TY - JOUR
T1 - Characterization of defects in ion transport and tissue development in Cystic Fibrosis Transmembrane Conductance Regulator (CFTR)-knockout rats
AU - Tuggle, Katherine L.
AU - Birket, Susan E.
AU - Cui, Xiaoxia
AU - Hong, Jeong
AU - Warren, Joe
AU - Reid, Lara
AU - Chambers, Andre
AU - Ji, Diana
AU - Gamber, Kevin
AU - Chu, Kengyeh K.
AU - Tearney, Guillermo
AU - Tang, Li Ping
AU - Fortenberry, James A.
AU - Du, Ming
AU - Cadillac, Joan M.
AU - Bedwell, David M.
AU - Rowe, Steven M.
AU - Sorscher, Eric J.
AU - Fanucchi, Michelle V.
N1 - Funding Information:
The authors have read the journal’s policy and have the following conflicts: XC, JW, LR, AC, DJ and KG are full-time employees of SAGE Labs, Inc., which sells genetically engineered rats and provides custom model creation services. KKC, EJS, SMR, and GT have filed a patent application related to use of µOCT technology in airways. The application serial number is PCT/US12/52553, entitled “Method for functional investigation of respiratory airways and other ciliated tissues using µOCT,” filed August 27, 2012. No financial benefit has yet been derived from this application by any author. SMR receives research support from the NIH, the Cystic Fibrosis Foundation (CFF), the American Lung Association, Synedgen Inc., and Forest Research Institute for basic and translational research. SMR also receives support from CFF Therapeutics (CFFT), Vertex Pharmaceuticals, PTC Therapeutics, N30 Therapeutics, and Novartis to conduct clinical trials related to the treatment and control of cystic fibrosis. SMR receives unrestricted research support for consulting services to Novartis, Kala Pharmaceuticals, Celtaxys Inc., and Bayer Healthcare. SMR receives no personal income from any of the sponsors noted above. GT receives research support from iLumen, Ninepoint Medical, Merck Research Laboratories, Canon, Samsung, and Air Liquide Medical Gases. GT. receives personal income from Ninepoint Medical, Terumo Corporation, and MIT through patent licensing arrangements. GT also receives consulting income from Samsung Advanced Institute of Technology and Ninepoint Medical. EJS receives research support from NIH, CFF, and CFFT. EJS serves as a scientific consultant to Genzyme, Pfizer, and Gilead. He receives consulting income from Gilead. KLT, SEB, JSH, LPT, JAF, MD, JMC, DMB, and MVF have no conflicts of interest to disclose. These disclosures do not alter the authors’ adherence to all PLOS ONE policies with regard to sharing data and materials.
PY - 2014/3/7
Y1 - 2014/3/7
N2 - Animal models for cystic fibrosis (CF) have contributed significantly to our understanding of disease pathogenesis. Here we describe development and characterization of the first cystic fibrosis rat, in which the cystic fibrosis transmembrane conductance regulator gene (CFTR) was knocked out using a pair of zinc finger endonucleases (ZFN). The disrupted Cftr gene carries a 16 base pair deletion in exon 3, resulting in loss of CFTR protein expression. Breeding of heterozygous (CFTR+/-) rats resulted in Mendelian distribution of wild-type, heterozygous, and homozygous (CFTR-/-) pups. Nasal potential difference and transepithelial short circuit current measurements established a robust CF bioelectric phenotype, similar in many respects to that seen in CF patients. Young CFTR-/- rats exhibited histological abnormalities in the ileum and increased intracellular mucus in the proximal nasal septa. By six weeks of age, CFTR-/- males lacked the vas deferens bilaterally. Airway surface liquid and periciliary liquid depth were reduced, and submucosal gland size was abnormal in CFTR-/- animals. Use of ZFN based gene disruption successfully generated a CF animal model that recapitulates many aspects of human disease, and may be useful for modeling other CF genotypes, including CFTR processing defects, premature truncation alleles, and channel gating abnormalities.
AB - Animal models for cystic fibrosis (CF) have contributed significantly to our understanding of disease pathogenesis. Here we describe development and characterization of the first cystic fibrosis rat, in which the cystic fibrosis transmembrane conductance regulator gene (CFTR) was knocked out using a pair of zinc finger endonucleases (ZFN). The disrupted Cftr gene carries a 16 base pair deletion in exon 3, resulting in loss of CFTR protein expression. Breeding of heterozygous (CFTR+/-) rats resulted in Mendelian distribution of wild-type, heterozygous, and homozygous (CFTR-/-) pups. Nasal potential difference and transepithelial short circuit current measurements established a robust CF bioelectric phenotype, similar in many respects to that seen in CF patients. Young CFTR-/- rats exhibited histological abnormalities in the ileum and increased intracellular mucus in the proximal nasal septa. By six weeks of age, CFTR-/- males lacked the vas deferens bilaterally. Airway surface liquid and periciliary liquid depth were reduced, and submucosal gland size was abnormal in CFTR-/- animals. Use of ZFN based gene disruption successfully generated a CF animal model that recapitulates many aspects of human disease, and may be useful for modeling other CF genotypes, including CFTR processing defects, premature truncation alleles, and channel gating abnormalities.
UR - http://www.scopus.com/inward/record.url?scp=84897426911&partnerID=8YFLogxK
U2 - 10.1371/journal.pone.0091253
DO - 10.1371/journal.pone.0091253
M3 - Article
C2 - 24608905
AN - SCOPUS:84897426911
VL - 9
JO - PLoS ONE
JF - PLoS ONE
SN - 1932-6203
IS - 3
M1 - e91253
ER -