{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,12]],"date-time":"2026-02-12T04:06:49Z","timestamp":1770869209665,"version":"3.50.1"},"reference-count":47,"publisher":"Oxford University Press (OUP)","issue":"3","license":[{"start":{"date-parts":[[2014,9,1]],"date-time":"2014-09-01T00:00:00Z","timestamp":1409529600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2014,9,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>The most common cystic fibrosis (CF) mutation, \u0394F508, causes protein misfolding, leading to proteosomal degradation. We recently showed that expression of miR-138 enhances CF transmembrane conductance regulator (CFTR) biogenesis and partially rescues \u0394F508-CFTR function in CF airway epithelia. We hypothesized that a genomic signature approach can be used to identify new bioactive small molecules affecting \u0394F508-CFTR rescue. The Connectivity Map was used to identify 27 small molecules with potential to restore \u0394F508-CFTR function in airway epithelia. The molecules were screened in vitro for efficacy in improving \u0394F508-CFTR trafficking, maturation, and chloride current. We identified four small molecules that partially restore \u0394F508-CFTR function in primary CF airway epithelia. Of these, pyridostigmine showed cooperativity with corrector compound 18 in improving \u0394F508-CFTR function. There are few CF therapies based on new molecular insights. Querying the Connectivity Map with relevant genomic signatures offers a method to identify new candidates for rescuing \u0394F508-CFTR function.<\/jats:p>","DOI":"10.1165\/rcmb.2014-0007oc","type":"journal-article","created":{"date-parts":[[2014,3,26]],"date-time":"2014-03-26T14:25:50Z","timestamp":1395843950000},"page":"354-362","source":"Crossref","is-referenced-by-count":12,"title":["A Genomic Signature Approach to Rescue \u0394F508-Cystic Fibrosis Transmembrane Conductance Regulator Biosynthesis and Function"],"prefix":"10.1093","volume":"51","author":[{"given":"Shyam","family":"Ramachandran","sequence":"first","affiliation":[{"name":"Department of Pediatrics"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Samantha R.","family":"Osterhaus","sequence":"additional","affiliation":[{"name":"Department of Pediatrics"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Philip H.","family":"Karp","sequence":"additional","affiliation":[{"name":"Deparment of Internal Medicine, and"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Michael J.","family":"Welsh","sequence":"additional","affiliation":[{"name":"Deparment of Internal Medicine, and"},{"name":"Howard Hughes Medical Institute, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, Iowa"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"suffix":"Jr.","given":"Paul B.","family":"McCray","sequence":"additional","affiliation":[{"name":"Department of Pediatrics"},{"name":"Deparment of Internal Medicine, and"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"286","published-online":{"date-parts":[[2014,9,1]]},"reference":[{"key":"2026021122274047600_bib1","doi-asserted-by":"crossref","first-page":"761","DOI":"10.1038\/358761a0","article-title":"Processing of mutant cystic fibrosis transmembrane conductance regulator is temperature-sensitive","volume":"358","author":"Denning","year":"1992","journal-title":"Nature"},{"key":"2026021122274047600_bib2","doi-asserted-by":"crossref","first-page":"117","DOI":"10.1379\/1466-1268(1996)001<0117:CCCTMP>2.3.CO;2","article-title":"Chemical chaperones correct the mutant phenotype of the delta F508 cystic fibrosis transmembrane conductance regulator protein","volume":"1","author":"Brown","year":"1996","journal-title":"Cell Stress