title: Evaluation of a systems biology approach to identify pharmacological correctors of the mutant CFTR chloride channel.
abstract: Mistrafficking of CFTR protein caused by F508del, the most frequent mutation in cystic fibrosis (CF), can be corrected by cell incubation at low temperature, an effect that may be mediated by altered expression of proteostasis genes.
  
  
  
  To identify small molecules mimicking low temperature, we compared gene expression profiles of cells kept at 27°C with those previously generated from more than 1300 compounds. The resulting candidates were tested with a functional assay on a bronchial epithelial cell line.
  
  
  
  We found that anti-inflammatory glucocorticoids, such as mometasone, budesonide, and fluticasone, increased mutant CFTR function. However, this activity was not confirmed in primary bronchial epithelial cells. Actually, glucocorticoids enhanced Na(+) absorption, an effect that could further impair mucociliary clearance in CF airways.
  
  
  
  Our results suggest that rescue of F508del-CFTR by low temperature cannot be easily mimicked by small molecules and that compounds with closer transcriptional and functional effects need to be found.
authors.affiliation: Istituto Giannina Gaslini, via Gerolamo Gaslini 5, 16147 Genova, Italy.
authors.forename: Emanuela
authors.initials: E
authors.lastname: Pesce
authors.affiliation: Istituto Giannina Gaslini, via Gerolamo Gaslini 5, 16147 Genova, Italy.
authors.forename: Giulia
authors.initials: G
authors.lastname: Gorrieri
authors.affiliation: Telethon Institute of Genetics and Medicine, Via Campi Flegrei 34, 80078 Pozzuoli, Italy.
authors.forename: Francesco
authors.initials: F
authors.lastname: Sirci
authors.affiliation: Telethon Institute of Genetics and Medicine, Via Campi Flegrei 34, 80078 Pozzuoli, Italy.
authors.forename: Francesco
authors.initials: F
authors.lastname: Napolitano
authors.affiliation: Telethon Institute of Genetics and Medicine, Via Campi Flegrei 34, 80078 Pozzuoli, Italy.
authors.forename: Diego
authors.initials: D
authors.lastname: Carrella
authors.affiliation: Istituto Giannina Gaslini, via Gerolamo Gaslini 5, 16147 Genova, Italy.
authors.forename: Emanuela
authors.initials: E
authors.lastname: Caci
authors.affiliation: Istituto Giannina Gaslini, via Gerolamo Gaslini 5, 16147 Genova, Italy.
authors.forename: Valeria
authors.initials: V
authors.lastname: Tomati
authors.affiliation: Istituto Giannina Gaslini, via Gerolamo Gaslini 5, 16147 Genova, Italy.
authors.forename: Olga
authors.initials: O
authors.lastname: Zegarra-Moran
authors.affiliation: Telethon Institute of Genetics and Medicine, Via Campi Flegrei 34, 80078 Pozzuoli, Italy.
authors.forename: Diego
authors.initials: D
authors.lastname: di Bernardo
authors.affiliation: Istituto Giannina Gaslini, via Gerolamo Gaslini 5, 16147 Genova, Italy.
authors.forename: Luis J V
authors.initials: LJ
authors.lastname: Galietta
mesh_terms: D001980:Bronchi / Q000473:pathology; D065101:Chloride Channel Agonists / Q000494:pharmacology*; D018118:Chloride Channels / Q000502:physiology*; D003080:Cold Temperature; D003550:Cystic Fibrosis / Q000235:genetics / Q000378:metabolism / Q000628:therapy; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000235:genetics / Q000378:metabolism; D058492:Drug Repositioning / Q000379:methods; D004847:Epithelial Cells / Q000378:metabolism*; D006801:Humans; D009079:Mucociliary Clearance / Q000502:physiology; D050505:Mutant Proteins / Q000378:metabolism; D009154:Mutation; D049490:Systems Biology / Q000379:methods; D059467:Transcriptome / Q000502:physiology
chemical_list: D065101:Chloride Channel Agonists; D018118:Chloride Channels; D050505:Mutant Proteins; D019005:Cystic Fibrosis Transmembrane Conductance Regulator
keywords: CFTR; Chloride channel; Corrector; F508del; Systems biology