title: Disease phenotype of a ferret CFTR-knockout model of cystic fibrosis.
abstract: Cystic fibrosis (CF) is a recessive disease that affects multiple organs. It is caused by mutations in CFTR. Animal modeling of this disease has been challenging, with species- and strain-specific differences in organ biology and CFTR function influencing the emergence of disease pathology. Here, we report the phenotype of a CFTR-knockout ferret model of CF. Neonatal CFTR-knockout ferrets demonstrated many of the characteristics of human CF disease, including defective airway chloride transport and submucosal gland fluid secretion; variably penetrant meconium ileus (MI); pancreatic, liver, and vas deferens disease; and a predisposition to lung infection in the early postnatal period. Severe malabsorption by the gastrointestinal (GI) tract was the primary cause of death in CFTR-knockout kits that escaped MI. Elevated liver function tests in CFTR-knockout kits were corrected by oral administration of ursodeoxycholic acid, and the addition of an oral proton-pump inhibitor improved weight gain and survival. To overcome the limitations imposed by the severe intestinal phenotype, we cloned 4 gut-corrected transgenic CFTR-knockout kits that expressed ferret CFTR specifically in the intestine. One clone passed feces normally and demonstrated no detectable ferret CFTR expression in the lung or liver. The animals described in this study are likely to be useful tools for dissecting CF disease pathogenesis and developing treatments.
authors.affiliation: Department of Anatomy and Cell Biology, Carver College of Medicine, University of Iowa, Iowa City, Iowa 52242, USA.
authors.forename: Xingshen
authors.initials: X
authors.lastname: Sun
authors.forename: Hongshu
authors.initials: H
authors.lastname: Sui
authors.forename: John T
authors.initials: JT
authors.lastname: Fisher
authors.forename: Ziying
authors.initials: Z
authors.lastname: Yan
authors.forename: Xiaoming
authors.initials: X
authors.lastname: Liu
authors.forename: Hyung-Ju
authors.initials: HJ
authors.lastname: Cho
authors.forename: Nam Soo
authors.initials: NS
authors.lastname: Joo
authors.forename: Yulong
authors.initials: Y
authors.lastname: Zhang
authors.forename: Weihong
authors.initials: W
authors.lastname: Zhou
authors.forename: Yaling
authors.initials: Y
authors.lastname: Yi
authors.forename: Joann M
authors.initials: JM
authors.lastname: Kinyon
authors.forename: Diana C
authors.initials: DC
authors.lastname: Lei-Butters
authors.forename: Michelle A
authors.initials: MA
authors.lastname: Griffin
authors.forename: Paul
authors.initials: P
authors.lastname: Naumann
authors.forename: Meihui
authors.initials: M
authors.lastname: Luo
authors.forename: Jill
authors.initials: J
authors.lastname: Ascher
authors.forename: Kai
authors.initials: K
authors.lastname: Wang
authors.forename: Timothy
authors.initials: T
authors.lastname: Frana
authors.forename: Jeffrey J
authors.initials: JJ
authors.lastname: Wine
authors.forename: David K
authors.initials: DK
authors.lastname: Meyerholz
authors.forename: John F
authors.initials: JF
authors.lastname: Engelhardt
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D002478:Cells, Cultured; D003550:Cystic Fibrosis / Q000235:genetics* / Q000378:metabolism / Q000628:therapy; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000096:biosynthesis / Q000235:genetics* / Q000378:metabolism; D004195:Disease Models, Animal; D005289:Ferrets / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008168:Lung / Q000378:metabolism / Q000473:pathology; D008297:Male; D009154:Mutation; D010641:Phenotype; D012137:Respiratory System / Q000378:metabolism / Q000473:pathology; D014649:Vas Deferens / Q000378:metabolism / Q000473:pathology
chemical_list: D019005:Cystic Fibrosis Transmembrane Conductance Regulator