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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：
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
项目类别：
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

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