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 ResearchMeSH KeywordsAnimalsCystic FibrosisCystic Fibrosis Transmembrane Conductance RegulatorDisease Models, AnimalFemaleGene EditingGenetic TherapyHumansMiceMutationNanoparticlesPregnancyConceptsUtero 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 ResearchMeSH KeywordsCystic FibrosisCystic Fibrosis Transmembrane Conductance RegulatorEpithelial Sodium ChannelsFemaleHumansMacrophagesMalePhagocytosisReactive Oxygen SpeciesConceptsCystic 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 expressionEvidence of secondary Notch signaling within the rat small intestine.
Zagoren E, Dias N, Santos A, Smith Z, Ameen N, Sumigray K. Evidence of secondary Notch signaling within the rat small intestine. Development 2025, 152 PMID: 40371707, PMCID: PMC12188240, DOI: 10.1242/dev.204277.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsCell LineageCystic Fibrosis Transmembrane Conductance RegulatorHumansIntestinal MucosaIntestine, SmallMaleMiceRatsReceptors, NotchSignal TransductionConceptsSecretory lineageRegulate luminal pHSecretory cellsNotch signalingSecretory cell typesSmall intestinal epithelial cellsRNA sequencing dataIntestinal epithelial cellsIntestinal stem cellsSmall intestineFate in vivoFibrosis pathophysiologyRat small intestineCrypt progenitorsTranscription factorsEpithelial cellsRat jejunumStem cellsPseudotime trajectory analysisRare populationLuminal pHRatsHigher expressionIntestinal functionIn vitroCFTR 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 ResearchMeSH KeywordsCell AdhesionCystic FibrosisCystic Fibrosis Transmembrane Conductance RegulatorHumansInflammationIntegrinsMonocytesMutationConceptsIntegrin 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
Pathophysiology of Cystic Fibrosis Liver Disease
Kasper V, Assis D. Pathophysiology of Cystic Fibrosis Liver Disease. Pediatric Pulmonology 2024, 59: s98-s106. PMID: 39105342, DOI: 10.1002/ppul.26869.Peer-Reviewed Original ResearchMeSH KeywordsCystic FibrosisCystic Fibrosis Transmembrane Conductance RegulatorHumansLiver DiseasesMutationConceptsComplication of cystic fibrosisCF liver diseaseHeterogeneity of clinical manifestationsManifestations of CFDisease-modifying factorsCFTR mutationsHepatobiliary complicationsBiliary stricturesBiliary cholestasisClinical manifestationsCystic fibrosisLiver diseaseTherapeutic approachesCF careDisease modelsDiseaseStructure-based discovery of CFTR potentiators and inhibitors
Liu F, Kaplan A, Levring J, Einsiedel J, Tiedt S, Distler K, Omattage N, Kondratov I, Moroz Y, Pietz H, Irwin J, Gmeiner P, Shoichet B, Chen J. Structure-based discovery of CFTR potentiators and inhibitors. Cell 2024, 187: 3712-3725.e34. PMID: 38810646, PMCID: PMC11262615, DOI: 10.1016/j.cell.2024.04.046.Peer-Reviewed Original ResearchMeSH KeywordsAllosteric SiteAminophenolsAnimalsCryoelectron MicroscopyCystic FibrosisCystic Fibrosis Transmembrane Conductance RegulatorDrug DiscoveryHumansLigandsMolecular Docking SimulationQuinolonesConceptsLarge-scale dockingIon channel drug discoveryStructure-based discoveryStructure-based optimizationMedicinal chemistryTested ligandsMolecular dockingSmall moleculesDrug discoveryCystic fibrosis transmembrane conductance regulatorMoleculesAllosteric siteIonsDockingLigandSecretory diarrheaCystic fibrosisCystic fibrosis transmembrane conductance regulator modulatorsChemistryTransmembrane conductance regulatorSuboptimal pharmacokineticsCFTR potentiators
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 ResearchMeSH KeywordsAnimalsCell DifferentiationCystic Fibrosis Transmembrane Conductance RegulatorEpithelial CellsHomeostasisHumansMiceMucinsTumor Necrosis Factor InhibitorsTumor Necrosis FactorsConceptsCystic 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 timeThe effects of elexafactor/tezafactor/ivacaftor beyond the epithelium: spurring macrophages to fight infections.
