Twenty-eight years after the discovery of the CFTR gene, the causes of cystic fibrosis (CF) airway disease remain controversial, we still lack answers to many critical questions, our therapies are inadequate, and CF remains a life limiting and too often lethal disease. A major impediment to progress has been lack of CF animal models with a lung disease phenotype resembling humans with CF. We developed pigs with targeted alterations of the CFTR gene. CF pigs spontaneously develop the hallmark features of CF lung disease, including airway infection, inflammation, airway wall remodeling, mucus accumulation, and airway obstruction. Within hours of birth, CF pigs fail to eradicate bacteria as effectively as wild-type pigs. At least two host defense defects, reduced antimicrobial activity in airway surface liquid (ASL) and impaired mucociliary transport (MCT) contribute. Both were caused by abnormally acidic airway liquid. In this Program three highly accomplished investigators will use CF pigs to answer fundamental questions about CF lung disease. Together, the three projects will discover how loss of CFTR function affects: a) submucosal gland function, the properties of mucus, and MCT; b) ASL pH and proton secretion via ATP12A; and, c) small airways function, a likely site of CF disease pathogenesis. The Project Leaders and their teams have an outstanding track record of collaborative CF research, and here they sharpen their focus to a common goal. Their highly creative research is supported by five cores that provide innovative infrastructure and services. By further educating CF pathogenesis, it will accelerate discovery of novel therapies for this lethal disease.

Public Health Relevance

Cystic fibrosis is a common life-shortening genetic disease that causes progressive lung failure due to recurrent infections and airway obstruction. These studies will use a cystic fibrosis animal model to investigate the origins of cystic fibrosis airway disease in hopes of accelerating development of new therapeutics for early lung disease.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Program Projects (P01)
Project #
5P01HL091842-13
Application #
9985154
Study Section
Heart, Lung, and Blood Initial Review Group (HLBP)
Program Officer
Lachowicz-Scroggins, Marrah Elizabeth
Project Start
2008-09-05
Project End
2023-06-30
Budget Start
2020-07-01
Budget End
2021-06-30
Support Year
13
Fiscal Year
2020
Total Cost
Indirect Cost
Name
University of Iowa
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
062761671
City
Iowa City
State
IA
Country
United States
Zip Code
52242
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Meyerholz, David K; Ofori-Amanfo, Georgina K; Leidinger, Mariah R et al. (2017) Immunohistochemical Markers for Prospective Studies in Neurofibromatosis-1 Porcine Models. J Histochem Cytochem 65:607-618
Li, Xiaopeng; Vargas Buonfiglio, Luis G; Adam, Ryan J et al. (2017) Cystic Fibrosis Transmembrane Conductance Regulator Potentiation as a Therapeutic Strategy for Pulmonary Edema: A Proof-of-Concept Study in Pigs. Crit Care Med 45:e1240-e1246

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