The Role of Airway Mucus in Infection and Inflammation

气道粘液在感染和炎症中的作用

基本信息

批准号：
10621783
负责人：
Susan Elizabeth Birket
金额：
$ 44.54万
依托单位：
UNIVERSITY OF ALABAMA AT BIRMINGHAM
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-06-01 至 2026-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10621783
关键词：
Ablation Acceleration Acute Age Age Months Agonist Airway Disease Airway Fibrosis Animal Model Appearance Bacteria Bacterial Infections Biological Models Bronchiectasis Characteristics Chronic Chronic Obstructive Pulmonary Disease Clinical Clinical Research Complementary DNA Cystic Fibrosis Cystic Fibrosis Transmembrane Conductance Regulator Data Defect Disease Environment Event Exhibits Exposure to FDA approved Genomics Genotype Gland Goals Human Hydration status Hyperviscosity Impairment In Situ Incidence Infection Inflammation Inflammatory Institution Interleukin-1 beta Interruption Intervention Laboratories Link Long-Term Effects Lung diseases Lung infections Modeling Mucins Mucociliary Clearance Mucous body substance Neutrophil Infiltration Obstruction Optical Coherence Tomography Pathology Patients Phenotype Population Predisposition Property Pseudomonas aeruginosa Pseudomonas aeruginosa infection Pulmonary Cystic Fibrosis Rattus Resolution Role Secondary to Staphylococcus aureus Staphylococcus aureus infection Submucosa Testing Toll-like receptors VX-770 Variant Virus Diseases Viscosity acute infection airway inflammation chronic infection cystic fibrosis airway cystic fibrosis patients cytokine imaging modality improved in vitro Model inflammatory marker innovation insight lung development muco-obstructive airway diseases mucus clearance neutrophil novel novel therapeutics overexpression pathogen patient population premature pulmonary function rat genome small molecule targeted treatment therapeutic development therapeutic target therapy resistant tool

项目摘要

Project Summary / Abstract Abnormal mucociliary clearance (MCC) is a critical component of cystic fibrosis (CF) lung disease, and is postulated to contribute to the high incidence of chronic pulmonary infections in this patient population; in turn the presence of chronic infection is thought to worsen the MCC defect, creating a cycle of mucus obstruction, infection, and inflammation that is difficult to interrupt or reverse. However, the mechanisms and interactions responsible for this phenomenon are not well understood. New animal models, such as the CF rat, developed at our institution, have been useful in identification of key factors that lead to chronic infection with the pathogen Pseudomonas aeruginosa in the CF airway. This animal model develops the MCC defect progressively, providing a model with which to study patients with early disease as well as late disease. In this model of CF, mucus must be abnormal before exposure to Pseudomonas aeruginosa to convert the infection to a chronic phenotype. CF rats exposed before the mucus abnormality develops are able to clear the infection. A new rat model harboring a humanized G551D-CFTR genomic insert respond to FDA-approved CFTR modulators that treat the fundamental defect of CF disease. Using the innovative Micro-Optical Coherence Tomography (µOCT), a high-resolution reflectance imaging modality that can simultaneously and non-invasively evaluate airway hydration, ciliary beating and mucus transport and viscosity in situ, we can analyze aspects of the mucus defect in both the CF rat model before and after infection, with or without CFTR modulators. Using these tools, this proposal will seek to investigate the mechanisms that cause patients with CF to transition acute infections into chronic ones, with the following independent but complimentary aims: 1. Determine if Muc5b is the specific component of mucus that promotes chronic Pseudomonas aeruginosa infection. 2. Determine if inflammation is necessary and sufficient to accelerate the mucus defect, predisposing the airway to chronic P. aeruginosa infection. 3. Determine if new highly effective CFTR modulators promote clearance of P. aeruginosa by normalizing abnormal mucus in the airway. This proposal will determine the early events that lead to infection and progression in CF pulmonary disease and how this relates to the conversion of P. aeruginosa from intermittent to chronic in this patient population, using a highly relevant animal model. The studies will provide new fundamental observations that will inform our understanding of the CF respiratory pathology and help identify robust therapeutic targets suitable for intervention.

项目概要/摘要粘液纤毛清除异常 (MCC) 是囊性纤维化 (CF) 肺病的一个重要组成部分，推测反过来又导致该患者群体中慢性肺部感染的高发病率；慢性感染的存在被认为会加重 MCC 缺陷，形成粘液阻塞的循环，然而，感染和炎症的机制和相互作用是难以中断或逆转的。造成这种现象的原因尚不清楚，例如 CF 大鼠等新动物模型的开发。在我们的机构，有助于确定导致慢性感染的关键因素 CF 气道中的病原体铜绿假单胞菌该动物模型出现 MCC 缺陷。逐步提供一个模型来研究早期疾病和晚期疾病的患者。 CF模型，在接触铜绿假单胞菌以转化感染之前，粘液必须异常在出现粘液异常之前暴露于慢性表型的CF大鼠能够清除粘液异常。一种携带人源化 G551D-CFTR 基因组插入片段的新大鼠模型对 FDA 批准的感染有反应。 CFTR 调节器利用创新的微光学治疗 CF 疾病的根本缺陷。相干断层扫描 (µOCT)，一种高分辨率反射成像模式，可以同时和非侵入性地评估气道水合作用、纤毛跳动以及粘液输送和原位粘度，我们可以分析 CF 大鼠模型感染前后（有或没有 CFTR）粘液缺陷的各个方面该提案将利用这些工具来研究导致患者出现这种症状的机制。 CF 将急性感染转变为慢性感染，具有以下独立但互补的目标： 1. 确定Muc5b是否是促进慢性铜绿假单胞菌感染的粘液特定成分感染。 2. 确定炎症是否必要且足以加速粘液缺陷，从而诱发慢性铜绿假单胞菌感染的气道。 3. 确定新的高效 CFTR 调节剂是否通过标准化促进铜绿假单胞菌的清除气道中有异常粘液。该提案将确定导致 CF 肺部疾病感染和进展的早期事件以及这与该患者群体中铜绿假单胞菌从间歇性到慢性的转变有何关系，使用高度相关的动物模型，这些研究将提供新的基本观察结果，为我们提供信息。我们对 CF 呼吸病理学的了解，有助于确定适合的稳健治疗靶点干涉。