2025
Systemic in utero gene editing as a treatment for cystic fibrosis
Ricciardi A, Barone C, Putman R, Quijano E, Gupta A, Nguyen R, Mandl H, Piotrowski-Daspit A, Lopez-Giraldez F, Luks V, Freedman-Weiss M, Farrelly J, Ahle S, Lynn A, Glazer P, Saltzman W, Stitelman D, Egan M. Systemic in utero gene editing as a treatment for cystic fibrosis. Proceedings Of The National Academy Of Sciences Of The United States Of America 2025, 122: e2418731122. PMID: 40493185, PMCID: PMC12184489, DOI: 10.1073/pnas.2418731122.Peer-Reviewed Original ResearchConceptsUtero gene editingCystic fibrosisCF transmembrane conductance regulatorTreat CF patientsTransmembrane conductance regulatorWild-type miceIrreversible organ damageNormal organ developmentTreat monogenic diseasesCFTR activityCF patientsConductance regulatorDisease-causing genesMultiorgan diseaseDisease improvementOrgan damageGene editingMonogenic diseasesMutation correctionPolymeric nanoparticlesGastrointestinal tissuesDiseaseBirthFibrosisReproductive systemENaC contributes to macrophage dysfunction in cystic fibrosis
Moran J, Pugh C, Brown N, Thomas A, Zhang S, McCauley E, Cephas A, Shrestha C, Partida-Sanchez S, Bai S, Bruscia E, Kopp B. ENaC contributes to macrophage dysfunction in cystic fibrosis. American Journal Of Physiology - Lung Cellular And Molecular Physiology 2025, 329: l61-l69. PMID: 40454714, PMCID: PMC12181047, DOI: 10.1152/ajplung.00009.2025.Peer-Reviewed Original ResearchConceptsCystic fibrosis transmembrane conductance regulatorCystic fibrosis transmembrane conductance regulator modulatorsMonocyte-derived macrophagesEpithelial sodium channelTransmembrane conductance regulatorCystic fibrosisImmune cellsProinflammatory cytokine productionENaC modulationENaC expressionConductance regulatorCystic fibrosis transmembrane conductance regulator inhibitionCytokine productionSodium channelsCF airway epithelial cellsReduced proinflammatory cytokine productionDecreased proinflammatory cytokine productionSodium channel expressionInfection controlTherapeutic targetAirway epithelial cellsIon channel dysfunctionReactive oxygen speciesIon channelsCFTR expressionCFTR dictates monocyte adhesion by facilitating integrin clustering but not activation
Younis D, Marosvari M, Liu W, Pulikkot S, Cao Z, Zhou B, Vella A, McArdle S, Hu L, Chen Y, Gan W, Yu J, Bruscia E, Fan Z. CFTR dictates monocyte adhesion by facilitating integrin clustering but not activation. Proceedings Of The National Academy Of Sciences Of The United States Of America 2025, 122: e2412717122. PMID: 39813254, PMCID: PMC11760921, DOI: 10.1073/pnas.2412717122.Peer-Reviewed Original ResearchConceptsIntegrin clusteringCF transmembrane conductance regulatorCystic fibrosisAdhesion defectsPathogenesis of cystic fibrosisClinically relevant disease modelsMembrane recruitmentTransmembrane conductance regulatorIntegrin activationTherapeutic strategy designRelevant disease modelsIntegrinCF monocytesCell adhesionMonocyte dysfunctionPatients' monocytesTissue infectionsConductance regulatorSuperresolution microscopyCortex formationLeukocyte-dependent inflammationInflammatory pathogenesisLeukocyte adhesionMonocytesInflammation
2024
Novel Approaches to Multidrug-Resistant Infections in Cystic Fibrosis