Bruscia E. The effects of elexafactor/tezafactor/ivacaftor beyond the epithelium: spurring macrophages to fight infections. European Respiratory Journal 2023, 61: 2300216. PMID: 37003613, DOI: 10.1183/13993003.00216-2023.Peer-Reviewed Original ResearchMeSH KeywordsAminophenolsCystic FibrosisCystic Fibrosis Transmembrane Conductance RegulatorEpitheliumHumansMacrophagesFuture therapies for cystic fibrosis
Allen L, Allen L, Carr S, Davies G, Downey D, Egan M, Forton J, Gray R, Haworth C, Horsley A, Smyth A, Southern K, Davies J. Future therapies for cystic fibrosis. Nature Communications 2023, 14: 693. PMID: 36755044, PMCID: PMC9907205, DOI: 10.1038/s41467-023-36244-2.Peer-Reviewed Original ResearchMeSH KeywordsCystic FibrosisCystic Fibrosis Transmembrane Conductance RegulatorGenetic TherapyHumansMutationConceptsMutation-specific drugsCystic fibrosisSymptom-directed treatmentMultisystem clinical manifestationsCystic fibrosis therapyCystic fibrosis transmembrane conductance regulatorGenetic variantsClinical manifestationsFuture therapiesFibrosis therapyTranslational research collaborationsModulator drugsCFTR modulatorsSingle gene disordersHealth inequalitiesTherapyGene variantsImproved treatmentDrugsPatientsFibrosisFibrosis transmembrane conductance regulatorGene disordersTransmembrane conductance regulatorStrategy group
2022
Recruited monocytes/macrophages drive pulmonary neutrophilic inflammation and irreversible lung tissue remodeling in cystic fibrosis
Öz H, Cheng E, Di Pietro C, Tebaldi T, Biancon G, Zeiss C, Zhang P, Huang P, Esquibies S, Britto C, Schupp J, Murray T, Halene S, Krause D, Egan M, Bruscia E. Recruited monocytes/macrophages drive pulmonary neutrophilic inflammation and irreversible lung tissue remodeling in cystic fibrosis. Cell Reports 2022, 41: 111797. PMID: 36516754, PMCID: PMC9833830, DOI: 10.1016/j.celrep.2022.111797.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsCystic FibrosisCystic Fibrosis Transmembrane Conductance RegulatorHumansInflammationLungMacrophagesMiceMonocytesPneumoniaReceptors, ChemokineTransforming Growth Factor betaConceptsC motif chemokine receptor 2Monocytes/macrophagesLung tissue damageCystic fibrosisTissue damageCF lungPulmonary neutrophilic inflammationPro-inflammatory environmentChemokine receptor 2CF lung diseaseNumber of monocytesSpecific therapeutic agentsGrowth factor βCF transmembrane conductance regulatorLung hyperinflammationLung neutrophiliaNeutrophilic inflammationNeutrophil inflammationInflammation contributesLung damageNeutrophil recruitmentLung diseaseLung tissueReceptor 2Therapeutic targetNon-Modulator Therapies Developing a Therapy for Every Cystic Fibrosis Patient
Egan M. Non-Modulator Therapies Developing a Therapy for Every Cystic Fibrosis Patient. Clinics In Chest Medicine 2022, 43: 717-725. PMID: 36344076, DOI: 10.1016/j.ccm.2022.06.011.Peer-Reviewed Original ResearchMeSH KeywordsCystic FibrosisCystic Fibrosis Transmembrane Conductance RegulatorGenetic TherapyHumansMutationConceptsModulator therapyCystic fibrosisCystic fibrosis transmembrane conductance regulator (CFTR) modulator therapiesCFTR modulator therapyTreatment of CFCystic fibrosis patientsGenetic-based therapiesMost patientsCF patientsFibrosis patientsTherapyPremature termination codon mutationsTherapeutic agentsPatientsDNA therapyRNA therapyTermination codon mutationsCodon mutationUpdate on Innate and Adaptive Immunity in Cystic Fibrosis
Bruscia E, Bonfield T. Update on Innate and Adaptive Immunity in Cystic Fibrosis. Clinics In Chest Medicine 2022, 43: 603-615. PMID: 36344069, DOI: 10.1016/j.ccm.2022.06.004.Peer-Reviewed Original ResearchMeSH KeywordsCystic FibrosisCystic Fibrosis Transmembrane Conductance RegulatorHumansImmunity, InnateInflammationLungPneumoniaConceptsChronic infectionCFTR modulator therapyRobust inflammatory responseCystic fibrosis pathophysiologyImmune dysregulationPatient ageExcessive inflammationModulator therapyLung microenvironmentLung infectionImmune mechanismsInflammatory responseAdaptive immunityMucociliary transportCF life expectancyCF lungCystic fibrosisInfectionLife expectancyImmunityCritical roleCurrent understandingMorbidityInflammationFibrosisEmerging Concepts in Defective Macrophage Phagocytosis in Cystic Fibrosis
