The Role of Airway Mucus in Infection and Inflammation

气道粘液在感染和炎症中的作用

• 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
• 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

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.

项目摘要 /摘要 异常粘膜缩减清除率（MCC）是囊性纤维化（CF）肺部疾病的关键组成部分，IS 发表是为了导致该患者人群中慢性肺部感染的高事件；反过来 慢性感染的存在被认为会担心MCC缺陷，从而产生粘液阻塞的循环， 感染和很难中断或逆转的感染。但是，机制和互动 对此现象负责。新动物模型，例如CF大鼠，开发了 在我们的机构中​​，对识别导致长期感染的关键因素很有用 CF气道中的病原体铜绿假单胞菌。这种动物模型发展了MCC缺陷 逐步提供了一种研究早期疾病和晚期疾病患者的模型。在这个 CF模型，粘液在暴露于铜绿假单胞菌之前必须是异常的 在粘液异常发展之前暴露的CF大鼠能够清除 感染。带有人源化G551D-CFTR基因组插入物的新大鼠模型对FDA批准 CFTR调节剂可治疗CF疾病的基本缺陷。使用创新的微光学 相干断层扫描（µOCT），一种高分辨率的反射成像方式，很容易，并且 非侵入性评估的气道水合，睫状跳动以及粘液运输和粘度原位，我们可以 分析感染前后CF大鼠模型中粘液缺陷的各个方面，有或没有CFTR 调节器。使用这些工具，该建议将寻求调查导致患者的机制 CF将急性感染转化为慢性感染，具有以下独立但免费的目的： 1。确定MUC5B是否是促进慢性假单胞菌的粘液的特定成分 感染。 2。确定感染是否需要且足以加速粘液缺陷，使人倾向于 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 气道异常粘液。 该建议将确定导致CF肺部疾病感染和进展的早期事件 以及这与铜绿假单胞菌在该患者人群中的间歇性转化为慢性的关系， 使用高度相关的动物模型。这些研究将提供新的基本观察，以告知 我们对CF呼吸病理学的理解，并有助于确定适合 干涉。