2023
Intrathecal delivery of nanoparticle PARP inhibitor to the cerebrospinal fluid for the treatment of metastatic medulloblastoma
Khang M, Lee J, Lee T, Suh H, Lee S, Cavaliere A, Rushing A, Geraldo L, Belitzky E, Rossano S, de Feyter H, Shin K, Huttner A, Roussel M, Thomas J, Carson R, Marquez-Nostra B, Bindra R, Saltzman W. Intrathecal delivery of nanoparticle PARP inhibitor to the cerebrospinal fluid for the treatment of metastatic medulloblastoma. Science Translational Medicine 2023, 15: eadi1617. PMID: 37910601, PMCID: PMC11078331, DOI: 10.1126/scitranslmed.adi1617.Peer-Reviewed Original ResearchConceptsCerebrospinal fluidDelivery of drugsEffective therapyTherapeutic indexPARP inhibitorsBlood-brain barrierSite of tumorRapid systemic clearanceXenograft mouse modelSolvent evaporation processAdministration of substancesLeptomeningeal spreadIntrathecal deliveryLeptomeningeal metastasesBrain penetrationSystemic clearanceTumor regressionPolymer nanoparticlesMetastatic medulloblastomaMouse modelPediatric medulloblastomaDrug accumulationCSF turnoverEncapsulated drugsPET imagingAnti-seed PNAs targeting multiple oncomiRs for brain tumor therapy
Wang Y, Malik S, Suh H, Xiao Y, Deng Y, Fan R, Huttner A, Bindra R, Singh V, Saltzman W, Bahal R. Anti-seed PNAs targeting multiple oncomiRs for brain tumor therapy. Science Advances 2023, 9: eabq7459. PMID: 36753549, PMCID: PMC9908025, DOI: 10.1126/sciadv.abq7459.Peer-Reviewed Original ResearchConceptsConvection-enhanced deliveryHigh recurrence rateOrthotopic mouse modelBrain tumor therapyTreatment of glioblastomaRecurrence ratePoor survivalLethal malignancyMouse modelGBM progressionTumor cellsGlioblastomaTumor therapyBioadhesive nanoparticlesOncomiRSurvivalTreatmentSeed regionMalignancyTemozolomideTherapy
2022
Cross-platform analysis reveals cellular and molecular landscape of glioblastoma invasion
Chen AT, Xiao Y, Tang X, Baqri M, Gao X, Reschke M, Sheu WC, Long G, Zhou Y, Deng G, Zhang S, Deng Y, Bai Z, Kim D, Huttner A, Kunes R, Günel M, Moliterno J, Saltzman WM, Fan R, Zhou J. Cross-platform analysis reveals cellular and molecular landscape of glioblastoma invasion. Neuro-Oncology 2022, 25: 482-494. PMID: 35901838, PMCID: PMC10013636, DOI: 10.1093/neuonc/noac186.Peer-Reviewed Original ResearchConceptsCrystallin alpha BTumor invasionGBM invasionHistology samplesMolecular landscapeTreatment of glioblastomaPostoperative recurrenceGBM patientsInvasive glioblastomaResection modelGlioblastomaNon-invasive counterpartsGBM samplesGlioblastoma invasionCD44PatientsInvasionAlpha BCellular levelTranscriptomic featuresRNA sequencing dataRecurrenceHistology stainsLevelsDisease
2021
Transcriptomic taxonomy and neurogenic trajectories of adult human, macaque, and pig hippocampal and entorhinal cells
Franjic D, Skarica M, Ma S, Arellano JI, Tebbenkamp ATN, Choi J, Xu C, Li Q, Morozov YM, Andrijevic D, Vrselja Z, Spajic A, Santpere G, Li M, Zhang S, Liu Y, Spurrier J, Zhang L, Gudelj I, Rapan L, Takahashi H, Huttner A, Fan R, Strittmatter SM, Sousa AMM, Rakic P, Sestan N. Transcriptomic taxonomy and neurogenic trajectories of adult human, macaque, and pig hippocampal and entorhinal cells. Neuron 2021, 110: 452-469.e14. PMID: 34798047, PMCID: PMC8813897, DOI: 10.1016/j.neuron.2021.10.036.Peer-Reviewed Original ResearchConceptsDisease-related proteinsCellular diversityCross-species analysisSingle-nucleus transcriptomesLipid droplet proteinsSpecies-specific propertiesImmature neuron populationTranscriptomic taxonomyAlzheimer's disease-related proteinsEndoplasmic reticulumCell typesHuman neuronsSpecies differencesHistologic signatureNeurogenic capabilityProteinExcitatory neuronsDiversityAdult miceGranule cellsAlzheimer's diseaseNeuron populationsCognitive functionEntorhinal cellsAdult humansSpreading of Alzheimer tau seeds is enhanced by aging and template matching with limited impact of amyloid-β
Nies SH, Takahashi H, Herber CS, Huttner A, Chase A, Strittmatter SM. Spreading of Alzheimer tau seeds is enhanced by aging and template matching with limited impact of amyloid-β. Journal Of Biological Chemistry 2021, 297: 101159. PMID: 34480901, PMCID: PMC8477193, DOI: 10.1016/j.jbc.2021.101159.Peer-Reviewed Original ResearchConceptsTau seedsAlzheimer's diseaseAD model miceWT mouse brainPathological tauSynaptic lossTau accumulationWT miceMouse tauTau pathologyTau burdenModel miceTau inclusionsPharmacological interventionsAD riskCognitive declineMouse brainTau aggregatesPyk2 kinaseKnowledge of factorsKinase inhibitorsMiceFyn kinase inhibitorAβMouse agingENT2 facilitates brain endothelial cell penetration and blood-brain barrier transport by a tumor-targeting anti-DNA autoantibody
