The Mechanisms Underlying Abnormal Mucus and its Clearance in the Cystic Fibrosis Rat

囊性纤维化大鼠异常粘液及其清除的机制

• 批准号: 10117036
• 负责人: Susan Elizabeth Birket
• 金额: $ 13.58万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-02-01 至 2023-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10117036
• 关键词: Adherence; Adhesions; Age; Age-Months; Airway Disease; Animal Model; Animals; Bicarbonates; Biochemical; Bronchi; Cell Culture Techniques; Chemosensitization; Chronic; Clinical; Clinical Trials; Complement; Complex; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Defect; Development; Disease; Evaluation; Event; Exhibits; Exposure to; Family suidae; Ferrets; Functional disorder; Gland; Glues; Host Defense; Human; Hydration status; In Situ; Incidence; Infection; Institution; Intervention; Ion Transport; Lead; Left; Link; Longitudinal Studies; Lung; Lung diseases; Lung infections; Methods; Modeling; Molecular; Mucins; Mucociliary Clearance; Mucous body substance; Mus; Mutation; Nature; Neonatal; Optical Coherence Tomography; Organism; Pathogenicity; Pathology; Patients; Pharmaceutical Preparations; Physiology; Positioning Attribute; Predisposition; Property; Pseudomonas aeruginosa; Pseudomonas aeruginosa infection; Pulmonary Cystic Fibrosis; Pulmonary Fibrosis; Rattus; Research; Resolution; Rheology; Role; Secondary to; Staphylococcus aureus; Surface; Techniques; Testing; Time; Trachea; Training; Training Programs; Viscosity; age related; airway epithelium; biophysical properties; career; chronic infection; clinically significant; cystic fibrosis airway; cystic fibrosis infection; cystic fibrosis mouse; cystic fibrosis mucus; cystic fibrosis patients; experimental study; human disease; imaging modality; innovation; microbiome analysis; mucoid; mucus clearance; novel; optical imaging; pathogen; pathogenic bacteria; pulmonary function; respiratory; response; therapeutic target; tool

Project Summary / Abstract Abnormal mucociliary clearance (MCC) is a critical component of cystic fibrosis (CF) lung disease, especially in the presence of infection; however, the mechanisms responsible for the defect are not well understood. Until recently, evaluation of this question has been primarily limited to cell culture models which do not replicate the complex nature of the airway surface or include contributions of the airway glands. Existing animal models of CF either do not accurately replicate lung pathophysiology (CF mice) or are very difficult and expensive to maintain for longitudinal studies to evaluate disease progress (CF ferret and pig). These challenges have left the CF research field deficient of an accessible animal model that can be readily used to evaluate airway physiology or response to pulmonary infection. Recently, I helped characterize the first CF rat, developed at our institution, which recapitulates a number of features highly relevant to human disease, due in part to expression of airway glands. This is a feature distinct from murine CF models, and provides an animal well suited for longitudinal evaluation and experimental manipulations. I have also recently established a method to chronically infect CF rats with mucoid Pseudomonas aeruginosa. To complement this, I have also advanced 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. Using these tools, this proposal will investigate the following independent but complimentary aims: 1. Establish the mechanism underlying abnormal mucociliary clearance in the CF rat. 2. Determine the mechanisms underlying increased susceptibility to Pseudomonas aeruginosa lung infection in the CF rat. 3. Does correction of the CFTR defect ameliorate P. aeruginosa susceptibility. This proposal will determine the early events that lead to infection and progression in CF pulmonary disease and how this relates to the formation and expression of airway glands. 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. Combined with a unique training program focused on optical imaging, mucus rheology, and microbiome analysis, this training period will position me for an independent scientific career investigating disorders of mucociliary clearance using cutting edge techniques.

项目摘要/摘要 粘液纤毛清除异常(MCC)是囊性纤维化(CF)肺部疾病的重要组成部分，尤其是在 感染的存在；然而，造成这种缺陷的机制还不是很清楚。直到 最近，对这个问题的评估主要局限于细胞培养模型，不能复制 呼吸道表面的复杂性质或包括气道腺的贡献。现有的动物模型 Cf要么不能准确复制肺病理生理学(cf小鼠)，要么非常难以和昂贵地 用于纵向研究以评估疾病进展(CF雪貂和猪)。这些挑战已经离开 慢性阻塞性肺疾病研究领域缺乏易于使用的可用于评估呼吸道的动物模型 对肺部感染的生理或反应。 最近，我帮助确定了我们研究所培育的第一只CF大鼠的特征，它概括了许多 与人类疾病高度相关的特征，部分原因是气道腺的表达。这是一个独特的特征 提供了一种非常适合于纵向评估和实验的动物 操纵。我最近还建立了一种用粘液慢性感染CF大鼠的方法 铜绿假单胞菌。为了补充这一点，我还改进了显微光学相干层析成像技术 (µOCT)，一种可以同时非侵入性评估的高分辨率反射成像方式 呼吸道水化、纤毛搏动、粘液运输和粘液原位粘滞。使用这些工具，该提案将 调查以下独立但互补的目标： 1.建立CF大鼠粘液纤毛清除异常的机制。 2.确定铜绿假单胞菌肺部感染易感性增加的机制 在CF大鼠中。 3.纠正cftr缺陷可改善铜绿假单胞菌的敏感性。 这项建议将确定导致CF肺部疾病感染和进展的早期事件 以及这与呼吸道腺体的形成和表达有何关系。这些研究将提供新的 基本观察将有助于我们了解CF呼吸道病理，并有助于识别 适合干预的强有力的治疗目标。与独特的培训计划相结合，专注于 光学成像、粘液流变学和微生物组分析，这段培训期间我将为 使用尖端技术研究粘液纤毛清除障碍的独立科学生涯。

项目成果

Acute Infection with a Tobramycin-Induced Small Colony Variant of Staphylococcus aureus Causes Increased Inflammation in the Cystic Fibrosis Rat Lung.

妥布霉素诱导的金黄色葡萄球菌小菌落变种的急性感染会导致囊性纤维化大鼠肺部炎症增加。

• DOI: 10.1128/iai.00237-22
• 发表时间: 2022
• 期刊: Infection and immunity
• 影响因子: 3.1
• 作者: Bollar,GretchenE;Keith,JohnathanD;Oden,AshleyM;Kiedrowski,MeganR;Birket,SusanE
• 通讯作者: Birket,SusanE