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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：
10078969
负责人：
Balazs Rada
金额：
$ 63.25万
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 2022-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10078969
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 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 pulmonary function pulmonary function decline respiratory pathogen 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)仍然是一种不治之症，影响着全球8万人。当前的不足新的CF疗法的出现是由于我们对疾病的发病机制缺乏了解。肺并发症是导致大多数CF死亡的原因。Cf航空公司的特点是慢性细菌感染和称为中性粒细胞的白细胞的强烈渗透 (PMN)。中性粒细胞释放颗粒、货物和DNA，造成肺损伤。虽然发布了中性粒细胞来源的炎症介质在CF中具有很高的临床相关性，其机制是未知。该项目的长期目标是确定中性粒细胞出于预防和治疗的目的，在CF中进行处理。这一特殊事件的目标是应用于确定中性粒细胞胞外TRAP的机制和临床意义 (净)在配置文件中发布。中心假设是，净形成不利于 CF：蚊帐中的宿主会导致肺损伤，但不会改善微生物的清除情况。这一假设是基于申请人实验室提供的强有力的初步数据而制定的。这项拟议研究的基本原理是，一旦研究的机制和临床相关性在CF中形成的网络将是清晰的，干扰它将使创新的发展成为可能以PMN/Net为基础的CF治疗。检验中心假设的方法是：1)确定铜绿假单胞菌和PMN/Net之间的复杂机制；2)确定如何形成影响慢性支气管炎小鼠模型的病理和感染；利用独特的慢性支气管炎临床应用加强NETS在慢性支气管炎呼吸道疾病中的临床相关性标本。这项研究具有创新性，因为它解决了一个研究不足但临床上非常重要的问题 CF呼吸道疾病的相关组件，使用申请人独家开发的新工具实验室对网络进行量化，并采用能够实现独特机制的老鼠模型对研究过程的理解。这项拟议的研究具有重要意义，因为它聚焦于关于利用原代人体细胞治疗慢性萎缩性胃炎的临床相关未解问题样本和动物模型。总而言之，我们的建议将向在慢性支气管炎、宿主-微生物相互作用和 PMN生物学。这一知识还可能导致几种潜在的翻译应用。