Chaperones"},{"key":"2026021122274047600_bib3","doi-asserted-by":"crossref","first-page":"805","DOI":"10.1126\/science.1191542","article-title":"Peripheral protein quality control removes unfolded CFTR from the plasma membrane","volume":"329","author":"Okiyoneda","year":"2010","journal-title":"Science"},{"key":"2026021122274047600_bib4","doi-asserted-by":"crossref","first-page":"625","DOI":"10.1093\/nar\/gkr754","article-title":"Nucleosome occupancy reveals regulatory elements of the CFTR promoter","volume":"40","author":"Ott","year":"2012","journal-title":"Nucleic Acids Res"},{"key":"2026021122274047600_bib5","doi-asserted-by":"crossref","first-page":"2564","DOI":"10.1172\/JCI24898","article-title":"Small-molecule correctors of defective DeltaF508-CFTR cellular processing identified by high-throughput screening","volume":"115","author":"Pedemonte","year":"2005","journal-title":"J Clin Invest"},{"key":"2026021122274047600_bib6","doi-asserted-by":"crossref","first-page":"18843","DOI":"10.1073\/pnas.1105787108","article-title":"Correction of the F508del-CFTR protein processing defect in vitro by the investigational drug VX-809","volume":"108","author":"Van Goor","year":"2011","journal-title":"Proc Natl Acad Sci USA"},{"key":"2026021122274047600_bib7","doi-asserted-by":"crossref","first-page":"C872","DOI":"10.1152\/ajpcell.00507.2010","article-title":"Rescue of the mutant CFTR chloride channel by pharmacological correctors and low temperature analyzed by gene expression profiling","volume":"301","author":"Sondo","year":"2011","journal-title":"Am J Physiol Cell Physiol"},{"key":"2026021122274047600_bib8","doi-asserted-by":"crossref","first-page":"1991","DOI":"10.1056\/NEJMoa0909825","article-title":"Effect of VX-770 in persons with cystic fibrosis and the G551D-CFTR mutation","volume":"363","author":"Accurso","year":"2010","journal-title":"N Engl J Med"},{"key":"2026021122274047600_bib9","doi-asserted-by":"crossref","first-page":"13362","DOI":"10.1073\/pnas.1210906109","article-title":"A microRNA network regulates expression and biosynthesis of wild-type and DeltaF508 mutant cystic fibrosis transmembrane conductance regulator","volume":"109","author":"Ramachandran","year":"2012","journal-title":"Proc Natl Acad Sci USA"},{"key":"2026021122274047600_bib10","doi-asserted-by":"crossref","first-page":"1929","DOI":"10.1126\/science.1132939","article-title":"The Connectivity Map: using gene-expression signatures to connect small molecules, genes, and disease","volume":"313","author":"Lamb","year":"2006","journal-title":"Science"},{"key":"2026021122274047600_bib11","doi-asserted-by":"crossref","first-page":"4078","DOI":"10.1200\/JCO.2007.13.4429","article-title":"Insulin-like growth factor-I activates gene transcription programs strongly associated with poor breast cancer prognosis","volume":"26","author":"Creighton","year":"2008","journal-title":"J Clin Oncol"},{"key":"2026021122274047600_bib12","doi-asserted-by":"crossref","first-page":"19432","DOI":"10.1073\/pnas.0806674105","article-title":"A genomic approach to colon cancer risk stratification yields biologic insights into therapeutic opportunities","volume":"105","author":"Garman","year":"2008","journal-title":"Proc Natl Acad Sci USA"},{"key":"2026021122274047600_bib13","doi-asserted-by":"crossref","first-page":"815","DOI":"10.1093\/jnci\/djn150","article-title":"Estrogen-dependent signaling in a molecularly distinct subclass of aggressive prostate cancer","volume":"100","author":"Setlur","year":"2008","journal-title":"J Natl Cancer Inst"},{"key":"2026021122274047600_bib14","doi-asserted-by":"crossref","first-page":"331","DOI":"10.1016\/j.ccr.2006.09.006","article-title":"Gene expression-based