Murray T, Stanley G, Koff J. Novel Approaches to Multidrug-Resistant Infections in Cystic Fibrosis. Infectious Disease Clinics Of North America 2024, 38: 149-162. PMID: 38280761, DOI: 10.1016/j.idc.2023.12.002.Peer-Reviewed Original ResearchConceptsMultidrug-resistant organismsCystic fibrosis transmembrane conductance regulatorCystic fibrosisBeta-lactam/beta-lactamase combinationDevelopment of inhaled formulationsMethicillin-resistant Staphylococcus aureusTherapeutic approachesMultidrug-resistant organism infectionSystemic adverse eventsMultidrug-resistant infectionsTransmembrane conductance regulatorRespiratory tract infectionsCystic fibrosis patientsGram-negative organismsInnovative therapeutic approachesPulmonary infectionTract infectionsConductance regulatorBurkholderia sp.Multidrug resistanceAdverse eventsTreatment optionsAntibiotic resistanceFibrosis patientsOptimal dose
2023
Epithelial TNF controls cell differentiation and CFTR activity to maintain intestinal mucin homeostasis
Reyes E, Castillo-Azofeifa D, Rispal J, Wald T, Zwick R, Palikuqi B, Mujukian A, Rabizadeh S, Gupta A, Gardner J, Boffelli D, Gartner Z, Klein O. Epithelial TNF controls cell differentiation and CFTR activity to maintain intestinal mucin homeostasis. Journal Of Clinical Investigation 2023, 133: e163591. PMID: 37643009, PMCID: PMC10575728, DOI: 10.1172/jci163591.Peer-Reviewed Original ResearchConceptsCystic fibrosis transmembrane conductance regulatorTumor necrosis factorInflammatory bowel diseaseCell differentiationRegulate mucin productionCystic fibrosis transmembrane conductance regulator inhibitionCystic fibrosis transmembrane conductance regulator activityTumor necrosis factor treatmentInflammatory cytokine tumor necrosis factorAnti-TNF therapyAbsence of tumor necrosis factorTransmembrane conductance regulatorCytokine tumor necrosis factorMucus-producing goblet cellsGenetic mouse modelsUpstream regulatorIncreased mucus accumulationAdult intestineConductance regulatorEpithelial signalsSignaling axisProgenitor cellsMouse modelNecrosis factorGut transit timeCFTR High Expresser Cells in cystic fibrosis and intestinal diseases
dos Reis D, Dastoor P, Santos A, Sumigray K, Ameen N. CFTR High Expresser Cells in cystic fibrosis and intestinal diseases. Heliyon 2023, 9: e14568. PMID: 36967909, PMCID: PMC10031467, DOI: 10.1016/j.heliyon.2023.e14568.Peer-Reviewed Original ResearchCystic fibrosisIntestinal diseaseCystic fibrosis transmembrane conductance regulatorQuality of lifeIntestinal dysfunctionGastrointestinal diseasesIntestinal physiologyFibrosisDiseasePathophysiologyFibrosis transmembrane conductance regulatorTransmembrane conductance regulatorCFTR leadConductance regulator
2020
Multi-dimensional clinical phenotyping of a national cohort of adult cystic fibrosis patients
Conrad D, Billings J, Teneback C, Koff J, Rosenbluth D, Bailey B, Jain R. Multi-dimensional clinical phenotyping of a national cohort of adult cystic fibrosis patients. Journal Of Cystic Fibrosis 2020, 20: 91-96. PMID: 32948498, DOI: 10.1016/j.jcf.2020.08.010.Peer-Reviewed Original ResearchConceptsCystic fibrosis transmembrane conductance regulatorCF patientsCystic fibrosisClinical phenotypeChronic P. aeruginosa infectionDistal intestinal obstruction syndromeAdult cystic fibrosis patientsPseudomonas aeruginosa colonizationUS CF centersAdult CF patientsIntestinal obstruction syndromeTransmembrane conductance regulatorHigh-risk phenotypeWell-nourished groupCholestatic liver diseaseGroup of patientsCystic fibrosis patientsRates of pancreatic insufficiencyMulti-system disorderPancreatic malabsorptionObstruction syndromeChronic sinusitisConductance regulatorPancreatic insufficiencyCF centers
2019
CFTR-PTEN–dependent mitochondrial metabolic dysfunction promotes Pseudomonas aeruginosa airway infection