Jaganathan D, Bruscia EM, Kopp BT. Emerging Concepts in Defective Macrophage Phagocytosis in Cystic Fibrosis. International Journal Of Molecular Sciences 2022, 23: 7750. PMID: 35887098, PMCID: PMC9319215, DOI: 10.3390/ijms23147750.Peer-Reviewed Original ResearchMeSH KeywordsCystic FibrosisCystic Fibrosis Transmembrane Conductance RegulatorHumansInflammationMacrophagesPhagocytosisConceptsPhagosome formationCystic fibrosis transmembrane conductance regulator (CFTR) geneTransmembrane conductance regulator geneInnate immunityTissue homeostasisRegulator geneMutant CFTRCF macrophagesCystic fibrosisPhagocytic mechanismsPathogenic microbesAdaptive immune systemDefective macrophage phagocytosisCFTRCurrent understandingTherapeutic developmentCentral roleMacrophage phagocytosisCFTR modulatorsPhagocytic cellsPhagocytosisNew therapeutic developmentsMacrophages contributesLung functionChronic inflammationColonic Fluid and Electrolyte Transport 2022: An Update
Negussie AB, Dell AC, Davis BA, Geibel JP. Colonic Fluid and Electrolyte Transport 2022: An Update. Cells 2022, 11: 1712. PMID: 35626748, PMCID: PMC9139964, DOI: 10.3390/cells11101712.Peer-Reviewed Original ResearchMeSH KeywordsColonCystic FibrosisCystic Fibrosis Transmembrane Conductance RegulatorElectrolytesEpithelial Sodium ChannelsHumansMembrane Transport ProteinsConceptsCystic fibrosis transmembrane regulatorCell death regulationSignal transduction pathwaysDeath regulationNa-K-Cl cotransporterEpithelial cell deathTransduction pathwaysIon homeostasisRegulatory relationshipsIon transportersTransepithelial ion transportEpithelial sodium channelTransmembrane regulatorCell deathColonic epithelial cellsEpithelial cellsTransportersSodium channelsNa-H exchangerRegulationIon transportCancer pathologyPH modulationIon movementOsmotic gradient
2021
Dissection of Barrier Dysfunction in Organoid-Derived Human Intestinal Epithelia Induced by Giardia duodenalis
Holthaus D, Kraft M, Krug S, Wolf S, Müller A, Delgado Betancourt E, Schorr M, Holland G, Knauf F, Schulzke J, Aebischer T, Klotz C. Dissection of Barrier Dysfunction in Organoid-Derived Human Intestinal Epithelia Induced by Giardia duodenalis. Gastroenterology 2021, 162: 844-858. PMID: 34822802, DOI: 10.1053/j.gastro.2021.11.022.Peer-Reviewed Original ResearchMeSH KeywordsApoptosisCaco-2 CellsChloridesCyclic AMPCyclic AMP-Dependent Protein KinasesCystic Fibrosis Transmembrane Conductance RegulatorDuodenumElectric ImpedanceGiardia lambliaGiardiasisHumansInterleukin-1Intestinal MucosaIon TransportNF-kappa BOrganoidsParasite LoadSignal TransductionSolute Carrier Family 12, Member 2Tight JunctionsTranscriptomeTumor Necrosis Factor-alphaConceptsG. duodenalis infectionBarrier dysfunctionGiardia duodenalisHuman duodenal tissueIntestinal barrier dysfunctionHuman intestinal epitheliumResponse element-binding proteinTight junction compositionProtozoan Giardia duodenalisAdequate cellular modelsChronic casesMajor expression changesPathophysiological mechanismsBarrier breakdownDuodenal mucosaGastrointestinal illnessDuodenal tissueBarrier lossPathogenic eventsHuman organoid systemEpithelial barrierTranswell systemChloride secretionIntestinal epitheliumTight junction componentsBACH1, the master regulator of oxidative stress, has a dual effect on CFTR expression
NandyMazumdar M, Paranjapye A, Browne J, Yin S, Leir SH, Harris A. BACH1, the master regulator of oxidative stress, has a dual effect on CFTR expression. Biochemical Journal 2021, 478: 3741-3756. PMID: 34605540, PMCID: PMC8589331, DOI: 10.1042/bcj20210252.Peer-Reviewed Original ResearchMeSH KeywordsBasic-Leucine Zipper Transcription FactorsCell Line, TumorCell ProliferationCystic Fibrosis Transmembrane Conductance RegulatorEpithelial CellsGene Expression ProfilingGene Expression RegulationGlutamate-Cysteine LigaseGlutathioneHeme Oxygenase-1HumansHydrogen PeroxideNF-E2-Related Factor 2Oxidative StressOxygenPromoter Regions, GeneticRNA, Small InterferingSignal TransductionConceptsCis-regulatory elementsTranscription factorsCFTR expressionMaster regulatorHigher-order chromatin structureOrder chromatin structureMultiple cis-regulatory elementsFine-tune expressionSpecific transcription factorsCystic fibrosis transmembrane conductance regulator (CFTR) geneCFTR gene expressionCell-specific expressionTransmembrane conductance regulator geneOxidative stressArchitectural proteinsChromatin structureLocus architectureTune expressionBTB domainCNC homolog 1SiRNA screenRegulator geneGene promoterEnvironmental cuesPhysiological oxygenEmerging technologies for cystic fibrosis transmembrane conductance regulator restoration in all people with CF
