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Science 321 (5897): 1837-1841

Copyright © 2008 by the American Association for the Advancement of Science

Disruption of the CFTR Gene Produces a Model of Cystic Fibrosis in Newborn Pigs

Christopher S. Rogers,1* David A. Stoltz,1* David K. Meyerholz,2* Lynda S. Ostedgaard,1 Tatiana Rokhlina,1 Peter J. Taft,1 Mark P. Rogan,1 Alejandro A. Pezzulo,1 Philip H. Karp,1,3 Omar A. Itani,1 Amanda C. Kabel,1 Christine L. Wohlford-Lenane,4 Greg J. Davis,1 Robert A. Hanfland,5 Tony L. Smith,5 Melissa Samuel,6 David Wax,6 Clifton N. Murphy,6 August Rieke,6 Kristin Whitworth,6 Aliye Uc,4 Timothy D. Starner,4 Kim A. Brogden,7 Joel Shilyansky,5 Paul B. McCray, Jr.,4 Joseph Zabner,1 Randall S. Prather,6 Michael J. Welsh1,3,8{dagger}

Abstract: Almost two decades after CFTR was identified as the gene responsible for cystic fibrosis (CF), we still lack answers to many questions about the pathogenesis of the disease, and it remains incurable. Mice with a disrupted CFTR gene have greatly facilitated CF studies, but the mutant mice do not develop the characteristic manifestations of human CF, including abnormalities of the pancreas, lung, intestine, liver, and other organs. Because pigs share many anatomical and physiological features with humans, we generated pigs with a targeted disruption of both CFTR alleles. Newborn pigs lacking CFTR exhibited defective chloride transport and developed meconium ileus, exocrine pancreatic destruction, and focal biliary cirrhosis, replicating abnormalities seen in newborn humans with CF. The pig model may provide opportunities to address persistent questions about CF pathogenesis and accelerate discovery of strategies for prevention and treatment.

1 Department of Internal Medicine, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA.
2 Department of Pathology, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA.
3 Howard Hughes Medical Institute (HHMI), Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA.
4 Department of Pediatrics, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA.
5 Department of Surgery, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA.
6 Division of Animal Sciences, University of Missouri, Columbia, MO 65211, USA.
7 Department of Periodontics and Dows Institute for Dental Research, College of Dentistry, University of Iowa, Iowa City, IA 52242, USA.
8 Department of Molecular Physiology and Biophysics, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA.

* These authors contributed equally to this work.

{dagger} To whom correspondence should be addressed. E-mail: michael-welsh{at}uiowa.edu

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