Neutrophil Activation after Traumatic Brain Injury

脑外伤后中性粒细胞激活

• 批准号: 10312034
• 负责人: ALI SYED ARBAB
• 金额: $ 37.36万
• 依托单位: AUGUSTA UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-12-15 至 2024-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10312034
• 关键词: Acquired Immunodeficiency Syndrome; Acute; Adhesions; American; Biological Markers; Biological Response Modifiers; Blood Platelets; Brain; Caring; Cause of Death; Cerebral Edema; Cerebrospinal Fluid; Cerebrovascular Circulation; Cerebrovascular Disorders; Cerebrum; Chromatin; Clinical; Coagulation Process; Complication; Coupled; Cytoplasmic Granules; Data; Deep Vein Thrombosis; Deoxyribonuclease I; Deoxyribonucleases; Deterioration; Development; Digestion; Economic Burden; Edema; FDA approved; Functional disorder; Generations; Genetic; HMGB1 Protein; Histone H3; Histones; Hour; Human; Impairment; Incidence; Individual; Infection; Injury; Intracranial Hypertension; Intracranial Pressure; Ischemic Stroke; Knowledge; Life; Link; Liquid substance; Mediating; Mediator of activation protein; Medical; Molecular; Multiple Sclerosis; Mus; Necrosis; Nervous System Trauma; Neurologic; Neurons; Neutrophil Activation; Operative Surgical Procedures; Outcome; Pathologic; Pathologic Processes; Patients; Pattern; Phagocytosis; Pharmaceutical Preparations; Pharmacology; Plasma; Population; Preventive measure; Protein-arginine deiminase; Proteins; Recombinants; Reporting; Research; Role; Secondary to; Sepsis; Serum; Severities; Signal Pathway; Signal Transduction; Site; Societies; Spinal cord injury; Supervision; Surgical Management; TLR4 gene; Testing; Therapeutic; Thrombus; Trauma; Traumatic Brain Injury; Venous; Venous Thrombosis; Vertebral column; antimicrobial; cerebral hypoperfusion; cerebrovascular; disability; extracellular; improved; inflammatory milieu; innovation; leukocyte activation; malignant breast neoplasm; mortality; neurovascular; neutrophil; novel; novel therapeutic intervention; pathogen; patient prognosis; postcapillary venule; prevent; recombinant human DNase; scaffold; stroke patient; targeted treatment; therapeutic development; thrombotic; translational study; venule

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. .

项目总结 创伤性脑损伤是世界范围内导致死亡和长期残疾的主要原因。超过170万 美国人每年都会遭受脑外伤，目前高达2%的人口患有长期的神经性疾病 前一次TBI的后果，每年给社会带来765亿美元的经济负担。预防性的 减少伤害发生率和/或严重程度的措施，然而三分之一的住院脑外伤患者死于伤害 与最初的创伤相比是次要的。脑水肿是一种危及生命的神经并发症， 促进颅内压升高，并导致脑外伤后数小时和数天的临床恶化。不幸的是， 控制升高的颅内压的神经外科方法是有限的和有效的药物治疗来控制 缺乏脑水肿，这是改善脑外伤后患者预后的关键障碍。这个 这项提议的目的是检验一个重要的假设，即中性粒细胞产生细胞外 陷阱(Net)会引发一系列有害的级联反应，最终导致脑外伤后神经功能的恶化。特定的 目的1验证TLR4激活介导脑损伤后神经网络形成的假说。建议的机械论 研究将证明TLR4信号通路的激活在TLR4信号通路的形成中起关键的调节作用 在TBI之后的篮网。《特定目标2》将验证以下假设：多肽精氨酸脱亚胺酶4(PAD4)促进 颅脑损伤后脑水肿。拟议的机制研究将使用遗传学和药理学方法来 TLR4诱导组蛋白高瓜氨酸化的中介物PAD4在人和鼠中性粒细胞中的作用 脑外伤后神经网络的形成和神经损伤。具体目标3将检验这样一种假设 NETS可改善脑外伤后的神经血管功能。概念验证研究将证明有针对性的 NETs的降解可防止脑微血栓的形成，从而改善脑再循环 减轻脑外伤后的脑水肿。这些发现将为重组蛋白的临床再利用提供理论依据。 人DNase I(RhDNase1)，一种安全的，FDA批准的非神经系统临床广泛使用的治疗方法 在急性颅脑损伤患者的治疗中，应加强对疾病的控制。拟议研究的预期结果包括 确认Net是脑外伤后急性脑血管功能障碍的关键启动者。除了……之外 我们的研究将为急性损伤后中性粒细胞的有害影响提供一个机制上的解释 建立一个关键的框架，用于开发靶向治疗，以改善脑外伤的结果。 。

项目成果

Cannabidiol (CBD) modulation of apelin in acute respiratory distress syndrome.

• DOI: 10.1111/jcmm.15883
• 发表时间: 2020-11
• 期刊: Journal of cellular and molecular medicine
• 影响因子: 5.3
• 作者: Salles ÉL;Khodadadi H;Jarrahi A;Ahluwalia M;Paffaro VA Jr;Costigliola V;Yu JC;Hess DC;Dhandapani KM;Baban B
• 通讯作者: Baban B

High Levels of Interferon-Alpha Expressing Macrophages in Human Breast Milk During SARS-CoV-2 Infection: A Case Report.

SARS-CoV-2 感染期间人母乳中表达高水平干扰素-α 的巨噬细胞：病例报告。

• DOI: 10.1089/bfm.2020.0369
• 发表时间: 2021
• 期刊: Breastfeeding medicine : the official journal of the Academy of Breastfeeding Medicine
• 作者: Yu,JackC;Khodadadi,Hesam;Salles,ÉvilaLopes;Pham,Quyen;Patel,Pinkal;Baban,Babak
• 通讯作者: Baban,Babak

Inflammaging, cellular senescence, and cognitive aging after traumatic brain injury.

• DOI: 10.1016/j.nbd.2023.106090
• 发表时间: 2023-05
• 期刊: NEUROBIOLOGY OF DISEASE
• 影响因子: 6.1
• 作者: Lu, Yujiao;Jarrahi, Abbas;Moore, Nicholas;Bartoli, Manuela;Brann, Darrell W.;Baban, Babak;Dhandapani, Krishnan M.
• 通讯作者: Dhandapani, Krishnan M.