From CFTR to a CF signalling network: a systems biology approach to study Cystic Fibrosis.
CF cellular phenotypes
CF signalling network
Cystic Fibrosis
Network topology
Therapeutic target
Journal
BMC genomics
ISSN: 1471-2164
Titre abrégé: BMC Genomics
Pays: England
ID NLM: 100965258
Informations de publication
Date de publication:
28 Sep 2024
28 Sep 2024
Historique:
received:
21
11
2023
accepted:
30
08
2024
medline:
29
9
2024
pubmed:
29
9
2024
entrez:
28
9
2024
Statut:
epublish
Résumé
Cystic Fibrosis (CF) is a monogenic disease caused by mutations in the gene coding the Cystic Fibrosis Transmembrane Regulator (CFTR) protein, but its overall physio-pathology cannot be solely explained by the loss of the CFTR chloride channel function. Indeed, CFTR belongs to a yet not fully deciphered network of proteins participating in various signalling pathways. We propose a systems biology approach to study how the absence of the CFTR protein at the membrane leads to perturbation of these pathways, resulting in a panel of deleterious CF cellular phenotypes. Based on publicly available transcriptomic datasets, we built and analyzed a CF network that recapitulates signalling dysregulations. The CF network topology and its resulting phenotypes were found to be consistent with CF pathology. Analysis of the network topology highlighted a few proteins that may initiate the propagation of dysregulations, those that trigger CF cellular phenotypes, and suggested several candidate therapeutic targets. Although our research is focused on CF, the global approach proposed in the present paper could also be followed to study other rare monogenic diseases.
Sections du résumé
BACKGROUND
BACKGROUND
Cystic Fibrosis (CF) is a monogenic disease caused by mutations in the gene coding the Cystic Fibrosis Transmembrane Regulator (CFTR) protein, but its overall physio-pathology cannot be solely explained by the loss of the CFTR chloride channel function. Indeed, CFTR belongs to a yet not fully deciphered network of proteins participating in various signalling pathways.
METHODS
METHODS
We propose a systems biology approach to study how the absence of the CFTR protein at the membrane leads to perturbation of these pathways, resulting in a panel of deleterious CF cellular phenotypes.
RESULTS
RESULTS
Based on publicly available transcriptomic datasets, we built and analyzed a CF network that recapitulates signalling dysregulations. The CF network topology and its resulting phenotypes were found to be consistent with CF pathology.
CONCLUSION
CONCLUSIONS
Analysis of the network topology highlighted a few proteins that may initiate the propagation of dysregulations, those that trigger CF cellular phenotypes, and suggested several candidate therapeutic targets. Although our research is focused on CF, the global approach proposed in the present paper could also be followed to study other rare monogenic diseases.
Identifiants
pubmed: 39342081
doi: 10.1186/s12864-024-10752-x
pii: 10.1186/s12864-024-10752-x
doi:
Substances chimiques
Cystic Fibrosis Transmembrane Conductance Regulator
126880-72-6
CFTR protein, human
0
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
892Informations de copyright
© 2024. The Author(s).
Références
Guo J, Garratt A, Hill A. Worldwide rates of diagnosis and effective treatment for cystic fibrosis. J Cyst Fibros. 2022;21(3):456–62. https://doi.org/10.1016/j.jcf.2022.01.009 .
doi: 10.1016/j.jcf.2022.01.009
pubmed: 35125294
Seibert FS, Loo TW, Clarke DM, Riordan JR. Cystic Fibrosis: Channel, Catalytic, and Folding Properties of the CFTR Protein. J Bioenerg Biomembr. 1997;29(5):429–42. https://doi.org/10.1023/A:1022478822214 .
doi: 10.1023/A:1022478822214
pubmed: 9511928
Veit G, Avramescu RG, Chiang AN, Houck SA, Cai Z, Peters KW, et al. From CFTR biology toward combinatorial pharmacotherapy: expanded classification of cystic fibrosis mutations. Mol Biol Cell. 2016;27(3):424–33. Publisher: American Society for Cell Biology (mboc). https://doi.org/10.1091/mbc.e14-04-0935 .
Hanssens LS, Duchateau J, Casimir GJ. CFTR Protein: Not Just a Chloride Channel? Cells. 2021;10(11):2844. Number: 11 Publisher: Multidisciplinary Digital Publishing Institute. https://doi.org/10.3390/cells10112844 .
Pereira C, Mazein A, Farinha CM, Gray MA, Kunzelmann K, Ostaszewski M, et al. CyFi-MAP: an interactive pathway-based resource for cystic fibrosis. Sci Rep. 2021;11(1):22223. Number: 1 Publisher: Nature Publishing Group. https://doi.org/10.1038/s41598-021-01618-3 .
Farinha CM, Gentzsch M. Revisiting CFTR Interactions: Old Partners and New Players. Int J Mol Sci. 2021;22(24):13196. Number: 24 Publisher: Multidisciplinary Digital Publishing Institute. https://doi.org/10.3390/ijms222413196 .
