Neutrophil Activation after Traumatic Brain Injury

脑外伤后中性粒细胞激活

基本信息

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
项目类别：
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

项目摘要

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. .

项目概要创伤性脑损伤（TBI）是全世界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 TBI，目前有多达 2% 的人患有长期神经系统疾病先前 TBI 的后果，每年给社会造成 765 亿美元的经济负担。预防性措施可减少伤害发生率和/或严重程度，但三分之一的住院 TBI 患者死于伤害这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。很遗憾，控制 ICP 升高的神经外科方法有限，有效的药物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。这该提案的目的是检验总体假设，即中性粒细胞胞外细胞的生成陷阱（NET）会引发有害的级联反应，最终导致 TBI 后神经功能恶化。具体的目标 1 将检验 TBI 后 TLR4 激活介导 NET 形成的假设。提出的机制研究将证明 TLR4 信号通路的激活在形成 TBI 后的 NET。具体目标 2 将检验肽基精氨酸脱亚胺酶 4 (PAD4) 促进的假设 TBI后脑水肿。拟议的机制研究将使用遗传和药理学方法 PAD4 是人类和小鼠中性粒细胞中 TLR4 诱导的组蛋白过度瓜氨酸化的介体， TBI 后 NET 的形成和神经损伤。具体目标 3 将检验以下假设： NETs 可改善 TBI 后的神经血管功能。概念验证研究将证明有针对性的 NET 的降解可防止脑微血栓形成，从而改善脑再循环并减少 TBI 后的水肿。这些发现将为重组体的临床再利用提供依据人 DNase I (rhDNase1)，一种安全的、经 FDA 批准的治疗药物，广泛用于非神经系统疾病的临床治疗疾病，在急性 TBI 患者的治疗中。拟议研究的预期成果包括确定 NETs 是 TBI 后急性脑血管功能障碍的关键引发因素。此外为急性损伤后中性粒细胞的有害影响提供机制解释，我们的研究将建立一个关键框架来开发靶向治疗以改善 TBI 的结果。。

项目成果

期刊论文数量（7）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

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
影响因子：
0
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.