Egan ME. Emerging technologies for cystic fibrosis transmembrane conductance regulator restoration in all people with CF. Pediatric Pulmonology 2021, 56: s32-s39. PMID: 32681713, PMCID: PMC8114183, DOI: 10.1002/ppul.24965.Peer-Reviewed Original ResearchCell- and Tissue-Based TherapyCystic FibrosisCystic Fibrosis Transmembrane Conductance RegulatorGenetic TherapyHumansMutationRNA, MessengerBiochemical characterization of an E. coli cell division factor FtsE shows ATPase cycles similar to the NBDs of ABC-transporters
Mallick S, Kumar A, Dodia H, Alexander C, Vasudevan D, Beuria T. Biochemical characterization of an E. coli cell division factor FtsE shows ATPase cycles similar to the NBDs of ABC-transporters. Bioscience Reports 2021, 41: bsr20203034. PMID: 33320186, PMCID: PMC7791547, DOI: 10.1042/bsr20203034.Peer-Reviewed Original ResearchMeSH KeywordsAdenosine TriphosphatasesAmino Acid SequenceATP-Binding Cassette TransportersBinding SitesCystic Fibrosis Transmembrane Conductance RegulatorDimerizationEscherichia coli ProteinsProtein DomainsSequence Homology, Amino AcidConceptsFtsEX complexPG hydrolysisABC transportersCytoplasmic loopBiochemical characterizationATPase cycleCouple ATP hydrolysisATP-binding siteATPase activityE. coliBacterial cell wallTransduce signalsInner membraneSequence similarityBacterial divisionSignal transductionPeptidoglycan layerMid cellATP hydrolysisCell wallSoluble expressionBiochemical propertiesFtsE.Direct interactionTransport molecules
2020
Glucocorticoids and serum- and glucocorticoid-inducible kinase 1 are potent regulators of CFTR in the native intestine: implications for stress-induced diarrhea
Ahsan MK, Figueroa-Hall L, Baratta V, Garcia-Milian R, Lam TT, Hoque K, Salas PJ, Ameen NA. Glucocorticoids and serum- and glucocorticoid-inducible kinase 1 are potent regulators of CFTR in the native intestine: implications for stress-induced diarrhea. AJP Gastrointestinal And Liver Physiology 2020, 319: g121-g132. PMID: 32567324, PMCID: PMC7500270, DOI: 10.1152/ajpgi.00076.2020.Peer-Reviewed Original Research14-3-3 ProteinsAnimalsBacterial ToxinsCystic Fibrosis Transmembrane Conductance RegulatorDexamethasoneDiarrheaDimethyl SulfoxideEnterotoxinsEscherichia coli ProteinsGene Expression RegulationImmediate-Early ProteinsMaleNedd4 Ubiquitin Protein LigasesPhosphatidylinositol 3-KinasesProtein Serine-Threonine KinasesProtein TransportProto-Oncogene Proteins c-aktPyruvate Dehydrogenase Acetyl-Transferring KinaseRatsRats, Sprague-DawleySodium-Hydrogen Exchanger 3Cystic fibrosis transmembrane conductance receptor modulator therapy in cystic fibrosis, an update.
Egan ME. Cystic fibrosis transmembrane conductance receptor modulator therapy in cystic fibrosis, an update. Current Opinion In Pediatrics 2020, 32: 384-388. PMID: 32374578, DOI: 10.1097/mop.0000000000000892.Peer-Reviewed Original ResearchMeSH KeywordsAminophenolsBenzodioxolesChildCystic FibrosisCystic Fibrosis Transmembrane Conductance RegulatorHumansIndolesMutationPyrazolesPyridinesPyrrolidinesQuality of LifeQuinolonesTreatment OutcomeConceptsModulator therapyCystic fibrosisCFTR modulatorsLung functionElexacaftor/tezacaftor/ivacaftorEffective CFTR modulatorsEffective triple therapyTezacaftor/ivacaftorMonths of ageQuality of lifeCystic fibrosis patientsLong-term usePulmonary exacerbationsTriple therapyFirst therapyLong-term benefitsReceptor modulatorsFibrosisFibrosis patientsTherapyUnderlying causeWeight gainPatientsImproved healthCFTR mutations
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