Cystic fibrosis (CF) airway disease begins during infancy. With the advent of universal newborn CF screening, there is an opportunity to intervene early to prevent the airway disease that ultimately destroys the lungs. However, to forestall CF airway disease, we must understand its initiation and progression. It is known that CF patients manifest a defect in airway host defense. One important component of host defense is mucociliary transport (MCT), the removal of particulates and pathogens from airways. It is widely assumed that impaired MCT causes CF lung disease. That assumption derives primarily from the fact that MCT is defective when disease is advanced. However by that time, bronchiectasis could be responsible. Unfortunately, current tests of MCT have limited sensitivity and often fail to detect defects, even in CF adults. Lack of a model has prevented elucidation of pathogenic mechanisms. Our long-term goal is to understand the causes of CF airway disease and use that knowledge to prevent and treat disease. The objective of this proposal is to learn how CF alters MCT and discover the responsible mechanisms. To achieve that objective, we will study a novel porcine model of CF that closely parallels the human disease, and we will answer three general questions.
Aim 1. Does loss of CFTR alter MCT in newborn pigs? We will focus on MCT in vivo at the genesis of disease. We have exciting preliminary data using a new in vivo MCT assay and interrogation of discrete particles. We predict that stimulating mucus secretion will reveal striking MCT heterogeneity in CF pigs, with some particles moving fast, some slow and some not moving at all.
Aim 2. Does the development of CF airway disease impair MCT in vivo? CF is not a static disease. Once it begins in neonates, inflammation, viral and bacterial infections, and airway wall remodeling accelerate disease. We will be able to learn for the first time how MCT changes with time and how those factors alter MCT in vivo.
Aim 3. What factors alter MCT in CF? To identify factors that disrupt MCT, we developed a novel ex vivo approach using freshly excised airways. Our intriguing preliminary data reveal that CF disrupts release of mucus from the airway surface. Our working hypothesis is that a reduced pH and/or HCO3"""""""" concentration in airway surface liquid impair the normal behavior of airway mucus.
This research will allow us to better understand how CF disrupts the MCT defense system at the commencement of disease, teach us how it changes as disease progresses, and identify factors that cause abnormalities. The results will provide new insights into both CF pathogenesis and pathophysiology and thereby accelerate discovery of novel therapies for this lethal disease.
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