2024
Early adversity causes sex-specific deficits in perforant pathway connectivity and contextual memory in adolescent mice
Islam R, White J, Arefin T, Mehta S, Liu X, Polis B, Giuliano L, Ahmed S, Bowers C, Zhang J, Kaffman A. Early adversity causes sex-specific deficits in perforant pathway connectivity and contextual memory in adolescent mice. Biology Of Sex Differences 2024, 15: 39. PMID: 38715106, PMCID: PMC11075329, DOI: 10.1186/s13293-024-00616-0.Peer-Reviewed Original ResearchConceptsLateral entorhinal cortexContextual fear conditioningDorsal hippocampusHippocampal developmentSex differencesFear conditioningEarly adversityLimited beddingSevere deficitsModel of early adversitySex-specific deficitsReelin-positive neuronsPerforant pathwayReelin-positive cellsDiffusion magnetic resonance imagingEx vivo diffusion magnetic resonance imagingContextual freezingContextual memoryAdolescent miceHippocampal functionLife adversityEntorhinal cortexHippocampusDeficitsAdolescent males
2023
MicroRNA-1 protects the endothelium in acute lung injury
Korde A, Haslip M, Pednekar P, Khan A, Chioccioli M, Mehta S, Lopez-Giraldez F, Bermejo S, Rojas M, Dela Cruz C, Matthay M, Pober J, Pierce R, Takyar S. MicroRNA-1 protects the endothelium in acute lung injury. JCI Insight 2023, 8: e164816. PMID: 37737266, PMCID: PMC10561733, DOI: 10.1172/jci.insight.164816.Peer-Reviewed Original ResearchConceptsAcute respiratory distress syndromeAcute lung injuryVascular endothelial growth factorAngiopoietin-2Lung injuryAcute injuryMiR-1MicroRNA-1Endothelial cell-specific overexpressionSevere endothelial dysfunctionRespiratory distress syndromeSurvival of miceIntrinsic protective effectContext of injuryCell-specific overexpressionEndothelial growth factorFamily member 3Pneumonia cohortMiR-1 targetsEndothelial dysfunctionDistress syndromeBarrier dysfunctionCapillary leakProtective effectSevere formA systems biology approach identifies the role of dysregulated PRDM6 in the development of hypertension
Gunawardhana K, Hong L, Rugira T, Uebbing S, Kucharczak J, Mehta S, Karunamuni D, Cabera-Mendoza B, Gandotra N, Scharfe C, Polimanti R, Noonan J, Mani A. A systems biology approach identifies the role of dysregulated PRDM6 in the development of hypertension. Journal Of Clinical Investigation 2023, 133: e160036. PMID: 36602864, PMCID: PMC9927944, DOI: 10.1172/jci160036.Peer-Reviewed Original ResearchConceptsDevelopment of hypertensionParallel reporter assaysRenin inhibitor aliskirenNeural crest-derived cellsRenin-producing cellsSystems biology approachRNA-seq analysisCell-specific disruptionCrest-derived cellsSmooth muscle cellsMuscle cell proteinsSystemic hypertensionBlood pressureWT miceAntihypertensive drugsBiology approachSuper enhancersFine mappingWT littermatesThird intronMultiple GWASCollagen depositionMouse aortaReporter assaysFate mapping
2022
Mitochondrial dysfunction induces ALK5-SMAD2-mediated hypovascularization and arteriovenous malformations in mouse retinas
Zhang H, Li B, Huang Q, López-Giráldez F, Tanaka Y, Lin Q, Mehta S, Wang G, Graham M, Liu X, Park I, Eichmann A, Min W, Zhou J. Mitochondrial dysfunction induces ALK5-SMAD2-mediated hypovascularization and arteriovenous malformations in mouse retinas. Nature Communications 2022, 13: 7637. PMID: 36496409, PMCID: PMC9741628, DOI: 10.1038/s41467-022-35262-w.Peer-Reviewed Original ResearchConceptsMitochondrial dysfunctionThioredoxin 2Single-cell RNA-seq analysisRNA-seq analysisMutant miceNuclear genesMitochondrial proteinsMitochondrial localizationHuman retinal diseasesTranscriptional factorsGene expressionMutant retinasMitochondrial activityExtracellular matrixNovel mechanismVascular maturationArteriovenous malformationsGenetic deficiencyVessel growthSmad2Mouse retinaVascular malformationsMechanistic studiesBasement membraneRetinal vascular malformationsNeuroinflammation in neuronopathic Gaucher disease: Role of microglia and NK cells, biomarkers, and response to substrate reduction therapy