chemical genomics identifies rapamycin as a modulator of MCL1 and glucocorticoid resistance","volume":"10","author":"Wei","year":"2006","journal-title":"Cancer Cell"},{"key":"2026021122274047600_bib15","doi-asserted-by":"crossref","first-page":"321","DOI":"10.1016\/j.ccr.2006.09.005","article-title":"Gene expression signature-based chemical genomic prediction identifies a novel class of HSP90 pathway modulators","volume":"10","author":"Hieronymus","year":"2006","journal-title":"Cancer Cell"},{"key":"2026021122274047600_bib16","doi-asserted-by":"crossref","first-page":"293","DOI":"10.1002\/cncr.27743","article-title":"Gene expression-based chemical genomics identifies heat-shock protein 90 inhibitors as potential therapeutic drugs in cholangiocarcinoma","volume":"119","author":"Chen","year":"2013","journal-title":"Cancer"},{"key":"2026021122274047600_bib17","author":"Edris","year":"2012"},{"key":"2026021122274047600_bib18","first-page":"67","article-title":"A gene expression signature of emphysema-related lung destruction and its reversal by the tripeptide GHK","volume":"4","author":"Campbell","year":"2012","journal-title":"Genome Med"},{"key":"2026021122274047600_bib19","doi-asserted-by":"crossref","first-page":"627","DOI":"10.1016\/j.cmet.2011.03.020","article-title":"mRNA expression signatures of human skeletal muscle atrophy identify a natural compound that increases muscle mass","volume":"13","author":"Kunkel","year":"2011","journal-title":"Cell Metab"},{"key":"2026021122274047600_bib20","author":"Lamb"},{"key":"2026021122274047600_bib21","doi-asserted-by":"crossref","first-page":"8942","DOI":"10.1074\/jbc.M009172200","article-title":"Conformational and temperature-sensitive stability defects of the delta F508 cystic fibrosis transmembrane conductance regulator in post-endoplasmic reticulum compartments","volume":"276","author":"Sharma","year":"2001","journal-title":"J Biol Chem"},{"key":"2026021122274047600_bib22","doi-asserted-by":"crossref","first-page":"522","DOI":"10.1165\/ajrcmb\/8.5.522","article-title":"An immortalized cystic fibrosis tracheal epithelial cell line homozygous for the delta F508 CFTR mutation","volume":"8","author":"Kunzelmann","year":"1993","journal-title":"Am J Respir Cell Mol Biol"},{"key":"2026021122274047600_bib23","doi-asserted-by":"crossref","first-page":"351","DOI":"10.1165\/rcmb.2002-0086OC","article-title":"Modulation of deltaF508 cystic fibrosis transmembrane regulator trafficking and function with 4-phenylbutyrate and flavonoids","volume":"31","author":"Lim","year":"2004","journal-title":"Am J Respir Cell Mol Biol"},{"key":"2026021122274047600_bib24","doi-asserted-by":"crossref","first-page":"175","DOI":"10.3389\/fphar.2012.00175","article-title":"Pharmacological correctors of mutant CFTR mistrafficking","volume":"3","author":"Pedemonte","year":"2012","journal-title":"Front Pharmacol"},{"key":"2026021122274047600_bib25","doi-asserted-by":"crossref","first-page":"35825","DOI":"10.1074\/jbc.M110.131623","article-title":"The cystic fibrosis-causing mutation deltaF508 affects multiple steps in cystic fibrosis transmembrane conductance regulator biogenesis","volume":"285","author":"Thibodeau","year":"2010","journal-title":"J Biol Chem"},{"key":"2026021122274047600_bib26","doi-asserted-by":"crossref","first-page":"393","DOI":"10.1007\/s40272-013-0035-3","article-title":"Managing the underlying cause of cystic fibrosis: a future role for potentiators and correctors","volume":"15","author":"Galietta","year":"2013","journal-title":"Paediatr Drugs"},{"key":"2026021122274047600_bib27","doi-asserted-by":"crossref","first-page":"444","DOI":"10.1038\/nchembio.1253","article-title":"Mechanism-based corrector