RGD Reference Report - Characterization of two rat models of cystic fibrosis-KO and F508del CFTR-Generated by Crispr-Cas9. - Rat Genome Database

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Characterization of two rat models of cystic fibrosis-KO and F508del CFTR-Generated by Crispr-Cas9.

Authors: Dreano, Elise  Bacchetta, Marc  Simonin, Juliette  Galmiche, Louise  Usal, Claire  Slimani, Lotfi  Sadoine, Jérémy  Tesson, Laurent  Anegon, Ignacio  Concordet, Jean-Paul  Hatton, Aurélie  Vignaud, Lucile  Tondelier, Danielle  Sermet-Gaudelus, Isabelle  Chanson, Marc  Cottart, Charles-Henry 
Citation: Dreano E, etal., Animal Model Exp Med. 2019 Nov 25;2(4):297-311. doi: 10.1002/ame2.12091. eCollection 2019 Dec.
RGD ID: 126928119
Pubmed: PMID:31942562   (View Abstract at PubMed)
PMCID: PMC6930998   (View Article at PubMed Central)
DOI: DOI:10.1002/ame2.12091   (Journal Full-text)


Background: Genetically engineered animals are essential for gaining a proper understanding of the disease mechanisms of cystic fibrosis (CF). The rat is a relevant laboratory model for CF because of its zootechnical capacity, size, and airway characteristics, including the presence of submucosal glands.
Methods: We describe the generation of a CF rat model (F508del) homozygous for the p.Phe508del mutation in the transmembrane conductance regulator (Cftr) gene. This model was compared to new Cftr-/- rats (CFTR KO). Target organs in CF were examined by histological staining of tissue sections and tooth enamel was quantified by micro-computed tomography. The activity of CFTR was evaluated by nasal potential difference (NPD) and short-circuit current measurements. The effect of VX-809 and VX-770 was analyzed on nasal epithelial primary cell cultures from F508del rats.
Results: Both newborn F508del and Knock out (KO) animals developed intestinal obstruction that could be partly compensated by special diet combined with an osmotic laxative. The two rat models exhibited CF phenotypic anomalies such as vas deferens agenesis and tooth enamel defects. Histology of the intestine, pancreas, liver, and lungs was normal. Absence of CFTR function in KO rats was confirmed ex vivo by short-circuit current measurements on colon mucosae and in vivo by NPD, whereas residual CFTR activity was observed in F508del rats. Exposure of F508del CFTR nasal primary cultures to a combination of VX-809 and VX-770 improved CFTR-mediated Cl- transport.
Conclusions: The F508del rats reproduce the phenotypes observed in CFTR KO animals and represent a novel resource to advance the development of CF therapeutics.



RGD Manual Disease Annotations    Click to see Annotation Detail View

  

Gene-Chemical Interaction Annotations    Click to see Annotation Detail View

  
Object SymbolSpeciesTermQualifierEvidenceWithNotesSourceOriginal Reference(s)
CFTRHumanamiloride increases activityISOCftr (Rattus norvegicus)Amiloride increases activity of Cftr protein in nasal cavity epitheliumRGD 
CftrRatamiloride increases activityEXP Amiloride increases activity of Cftr protein in nasal cavity epitheliumRGD 
CftrMouseamiloride increases activityISOCftr (Rattus norvegicus)Amiloride increases activity of Cftr protein in nasal cavity epitheliumRGD 

Gene Ontology Annotations    Click to see Annotation Detail View

Biological Process

  
Object SymbolSpeciesTermQualifierEvidenceWithNotesSourceOriginal Reference(s)
CftrRatenamel mineralization  IMP  RGD 
CftrRatresponse to xenobiotic stimulus  IMP  RGD 
CftrRatsodium ion transmembrane transport  IMP  RGD 
CftrRattransepithelial chloride transport  IMP  RGD 

