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: 9243523
• 负责人: Susan Elizabeth Birket
• 金额: $ 11.71万
• 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 2022-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9243523
• 关键词: Adherence; Adhesions; Age; Age-Months; 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; 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; 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; 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; clinically significant; cystic fibrosis airway; cystic fibrosis mouse; cystic fibrosis patients; experimental study; human disease; imaging modality; innovation; microbiome; mucoid; 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.

项目概要/摘要 粘膜纤毛清除异常 (MCC) 是囊性纤维化 (CF) 肺病的一个重要组成部分，尤其是在 是否存在感染；然而，造成该缺陷的机制尚不清楚。直到 最近，对这个问题的评估主要限于细胞培养模型，这些模型不能复制 气道表面的复杂性质或包括气道腺体的贡献。现有动物模型 CF 要么不能准确复制肺病理生理学（CF 小鼠），要么非常困难且昂贵 维持纵向研究以评估疾病进展（CF雪貂和猪）。这些挑战已经离开 CF 研究领域缺乏可轻松用于评估气道的动物模型 生理学或对肺部感染的反应。 最近，我帮助描述了我们机构开发的第一个 CF 大鼠的特征，它概括了许多 其特征与人类疾病高度相关，部分原因在于气道腺的表达。这是一个鲜明的特点 来自小鼠 CF 模型，并提供了一种非常适合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，我还拥有先进的微光学相干断层扫描 (μOCT)，一种高分辨率反射成像模式，可以同时、非侵入性地评估 气道水合作用、纤毛跳动和粘液运输以及原位粘度。使用这些工具，该提案将 研究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. CFTR 缺陷的纠正是否可以改善铜绿假单胞菌的易感性。 该提案将确定导致 CF 肺部疾病感染和进展的早期事件 以及这与气道腺体的形成和表达有何关系。这些研究将提供新的 基本观察结果将有助于我们了解 CF 呼吸病理学并帮助识别 适合干预的稳健治疗目标。结合独特的培训计划，重点关注 光学成像、粘液流变学和微生物组分析，这个培训期将使我能够 使用尖端技术研究粘膜纤毛清除障碍的独立科学事业。