Neutrophil Extracellular Traps in Cystic Fibrosis

囊性纤维化中的中性粒细胞胞外陷阱

• 批准号: 9324418
• 负责人: Balazs Rada
• 金额: $ 37.97万
• 依托单位: UNIVERSITY OF GEORGIA
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-01 至 2018-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9324418
• 关键词: Affect; Antibodies; Autoantibodies; Autoimmune Process; Bacteria; Bacterial Infections; Blocking Antibodies; Blood; Cells; Chronic; Clinical; Correlation Studies; Cystic Fibrosis; Cytoplasmic Granules; DNA; Data; Disease; Environment; Flagella; Functional disorder; Future; Genes; Goals; Histones; Homing; Human; In Vitro; Infiltration; Inflammation Mediators; Inflammatory; Interleukin-1 beta; Internet; Knowledge; Laboratories; Leukocyte Elastase; Leukocytes; Link; Lung; Lung diseases; Measures; Mediating; Mission; Molecular; Mus; Outcome; Pathogenesis; Peroxidases; Ploidies; Preventive; Protein-arginine deiminase; Pseudomonas; Pseudomonas aeruginosa; Public Health; Publishing; Pulmonary Cystic Fibrosis; Recruitment Activity; Research; Respiratory physiology; Sampling; Severity of illness; Signal Transduction; System; TLR5 gene; Testing; Therapeutic; Tissues; United States National Institutes of Health; Work; airway inflammation; base; bench to bedside; candidate marker; cell motility; citrullinated protein; clinically relevant; cystic fibrosis airway; cystic fibrosis patients; cytokine; design; extracellular; fighting; flagellum motility; granulocyte; human disease; innovation; mortality; neutrophil; novel; novel marker; novel strategies; receptor; tool

Cystic fibrosis (CF) is still an incurable disease affecting 70,000 people worldwide. Lack of new CF therapies is due to poor understanding of disease pathogenesis. Lung complications are responsible for majority of CF mortality. CF airways are characterized by chronic bacterial infections and robust infiltration of leukocytes called neutrophil granulocytes. Neutrophils release their granule cargo and DNA to cause lung damage. Although release of neutrophil-derived inflammatory mediators is of high clinical relevance in CF, its mechanism is unknown. The long-term goal of this project is to determine how neutrophils could be manipulated in CF for preventive and therapeutic purposes. The objective in this particular application is to determine the mechanism and clinical relevance of neutrophil extracellular trap (NET) release in CF. The central hypothesis is that NET formation in CF is mainly triggered by P. aeruginosa flagellar motility, enhanced by the airway inflammatory environment and is associated with clinical measures of lung disease. This hypothesis has been formulated based on strong preliminary data produced in the applicant's laboratory. NETs are composed of a DNA web decorated with histones and granule components. The rationale for the proposed research is that, once the mechanism and clinical importance of Pseudomonas-triggered NET formation will be clear, interfering with it will offer a novel approach to develop innovative new CF therapies. This hypothesis will be tested by pursuing the following specific aims: 1) Establish the clinical relevance of NETs in CF airway disease, 2) dissect the mechanism of P. aeruginosa-triggered NET release, and 3) determine the effect of the CF airway inflammatory environment on NET formation. Based on our preliminary data showing clinical relevance of NETs in CF, in the first aim, correlation studies will be performed between neutrophil markers and measures of CF lung disease severity using CF clinical samples. These data will reveal whether NETs can predict CF lung function decline or are linked to CF pulmonary exacerbations. In the second aim, we will identify the mechanism of P. aeruginosa-stimulated NET formation. In the third aim, we will determine the mechanism how inflammatory molecules present in CF affect NET formation. This research is innovative because it uses novel tools developed by the applicant laboratories to quantitate NETs, it detected several novel NET-related markers in CF clinical samples, it suggests that CF has a significant autoimmune component, and it has the potential to identify new CF biomarker candidates. The proposed research is significant because it focuses on a clinically relevant, unsolved question of CF by using primary human cells and CF clinical samples. In summary, our proposal will deliver essential data to provide a major impact on the field of CF airway inflammation and to be able to design better CF therapies.

囊性纤维化（CF）仍然是一种无法治愈的疾病，影响了全球70,000人。缺乏新的CF疗法是 由于对疾病发病机理的了解不足。肺并发症是大多数CF的原因 死亡。 CF气道的特征是慢性细菌感染和白细胞的稳健浸润 称为中性粒细胞粒细胞。中性粒细胞释放其颗粒货物和DNA导致肺损伤。 尽管中性粒细胞衍生的炎症介质的释放在CF中具有很高的临床相关性，但 机制是未知的。该项目的长期目标是确定中性粒细胞如何 在CF中操纵以进行预防和治疗目的。此特定应用中的目的是 确定中性粒细胞外陷阱（净）释放的机制和临床相关性。这 中心假设是CF中的净形成主要是由铜绿假单胞菌鞭毛运动触发的，增强了 通过气道炎症环境，与肺部疾病的临床指标有关。这 基于申请人实验室中产生的强有初步数据提出了假设。网 由用组蛋白和颗粒组件装饰的DNA网络组成。提议的理由 研究是，一旦假单胞菌触发的净形成的机制和临床重要性将是 清晰，干扰它将提供一种新颖的方法来开发创新的新CF疗法。这个假设将会 通过追求以下特定目的进行测试：1）在CF气道中建立网络的临床相关性 疾病，2）剖析铜绿假单胞菌触发的净释放的机制，3）确定 CF气道炎症环境净形成。根据我们的初步数据显示临床 在第一个目的中，网络在CF中的相关性将在中性粒细胞标记和 使用CF临床样本的CF肺疾病严重程度的度量。这些数据将揭示网是否可以 预测CF肺功能下降或与CF肺部恶化有关。在第二个目标中，我们将 确定铜绿假单胞菌刺激的净形成的机制。在第三个目标中，我们将确定 机理CF中存在的炎症分子如何影响净形成。这项研究是创新的 因为它使用申请人实验室开发的新颖工具来定量网络，所以它检测到了几个 CF临床样品中的新型网络相关标记，这表明CF具有明显的自身免疫性 组件，它有可能识别新的CF生物标志物候选者。拟议的研究是 意义重大，因为它通过使用原代人类细胞着重于CF的临床相关，未解决的问题 和CF临床样品。总而言之，我们的建议将提供基本数据，以对 CF气道炎症领域，并能够设计更好的CF疗法。