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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.

SUBMITTER: Sun X

PROVIDER: S-EPMC2929732 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Defective innate immunity and hyperinflammation in newborn cystic fibrosis transmembrane conductance regulator-knockout ferret lungs.

Project description:Mucociliary clearance (MCC) and submucosal glands are major components of airway innate immunity that have impaired function in cystic fibrosis (CF). Although both of these defense systems develop postnatally in the ferret, the lungs of newborn ferrets remain sterile in the presence of a functioning cystic fibrosis transmembrane conductance regulator gene. We evaluated several components of airway innate immunity and inflammation in the early CF ferret lung. At birth, the rates of MCC did not differ between CF and non-CF animals, but the height of the airway surface liquid was significantly reduced in CF newborn ferrets. CF ferrets had impaired MCC after 7 days of age, despite normal rates of ciliogenesis. Only non-CF ferrets eradicated Pseudomonas directly introduced into the lung after birth, whereas both genotypes could eradicate Staphylococcus. CF bronchoalveolar lavage fluid (BALF) had significantly lower antimicrobial activity selectively against Pseudomonas than non-CF BALF, which was insensitive to changes in pH and bicarbonate. Liquid chromatography-tandem mass spectrometry and cytokine analysis of BALF from sterile Caesarean-sectioned and nonsterile naturally born animals demonstrated CF-associated disturbances in IL-8, TNF-α, and IL-β, and pathways that control immunity and inflammation, including the complement system, macrophage functions, mammalian target of rapamycin signaling, and eukaryotic initiation factor 2 signaling. Interestingly, during the birth transition, IL-8 was selectively induced in CF BALF, despite no genotypic difference in bacterial load shortly after birth. These results suggest that newborn CF ferrets have defects in both innate immunity and inflammatory signaling that may be important in the early onset and progression of lung disease in these animals.

| S-EPMC4491130 | biostudies-literature

Pancreatic and Islet Remodeling in Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) Knockout Ferrets.

Project description:In cystic fibrosis (CF), there is early destruction of the exocrine pancreas, and this results in a unique form of diabetes that affects approximately half of adult CF individuals. An animal model of cystic fibrosis-related diabetes has been developed in the ferret, which progresses through phases of glycemic abnormalities because of islet remodeling during and after exocrine destruction. Herein, we quantified the pancreatic histopathological changes that occur during these phases. There was an increase in percentage ductal, fat, and islet area in CF ferrets over time compared with age-matched wild-type controls. We also quantified islet size, shape, islet cell composition, cell proliferation (Ki-67), and expression of remodeling markers (matrix metalloprotease-7, desmin, and ?-smooth muscle actin). Pancreatic ducts were dilated with scattered proliferating cells and were surrounded by activated stellate cells, indicative of tissue remodeling. The timing of islet and duct proliferation, stellate cell activation, and matrix remodeling coincided with the previously published stages of glycemic crisis and inflammation. This mapping of remodeling events in the CF ferret pancreas provides insights into early changes that control glycemic intolerance and subsequent recovery during the evolution of CF pancreatic disease.

| S-EPMC5963477 | biostudies-literature

Unraveling the CFTR Function-Phenotype Connection for Precision Treatment in Cystic Fibrosis.

Project description: Not available

| S-EPMC6515879 | biostudies-literature

In utero and postnatal VX-770 administration rescues multiorgan disease in a ferret model of cystic fibrosis.

Project description:Cystic fibrosis (CF) is a multiorgan disease caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR). In patients with CF, abnormalities initiate in several organs before birth. However, the long-term impact of these in utero pathologies on disease pathophysiology is unclear. To address this issue, we generated ferrets harboring a VX-770 (ivacaftor)-responsive CFTRG551D mutation. In utero VX-770 administration provided partial protection from developmental pathologies in the pancreas, intestine, and male reproductive tract. Homozygous CFTRG551D/G551D animals showed the greatest VX-770-mediated protection from these pathologies. Sustained postnatal VX-770 administration led to improved pancreatic exocrine function, glucose tolerance, growth and survival, and to reduced mucus accumulation and bacterial infections in the lung. VX-770 withdrawal at any age reestablished disease, with the most rapid onset of morbidity occurring when withdrawal was initiated during the first 2 weeks after birth. The results suggest that CFTR is important for establishing organ function early in life. Moreover, this ferret model provides proof of concept for in utero pharmacologic correction of genetic disease and offers opportunities for understanding CF pathogenesis and improving treatment.

| S-EPMC6489481 | biostudies-literature

Cystic Fibrosis, CFTR, and Colorectal Cancer.

