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. .

项目摘要 创伤性脑损伤（TBI）是全球死亡率和长期残疾的主要原因。超过170万 美国人每年遭受TBI，目前最多有2％的人口患有长期神经系统 以前的TBI的后果，给社会带来了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 最初是最初创伤的原因。大脑水肿是一种威胁生命的神经系统并发症 促进ICP升高，并在TBI后几小时和几天内导致临床恶化。很遗憾， 控制升高ICP的神经外科手术方法有限，有效的医疗疗法可以控制 缺乏脑水肿，这是改善TBI后患者预后的关键障碍。这 该提议的目的是检验总体假设，即中性粒细胞外产生 陷阱（网）引发了有害的级联，该级联导致TBI后神经系统恶化。具体的 AIM 1将检验以下假设：TLR4激活介导TBI后的净形成。提出的机械 研究将证明在形成中激活TLR4信号通路的关键调节作用 TBI之后的网。特定的目标2将检验肽基金氨酸脱氨酶4（PAD4）促进的假设 TBI之后的脑水肿。建议的机械研究将使用遗传和药理方法来 暗示PAD4是人和小鼠嗜中性粒细胞中TLR4诱导的组蛋白过度乳腺癌的介体 TBI后的净形成和神经损伤。特定目标3将检验以下假设 NETS改善了TBI后神经血管功能。概念研究证明将证明针对性 网的降解可防止脑微孔形成，从而改善脑再循环 并减少了TBI之后的水肿。这些发现将提供重组临床重组的基本原理 人类DNase I（Rhdnase1），一种安全的FDA批准的治疗性，用于非神经学的广泛临床用途 疾病，在急性TBI患者的管理中。拟议研究的预期结果包括 TBI后，将网鉴定为急性脑血管功能障碍的关键发起人。此外 为急性损伤后中性粒细胞的有害作用提供了机械解释，我们的研究将 建立一个关键的框架，以开发有针对性的疗法以改善TBI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.