Riquelme SA, Lozano C, Moustafa AM, Liimatta K, Tomlinson KL, Britto C, Khanal S, Gill SK, Narechania A, Azcona-Gutiérrez JM, DiMango E, Saénz Y, Planet P, Prince A. CFTR-PTEN–dependent mitochondrial metabolic dysfunction promotes Pseudomonas aeruginosa airway infection. Science Translational Medicine 2019, 11 PMID: 31270271, PMCID: PMC6784538, DOI: 10.1126/scitranslmed.aav4634.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsCarboxy-LyasesColony Count, MicrobialCystic FibrosisCystic Fibrosis Transmembrane Conductance RegulatorHCT116 CellsHumansHypoxia-Inducible Factor 1, alpha SubunitImmunityInterleukin-1betaLungMice, Inbred C57BLMiddle AgedMitochondriaOxidantsOxidative StressPseudomonas aeruginosaPseudomonas InfectionsPTEN PhosphohydrolaseReactive Oxygen SpeciesSuccinatesConceptsCystic fibrosis transmembrane conductance regulatorImmune-responsive gene 1Fibrosis transmembrane conductance regulatorEffect of PTENTransmembrane conductance regulatorPlasma membraneChromosome 10Reactive oxygen speciesConductance regulatorTumor suppressorTensin homologGene 1Mitochondrial functionMitochondrial activityAnti-inflammatory host responsesCell proliferationOxygen speciesPTENMyeloid cellsCFTR dysfunctionMetabolic defectsHost responseActivity contributesHomologComplexesPathophysiology of Cystic Fibrosis Liver Disease: A Channelopathy Leading to Alterations in Innate Immunity and in Microbiota
Fiorotto R, Strazzabosco M. Pathophysiology of Cystic Fibrosis Liver Disease: A Channelopathy Leading to Alterations in Innate Immunity and in Microbiota. Cellular And Molecular Gastroenterology And Hepatology 2019, 8: 197-207. PMID: 31075352, PMCID: PMC6664222, DOI: 10.1016/j.jcmgh.2019.04.013.Peer-Reviewed Reviews, Practice Guidelines, Standards, and Consensus StatementsConceptsCF-associated liver diseaseLiver diseaseCystic fibrosisInnate immunityCystic fibrosis liver diseaseEpithelial innate immunityCystic fibrosis transmembrane conductance regulatorFibrosis transmembrane conductance regulatorNonpulmonary causesCF adultsTransmembrane conductance regulatorLiver complicationsMutations of CFTRPediatric populationAltered microbiotaIntestinal diseaseBile secretionCF mortalityDiseaseNew drugsConductance regulatorPotential targetLife expectancyBasic defectPathophysiology
2017
Ezrin links CFTR to TLR4 signaling to orchestrate anti-bacterial immune response in macrophages
Di Pietro C, Zhang PX, O’Rourke T, Murray TS, Wang L, Britto CJ, Koff JL, Krause DS, Egan ME, Bruscia EM. Ezrin links CFTR to TLR4 signaling to orchestrate anti-bacterial immune response in macrophages. Scientific Reports 2017, 7: 10882. PMID: 28883468, PMCID: PMC5589856, DOI: 10.1038/s41598-017-11012-7.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsCell LineCystic FibrosisCystic Fibrosis Transmembrane Conductance RegulatorCytoskeletal ProteinsDisease Models, AnimalMacrophage ActivationMacrophagesMicePhosphatidylinositol 3-KinasesProto-Oncogene Proteins c-aktPseudomonas aeruginosaPseudomonas InfectionsSignal TransductionToll-Like Receptor 4ConceptsCystic fibrosis transmembrane conductance regulatorPI3K/AktFibrosis transmembrane conductance regulatorTransmembrane conductance regulatorPI3K/Akt signalingConductance regulatorAnti-bacterial immune responseAkt signalingAltered localizationEzrinCystic fibrosis diseaseMφ activationAktProtein levelsFibrosis diseaseActivationImmune regulationPhagocytosisInductionDirect linkSignalingRegulatorImmune responseMΦMacrophages
2013
Regulated traffic of anion transporters in mammalian Brunner's glands: a role for water and fluid transport
