Neutrophil Activation after Traumatic Brain Injury

项目摘要 创伤性脑损伤（TBI）是世界范围内死亡和长期残疾的主要原因。超过170万 美国人每年遭受TBI，目前有多达2%的人口患有长期神经系统疾病。 上一次TBI的后果，每年给社会带来765亿美元的经济负担。预防性 措施降低了伤害发生率和/或严重程度，但三分之一的住院TBI患者死于伤害 是继发于最初创伤的脑水肿是一种危及生命的神经系统并发症， 促进颅内压升高，并导致TBI后数小时和数天内临床恶化。不幸的是， 控制ICP升高的神经外科方法有限， 缺乏脑水肿，这是TBI后改善患者病情的关键障碍。的 本提案的目的是检验总体假设，即中性粒细胞胞外生成 陷阱（NET）引发有害级联，其在TBI后的神经恶化中达到高潮。具体 目的1将检验TBI后TLR 4激活介导NET形成的假设。拟议机制 研究将证明TLR 4信号通路的激活在形成中的关键调节作用。 TBI后的NET。特异性目的2将检验肽基精氨酸脱亚胺酶4（PAD 4）促进 脑水肿。拟议的机制研究将使用遗传和药理学方法， 在人类和小鼠嗜中性粒细胞中，Toll样受体4诱导组蛋白高瓜氨酸酶介导物PAD 4与 创伤性脑损伤后NET形成与神经损伤具体目标3将检验以下假设： NET改善TBI后的神经血管功能。概念验证研究将表明， NET的降解可防止脑微血栓形成，从而改善脑再循环 减轻脑外伤后的水肿这些发现将为临床上重新利用重组 人DNA酶I（rhDNase 1），一种安全的、FDA批准的治疗药物，广泛用于非神经系统疾病的临床应用 疾病，在急性TBI患者的管理。拟议研究的预期成果包括 鉴定NET作为TBI后急性脑血管功能障碍的关键起始物。除了 我们的研究为急性损伤后中性粒细胞的有害作用提供了一种机制解释， 建立一个关键的框架，为发展有针对性的治疗，以改善创伤性脑损伤的结果。 .

PROJECT SUMMARY 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, presenting a critical barrier to improving patient prognoses after TBI. The objective of this proposal is to test the overarching hypothesis that generation of neutrophil extracellular traps (NETs) initiates a detrimental cascade that culminates in neurological deterioration after TBI. Specific Aim 1 will test the hypothesis that TLR4 activation mediates NET formation after TBI. Proposed mechanistic studies will demonstrate a key regulatory role for activation of the TLR4 signaling pathway in the formation of NETs after TBI. Specific Aim 2 will test the hypothesis that peptidylarginine deiminase 4 (PAD4) promotes cerebral edema after TBI. Proposed mechanistic studies will use genetic and pharmacological approaches to implicate PAD4, a mediator of TLR4-induced histone hypercitrullination in human and mouse neutrophils, in NET formation and neurological injury after TBI. Specific Aim 3 will test the hypothesis that degradation of NETs improves neurovascular function after TBI. Proof of concept studies will demonstrate that targeted degradation of NETs prevents cerebral microthrombus formation, leading to improved cerebral recirculation and reduced edema after TBI. These findings will provide the rationale for clinical repurposing of recombinant human DNase I (rhDNase1), a safe, FDA-approved therapeutic in widespread clinical use for non-neurological diseases, in the management of acute TBI patients. Expected outcomes of the proposed research include the identification of NETs as critical initiators of acute cerebrovascular dysfunction after TBI. In addition to providing a mechanistic explanation for the deleterious effects of neutrophils after acute injury, our studies will establish a critical framework for the development of targeted therapies to improve TBI outcomes. .