Boddupalli CS, Nair S, Belinsky G, Gans J, Teeple E, Nguyen TH, Mehta S, Guo L, Kramer ML, Ruan J, Wang H, Davison M, Kumar D, Vidyadhara D, Zhang B, Klinger K, Mistry PK. Neuroinflammation in neuronopathic Gaucher disease: Role of microglia and NK cells, biomarkers, and response to substrate reduction therapy. ELife 2022, 11: e79830. PMID: 35972072, PMCID: PMC9381039, DOI: 10.7554/elife.79830.Peer-Reviewed Original ResearchConceptsNeuronopathic Gaucher diseaseAmelioration of neuroinflammationNK cellsGaucher diseaseSerum neurofilament light chainInvolvement of microgliaActivation of microgliaRole of microgliaProminent pathological featureNeurofilament light chainBlood-derived macrophagesRare neurodegenerative disorderGlucosylceramide synthaseNeuroinflammation pathwaysSerum NFMicroglia activationNeuronal injuryImmune infiltratesImproved survivalBrain macrophagesPathological featuresGD patientsClinical trialsMacrophage compartmentPatient managementPrdm6 controls heart development by regulating neural crest cell differentiation and migration
Hong L, Li N, Gasque V, Mehta S, Ye L, Wu Y, Li J, Gewies A, Ruland J, Hirschi KK, Eichmann A, Hendry C, van Dijk D, Mani A. Prdm6 controls heart development by regulating neural crest cell differentiation and migration. JCI Insight 2022, 7: e156046. PMID: 35108221, PMCID: PMC8876496, DOI: 10.1172/jci.insight.156046.Peer-Reviewed Original ResearchConceptsCardiac NCCNeural crest cell fateNeural crest cell differentiationSingle-cell RNA-seq analysisRNA-seq analysisDorsal neural tubeG1-S progressionFate-mapping approachCNCC migrationSpecification genesH4K20 monomethylationCell fateTranscriptomic analysisEpigenetic modifiersHeart developmentRegulated networkTranscript levelsKey regulatorMolecular mechanismsCell differentiationNeural tubePRDM6Ductus arteriosusPotential targetDifferentiation
2021
The Lyme Disease agent co-opts adiponectin receptor-mediated signaling in its arthropod vector
Tang X, Cao Y, Arora G, Hwang J, Sajid A, Brown CL, Mehta S, Marín-López A, Chuang YM, Wu MJ, Ma H, Pal U, Narasimhan S, Fikrig E. The Lyme Disease agent co-opts adiponectin receptor-mediated signaling in its arthropod vector. ELife 2021, 10: e72568. PMID: 34783654, PMCID: PMC8639152, DOI: 10.7554/elife.72568.Peer-Reviewed Original ResearchConceptsReceptor-mediated signalingAdiponectin receptorsAdiponectinLyme disease agentLyme disease spirochetePhospholipid metabolismPhosphatidylserine synthase ITick gutReceptor-like proteinMammalian homeostasisArthropod vectorsDisease agentsRNAi assaysRNA interferenceAlternative pathwaySynthase IPathwayMetabolic pathwaysTicksInfectionExcessive adventitial stress drives inflammation-mediated fibrosis in hypertensive aortic remodelling in mice
Spronck B, Latorre M, Wang M, Mehta S, Caulk AW, Ren P, Ramachandra AB, Murtada SI, Rojas A, He CS, Jiang B, Bersi MR, Tellides G, Humphrey JD. Excessive adventitial stress drives inflammation-mediated fibrosis in hypertensive aortic remodelling in mice. Journal Of The Royal Society Interface 2021, 18: 20210336. PMID: 34314650, PMCID: PMC8315831, DOI: 10.1098/rsif.2021.0336.Peer-Reviewed Original ResearchConceptsAortic remodellingWall stressAngiotensin II infusionInflammatory cell infiltrationC57BL/6 J miceSmooth muscle contractile processHigh wall stressVasoconstrictive capacityII infusionBlood pressureInflammatory cellsCell infiltrationMean wall stressJ miceThoracic aortaMaladaptive remodellingImmune processesAortaBulk RNA sequencingBiomechanical assessmentAdaptive remodellingContractile processMarked increaseRemodellingVasoconstriction
2020
Repeat tick exposure elicits distinct immune responses in guinea pigs and mice