Crites KSM, Morin G, Orlando V, Patey N, Cantin C, Martel J, et al. CFTR Knockdown induces proinflammatory changes in intestinal epithelial cells. J Inflamm. 2015;12(1):62. https://doi.org/10.1186/s12950-015-0107-y .
doi: 10.1186/s12950-015-0107-y
Fleurot I, López-Gálvez R, Barbry P, Guillon A, Si-Tahar M, Bähr A, et al. TLR5 signalling is hyper-responsive in porcine cystic fibrosis airways epithelium. J Cyst Fibros. 2022;21(2):e117–21. https://doi.org/10.1016/j.jcf.2021.08.002 .
doi: 10.1016/j.jcf.2021.08.002
pubmed: 34420900
Hao S, Roesch EA, Perez A, Weiner RL, Henderson LC, Cummings L, et al. Inactivation of CFTR by CRISPR/Cas9 alters transcriptional regulation of inflammatory pathways and other networks. J Cyst Fibros. 2020;19(1):34–9. https://doi.org/10.1016/j.jcf.2019.05.003 .
doi: 10.1016/j.jcf.2019.05.003
pubmed: 31126900
Jacquot J, Tabary O, Le Rouzic P, Clement A. Airway epithelial cell inflammatory signalling in cystic fibrosis. Int J Biochem Cell Biol. 2008;40(9):1703–15. https://doi.org/10.1016/j.biocel.2008.02.002 .
doi: 10.1016/j.biocel.2008.02.002
pubmed: 18434235
Jeanson L, Kelly M, Coste A, Guerrera IC, Fritsch J, Nguyen-Khoa T, et al. Oxidative stress induces unfolding protein response and inflammation in nasal polyposis. Allergy. 2012;67(3):403–12. https://doi.org/10.1111/j.1398-9995.2011.02769.x .
doi: 10.1111/j.1398-9995.2011.02769.x
pubmed: 22188019
Conese M, Di Gioia S. Pathophysiology of Lung Disease and Wound Repair in Cystic Fibrosis. Pathophysiology. 2021;28(1):155–88. Number: 1 Publisher: Multidisciplinary Digital Publishing Institute. https://doi.org/10.3390/pathophysiology28010011 .
Pankonien I, Quaresma MC, Rodrigues CS, Amaral MD. CFTR, Cell Junctions and the Cytoskeleton. Int J Mol Sci. 2022;23(5):2688. Number: 5 Publisher: Multidisciplinary Digital Publishing Institute. https://doi.org/10.3390/ijms23052688 .
Ideozu JE, Zhang X, McColley S, Levy H. Transcriptome Profiling and Molecular Therapeutic Advances in Cystic Fibrosis: Recent Insights. Genes. 2019;10(3). https://doi.org/10.3390/genes10030180 .
Ghigo A, Prono G, Riccardi E, De Rose V. Dysfunctional Inflammation in Cystic Fibrosis Airways: From Mechanisms to Novel Therapeutic Approaches. Int J Mol Sci. 2021;22(4):1952. Number: 4 Publisher: Multidisciplinary Digital Publishing Institute. https://doi.org/10.3390/ijms22041952 .
Hornberg JJ, Bruggeman FJ, Westerhoff HV, Lankelma J. Cancer: A Systems Biology disease. Biosystems. 2006;83(2):81–90. https://doi.org/10.1016/j.biosystems.2005.05.014 .
doi: 10.1016/j.biosystems.2005.05.014
pubmed: 16426740
Pankow S, Bamberger C, Calzolari D, Martínez-Bartolomé S, Lavallée-Adam M, Balch WE, et al. ΔF508 CFTR interactome remodelling promotes rescue of cystic fibrosis. Nature. 2015;528(7583):510–6. Number: 7583 Publisher: Nature Publishing Group. https://doi.org/10.1038/nature15729 .
Trivedi TS, Bhadresha KP, Patel MP, Mankad AU, Rawal RM, Patel SK. Identification of hub genes associated with human cystic fibrosis: A Meta-analysis approach. Hum Gene. 2023;35:201139. https://doi.org/10.1016/j.humgen.2022.201139 .
doi: 10.1016/j.humgen.2022.201139
Buccitelli C, Selbach M. mRNAs, proteins and the emerging principles of gene expression control. Nat Rev Genet. 2020;21(10):630–44. Number: 10 Publisher: Nature Publishing Group. https://doi.org/10.1038/s41576-020-0258-4 .
Szalai B, Saez-Rodriguez J. Why do pathway methods work better than they should? FEBS Lett. 2020;594(24):4189–200. https://doi.org/10.1002/1873-3468.14011 .
doi: 10.1002/1873-3468.14011
pubmed: 33270910
Clarke LA, Sousa L, Barreto C, Amaral MD. Changes in transcriptome of native nasal epithelium expressing F508del-CFTR and intersecting data from comparable studies. Respir Res. 2013;14:38. https://doi.org/10.1186/1465-9921-14-38 .
doi: 10.1186/1465-9921-14-38
pubmed: 23537407
pmcid: 3637641
Virella-Lowell I, Herlihy JD, Liu B, Lopez C, Cruz P, Muller C, et al. Effects of CFTR, interleukin-10, and Pseudomonas aeruginosa on gene expression profiles in a CF bronchial epithelial cell Line. Mol Ther. 2004;10(3):562–73. Publisher: Elsevier. https://doi.org/10.1016/j.ymthe.2004.06.215 .
