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

查看全文 作　　者：Elise [1]Dreano;Marc [2]Bacchetta;Juliette [2]Simonin;Louise [3]Galmiche;Claire [4,5]Usal;Lotfi [6,7]Slimani;Jérémy [6]Sadoine;Laurent [4,5]Tesson;Ignacio [4,5]Anegon;Jean-Paul [8]Concordet;Aurélie [1]Hatton;Lucile [1]Vignaud;Danielle [1]Tondelier;Isabelle Sermet-[1,9,10]Gaudelus;Marc [2]Chanson;Charles-Henry [1,9,11]Cottart

机构地区：[1]INSERM 1151,INEM,Universitéde Paris,Paris,France;[2]Département de Pédiatrie,Gynécologie&Obstétrique et Département de Physiologie Cellulaire&Métabolisme,Universitéde Genève,Genève,Switzerland;[3]Département de Pathologie,APHP,CHU Necker-Enfants Malades,Paris,France;[4]Centre de Recherche en Transplantation&Immunologie,UMR 1064,INSERM,Universitéde Nantes,Nantes,France;[5]Plateforme Trangénèse Rat&ImmunoPhénomique,INSERM 1064&SFR François Bonamy,CNRS UMS3556,Nantes,France;[6]Pathologie,Imagerie&Biothérapies Orofaciales,Montrouge,France;[7]Plateforme Imageries du vivant,Facultéde chirurgie dentaire,Universitéde Paris,Paris,France;[8]INSERM U1154,CNRS UMR7196,MNHN,TACGENE,Paris,France;[9]AP-HP,Centre Maladie Rare Mucoviscidose et Maladies du CFTR,Assistance Publique Hôpitaux de Paris,Hôpital Necker-Enfants Malades,Paris,France;[10]Facultéde Médecine de Paris,Universitéde Paris,Paris,France;[11]Facultéde Pharmacie de Paris,Universitéde Paris,Paris,France

出　　处：《Animal Models and Experimental Medicine》索引2019年第2卷第4期,共15页

基　　金：TEFOR,Grant/Award Number:RIIINSB-0014;France Life Imaging,Grant/Award Number:ANR-11-INBS-0006;Swiss Cystic Fibrosis Foundation CFCH;Fondation Maladies Rares;Infrastructures Biologie-Santé;IHU-CESTI,Grant/Award Number:ANR-10-IBHU-005;IRSR Pays de la Loire;Vaincre la Mucoviscidose;Swiss National Foundation,Grant/Award Number:310030_172909 摘　　要：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(F508 del) homozygous for the p.Phe508 del 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 F508 del rats.Results: Both newborn F508 del 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 F508 del rats. Exposure of F508 del CFTR nasal primary cultures to a combination of VX-809 and VX-770 improved CFTR-mediated Cl-transport.Conclusions: The F508 del rats reproduce the phenotypes observed in CFTR KO animals and represent a novel resource to advance the development of CF therapeutics. 关键词：animal models CFTR channel activity CFTR modulators cystic fibrosis primary cultures RAT

相关文献

参考文献（30）
引证文献（4）
耦合文献（3）

参考文献(30)

引证文献(4)

耦合文献(3)

互联网出版许可证新出网证(渝)字10号全国400电话 - 免长途话费

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

参考文献(30)

引证文献(4)

耦合文献(3)

用户提示