Kurokawa C, Narasimhan S, Vidyarthi A, Booth CJ, Mehta S, Meister L, Diktas H, Strank N, Lynn GE, DePonte K, Craft J, Fikrig E. Repeat tick exposure elicits distinct immune responses in guinea pigs and mice. Ticks And Tick-borne Diseases 2020, 11: 101529. PMID: 32993942, PMCID: PMC7530331, DOI: 10.1016/j.ttbdis.2020.101529.Peer-Reviewed Original ResearchConceptsGuinea pigsElicit distinct immune responsesDistinct immune responsesGuinea pig modelLocal blood flowImmune animalsInflammatory pathwaysTick rejectionMechanisms of resistanceImmune responseMouse modelVaccine candidatesBite siteBlood flowPig modelCoagulation pathwayComplement activationAcquired ResistanceProtective antigenTick detachmentTick proteinsBlood mealMiceTick infestationRNA sequencingEndothelial cell–glucocorticoid receptor interactions and regulation of Wnt signaling
Zhou H, Mehta S, Srivastava SP, Grabinska K, Zhang X, Wong C, Hedayat A, Perrotta P, Fernández-Hernando C, Sessa WC, Goodwin JE. Endothelial cell–glucocorticoid receptor interactions and regulation of Wnt signaling. JCI Insight 2020, 5: e131384. PMID: 32051336, PMCID: PMC7098785, DOI: 10.1172/jci.insight.131384.Peer-Reviewed Original ResearchConceptsEndothelial glucocorticoid receptorVascular inflammationGlucocorticoid receptorGlucocorticoid receptor regulationGlucocorticoid receptor resultsUpregulation of WntEndogenous glucocorticoidsExogenous glucocorticoidsGlucocorticoid response elementCardiovascular diseaseMouse endothelial cellsMouse modelEndothelial WNTInflammationReceptor regulationEndothelial cellsReceptors resultsNext-generation sequencingReceptor interactionReceptorsRegulation of WntWnt pathwayGlucocorticoidsRecent dataWntChronic mTOR activation induces a degradative smooth muscle cell phenotype
Li G, Wang M, Caulk AW, Cilfone NA, Gujja S, Qin L, Chen PY, Chen Z, Yousef S, Jiao Y, He C, Jiang B, Korneva A, Bersi MR, Wang G, Liu X, Mehta S, Geirsson A, Gulcher JR, Chittenden TW, Simons M, Humphrey JD, Tellides G. Chronic mTOR activation induces a degradative smooth muscle cell phenotype. Journal Of Clinical Investigation 2020, 130: 1233-1251. PMID: 32039915, PMCID: PMC7269581, DOI: 10.1172/jci131048.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsAortaAortic Aneurysm, ThoracicAortic DissectionBeta CateninDisease Models, AnimalLysosomesMechanistic Target of Rapamycin Complex 1MiceMice, Knockout, ApoEMicrophthalmia-Associated Transcription FactorMyocytes, Smooth MuscleSignal TransductionTOR Serine-Threonine KinasesTuberous Sclerosis Complex 1 ProteinConceptsMTOR activationMTOR complex 1Smooth muscle cell phenotypeMuscle cell phenotypeContext of hyperlipidemiaSmooth muscle cell proliferationThoracic aortic aneurysmDegradative organellesMuscle cell proliferationHematopoietic lineage markersSMC phenotypeLysosomal clearanceAdvanced diseaseMedial degenerationAortic diseaseLysosomal markersAortic aneurysmExtracellular matrixPhenotypic modulationConventional macrophagesMacrophage markersMedial SMCsConditional disruptionLineage markersImmune effectors
2019
Suppressing miR-21 activity in tumor-associated macrophages promotes an antitumor immune response
Sahraei M, Chaube B, Liu Y, Sun J, Kaplan A, Price NL, Ding W, Oyaghire S, García-Milian R, Mehta S, Reshetnyak YK, Bahal R, Fiorina P, Glazer PM, Rimm DL, Fernández-Hernando C, Suárez Y. Suppressing miR-21 activity in tumor-associated macrophages promotes an antitumor immune response. Journal Of Clinical Investigation 2019, 129: 5518-5536. PMID: 31710308, PMCID: PMC6877327, DOI: 10.1172/jci127125.Peer-Reviewed Original ResearchConceptsTumor-associated macrophagesMiR-21 expressionTumor growthMiR-21Immune responseCytotoxic T cell responsesC motif chemokine 10Antitumor immune responseT cell responsesAntitumoral immune responseTumor immune infiltratesInduction of cytokinesPotential therapeutic implicationsMiR-21 inhibitionStages of carcinogenesisAngiostatic phenotypeTumor cell deathIL-12Immune infiltratesTherapeutic implicationsSolid tumorsTumor neovascularizationTumor progressionTumor microenvironmentTumor pathogenesisPrefrontal cortex interneurons display dynamic sex-specific stress-induced transcriptomes