Rehman T, Karp PH, Tan P, Goodell BJ, Pezzulo AA, Thurman AL, et al. Inflammatory cytokines TNF-[Formula: see text] and IL-17 enhance the efficacy of cystic fibrosis transmembrane conductance regulator modulators. J Clin Investig. 2021;131(16):150398. https://doi.org/10.1172/JCI150398 .
Verhaeghe C, Remouchamps C, Hennuy B, Vanderplasschen A, Chariot A, Tabruyn SP, et al. Role of IKK and ERK pathways in intrinsic inflammation of cystic fibrosis airways. Biochem Pharmacol. 2007;73(12):1982–94. https://doi.org/10.1016/j.bcp.2007.03.019 .
doi: 10.1016/j.bcp.2007.03.019
pubmed: 17466952
Ogilvie V, Passmore M, Hyndman L, Jones L, Stevenson B, Wilson A, et al. Differential global gene expression in cystic fibrosis nasal and bronchial epithelium. Genomics. 2011;98(5):327–36. https://doi.org/10.1016/j.ygeno.2011.06.008 .
doi: 10.1016/j.ygeno.2011.06.008
pubmed: 21756994
Voisin G, Bouvet GF, Legendre P, Dagenais A, Massé C, Berthiaume Y. Oxidative stress modulates the expression of genes involved in cell survival in ΔF508 cystic fibrosis airway epithelial cells. Physiol Genomics. 2014;46(17):634–46. Publisher: American Physiological Society. https://doi.org/10.1152/physiolgenomics.00003.2014 .
Balloy V, Varet H, Dillies MA, Proux C, Jagla B, Coppée JY, et al. Normal and Cystic Fibrosis Human Bronchial Epithelial Cells Infected with Pseudomonas aeruginosa Exhibit Distinct Gene Activation Patterns. PLoS ONE. 2015;10(10):e0140979. Publisher: Public Library of Science. https://doi.org/10.1371/journal.pone.0140979 .
Zoso A, Sofoluwe A, Bacchetta M, Chanson M. Transcriptomic profile of cystic fibrosis airway epithelial cells undergoing repair. Sci Data. 2019;6(1):1–7. Number: 1 Publisher: Nature Publishing Group. https://doi.org/10.1038/s41597-019-0256-6 .
Ling KM, Garratt LW, Gill EE, Lee AHY, Agudelo-Romero P, Sutanto EN, et al. Rhinovirus Infection Drives Complex Host Airway Molecular Responses in Children With Cystic Fibrosis. Front Immunol. 2020;11:1327. https://doi.org/10.3389/fimmu.2020.01327 .
doi: 10.3389/fimmu.2020.01327
pubmed: 32765492
pmcid: 7378398
Saint-Criq V, Delpiano L, Casement J, Onuora JC, Lin J, Gray MA. Choice of Differentiation Media Significantly Impacts Cell Lineage and Response to CFTR Modulators in Fully Differentiated Primary Cultures of Cystic Fibrosis Human Airway Epithelial Cells. Cells. 2020;9(9):2137. Number: 9 Publisher: Multidisciplinary Digital Publishing Institute. https://doi.org/10.3390/cells9092137 .
Liberzon A, Birger C, Thorvaldsdóttir H, Ghandi M, Mesirov JP, Tamayo P. The Molecular Signatures Database (MSigDB) hallmark gene set collection. Cell Syst. 2015;1(6):417–25. https://doi.org/10.1016/j.cels.2015.12.004 .
doi: 10.1016/j.cels.2015.12.004
pubmed: 26771021
pmcid: 4707969
Schaefer CF, Anthony K, Krupa S, Buchoff J, Day M, Hannay T, et al. PID: the Pathway Interaction Database. Nucleic Acids Res. 2009;37(Database issue):D674–9. https://doi.org/10.1093/nar/gkn653 .
Kanehisa M, Furumichi M, Sato Y, Ishiguro-Watanabe M, Tanabe M. KEGG: integrating viruses and cellular organisms. Nucleic Acids Res. 2021;49(D1):D545–51. https://doi.org/10.1093/nar/gkaa970 .
doi: 10.1093/nar/gkaa970
pubmed: 33125081
Wang K, Li M, Hakonarson H. Analysing biological pathways in genome-wide association studies. Nat Rev Genet. 2010;11(12):843–54. Number: 12 Publisher: Nature Publishing Group. https://doi.org/10.1038/nrg2884 .
Martignetti L, Calzone L, Bonnet E, Barillot E, Zinovyev A. ROMA: Representation and Quantification of Module Activity from Target Expression Data. Front Genet. 2016;7. https://doi.org/10.3389/fgene.2016.00018 .
Landais Y, Vallot C. Multi-modal quantification of pathway activity with MAYA. Nat Commun. 2023;14(1):1668. Number: 1 Publisher: Nature Publishing Group. https://doi.org/10.1038/s41467-023-37410-2 .