Collaco AM, Jakab RL, Hoekstra NE, Mitchell KA, Brooks A, Ameen NA. Regulated traffic of anion transporters in mammalian Brunner's glands: a role for water and fluid transport. AJP Gastrointestinal And Liver Physiology 2013, 305: g258-g275. PMID: 23744739, PMCID: PMC3742856, DOI: 10.1152/ajpgi.00485.2012.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsAnion Transport ProteinsAquaporin 5BicarbonatesBiological TransportBrunner GlandsCarbacholCeliac DiseaseChloridesCyclic AMPCystic FibrosisCystic Fibrosis Transmembrane Conductance RegulatorDuodenumHumansMaleProtonsRatsRats, Sprague-DawleySecond Messenger SystemsVacuolar Proton-Translocating ATPasesWaterConceptsCystic fibrosis transmembrane conductance regulatorV-ATPaseProton-pumping vacuolar ATPaseApical membraneDistinct membrane domainsFibrosis transmembrane conductance regulatorRat Brunner's glandsTransmembrane conductance regulatorSodium bicarbonate cotransporterAnion transportersApical traffickingMembrane domainsChloride cotransporter 1Secretion of glycoproteinsVacuolar ATPaseSecond messenger activationTransporter localizationConductance regulatorSubcellular distributionAquaporin 5 water channelFunctional transportPKA inhibitorAntimicrobial peptidesTransportersBasolateral membraneReduced Caveolin-1 Promotes Hyperinflammation due to Abnormal Heme Oxygenase-1 Localization in Lipopolysaccharide-Challenged Macrophages with Dysfunctional Cystic Fibrosis Transmembrane Conductance Regulator
Zhang PX, Murray TS, Villella VR, Ferrari E, Esposito S, D'Souza A, Raia V, Maiuri L, Krause DS, Egan ME, Bruscia EM. Reduced Caveolin-1 Promotes Hyperinflammation due to Abnormal Heme Oxygenase-1 Localization in Lipopolysaccharide-Challenged Macrophages with Dysfunctional Cystic Fibrosis Transmembrane Conductance Regulator. The Journal Of Immunology 2013, 190: 5196-5206. PMID: 23606537, PMCID: PMC3711148, DOI: 10.4049/jimmunol.1201607.Peer-Reviewed Original ResearchMeSH KeywordsAdolescentAdultAnimalsCaveolin 1Cells, CulturedChildChild, PreschoolCystic FibrosisCystic Fibrosis Transmembrane Conductance RegulatorFemaleHeme Oxygenase-1HumansInflammationLipopolysaccharidesLung DiseasesMacrophagesMaleMembrane ProteinsMiceMice, KnockoutNasal PolypsReactive Oxygen SpeciesSignal TransductionToll-Like Receptor 4Young AdultConceptsCav-1 expressionHeme oxygenase-1Dysfunctional cystic fibrosis transmembrane conductance regulatorCystic fibrosis transmembrane conductance regulatorCell surfaceFibrosis transmembrane conductance regulatorProtein caveolin-1Cellular redox statusCell surface localizationCellular oxidative stateTransmembrane conductance regulatorHO-1 enzymePositive feed-forward loopCystic fibrosis macrophagesNegative regulatorCaveolin-1Conductance regulatorCell survivalHO-1 deliverySurface localizationRedox statusMΦ responsesHO-1/CO pathwayPathwayPotential targetTargeting the Intracellular Environment in Cystic Fibrosis: Restoring Autophagy as a Novel Strategy to Circumvent the CFTR Defect
Villella VR, Esposito S, Bruscia EM, Maiuri MC, Raia V, Kroemer G, Maiuri L. Targeting the Intracellular Environment in Cystic Fibrosis: Restoring Autophagy as a Novel Strategy to Circumvent the CFTR Defect. Frontiers In Pharmacology 2013, 4: 1. PMID: 23346057, PMCID: PMC3549520, DOI: 10.3389/fphar.2013.00001.Peer-Reviewed Original ResearchCF transmembrane conductance regulatorIntracellular environmentMutant CF transmembrane conductance regulatorF508del-CFTR proteinBeclin-1CFTR channel activityTransmembrane conductance regulatorDefective CF transmembrane conductance regulatorDirect gene transferGeneral proteostasisProteostasis regulatorsConformational diseasesDisabled autophagyCFTR mutantsAutophagosome formationPlasma membraneConductance regulatorF508del-CFTRCommon deletion mutationsDeletion mutationsRecent pre-clinical evidenceIntracellular retentionGene transferCFTR defectProteostasis