Phenotype Annotations    Click to see Annotation Detail View

Mammalian Phenotype

Object SymbolSpeciesTermQualifierEvidenceWithNotesSourceOriginal Reference(s)
CftrRatabnormal enamel development  IMP  RGD 
Cftrem1AngRatabnormal enamel development  IMP  RGD 
Cftrem2AngRatabnormal enamel development  IMP  RGD 
SD-Cftrem1AngRatabnormal enamel development  IMP  RGD 
SD-Cftrem2AngRatabnormal enamel development  IMP  RGD 
CftrRatabnormal olfactory epithelium physiology  IMP  RGD 
Cftrem1AngRatabnormal olfactory epithelium physiology  IMP  RGD 
Cftrem2AngRatabnormal olfactory epithelium physiology  IMP  RGD 
SD-Cftrem1AngRatabnormal olfactory epithelium physiology  IMP  RGD 
SD-Cftrem2AngRatabnormal olfactory epithelium physiology  IMP  RGD 
CftrRatabsent vas deferens  IMP  RGD 
Cftrem2AngRatabsent vas deferens  IMP  RGD 
SD-Cftrem2AngRatabsent vas deferens  IMP  RGD 
CftrRatdecreased body weight  IMP  RGD 
Cftrem1AngRatdecreased body weight  IMP  RGD 
Cftrem2AngRatdecreased body weight  IMP  RGD 
SD-Cftrem1AngRatdecreased body weight  IMP  RGD 
SD-Cftrem2AngRatdecreased body weight  IMP  RGD 
CftrRatdecreased respiratory epithelial chloride transmembrane transport  IMP  RGD 
Cftrem1AngRatdecreased respiratory epithelial chloride transmembrane transport  IMP  RGD 
Cftrem2AngRatdecreased respiratory epithelial chloride transmembrane transport  IMP  RGD 
SD-Cftrem1AngRatdecreased respiratory epithelial chloride transmembrane transport  IMP  RGD 
SD-Cftrem2AngRatdecreased respiratory epithelial chloride transmembrane transport  IMP  RGD 
CftrRatdecreased survivor rate treatmentIMP DietGel 31M and 6% osmotic laxative PEG3350 and DietGel Boost added to drinking waterRGD 
CftrRatdecreased survivor rate  IMP  RGD 
Cftrem1AngRatdecreased survivor rate  IMP  RGD 
Cftrem1AngRatdecreased survivor rate treatmentIMP DietGel 31M and 6% osmotic laxative PEG3350 and DietGel Boost added to drinking waterRGD 
Cftrem2AngRatdecreased survivor rate  IMP  RGD 
Cftrem2AngRatdecreased survivor rate treatmentIMP DietGel 31M and 6% osmotic laxative PEG3350 and DietGel Boost added to drinking waterRGD 
SD-Cftrem1AngRatdecreased survivor rate treatmentIMP DietGel 31M and 6% osmotic laxative PEG3350 and DietGel Boost added to drinking waterRGD 
SD-Cftrem1AngRatdecreased survivor rate  IMP  RGD 
SD-Cftrem2AngRatdecreased survivor rate treatmentIMP DietGel 31M and 6% osmotic laxative PEG3350 and DietGel Boost added to drinking waterRGD 
SD-Cftrem2AngRatdecreased survivor rate  IMP  RGD 
CftrRatincreased respiratory epithelial sodium ion transmembrane transport  IMP  RGD 
Cftrem1AngRatincreased respiratory epithelial sodium ion transmembrane transport  IMP  RGD 
Cftrem2AngRatincreased respiratory epithelial sodium ion transmembrane transport  IMP  RGD 
SD-Cftrem1AngRatincreased respiratory epithelial sodium ion transmembrane transport  IMP  RGD 
SD-Cftrem2AngRatincreased respiratory epithelial sodium ion transmembrane transport  IMP  RGD 
CftrRatpostnatal growth retardation treatmentIMP DietGel 31M and 6% osmotic laxative PEG3350 and DietGel Boost added to drinking waterRGD 
CftrRatpostnatal growth retardation  IMP  RGD 
Cftrem1AngRatpostnatal growth retardation  IMP  RGD 
Cftrem1AngRatpostnatal growth retardation treatmentIMP DietGel 31M and 6% osmotic laxative PEG3350 and DietGel Boost added to drinking waterRGD 
Cftrem2AngRatpostnatal growth retardation  IMP  RGD 
Cftrem2AngRatpostnatal growth retardation treatmentIMP DietGel 31M and 6% osmotic laxative PEG3350 and DietGel Boost added to drinking waterRGD 
SD-Cftrem1AngRatpostnatal growth retardation treatmentIMP DietGel 31M and 6% osmotic laxative PEG3350 and DietGel Boost added to drinking waterRGD 
SD-Cftrem1AngRatpostnatal growth retardation  IMP  RGD 
SD-Cftrem2AngRatpostnatal growth retardation treatmentIMP DietGel 31M and 6% osmotic laxative PEG3350 and DietGel Boost added to drinking waterRGD 
SD-Cftrem2AngRatpostnatal growth retardation  IMP  RGD 
Objects Annotated

Genes (Rattus norvegicus)
Cftr  (CF transmembrane conductance regulator)
Cftrem1Ang  (cystic fibrosis transmembrane conductance regulator; CRISPR/Cas9 induced mutant 1, Ang)
Cftrem2Ang  (cystic fibrosis transmembrane conductance regulator; CRISPR/Cas9 induced mutant 2, Ang)

Genes (Mus musculus)
Cftr  (cystic fibrosis transmembrane conductance regulator)

Genes (Homo sapiens)
CFTR  (CF transmembrane conductance regulator)

Strains
SD-Cftrem1Ang  (NA)
SD-Cftrem2Ang  (NA)


Additional Information