Schubert M, Klinger B, Klünemann M, Sieber A, Uhlitz F, Sauer S, et al. Perturbation-response genes reveal signaling footprints in cancer gene expression. Nat Commun. 2018;9(1):20. Number: 1 Publisher: Nature Publishing Group. https://doi.org/10.1038/s41467-017-02391-6 .
Vaske CJ, Benz SC, Sanborn JZ, Earl D, Szeto C, Zhu J, et al. Inference of patient-specific pathway activities from multi-dimensional cancer genomics data using PARADIGM. Bioinformatics. 2010;26(12):i237–45. https://doi.org/10.1093/bioinformatics/btq182 .
doi: 10.1093/bioinformatics/btq182
pubmed: 20529912
pmcid: 2881367
Subramanian A, Tamayo P, Mootha VK, Mukherjee S, Ebert BL, Gillette MA, et al. Gene set enrichment analysis: A knowledge-based approach for interpreting genome-wide expression profiles. Proc Natl Acad Sci. 2005;102(43):15545–50. Publisher: National Academy of Sciences Section: Biological Sciences. https://doi.org/10.1073/pnas.0506580102 .
Hsu D, Taylor P, Fletcher D, van Heeckeren R, Eastman J, van Heeckeren A, et al. Interleukin-17 Pathophysiology and Therapeutic Intervention in Cystic Fibrosis Lung Infection and Inflammation. Infect Immun. 2016;84(9):2410–21. Publisher: American Society for Microbiology. https://doi.org/10.1128/iai.00284-16 .
Dumortier C, Danopoulos S, Velard F, Al Alam D. Bone cells differentiation: how CFTR mutations may rule the game of stem cells commitment? Front Cell Dev Biol. 2021;9:611921.
Kosamo S, Hisert KB, Dmyterko V, Nguyen C, Black RA, Holden TD, et al. Strong toll-like receptor responses in cystic fibrosis patients are associated with higher lung function. J Cyst Fibros. 2020;19(4):608–13. https://doi.org/10.1016/j.jcf.2019.11.009 .
doi: 10.1016/j.jcf.2019.11.009
pubmed: 31813753
Curutiu C, Iordache F, Lazar V, Pisoschi AM, Pop A, Chifiriuc MC, et al. Impact of Pseudomonas aeruginosa quorum sensing signaling molecules on adhesion and inflammatory markers in endothelial cells. Beilstein J Org Chem. 2018;14:2580–8. https://doi.org/10.3762/bjoc.14.235 .
doi: 10.3762/bjoc.14.235
pubmed: 30410619
pmcid: 6204754
Türei D, Korcsmáros T, Saez-Rodriguez J. OmniPath: guidelines and gateway for literature-curated signaling pathway resources. Nat Methods. 2016;13(12):966–7. Number: 12 Publisher: Nature Publishing Group. https://doi.org/10.1038/nmeth.4077 .
Venerando A, Pagano MA, Tosoni K, Meggio F, Cassidy D, Stobbart M, et al. Understanding protein kinase CK2 mis-regulation upon F508del CFTR expression. Naunyn-Schmiedebergs Arch Pharmacol. 2011;384(4):473–88. https://doi.org/10.1007/s00210-011-0650-x .
doi: 10.1007/s00210-011-0650-x
pubmed: 21607646
pmcid: 3208816
Wang H, Cebotaru L, Lee HW, Yang Q, Pollard BS, Pollard HB, et al. CFTR Controls the Activity of NF-[Formula: see text]B by Enhancing the Degradation of TRADD. Cell Physiol Biochem. 2016;40(5):1063–78. Publisher: Karger Publishers. https://doi.org/10.1159/000453162 .
Massip Copiz MM, Santa Coloma TA. c- Src and its role in cystic fibrosis. Eur J Cell Biol. 2016;95(10):401–13. https://doi.org/10.1016/j.ejcb.2016.08.001 .
doi: 10.1016/j.ejcb.2016.08.001
pubmed: 27530912
Rimessi A, Bezzerri V, Salvatori F, Tamanini A, Nigro F, Dechecchi MC, et al. PLCB3 Loss of Function Reduces Pseudomonas aeruginosa-Dependent IL-8 Release in Cystic Fibrosis. Am J Respir Cell Mol Biol. 2018;59(4):428–36. Publisher: American Thoracic Society - AJRCMB. https://doi.org/10.1165/rcmb.2017-0267OC .
Favia M, Guerra L, Fanelli T, Cardone RA, Monterisi S, Di Sole F, et al. Na+/H+ Exchanger Regulatory Factor 1 Overexpression-dependent Increase of Cytoskeleton Organization Is Fundamental in the Rescue of F508del Cystic Fibrosis Transmembrane Conductance Regulator in Human Airway CFBE41o- Cells. Mol Biol Cell. 2010;21(1):73–86. Publisher: American Society for Cell Biology (mboc). https://doi.org/10.1091/mbc.e09-03-0185 .
Wu Q, Eickelberg O. Ezrin in Asthma: A First Step to Early Biomarkers of Airway Epithelial Dysfunction. Am J Respir Crit Care Med. 2019;199(4):408–10. Publisher: American Thoracic Society - AJRCCM. https://doi.org/10.1164/rccm.201810-1964ED .