Project description:Cystic fibrosis (CF), caused by biallelic inactivating mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene, has recently been categorized as a familial colorectal cancer (CRC) syndrome. CF patients are highly susceptible to early, aggressive colorectal tumor development. Endoscopic screening studies have revealed that by the age of forty 50% of CF patients will develop adenomas, with 25% developing aggressive advanced adenomas, some of which will have already advanced to adenocarcinomas. This enhanced risk has led to new CF colorectal cancer screening recommendations, lowering the initiation of endoscopic screening to age forty in CF patients, and to age thirty in organ transplant recipients. The enhanced risk for CRC also extends to the millions of people (more than 10 million in the US) who are heterozygous carriers of CFTR gene mutations. Further, lowered expression of CFTR is reported in sporadic CRC, where downregulation of CFTR is associated with poor survival. Mechanisms underlying the actions of CFTR as a tumor suppressor are not clearly understood. Dysregulation of Wnt/?-catenin signaling and disruption of intestinal stem cell homeostasis and intestinal barrier integrity, as well as intestinal dysbiosis, immune cell infiltration, stress responses, and intestinal inflammation have all been reported in human CF patients and in animal models. Notably, the development of new drug modalities to treat non-gastrointestinal pathologies in CF patients, especially pulmonary disease, offers hope that these drugs could be repurposed for gastrointestinal cancers.

| S-EPMC7215855 | biostudies-literature

Intestinal Phenotype of Variable Weight Cystic Fibrosis Knockout Mice

Project description:Cystic fibrosis transmembrane conductance regulator (Cftr) knockout mice present the clinical features of low body weight and intestinal disease permitting an assessment of the interrelatedness of these phenotypes in a controlled environment. To identify intestinal alterations which affect body weight in CF mice the histological phenotypes of crypt-villus axis height, goblet cell hyperplasia, and mast cell infiltrate were measured, cardiac blood samples assessed, and gene expression profiling of the ileum was completed for 12 week old (C57BL/6xBALB) F2 Cftrtm1UNC and non-CF mice presenting a range of body weight. Crypt-villus axis height decreased with increasing weight in CF, but not control, mice. Goblet cell hyperplasia and mast cell infiltration in the submucosa and muscularis externa layers of the CF intestine, were identified to be independent of bodyweight. Blood triglyceride levels were found to be significantly lower in CF mice than control mice (p = 3.02 x 10-5) but were not dependent on CF mouse body weight. By expression profiling, genes of DNA replication and lipid metabolism were among those altered in CF mice relative to non-CF controls; and no differences in gene expression were measured between samples from CF mice in the 25th and 75th percentile for weight. This study indicates that the absence of Cftr leads to altered morphology in the CF intestine the extent of which is correlated with body weight in CF mice while CF related changes in blood triglyceride levels and in the intestinal gene expression profile were not dependent on body weight in this model. Keywords: disease state analysis

2007-05-21 | GSE5715 | GEO

Urinary Exosomes of Patients with Cystic Fibrosis Unravel CFTR-Related Renal Disease.

Project description:Background: The prevalence of chronic kidney disease is increased in patients with cystic fibrosis (CF). The study of urinary exosomal proteins might provide insight into the pathophysiology of CF kidney disease. Methods: Urine samples were collected from 19 CF patients (among those 7 were treated by cystic fibrosis transmembrane conductance regulator (CFTR) modulators), and 8 healthy subjects. Urine exosomal protein content was determined by high resolution mass spectrometry. Results: A heatmap of the differentially expressed proteins in urinary exosomes showed a clear separation between control and CF patients. Seventeen proteins were upregulated in CF patients (including epidermal growth factor receptor (EGFR); proteasome subunit beta type-6, transglutaminases, caspase 14) and 118 were downregulated (including glutathione S-transferases, superoxide dismutase, klotho, endosomal sorting complex required for transport, and matrisome proteins). Gene set enrichment analysis revealed 20 gene sets upregulated and 74 downregulated. Treatment with CFTR modulators yielded no significant modification of the proteomic content. These results highlight that CF kidney cells adapt to the CFTR defect by upregulating proteasome activity and that autophagy and endosomal targeting are impaired. Increased expression of EGFR and decreased expression of klotho and matrisome might play a central role in this CF kidney signature by inducing oxidation, inflammation, accelerated senescence, and abnormal tissue repair. Conclusions: Our study unravels novel insights into consequences of CFTR dysfunction in the urinary tract, some of which may have clinical and therapeutic implications.

| S-EPMC7554933 | biostudies-literature

CFTR Modulators for the Treatment of Cystic Fibrosis.

Project description:Defects in a single gene lead to the defective proteins that cause cystic fibrosis, making the disease an ideal candidate for mutation-targeted therapy. Although ivacaftor is currently the only FDA-approved CFTR modifier, others are in development.

| S-EPMC4103577 | biostudies-other

Characterization of defects in ion transport and tissue development in cystic fibrosis transmembrane conductance regulator (CFTR)-knockout rats.

Project description: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.

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Fixing cystic fibrosis by correcting CFTR domain assembly.

Project description:For cystic fibrosis (CF) patients most therapies focus on alleviating the disease symptoms. Yet the cellular basis of the disease has been well studied; mutations in the CF gene can impair folding, secretion, cell surface stability, and/or function of the CFTR chloride channel. Correction of these basic defects has been a challenge, but indicates that a deeper understanding of the molecular and cellular mechanism of mutations is a prerequisite for developing more efficient therapies.

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