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

基本信息

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
项目类别：
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

项目摘要

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，尤其是在感染的存在；但是，对缺陷负责的机制尚不清楚。直到最近，对这个问题的评估主要仅限于细胞培养模型，这些模型不复制气道表面的复杂性质或包括气道电网的贡献。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步（CF雪貂和猪）。这些挑战已经剩下 CF研究领域缺陷可访问的动物模型的缺陷，可容易用于评估气道生理或对肺部感染的反应。最近，我帮助表征了我们机构开发的第一只CF老鼠，该老鼠概括了许多与人类疾病高度相关的特征，部分归因于气道烤架的表达。这是一个独特的功能来自Murine CF模型，并提供了一种适合纵向评估和实验性的动物操纵。我最近还建立了一种慢性感染的CF大鼠的方法铜绿假单胞菌。为了补充这一点，我还具有先进的微光相干断层扫描（µOCT），一种高分辨率反射成像方式，可以轻松且无创地评估气道水合，睫状跳动以及粘液运输和粘度原位。使用这些工具，该建议将调查以下独立但免费的目的： 1。建立CF大鼠中粘膜纤毛异常清除的基础机制。 2。确定铜绿假单胞菌肺部感染的敏感性增加的机制在CF大鼠中。 3。确实校正CFTR缺陷可以改善铜绿假单胞菌的敏感性。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气道腺体的形成和表达之间的关系。研究将提供新的基本观察将为我们了解CF呼吸病理学的理解并帮助识别强大的理论目标适合干预。结合一个独特的培训计划光学成像，粘液流变学和微生物组分析，此训练期将使我适应独立的科学职业调查了使用尖端技术的粘膜钙清除率的疾病。

项目成果

期刊论文数量（1）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

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