Mendes AI, Matos P, Moniz S, Luz S, Amaral MD, Farinha CM, et al. Antagonistic Regulation of Cystic Fibrosis Transmembrane Conductance Regulator Cell Surface Expression by Protein Kinases WNK4 and Spleen Tyrosine Kinase. Mol Cell Biol. 2011;31(19):4076–86. Publisher: Taylor & Francis _eprint: https://doi.org/10.1128/MCB.05152-11 .
Egan M, Flotte T, Afione S, Solow R, Zeitlin PL, Carter BJ, et al. Defective regulation of outwardly rectifying Cl channels by protein kinase A corrected by insertion of CFTR. Nature. 1992;358(6387):581–4. Number: 6387 Publisher: Nature Publishing Group. https://doi.org/10.1038/358581a0 .
Bérubé J, Roussel L, Nattagh L, Rousseau S. Loss of Cystic Fibrosis Transmembrane Conductance Regulator Function Enhances Activation of p38 and ERK MAPKs, Increasing Interleukin-6 Synthesis in Airway Epithelial Cells Exposed to Pseudomonas aeruginosa. J Biol Chem. 2010;285(29):22299–307. Publisher: American Society for Biochemistry and Molecular Biology. https://doi.org/10.1074/jbc.M109.098566 .
Wellmerling J, Rayner RE, Chang SW, Kairis EL, Kim SH, Sharma A, et al. Targeting the EGFR-ERK axis using the compatible solute ectoine to stabilize CFTR mutant F508del. FASEB J Off Publ Fed Am Soc Exp Biol. 2022;36(5):e22270. https://doi.org/10.1096/fj.202100458RRR .
doi: 10.1096/fj.202100458RRR
Cannon CL, Kowalski MP, Stopak KS, Pier GB. Pseudomonas aeruginosa-Induced Apoptosis Is Defective in Respiratory Epithelial Cells Expressing Mutant Cystic Fibrosis Transmembrane Conductance Regulator. Am J Respir Cell Mol Biol. 2003;29(2):188–97. Publisher: American Thoracic Society - AJRCMB. https://doi.org/10.1165/rcmb.4898 .
Gottlieb RA, Dosanjh A. Mutant cystic fibrosis transmembrane conductance regulator inhibits acidification and apoptosis in C127 cells: possible relevance to cystic fibrosis. Proc Natl Acad Sci. 1996;93(8):3587–91. Publisher: Proceedings of the National Academy of Sciences. https://doi.org/10.1073/pnas.93.8.3587 .
Chen Q, Pandi SPS, Kerrigan L, McElvaney NG, Greene CM, Elborn JS, et al. Cystic fibrosis epithelial cells are primed for apoptosis as a result of increased Fas (CD95). J Cyst Fibros. 2018;17(5):616–23. https://doi.org/10.1016/j.jcf.2018.01.010 .
doi: 10.1016/j.jcf.2018.01.010
pubmed: 29486923
Yalçin E, Talim B, Özçelik U, Doğru D, Çobanoğlu N, Pekcan S, et al. Does Defective Apoptosis Play A Role in Cystic Fibrosis Lung Disease? Arch Med Res. 2009;40(7):561–4. https://doi.org/10.1016/j.arcmed.2009.07.005 .
doi: 10.1016/j.arcmed.2009.07.005
pubmed: 20082869
Rottner M, Kunzelmann C, Mergey M, Freyssinet JM, Martínez MC. Exaggerated apoptosis and NF-kappaB activation in pancreatic and tracheal cystic fibrosis cells. FASEB J Off Publ Fed Am Soc Exp Biol. 2007;21(11):2939–48. https://doi.org/10.1096/fj.06-7614com .
doi: 10.1096/fj.06-7614com
Lasalvia M, Castellani S, D’Antonio P, Perna G, Carbone A, Colia AL, et al. Human airway epithelial cells investigated by atomic force microscopy: A hint to cystic fibrosis epithelial pathology. Exp Cell Res. 2016;348(1):46–55. https://doi.org/10.1016/j.yexcr.2016.08.025 .
doi: 10.1016/j.yexcr.2016.08.025
pubmed: 27590528
Burat B, Reynaerts A, Baiwir D, Fléron M, Gohy S, Eppe G, et al. Sweat Proteomics in Cystic Fibrosis: Discovering Companion Biomarkers for Precision Medicine and Therapeutic Development. Cells. 2022;11(15):2358. Number: 15 Publisher: Multidisciplinary Digital Publishing Institute. https://doi.org/10.3390/cells11152358 .
De Lisle RC. Disrupted tight junctions in the small intestine of cystic fibrosis mice. Cell Tissue Res. 2014;355(1):131–42. Available from: https://doi.org/10.1007/s00441-013-1734-3 . https://doi.org/10.1007/s00441-013-1734-3 .
