Cystic fibrosis (CF) is a genetic disease caused by loss of cystic fibrosis transmembrane conductance regulator (CFTR). The disease involves many organs, and lung disease is the current major cause of morbidity and mortality. Gene transfer offers the potential to express CFTR in the lungs of patients and thereby slow or prevent disease progression. Yet despite outstanding research progress, we still lack answers to many crucial questions. A major impediment to progress has been the lack of an animal model that replicates disease typically found in humans. To circumvent limitations of current animal models, we have produced CFTR-/- and CFTRAF/- pigs. Newborn animals exhibit defective CI'transport and replicate abnormalities in newborn humans. Our preliminary data suggest that CFTR-/- pigs may also develop respiratory disease like humans. We will use this novel model to address questions key to CF.
Aim 1. Will intestinal expression of CFTR prevent meconium ileus in CFTRAF508/- pigs? To answer this question, we will generate CFTRAF508/- pigs carrying a transgene expressing CFTR in the intestine. The resulting animals may be of value to other projects in the program, and the results may shed light on the underlying pathogenesis of meconium ileus and distal intestinal obstruction syndrome.
Aim 2. Do genetic modifiers influence the clinical phenotype of CFTRAF508/AF508 pigs? We will cross our pigs to genetically diverse strains of pigs and ask how the CF phenotypes are altered. Discovering phenotypic changes could help identify pathways that modify the AF508 mutant protein or affect manifestations of the disease, thereby revealing novel therapeutic targets.
Aim 3. When is CFTR expression required to alter the CF phenotype? We will generate CFTRAF508 pigs that express CFTR under control of an inducible promoter to answer key questions. Will CFTR expression in utero prevent disease in newborns? Will epithelial CFTR expression that begins after birth prevent lung disease? Will CFTR expression treat or slow the progression of established ainway disease? The answers will serve as a benchmark to guide therapeutic strategies including gene transfer.

Public Health Relevance

Research in cystic fibrosis (CF) has been impeded by lack of an animal model that replicates the typical manifestations of the disease. Our Program recently developed a porcine model of CF. We will use this novel model to better understand CF and hopefully accelerate the discovery and testing of gene transfer and other novel preventions and treatments.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Program Projects (P01)
Project #
5P01HL051670-18
Application #
8310188
Study Section
Heart, Lung, and Blood Initial Review Group (HLBP)
Project Start
Project End
Budget Start
2011-08-01
Budget End
2012-07-31
Support Year
18
Fiscal Year
2011
Total Cost
$282,820
Indirect Cost
Name
University of Iowa
Department
Type
DUNS #
062761671
City
Iowa City
State
IA
Country
United States
Zip Code
52242
O'Malley, Yunxia; Rotti, Pavana G; Thornell, Ian M et al. (2018) Development of a polarized pancreatic ductular cell epithelium for physiological studies. J Appl Physiol (1985) 125:97-106
Rosen, Bradley H; Chanson, Marc; Gawenis, Lara R et al. (2018) Animal and model systems for studying cystic fibrosis. J Cyst Fibros 17:S28-S34
Meyerholz, David K; Sieren, Jessica C; Beck, Amanda P et al. (2018) Approaches to Evaluate Lung Inflammation in Translational Research. Vet Pathol 55:42-52
Rosen, Bradley H; Evans, T Idil Apak; Moll, Shashanna R et al. (2018) Infection Is Not Required for Mucoinflammatory Lung Disease in CFTR-Knockout Ferrets. Am J Respir Crit Care Med 197:1308-1318
Mao, Suifang; Shah, Alok S; Moninger, Thomas O et al. (2018) Motile cilia of human airway epithelia contain hedgehog signaling components that mediate noncanonical hedgehog signaling. Proc Natl Acad Sci U S A 115:1370-1375
Montoro, Daniel T; Haber, Adam L; Biton, Moshe et al. (2018) A revised airway epithelial hierarchy includes CFTR-expressing ionocytes. Nature 560:319-324
Lynch, Thomas J; Anderson, Preston J; Rotti, Pavana G et al. (2018) Submucosal Gland Myoepithelial Cells Are Reserve Stem Cells That Can Regenerate Mouse Tracheal Epithelium. Cell Stem Cell 22:653-667.e5
Meyerholz, David K; Stoltz, David A; Gansemer, Nick D et al. (2018) Lack of cystic fibrosis transmembrane conductance regulator disrupts fetal airway development in pigs. Lab Invest 98:825-838
Gray, Robert D; Hardisty, Gareth; Regan, Kate H et al. (2018) Delayed neutrophil apoptosis enhances NET formation in cystic fibrosis. Thorax 73:134-144
Thornell, Ian M; Li, Xiaopeng; Tang, Xiao Xiao et al. (2018) Nominal carbonic anhydrase activity minimizes airway-surface liquid pH changes during breathing. Physiol Rep 6:

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