Neutrophil extracellular traps in cystic fibrosis

囊性纤维化中的中性粒细胞胞外陷阱

基本信息

批准号：
9898433
负责人：
Balazs Rada
金额：
$ 63.89万
依托单位：
UNIVERSITY OF GEORGIA
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：
2018-01-01 至 2021-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9898433
关键词：
Address Adolescent Affect Airway Disease Animal Model Apoptosis Attenuated Bacteria Bacterial Infections Biology Cells Chronic Clinical Complex Cross-Sectional Studies Cystic Fibrosis Cystic Fibrosis Transmembrane Conductance Regulator Cystic Fibrosis sputum Cytoplasmic Granules DNA Data Development Disease Enzymes Flagellin Future Goals Growth Histones Human In Vitro Infection Infiltration Inflammation Inflammation Mediators Internet Intervention Knowledge Laboratories Lead Leukocyte Elastase Leukocytes Link Lung Lung diseases Mediating Microbe Microbial Biofilms Mission Morbidity - disease rate Mus Nature Necrosis Outcome Pathogenesis Pathology Patients Peroxidases Phagocytes Phagocytosis Pharmacologic Substance Preventive Process Prospective Studies Protein-arginine deiminase Pseudomonas aeruginosa Pseudomonas aeruginosa infection Public Health Pulmonary Cystic Fibrosis Pulmonary Pathology Research Respiratory physiology Role Sampling Severity of illness Specimen Testing Therapeutic Therapeutic Intervention Tissues United States National Institutes of Health Work adolescent patient airway inflammation base candidate marker cell motility clinically relevant cohort cystic fibrosis airway cystic fibrosis patients design epithelial Na+ channel extracellular fighting functional decline host-microbe interactions human disease improved in vivo inflammatory marker inhibitor/antagonist innovation lung injury microbial mortality mouse model neglect neutrophil novel overexpression pathogen respiratory scaffold targeted treatment tool

项目摘要

Cystic fibrosis (CF) is still an incurable disease affecting 80,000 people worldwide. Current lack of new CF therapies is due to our 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 (PMN). PMNs 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 is disadvantageous for the host in CF: NETs cause lung damage without improving microbial clearance. This hypothesis has been formulated based on strong preliminary data produced in the applicant’s laboratory. The rationale for the proposed research is that, once the mechanism and clinical relevance of NET formation in CF will be clear, interfering with it will enable development of innovative PMN/NET-based CF therapies. The central hypothesis will be tested by 1) Determining the complex mechanisms between P. aeruginosa and PMNs/NETs; 2) Determining how NET formation affects pathology and infection in murine models of CF airway disease; and 3) Strengthening the clinical relevance of NETs in CF airway disease using unique CF clinical specimens. This research is innovative because it addresses an understudied but clinically very relevant component of CF airway disease, uses novel tools uniquely developed by the applicant laboratories to quantitate NETs, and employs mouse models that enable a unique mechanistic understanding of the studied process. The proposed research is significant because it focuses on a clinically relevant, unsolved question in CF by using primary human cells, CF clinical samples and animal models. In summary, our proposal will deliver essential knowledge to provide a major impact in the fields of CF airway inflammation, host-microbe interactions and PMN biology. This knowledge can also lead to several potential translational applications.

囊性纤维化（CF）仍然是一种无法治愈的疾病，影响了全球80,000人。当前缺乏新的CF疗法是由于我们对疾病发病机理的不良理解。肺并发症导致大多数CF死亡率。 CF气道的特征是慢性细菌感染和称为嗜中性粒细胞粒细胞的白细胞的稳健浸润（PMN）。 PMN释放其颗粒货物和DNA导致肺部损伤。虽然释放中性粒细胞衍生的炎症介质在CF中具有很高的临床相关性，其机制为未知。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。这个特定的目标应用是确定中性粒细胞外陷阱的机制和临床相关性（NET）在CF中释放。中心假设是净形成对 CF中的宿主：网中造成肺损伤，而不会改善微生物清除率。这个假设已根据申请人实验室中产生的强大初步数据制定。拟议研究的理由是，一旦一旦机制和临床相关性 CF中的净形成将是清晰的，干扰它将能够开发创新 PMN/基于网络的CF疗法。中央假设将通过1）确定铜绿假单胞菌和PMN/网络之间的复杂机制； 2）确定如何净形成会影响CF气道疾病的鼠模型中的病理和感染； 3）使用独特的CF临床来增强CF气道疾病中网的临床相关性标本。这项研究具有创新性，因为它解决了一种理解，但在临床上非常非常 CF气道疾病的相关组成部分，使用申请人独特开发的新颖工具实验室定量网和员工鼠标模型，以实现独特的机制了解研究案过程。拟议的研究很重要，因为它重点在CF中使用原代人细胞中，CF临床上的临床相关，未解决的问题样品和动物模型。总而言之，我们的建议将为在CF气道注入，宿主 - 微杆相互作用和 PMN生物学。这些知识还可以导致几种潜在的翻译应用。