2011
Divergent CFTR orthologs respond differently to the channel inhibitors CFTRinh-172, glibenclamide, and GlyH-101
Stahl M, Stahl K, Brubacher MB, Forrest JN. Divergent CFTR orthologs respond differently to the channel inhibitors CFTRinh-172, glibenclamide, and GlyH-101. American Journal Of Physiology - Cell Physiology 2011, 302: c67-c76. PMID: 21940661, PMCID: PMC3328903, DOI: 10.1152/ajpcell.00225.2011.Peer-Reviewed Original ResearchConceptsCystic fibrosis transmembrane conductance regulatorGlyH-101Expression studiesChannel proteinsCFTR chloride channel proteinFibrosis transmembrane conductance regulatorChloride channel proteinSite-directed mutagenesisShark rectal glandAmino acid residuesTransmembrane conductance regulatorDifferent orthologsSingle amino acidPrevious site-directed mutagenesisOocyte expression studiesThree-dimensional structureRegulatory regionsXenopus laevis oocytesCFTR proteinAdditional residuesConductance regulatorOrthologsAcid residuesRectal glandSpecific inhibitorActivating AMP-activated protein kinase (AMPK) slows renal cystogenesis
Takiar V, Nishio S, Seo-Mayer P, King JD, Li H, Zhang L, Karihaloo A, Hallows KR, Somlo S, Caplan MJ. Activating AMP-activated protein kinase (AMPK) slows renal cystogenesis. Proceedings Of The National Academy Of Sciences Of The United States Of America 2011, 108: 2462-2467. PMID: 21262823, PMCID: PMC3038735, DOI: 10.1073/pnas.1011498108.Peer-Reviewed Original ResearchConceptsCystic fibrosis transmembrane conductance regulatorRenal cystogenesisProtein kinaseAutosomal dominant polycystic kidney diseaseFibrosis transmembrane conductance regulatorTransmembrane conductance regulatorEpithelial cellsCyst epithelial cellsRenal cyst developmentCyst-lining epithelial cellsAMPK activationConductance regulatorRapamycin (mTOR) pathwayMammalian targetPharmacological activatorsChloride channelsMTOR pathwayCystogenesisCyst developmentKinaseAMPKContext of ADPKDSignificant arrestDominant polycystic kidney diseasePolycystic kidney disease
2010
Mouse cystic fibrosis transmembrane conductance regulator forms cAMP-PKA–regulated apical chloride channels in cortical collecting duct
Lu M, Dong K, Egan ME, Giebisch GH, Boulpaep EL, Hebert SC. Mouse cystic fibrosis transmembrane conductance regulator forms cAMP-PKA–regulated apical chloride channels in cortical collecting duct. Proceedings Of The National Academy Of Sciences Of The United States Of America 2010, 107: 6082-6087. PMID: 20231442, PMCID: PMC2851921, DOI: 10.1073/pnas.0902661107.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsBenzoatesChloride ChannelsCyclic AMPCyclic AMP-Dependent Protein KinasesCystic Fibrosis Transmembrane Conductance RegulatorFemaleIn Vitro TechniquesKidney CortexKidney Tubules, CollectingKineticsMiceMice, Inbred C57BLMice, Inbred CFTRMice, KnockoutMice, TransgenicMutationOocytesPatch-Clamp TechniquesPotassium Channels, Inwardly RectifyingRecombinant ProteinsThiazolidinesXenopus laevisConceptsCystic fibrosis transmembrane conductance regulatorFibrosis transmembrane conductance regulatorTransmembrane conductance regulatorCl- channel activityConductance regulatorCl- channelsApical membrane proteinsExpression of CFTRChannel activityCFTR Cl- channelApical chloride channelApical cell membraneDeltaF508 CFTR mutationMembrane proteinsCatalytic subunitXenopus laevis oocytesForm proteinPrincipal cellsCFTR channelsROMK null miceApical patchesApical membraneSingle-channel conductanceChloride channelsCell membrane
2009
How useful are cystic fibrosis mouse models?