Castellani S, Guerra L, Favia M, Di Gioia S, Casavola V, Conese M. NHERF1 and CFTR restore tight junction organisation and function in cystic fibrosis airway epithelial cells: role of ezrin and the RhoA/ROCK pathway. Lab Investig. 2012;92(11):1527–40. Number: 11 Publisher: Nature Publishing Group. https://doi.org/10.1038/labinvest.2012.123 .
Gillan JL, Chokshi M, Hardisty GR, Clohisey Hendry S, Prasca-Chamorro D, Robinson NJ, et al. CAGE sequencing reveals CFTR-dependent dysregulation of type I IFN signaling in activated cystic fibrosis macrophages. Sci Adv. 2023;9(21):eadg5128. Publisher: American Association for the Advancement of Science. https://doi.org/10.1126/sciadv.adg5128 .
Dugger DT, Fung M, Zlock L, Caldera S, Sharp L, Hays SR, et al. Cystic Fibrosis Lung Transplant Recipients Have Suppressed Airway Interferon Responses during Pseudomonas Infection. Cell Rep Med. 2020;1(4):100055. https://doi.org/10.1016/j.xcrm.2020.100055 .
doi: 10.1016/j.xcrm.2020.100055
pubmed: 32754722
pmcid: 7402593
Durón C, Pan Y, Gutmann DH, Hardin J, Radunskaya A. Variability of Betweenness Centrality and Its Effect on Identifying Essential Genes. Bull Math Biol. 2019;81(9):3655–73. Available from: https://doi.org/10.1007/s11538-018-0526-z . https://doi.org/10.1007/s11538-018-0526-z .
Ferenc Karpati LH Bengt Wretlind. TNF-A and IL-8 in Consecutive Sputum Samples from Cystic Fibrosis Patients During Antibiotic Treatment. Scand J Infect Dis. 2000;32(1):75–9. Publisher: Taylor & Francis _eprint: https://doi.org/10.1080/00365540050164263 .
Riccaboni M, Bianchi I, Petrillo P. Spleen tyrosine kinases: biology, therapeutic targets and drugs. Drug Discov Today. 2010;15(13):517–30. https://doi.org/10.1016/j.drudis.2010.05.001 .
doi: 10.1016/j.drudis.2010.05.001
pubmed: 20553955
Wong BR, Grossbard EB, Payan DG, Masuda ES. Targeting Syk as a treatment for allergic and autoimmune disorders. Expert Opin Investig Drugs. 2004;13(7):743–62. Publisher: Taylor & Francis _eprint: https://doi.org/10.1517/13543784.13.7.743 .
Bezzerri V, d’Adamo P, Rimessi A, Lanzara C, Crovella S, Nicolis E, et al. Phospholipase C-[Formula: see text]3 Is a Key Modulator of IL-8 Expression in Cystic Fibrosis Bronchial Epithelial Cells. J Immunol. 2011;186(8):4946–58. https://doi.org/10.4049/jimmunol.1003535 .
Bell SC, Mall MA, Gutierrez H, Macek M, Madge S, Davies JC, et al. The Lancet Respiratory Medicine Commission on the Future of Care of Cystic Fibrosis. Lancet Respir Med. 2020;8(1):65–124. https://doi.org/10.1016/S2213-2600(19)30337-6 .
doi: 10.1016/S2213-2600(19)30337-6
pubmed: 31570318
Cooper N, Ghanima W, Hill QA, Nicolson PL, Markovtsov V, Kessler C. Recent advances in understanding spleen tyrosine kinase (SYK) in human biology and disease, with a focus on fostamatinib. Platelets. 2023;34(1):2131751. Publisher: Taylor & Francis _eprint: https://doi.org/10.1080/09537104.2022.2131751 .
Fiorotto R, Amenduni M, Mariotti V, Fabris L, Spirli C, Strazzabosco M. Src kinase inhibition reduces inflammatory and cytoskeletal changes in ΔF508 human cholangiocytes and improves cystic fibrosis transmembrane conductance regulator correctors efficacy: Fiorotto, Amenduni, et al. Hepatology. 2018;67(3):972–88. Number: 3. https://doi.org/10.1002/hep.29400 .
Natarajan V. Is PI3K a Villain in Cystic Fibrosis? Am J Respir Cell Mol Biol. 2020;62(5):552–3. Publisher: American Thoracic Society - AJRCMB. https://doi.org/10.1165/rcmb.2020-0029ED .
Dorfman R, Sandford A, Taylor C, Huang B, Frangolias D, Wang Y, et al. Complex two-gene modulation of lung disease severity in children with cystic fibrosis. J Clin Investig. 2008;118(3):1040–9. Publisher: American Society for Clinical Investigation. https://doi.org/10.1172/JCI33754 .
Sagwal S, Chauhan A, Kaur J, Prasad R, Singh M, Singh M. Association of Serum TGF-[Formula: see text]1 Levels with Different Clinical Phenotypes of Cystic Fibrosis Exacerbation. Lung. 2020;198(2):377–83. https://doi.org/10.1007/s00408-020-00320-x .
Kramer EL, Clancy JP. TGFB as a therapeutic target in cystic fibrosis. Expert Opin Ther Targets. 2018;22(2):177–89. Publisher: Taylor & Francis _eprint: https://doi.org/10.1080/14728222.2018.1406922 .
