NLRP3 inflammasome and TBI

NLRP3 炎性体和 TBI

• 批准号: 8570673
• 负责人: KRISHNAN M. DHANDAPANI
• 金额: $ 7.5万
• 依托单位: AUGUSTA UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-06-01 至 2015-05-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8570673
• 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; Interleukins; 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

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，目前有高达2%的人口患有以前TBI的长期神经系统后果，每年给社会带来765亿美元的经济负担。预防性措施降低了损伤的发生率和/或严重程度，但三分之一的住院TBI患者死于继发于初始创伤的损伤。脑水肿是一种危及生命的神经系统并发症，可促进颅内压升高，并导致TBI后数小时和数天内的临床恶化。不幸的是，控制颅内压升高的神经外科方法有限，缺乏控制脑水肿的有效药物治疗。一个关键的障碍 TBI后仍缺乏临床有效的治疗选择。该建议的目的是暗示NLRP 3作为TBI后神经血管损伤的功能介质。具体目标1将检验P2 X7在TBI后促进NLRP 3炎性体活化的假设。具体目标2将检验抑制NLRP 3炎性体减弱TBI后神经损伤的假设。所提出的研究的预期结果包括：（1）鉴定P2 X7作为TBI后NLRP 3炎性小体形成的关键介质，以及（2）证明NLRP 3促进脑水肿和TBI后神经学结果。这些研究可能具有深远的翻译意义，因为NLRP 3作为继发性损伤的关键介质的鉴定将为治疗干预提供新的靶点。这些研究还将提供两种临床上有用的治疗剂控制创伤后水肿的作用机制，为TBI后这些发现的快速临床转化提供理论基础。!