combination restores DeltaF508-CFTR folding and function","volume":"9","author":"Okiyoneda","year":"2013","journal-title":"Nat Chem Biol"},{"key":"2026021122274047600_bib28","doi-asserted-by":"crossref","first-page":"971","DOI":"10.1007\/s10822-010-9390-0","article-title":"Small molecule correctors of F508del-CFTR discovered by structure-based virtual screening","volume":"24","author":"Kalid","year":"2010","journal-title":"J Comput Aided Mol Des"},{"key":"2026021122274047600_bib29","doi-asserted-by":"crossref","first-page":"25","DOI":"10.1038\/nchembio.275","article-title":"Reduced histone deacetylase 7 activity restores function to misfolded CFTR in cystic fibrosis","volume":"6","author":"Hutt","year":"2010","journal-title":"Nat Chem Biol"},{"key":"2026021122274047600_bib30","doi-asserted-by":"crossref","first-page":"685","DOI":"10.2119\/molmed.2012.00001","article-title":"Pharmacological rescue of mutant CFTR detected using a novel fluorescence platform","volume":"18","author":"Holleran","year":"2012","journal-title":"Mol Med"},{"key":"2026021122274047600_bib31","doi-asserted-by":"crossref","first-page":"683","DOI":"10.1124\/mol.111.073056","article-title":"Cyanoquinolines with independent corrector and potentiator activities restore DeltaPhe508-cystic fibrosis transmembrane conductance regulator chloride channel function in cystic fibrosis","volume":"80","author":"Phuan","year":"2011","journal-title":"Mol Pharmacol"},{"key":"2026021122274047600_bib32","doi-asserted-by":"crossref","first-page":"803","DOI":"10.1016\/j.cell.2006.09.043","article-title":"Hsp90 cochaperone Aha1 downregulation rescues misfolding of CFTR in cystic fibrosis","volume":"127","author":"Wang","year":"2006","journal-title":"Cell"},{"key":"2026021122274047600_bib33","doi-asserted-by":"crossref","first-page":"176","DOI":"10.3389\/fphar.2012.00176","article-title":"Ouabain mimics low temperature rescue of F508del-CFTR in cystic fibrosis epithelial cells","volume":"3","author":"Zhang","year":"2012","journal-title":"Front Pharmacol"},{"key":"2026021122274047600_bib34","doi-asserted-by":"crossref","first-page":"12","DOI":"10.1136\/thoraxjnl-2011-200393","article-title":"Results of a phase IIa study of VX-809, an investigational CFTR corrector compound, in subjects with cystic fibrosis homozygous for the F508del-CFTR mutation","volume":"67","author":"Clancy","year":"2012","journal-title":"Thorax"},{"key":"2026021122274047600_bib35","doi-asserted-by":"crossref","first-page":"2163","DOI":"10.1038\/mt.2011.206","article-title":"Uptake, efficacy, and systemic distribution of naked, inhaled short interfering RNA (siRNA) and locked nucleic acid (LNA) antisense","volume":"19","author":"Moschos","year":"2011","journal-title":"Mol Ther"},{"key":"2026021122274047600_bib36","doi-asserted-by":"crossref","first-page":"329","DOI":"10.1038\/nrg2968","article-title":"Current prospects for RNA interference-based therapies","volume":"12","author":"Davidson","year":"2011","journal-title":"Nat Rev Genet"},{"key":"2026021122274047600_bib37","doi-asserted-by":"crossref","first-page":"727","DOI":"10.1038\/nrd892","article-title":"The druggable genome","volume":"1","author":"Hopkins","year":"2002","journal-title":"Nat Rev Drug Discov"},{"key":"2026021122274047600_bib38","author":"ClinicalTrials.gov results database. Study of VX-809 alone and in combination with VX-770 in cystic fibrosis (CF) patients homozygous or heterozygous for the F508del-CFTR mutation. ClinicalTrials.gov Identifier: NCT01225211. National Library of Medicine (NLM) at the National Institutes of Health (NIH); 2010 [updated 2014 Feb 27]."