Zabner J, Scheetz TE, Almabrazi HG, Casavant TL, Huang J, Keshavjee S, et al. CFTR ΔF508 mutation has minimal effect on the gene expression profile of differentiated human airway epithelia. American Journal of Physiology-Lung Cellular and Molecular Physiology. 2005;289(4):L545–53. Publisher: American Physiological Society. https://doi.org/10.1152/ajplung.00065.2005 .
Wright JM, Merlo CA, Reynolds JB, Zeitlin PL, Garcia JGN, Guggino WB, et al. Respiratory epithelial gene expression in patients with mild and severe cystic fibrosis lung disease. Am J Respir Cell Mol Biol. 2006;35(3):327–36. https://doi.org/10.1165/rcmb.2005-0359OC .
doi: 10.1165/rcmb.2005-0359OC
pubmed: 16614352
pmcid: 2643286
Bampi GB, Rauscher R, Kirchner S, Oliver KE, Bijvelds MJC, Santos LA, et al. Global assessment of the integrated stress response in CF patient-derived airway and intestinal tissues. J Cyst Fibros. 2020;19(6):1021–6. https://doi.org/10.1016/j.jcf.2020.04.005 .
doi: 10.1016/j.jcf.2020.04.005
pubmed: 32451204
pmcid: 7932027
Veltman M, De Sanctis JB, Stolarczyk M, Klymiuk N, Bähr A, Brouwer RW, et al. CFTR correctors and antioxidants partially normalize lipid imbalance but not abnormal basal inflammatory cytokine profile in CF bronchial epithelial cells. Front Physiol. 2021;12:619442.
Law CW, Alhamdoosh M, Su S, Dong X, Tian L, Smyth GK, et al. RNA-seq analysis is easy as 1-2-3 with limma, Glimma and edgeR. F1000Research. 2018;5:ISCB Comm J–1408. https://doi.org/10.12688/f1000research.9005.3 .
Robinson MD, Oshlack A. A scaling normalization method for differential expression analysis of RNA-seq data. Genome Biol. 2010;11(3):R25. https://doi.org/10.1186/gb-2010-11-3-r25 .
doi: 10.1186/gb-2010-11-3-r25
pubmed: 20196867
pmcid: 2864565
Korotkevich G, Sukhov V, Budin N, Shpak B, Artyomov MN, Sergushichev A. Fast gene set enrichment analysis. bioRxiv. 2021. Pages: 060012 Section: New Results. https://doi.org/10.1101/060012 .
Ritchie ME, Phipson B, Wu D, Hu Y, Law CW, Shi W, et al. limma powers differential expression analyses for RNA-sequencing and microarray studies. Nucleic Acids Res. 2015;43(7):e47. https://doi.org/10.1093/nar/gkv007 .
doi: 10.1093/nar/gkv007
pubmed: 25605792
pmcid: 4402510
Robinson MD, McCarthy DJ, Smyth GK. edgeR: a Bioconductor package for differential expression analysis of digital gene expression data. Bioinformatics. 2010;26(1):139–40. https://doi.org/10.1093/bioinformatics/btp616 .
doi: 10.1093/bioinformatics/btp616
pubmed: 19910308
Durinck S, Spellman PT, Birney E, Huber W. Mapping Identifiers for the Integration of Genomic Datasets with the R/Bioconductor package biomaRt. Nat Protoc. 2009;4(8):1184–91. https://doi.org/10.1038/nprot.2009.97 .
doi: 10.1038/nprot.2009.97
pubmed: 19617889
pmcid: 3159387
Lo Surdo P, Iannuccelli M, Contino S, Castagnoli L, Licata L, Cesareni G, et al. SIGNOR 3.0, the SIGnaling network open resource 3.0: 2022 update. Nucleic Acids Res. 2022;gkac883. https://doi.org/10.1093/nar/gkac883 .
Drew K, Wallingford JB, Marcotte EM. hu.MAP 2.0: integration of over 15,000 proteomic experiments builds a global compendium of human multiprotein assemblies. Mol Syst Biol. 2021;17(5):e10016. Publisher: John Wiley & Sons, Ltd. https://doi.org/10.15252/msb.202010016 .
Garcia-Alonso L, Holland CH, Ibrahim MM, Turei D, Saez-Rodriguez J. Benchmark and integration of resources for the estimation of human transcription factor activities. Genome Res. 2019;29(8):1363–75. Company: Cold Spring Harbor Laboratory Press Distributor: Cold Spring Harbor Laboratory Press Institution: Cold Spring Harbor Laboratory Press Label: Cold Spring Harbor Laboratory Press Publisher: Cold Spring Harbor Lab. https://doi.org/10.1101/gr.240663.118 .
Seal RL, Braschi B, Gray K, Jones TEM, Tweedie S, Haim-Vilmovsky L, et al. Genenames.org: the HGNC resources in 2023. Nucleic Acids Res. 2023;51(D1):D1003–9. https://doi.org/10.1093/nar/gkac888 .
Csardi G, Nepusz T. The Igraph Software Package for Complex Network Research. InterJournal. 2005;Complex Systems:1695.