Egan M. How useful are cystic fibrosis mouse models? Drug Discovery Today Disease Models 2009, 6: 35-41. DOI: 10.1016/j.ddmod.2009.03.009.Peer-Reviewed Original ResearchCystic fibrosis transmembrane conductance regulatorFibrosis transmembrane conductance regulatorTransmembrane conductance regulatorConductance regulatorLethal genetic disorderHuman diseasesCF pathophysiologyCystic fibrosis mouse modelCF mouse modelsMouse modelGenetic disordersSignificant insightsDrug developmentGenes
2006
ΔF508 Mutation Results in Impaired Gastric Acid Secretion*
Sidani SM, Kirchhoff P, Socrates T, Stelter L, Ferreira E, Caputo C, Roberts KE, Bell RL, Egan ME, Geibel JP. ΔF508 Mutation Results in Impaired Gastric Acid Secretion*. Journal Of Biological Chemistry 2006, 282: 6068-6074. PMID: 17178714, DOI: 10.1074/jbc.m608427200.Peer-Reviewed Original ResearchConceptsCystic fibrosis transmembrane conductance regulatorATP-binding cassette (ABC) transportersFibrosis transmembrane conductance regulatorTransmembrane conductance regulatorMouse gastric glandsParietal cellsMultifunctional proteinCFTR proteinRegulatory proteinsTransport proteinsCassette transportersConductance regulatorRegulatory roleApical poleSecretagogue-induced acid secretionGland lumenGastric glandsSulfonylurea receptorProteinImpaired gastric acid secretionK-ATPaseCl(-) secretionImmunofluorescent localizationCl- channelsATP-sensitive potassium channels
2004
Curcumin, a Major Constituent of Turmeric, Corrects Cystic Fibrosis Defects
Egan ME, Pearson M, Weiner SA, Rajendran V, Rubin D, Glöckner-Pagel J, Canny S, Du K, Lukacs GL, Caplan MJ. Curcumin, a Major Constituent of Turmeric, Corrects Cystic Fibrosis Defects. Science 2004, 304: 600-602. PMID: 15105504, DOI: 10.1126/science.1093941.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsCalciumCalnexinCell LineCell MembraneCricetinaeCurcuminCystic FibrosisCystic Fibrosis Transmembrane Conductance RegulatorElectrolytesEndoplasmic ReticulumGene TargetingGlycosylationHumansIntestinal MucosaIntestinal ObstructionIsoproterenolMembrane PotentialsMiceMice, KnockoutMutationNasal MucosaPolyethylene GlycolsProtein FoldingRectumTransfectionConceptsCystic fibrosis transmembrane conductance regulatorCFTR proteinDeltaF508 cystic fibrosis transmembrane conductance regulatorDeltaF508 CFTR proteinFibrosis transmembrane conductance regulatorTransmembrane conductance regulatorBaby hamster kidney cellsPlasma membraneComplete knockoutConductance regulatorHamster kidney cellsEndoplasmic reticulumCystic fibrosis defectCFTR geneKidney cellsCFTR miceGenesProteinMutationsCommon mutationsHomozygous expressionCurcumin treatmentFunctional appearanceWeight basisRegulator
2000
Subcellular distribution of CFTR in rat intestine supports a physiologic role for CFTR regulation by vesicle traffic
Ameen N, van Donselaar E, Posthuma G, de Jonge H, McLaughlin G, Geuze H, Marino C, Peters P. Subcellular distribution of CFTR in rat intestine supports a physiologic role for CFTR regulation by vesicle traffic. Histochemistry And Cell Biology 2000, 114: 219-228. PMID: 11083465, DOI: 10.1007/s004180000167.Peer-Reviewed Original ResearchConceptsCystic fibrosis transmembrane conductance regulatorVesicle trafficSubcellular distributionVesicle insertionCAMP stimulationCAMP-activated chloride channelCryoimmunogold electron microscopyFibrosis transmembrane conductance regulatorApical plasma membraneTransmembrane conductance regulatorCultured intestinal cellsCFTR regulationCHE cellsPhysiologic roleVesicular compartmentsPlasma membraneApical redistributionConductance regulatorSubapical vesiclesCellular distributionChloride channelsSecretory cellsIntestinal cellsEpithelial cellsCells
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