},{"key":"2026021122274047600_bib39","doi-asserted-by":"crossref","first-page":"204","DOI":"10.1152\/physiolgenomics.00160.2003","article-title":"Gene expression profile analysis of 4-phenylbutyrate treatment of IB3\u20131 bronchial epithelial cell line demonstrates a major influence on heat-shock proteins","volume":"16","author":"Wright","year":"2004","journal-title":"Physiol Genomics"},{"key":"2026021122274047600_bib40","doi-asserted-by":"crossref","first-page":"257","DOI":"10.1042\/BJ20070478","article-title":"Additive effect of multiple pharmacological chaperones on maturation of CFTR processing mutants","volume":"406","author":"Wang","year":"2007","journal-title":"Biochem J"},{"key":"2026021122274047600_bib41","doi-asserted-by":"crossref","first-page":"536","DOI":"10.1096\/fj.12-216119","article-title":"Correctors of DeltaF508 CFTR restore global conformational maturation without thermally stabilizing the mutant protein","volume":"27","author":"He","year":"2013","journal-title":"FASEB J"},{"key":"2026021122274047600_bib42","doi-asserted-by":"crossref","first-page":"175","DOI":"10.1038\/nature08506","article-title":"Predicting new molecular targets for known drugs","volume":"462","author":"Keiser","year":"2009","journal-title":"Nature"},{"key":"2026021122274047600_bib43","doi-asserted-by":"crossref","first-page":"695","DOI":"10.1007\/s00894-008-0353-5","article-title":"Meta-basic estimates the size of druggable human genome","volume":"15","author":"Plewczynski","year":"2009","journal-title":"J Mol Model"},{"key":"2026021122274047600_bib44","doi-asserted-by":"crossref","first-page":"3317","DOI":"10.1093\/bioinformatics\/btr548","article-title":"ProfileChaser: searching microarray repositories based on genome-wide patterns of differential expression","volume":"27","author":"Engreitz","year":"2011","journal-title":"Bioinformatics"},{"key":"2026021122274047600_bib45","doi-asserted-by":"crossref","first-page":"548","DOI":"10.1186\/1471-2105-9-548","article-title":"GeneChaser: identifying all biological and clinical conditions in which genes of interest are differentially expressed","volume":"9","author":"Chen","year":"2008","journal-title":"BMC Bioinformatics"},{"key":"2026021122274047600_bib46","doi-asserted-by":"crossref","first-page":"7049","DOI":"10.1073\/pnas.1114513109","article-title":"Expression-based genome-wide association study links the receptor CD44 in adipose tissue with type 2 diabetes","volume":"109","author":"Kodama","year":"2012","journal-title":"Proc Natl Acad Sci USA"},{"key":"2026021122274047600_bib47","first-page":"93","article-title":"Computational repositioning of the anticonvulsant topiramate for inflammatory bowel disease","volume":"17","author":"Dudley","year":"2011","journal-title":"Sci Transl Med"}],"container-title":["American Journal of Respiratory Cell and Molecular Biology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/ajrcmb\/article-pdf\/51\/3\/354\/66807807\/ajrcmb_51_3_354.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/ajrcmb\/article-pdf\/51\/3\/354\/66807807\/ajrcmb_51_3_354.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,2,12]],"date-time":"2026-02-12T03:28:27Z","timestamp":1770866907000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/ajrcmb\/article\/51\/3\/354\/8467654"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2014,9,1]]},"references-count":47,"journal-issue":{"issue":"3","published-online":{"date-parts":[[2014,9,1]]},"published-print":{"date-parts":[[2014,9,1]]}},"URL":"https:\/\/doi.org\/10.1165\/rcmb.2014-0007oc","relation":{},"ISSN":["1044-1549","1535-4989"],"issn-type":[{"value":"1044-1549","type":"print"},{"value":"1535-4989","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2014,9]]},"published":{"date-parts":[[2014,9,1]]}}}