 inflammasome activation after TBI. Specific Aim 2 will test the hypothesis that inhibition of the NLRP3 inflammasome attenuates neurological injury after TBI. Expected outcomes of the proposed research include: (1) identification of P2X7 as a key mediator of NLRP3 inflammasome formation following TBI, and (2) demonstration that NLRP3 promotes cerebral edema and worsens neurological outcomes after TBI. These studies may have far-reaching translational implications as the identification of NLRP3 as a key mediator of secondary injury will provide a novel target for therapeutic intervention. These studies also will provide a mechanism of action whereby two-clinically useful therapeutics control post-traumatic edema, providing rationale for rapid clinical translational of these findings after TBI. !

描述（由申请人提供）：创伤性脑损伤（TBI）是全球死亡率和长期残疾的主要原因。每年有超过170万美国人遭受TBI，目前有2％的人口占据了先前TBI的长期神经系统后果，这给社会上带来了765亿美元的经济负担。预防措施减少了伤害的发生率和/或严重程度，但三分之一的住院TBI患者死于最初创伤的伤害。大脑水肿是一种威胁生命的神经系统并发症，可促进ICP升高，并在TBI后几小时和几天内导致临床恶化。不幸的是，控制升高的ICP的神经外科手术方法是有限的，并且缺乏有效的医疗疗法来控制脑水肿。一个关键的障碍在TBI之后，改善患者预后仍然缺乏临床有效的治疗选择。该提案的目的是将NLRP3视为TBI后神经血管损伤的功能介体。具体目标1将检验以下假设：P2X7促进TBI后NLRP3炎性体激活。具体目标2将检验以下假设：抑制NLRP3炎症体会减轻TBI后神经损伤。拟议研究的预期结果包括：（1）将P2X7鉴定为TBI后NLRP3炎性体形成的关键介体，以及（2）证明NLRP3促进了脑水肿并在TBI后促进神经系统效果。这些研究可能具有深远的翻译意义，因为将NLRP3鉴定为继发性损伤的关键介体将为治疗干预提供新的目标。这些研究还将提供一种作用机理，从而在创伤后两链术的治疗方法进行控制，从而为TBI后这些发现的快速临床翻译提供了基本原理。呢