Shannon P, Markiel A, Ozier O, Baliga NS, Wang JT, Ramage D, et al. Cytoscape: A Software Environment for Integrated Models of Biomolecular Interaction Networks. Genome Res. 2003;13(11):2498–504. Company: Cold Spring Harbor Laboratory Press Distributor: Cold Spring Harbor Laboratory Press Institution: Cold Spring Harbor Laboratory Press Label: Cold Spring Harbor Laboratory Press Publisher: Cold Spring Harbor Lab. https://doi.org/10.1101/gr.1239303 .
Luna A, Shah O, Sander C, Shannon P. cyjShiny: A cytoscape.js R Shiny Widget for network visualization and analysis. PLoS ONE. 2023;18(8):e0285339. Publisher: Public Library of Science. https://doi.org/10.1371/journal.pone.0285339 .
Carraro G, Langerman J, Sabri S, Lorenzana Z, Purkayastha A, Zhang G, et al. Transcriptional analysis of cystic fibrosis airways at single-cell resolution reveals altered epithelial cell states and composition. Nat Med. 2021;27(5):806–14. Bandiera_abtest: a Cg_type: Nature Research Journals Number: 5 Primary_atype: Research Publisher: Nature Publishing Group Subject_term: Diseases;Respiratory tract diseases Subject_term_id: diseases;respiratory-tract-diseases. https://doi.org/10.1038/s41591-021-01332-7 .
Thurman AL, Li X, Villacreses R, Yu W, Gong H, Mather SE, et al. A Single-Cell Atlas of Large and Small Airways at Birth in a Porcine Model of Cystic Fibrosis. Am J Respir Cell Mol Biol. 2022;66(6):612–22. Publisher: American Thoracic Society - AJRCMB. https://doi.org/10.1165/rcmb.2021-0499OC .
Okuda K, Dang H, Kobayashi Y, Carraro G, Nakano S, Chen G, et al. Secretory Cells Dominate Airway CFTR Expression and Function in Human Airway Superficial Epithelia. Am J Respir Crit Care Med. 2021;Publisher: American Thoracic Society. https://doi.org/10.1164/rccm.202008-3198OC .
Duan Y, Li G, Xu M, Qi X, Deng M, Lin X, et al. CFTR is a negative regulator of [Formula: see text] T cell IFN-γ production and antitumor immunity. Cell Mol Immunol. 2021;18(8):1934–44. Number: 8 Publisher: Nature Publishing Group. https://doi.org/10.1038/s41423-020-0499-3 .
Stelzer G, Rosen N, Plaschkes I, Zimmerman S, Twik M, Fishilevich S, et al. The GeneCards Suite: From Gene Data Mining to Disease Genome Sequence Analyses. Curr Protoc Bioinforma. 2016;54(1):1.30.1–1.30.33. _eprint: https://doi.org/10.1002/cpbi.5 .
Keating D, Marigowda G, Burr L, Daines C, Mall MA, McKone EF, et al. VX-445-Tezacaftor-Ivacaftor in Patients with Cystic Fibrosis and One or Two Phe508del Alleles. N Engl J Med. 2018;379(17):1612–20. Publisher: Massachusetts Medical Society _eprint: https://doi.org/10.1056/NEJMoa1807120 .
Santos L, Nascimento R, Duarte A, Railean V, Amaral MD, Harrison PT, et al. Mutation-class dependent signatures outweigh disease-associated processes in cystic fibrosis cells. Cell Biosci. 2023;13(1):26. https://doi.org/10.1186/s13578-023-00975-y .
doi: 10.1186/s13578-023-00975-y
pubmed: 36759923
pmcid: 9912517
Saint-Criq V, Gray MA. Role of CFTR in epithelial physiology. Cell Mol Life Sci. 2017;74(1):93–115. https://doi.org/10.1007/s00018-016-2391-y .
doi: 10.1007/s00018-016-2391-y
pubmed: 27714410
Simões FB, Kmit A, Amaral MD. Cross-talk of inflammatory mediators and airway epithelium reveals the cystic fibrosis transmembrane conductance regulator as a major target. ERJ Open Res. 2021;7(4):00247–2021. https://doi.org/10.1183/23120541.00247-2021 .
doi: 10.1183/23120541.00247-2021
pubmed: 34912883
pmcid: 8666577
Valdivieso AG, Dugour AV, Sotomayor V, Clauzure M, Figueroa JM, Santa-Coloma TA. N-acetyl cysteine reverts the proinflammatory state induced by cigarette smoke extract in lung Calu-3 cells. Redox Biol. 2018;16:294–302. https://doi.org/10.1016/j.redox.2018.03.006 .
doi: 10.1016/j.redox.2018.03.006
pubmed: 29573703
pmcid: 5953002
Wang Y, Tang L, Yang L, Lv P, Mai S, Xu L, et al. DNA Methylation-Mediated Low Expression of CFTR Stimulates the Progression of Lung Adenocarcinoma. Biochem Genet. 2022;60(2):807–21. https://doi.org/10.1007/s10528-021-10128-w .
doi: 10.1007/s10528-021-10128-w
pubmed: 34498165