Loss of the cystic fibrosis transmembrane conductance regulator (CFTR) causes lung disease that is themajor cause of morbidity and mortality in people with cystic fibrosis (CF). Yet despite outstanding progress inseveral areas of basic, translational and clinical research, we still do not know why do CF lungs becomecolonized with bacteria. On the basis of combined culture and serologic results, over 97% of patients withCF are infected with P. aeruginosa by the age of 3. Infection with P. aeruginosa is associated with pulmonaryfunction decline and early mortality. Most current research on P. aeruginosa in patients with CF focuses onchronic infection. Knowledge of the mechanisms that allow the initial colonization of the CF airways is limitedby the difficulty of clinical research, technical problems and ethical considerations. Although CF mice havebeen developed, during their limited lifespan they do not develop the airway disease typically found inhumans. A major impediment to studying airway colonization with bacteria is the lack of an animal model(non-murine) that replicates the lung disease in humans with CF. We generated pigs with disruption of theCFTR gene. We decided to study pigs because their lungs are very similar to humans. If the CFTR-null pigsare colonized with P. aeruginosa or any other bacteria, it will be an extremely exiting discovery. It willprovide an animal model that will allow investigators to fully describe mechanistically the pathogenesis of CFlung infections, in particular at the earliest period: the initial colonization of the CF airways. Our overarchinghypothesis is that lack of CFTR will result in bacterial airway colonization in pig airways. We propose 3specific aims.
Specific Aim 1 : CFTR null pigs are susceptible to bacteria and viral colonization.
This aim will be critical inestablishing how the CF lung and environmentally encountered microorganisms interact and lead to the CFphenotype. We will also determine whether CF pigs develop airway obstruction.
Specific Aim 2 : The airways of CFTR null pigs can be experimentally colonized by CF bacterial pathogens.Challenging the airways with bacteria that infect human CF lungs and with porcine respiratory bacterialpathogens will allow us to investigate the early pathogenesis of disease, elucidate the response to infection,and provide models for many future studies.
Specific Aim 3 : Lack of CFTR in pig results in abnormal mucociliary clearance, defective antimicrobialactivity, and/or altered phagocyte function of macrophages. We will investigate if CFTR plays a role in eachone of these antimicrobial mechanisms in pigs. We will investigate the ability of pig CF airways to cleanbacterial-sized particles, transport thiocyanate, generate hypothiocyanite, and the acidification ofphagosomes in both pig neutrophils and macrophages.
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