Neutrophils in polytrauma – from recruitment to phenotypic and functional reprogramming

多发伤中的中性粒细胞 — 从招募到表型和功能重编程

• 批准号: 10656555
• 负责人: SOFIA DE OLIVEIRA
• 金额: $ 42万
• 依托单位: ALBERT EINSTEIN COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-07-01 至 2027-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10656555
• 关键词: Affect; Age; Animal Model; Animals; Cause of Death; Cessation of life; Chronic; Complex; Disease; Exhibits; Genetic; Goals; Health; Immune System Diseases; Impairment; Infection; Inflammation; Inflammatory; Inflammatory Response; Injury; Knowledge; Life; Lipids; Metabolic; Metabolic syndrome; Modeling; Molecular; Multiple Organ Failure; Multiple Trauma; Neutrophil Infiltration; Nosocomial Infections; Optics; Pathologic; Patient-Focused Outcomes; Patients; Persons; Phenotype; Play; Population; Predisposition; Process; Proteins; Public Health; Recovery; Research; Role; Sepsis; Site; Time; Tissues; Transcript; Trauma; Traumatic injury; Visualization; Work; Zebrafish; disability; epigenetic profiling; fighting; genetic manipulation; high risk; high risk population; imaging approach; improved; migration; mortality; neutrophil; pharmacologic; recruit; response; systemic inflammatory response

Abstract: My long-term goal is to determine the mechanisms that regulate neutrophil response in health and disease and how they are altered by the presence of chronic low-grade systemic inflammation. Traumatic injuries are a leading cause of death and disability in younger people being a major public health problem worldwide. Neutrophils are known for their fast and moldable inflammatory response upon injury, which are massively recruited after trauma. Neutrophils play a crucial pathological role in the complex systemic inflammatory response that leads to life-threaten situations. Patients with chronic low-grade systemic "metabolic" inflammation display a dysregulated neutrophil response and function. Consequently, these patients are at high risk of developing serious complications and exhibit a high mortality rate after trauma. Knowledge of how metainflammation impacts neutrophil response in polytrauma is limited, particularly in what concerns the regulatory mechanisms that coordinate and direct neutrophil recruitment to sites of concurrent traumatic injuries. Trauma affects the phenotype and function of neutrophils, which impairs the neutrophil capacity to fight infections while at the same time promotes tissue damage phenotypes that contribute to the overall immune dysfunction. These alterations on neutrophil populations set the stage for secondary inflammatory complications such as sepsis, multiple organ failure (MOF), and nosocomial infections that delay recovery and can lead to disability or death. It is also unclear how traumatic injury sites reprogrammed neutrophils and if it is dependent of trauma localization, or the patient’s overall inflammatory status. In this MIRA application, we plan to investigate mechanisms involved in neutrophil phenotypic and functional modulation in polytrauma. We will take advantage of the remarkable zebrafish animal model known for its optical transparency and ease of genetic and pharmacological manipulation to visualize, track and deconvolute the molecular mechanism involved in the neutrophil response in polytrauma at a whole-animal context. We will combine our zebrafish polytrauma model and unique whole-animal non-invasive live imaging approach with genetic manipulation and protein, lipid, transcript, and epigenetic profiling of neutrophils and concurrent traumatic injury sites to evaluate 1) the regulatory mechanisms that coordinate neutrophil recruitment to concurrent traumatic injuries, 2) how neutrophils are reprogrammed at sites of traumatic injury to generate specific neutrophil subsets that reverse migrate and disseminate inflammation in trauma, and 3) how chronic inflammation impacts such processes. Our research will allow us to gain a deeper understanding of the neutrophil mechanisms involved in polytrauma inflammatory response in healthy and metainflammation settings. The knowledge achieved by the proposed research will enable us to manipulate neutrophil response as a means by which to improve patient outcomes following trauma, particularly in high-risk groups.

抽象的： 我的长期目标是确定调节健康和疾病中嗜中性粒细胞反应的机制以及 存在慢性低级全身炎症的情况如何改变它们。创伤是一个 年轻人的死亡和残疾主要原因是全球一个主要的公共卫生问题。 嗜中性粒细胞以其快速和可造的炎症反应而闻名，损伤大体 创伤后招募。中性粒细胞在复杂的全身炎症中起着至关重要的病理作用 导致威胁生命的情况的反应。慢性低度全身注射患者 显示失调的中性粒细胞反应和功能。因此，这些患者有高风险 产生严重的并发症并在创伤后表现出高死亡率。了解如何 元炎症会影响多发性嗜性嗜中性粒细胞的反应是有限的，特别是在涉及的情况下 调节机制，这些机制将中性粒细胞募集到并发创伤性损伤部位。 创伤会影响中性粒细胞的表型和功能，这会损害中性粒细胞的能力。 同时，促进组织损伤表型，导致整体免疫功能障碍。 这些对中性粒细胞种群的改变为二次炎症并发症（例如 败血症，多器官衰竭（MOF）和医院感染延迟恢复并可能导致残疾或 死亡。目前尚不清楚创伤部位如何重编程的中性粒细胞以及依赖创伤 本地化或患者的整体炎症状态。在此MIRA应用中，我们计划调查 涉及嗜中性粒细胞表型和功能调制的机制。我们将利用 斑马鱼动物模型以其光学透明度和遗传和易于性而闻名 可视化，跟踪和反应的药理学操纵 在整个动物环境中，多核中嗜中性粒细胞反应。我们将结合斑马鱼多曲霉模型 以及独特的全动物非侵入性实时成像方法，具有遗传操纵和蛋白质，脂质，脂质， 中性粒细胞和同时创伤部位的成绩单和表观遗传分析以评估1） 调节中性粒细胞募集到并发创伤损伤的调节机制，2）中性粒细胞如何 在创伤性损伤部位进行重编程，以产生逆向迁移和的特定中性粒细胞子集 在创伤中传播注射，3）慢性感染如何影响这种过程。我们的研究 将使我们能够更深入地了解中性粒细胞机制 在健康和元炎症设置中的响应。拟议的研究获得的知识将 使我们能够操纵嗜中性粒细胞反应，以此作为一种改善创伤后患者结果的手段， 特别是在高风险群体中。