Girgenti MJ, Wohleb ES, Mehta S, Ghosal S, Fogaca MV, Duman RS. Prefrontal cortex interneurons display dynamic sex-specific stress-induced transcriptomes. Translational Psychiatry 2019, 9: 292. PMID: 31712551, PMCID: PMC6848179, DOI: 10.1038/s41398-019-0642-z.Peer-Reviewed Original ResearchConceptsFluorescence-activated cell sortingInitiation factor 2Distinct transcriptome profilesTranslational machineryTranscriptome profilesEnriched pathwaysTranscriptional pathwaysTranscriptional profilesRNA sequencingDepressive-like behaviorSST interneuronsKey pathwaysChronic stressInterneuron subtypesSex-specific differencesPrefrontal cortexCell sortingSignificant dysregulationFactor 2PathwayStress-induced depressive-like behaviorDecreased expressionReporter miceGrowth factorNon-stressed femalesHistone H2B monoubiquitination regulates heart development via epigenetic control of cilia motility
Robson A, Makova SZ, Barish S, Zaidi S, Mehta S, Drozd J, Jin SC, Gelb BD, Seidman CE, Chung WK, Lifton RP, Khokha MK, Brueckner M. Histone H2B monoubiquitination regulates heart development via epigenetic control of cilia motility. Proceedings Of The National Academy Of Sciences Of The United States Of America 2019, 116: 14049-14054. PMID: 31235600, PMCID: PMC6628794, DOI: 10.1073/pnas.1808341116.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsCell MovementCell ProliferationChromatin Assembly and DisassemblyCiliaDisease Models, AnimalEpigenesis, GeneticGene Expression Regulation, NeoplasticHeartHeart Defects, CongenitalHistonesHumansLoss of Function MutationMiceRegulatory Factor X Transcription FactorsSignal TransductionUbiquitinationUbiquitin-Conjugating EnzymesUbiquitin-Protein LigasesXenopusConceptsHistone H2B monoubiquitinationCilia genesH2B monoubiquitinationCilia motilityFunctional gene ontologyHuman congenital heart diseaseUpstream transcriptional regulatorsTissue-specific expressionChromatin remodeling genesChromatin remodelingEpigenetic controlH2Bub1 levelsTranscriptional regulatorsChIP-seqDepletion phenotypeGene OntologyGenomic analysisTranscription factorsKnockdown resultsLeft-right asymmetryCilia functionHeart developmentH2Bub1RNF20Complex consisting
2018
Dppa2/4 Facilitate Epigenetic Remodeling during Reprogramming to Pluripotency
Hernandez C, Wang Z, Ramazanov B, Tang Y, Mehta S, Dambrot C, Lee YW, Tessema K, Kumar I, Astudillo M, Neubert TA, Guo S, Ivanova NB. Dppa2/4 Facilitate Epigenetic Remodeling during Reprogramming to Pluripotency. Cell Stem Cell 2018, 23: 396-411.e8. PMID: 30146411, PMCID: PMC6128737, DOI: 10.1016/j.stem.2018.08.001.Peer-Reviewed Original ResearchConceptsInduced pluripotent stem cellsDNA damage response pathwayAcquisition of pluripotencyDamage response pathwayDNA methylation patternsStem cellsEmbryonic stem cellsESC enhancersPluripotent stem cellsMyc factorsPluripotent stateSomatic genesChromatin decompactionMolecular machineryEpigenetic remodelingEfficient reprogrammingResponse pathwaysSomatic cellsMethylation patternsPluripotencyHuman cellsEpigenomeEnhancerCellsKey roleTranslocation of a gut pathobiont drives autoimmunity in mice and humans
Vieira S, Hiltensperger M, Kumar V, Zegarra-Ruiz D, Dehner C, Khan N, Costa FRC, Tiniakou E, Greiling T, Ruff W, Barbieri A, Kriegel C, Mehta SS, Knight JR, Jain D, Goodman AL, Kriegel MA. Translocation of a gut pathobiont drives autoimmunity in mice and humans. Science 2018, 359: 1156-1161. PMID: 29590047, PMCID: PMC5959731, DOI: 10.1126/science.aar7201.Peer-Reviewed Original ResearchConceptsGut pathobiontAutoimmune-prone miceMurine findingsIntramuscular vaccinePathogenic autoantibodiesLiver biopsyAutoimmune responseAutoimmune patientsAntibiotic treatmentT cellsImmune diseasesAutoimmunitySusceptible humansPathobiontsSystemic tissuesHuman hepatocytesAutoantibodiesMortalityMiceCocultureHepatocytesGenetic backgroundTissueBiopsyPatients