Rattray Z, Deng G, Zhang S, Shirali A, May CK, Chen X, Cuffari BJ, Liu J, Zou P, Rattray N, Johnson CH, Dubljevic V, Campbell JA, Huttner A, Baehring JM, Zhou J, Hansen JE. ENT2 facilitates brain endothelial cell penetration and blood-brain barrier transport by a tumor-targeting anti-DNA autoantibody. JCI Insight 2021, 6: e145875. PMID: 34128837, PMCID: PMC8410084, DOI: 10.1172/jci.insight.145875.Peer-Reviewed Original ResearchConceptsBlood-brain barrierAnti-DNA autoantibodiesBrain tumorsBreast cancer brain metastasesBlood-brain barrier transportBrain tumor immunotherapyCancer brain metastasesBrain endothelial cellsEndothelial cell penetrationCNS lupusNeurotoxic autoantibodiesBrain metastasesTumor immunotherapyBarrier transportAntibody-based approachesCNS penetrationAutoantibodiesEfficacy studiesOrthotopic glioblastomaEndothelial cellsTumorsCancer cellsNucleoside fluxesActionable mechanismsKey transportersTET2 Protects Against Vascular Smooth Muscle Cell Apoptosis and Intimal Thickening in Transplant Vasculopathy
Ostriker AC, Xie Y, Chakraborty R, Sizer AJ, Bai Y, Ding M, Song WL, Huttner A, Hwa J, Martin KA. TET2 Protects Against Vascular Smooth Muscle Cell Apoptosis and Intimal Thickening in Transplant Vasculopathy. Circulation 2021, 144: 455-470. PMID: 34111946, PMCID: PMC8643133, DOI: 10.1161/circulationaha.120.050553.Peer-Reviewed Original ResearchMeSH KeywordsAllograftsAnimalsApoptosisBiomarkersDioxygenasesDisease Models, AnimalDisease SusceptibilityDNA-Binding ProteinsHeart TransplantationHumansImmunohistochemistryInterferon-gammaMiceMice, KnockoutMyocytes, Smooth MuscleSignal TransductionSTAT1 Transcription FactorTunica IntimaVascular DiseasesConceptsCoronary allograft vasculopathyGraft arteriopathyIntimal thickeningCAV progressionRole of TET2VSMC apoptosisTransplant samplesGraft modelHigh-dose ascorbic acidTET2 expressionVSMC phenotypeContext of transplantCoronary blood flowEffect of IFNγTET2 activityTET2 depletionSmooth muscle cell apoptosisVascular smooth muscle cell apoptosisMuscle cell apoptosisAllograft vasculopathyDevastating sequelaeMedial thinningAortic graftHeart transplantTransplant failureNanoparticle-mediated convection-enhanced delivery of a DNA intercalator to gliomas circumvents temozolomide resistance
Wang Y, Jiang Y, Wei D, Singh P, Yu Y, Lee T, Zhang L, Mandl HK, Piotrowski-Daspit AS, Chen X, Li F, Li X, Cheng Y, Josowitz A, Yang F, Zhao Y, Wang F, Zhao Z, Huttner A, Bindra RS, Xiao H, Mark Saltzman W. Nanoparticle-mediated convection-enhanced delivery of a DNA intercalator to gliomas circumvents temozolomide resistance. Nature Biomedical Engineering 2021, 5: 1048-1058. PMID: 34045730, PMCID: PMC8497438, DOI: 10.1038/s41551-021-00728-7.Peer-Reviewed Original ResearchConceptsConvection-enhanced deliveryPatient-derived xenograftsTMZ-resistant gliomasTMZ-resistant cellsGlioma cell linesSurvival benefitTemozolomide resistanceChemotherapeutic temozolomideDetectable toxicityTemozolomideOxaliplatin prodrugHuman glioblastomaGenome-wide RNA profilingTranslational strategiesDrugsCell linesGliomasAnticancer drugsMetabolomic analysisGlioblastomaDeliveryDistinct mechanismsRNA profilingMetabolic pathwaysPatientsNeuroinvasion of SARS-CoV-2 in human and mouse brain
Song E, Zhang C, Israelow B, Lu-Culligan A, Prado AV, Skriabine S, Lu P, Weizman OE, Liu F, Dai Y, Szigeti-Buck K, Yasumoto Y, Wang G, Castaldi C, Heltke J, Ng E, Wheeler J, Alfajaro MM, Levavasseur E, Fontes B, Ravindra NG, Van Dijk D, Mane S, Gunel M, Ring A, Kazmi SAJ, Zhang K, Wilen CB, Horvath TL, Plu I, Haik S, Thomas JL, Louvi A, Farhadian SF, Huttner A, Seilhean D, Renier N, Bilguvar K, Iwasaki A. Neuroinvasion of SARS-CoV-2 in human and mouse brain. Journal Of Experimental Medicine 2021, 218: e20202135. PMID: 33433624, PMCID: PMC7808299, DOI: 10.1084/jem.20202135.Peer-Reviewed Original ResearchConceptsSARS-CoV-2Central nervous systemSARS-CoV-2 neuroinvasionImmune cell infiltratesCOVID-19 patientsType I interferon responseMultiple organ systemsCOVID-19I interferon responseHuman brain organoidsNeuroinvasive capacityCNS infectionsCell infiltrateNeuronal infectionPathological featuresCortical neuronsRespiratory diseaseDirect infectionCerebrospinal fluidNervous systemMouse brainInterferon responseOrgan systemsHuman ACE2Infection
2018
Metabolic regulation and glucose sensitivity of cortical radial glial cells
Rash BG, Micali N, Huttner AJ, Morozov YM, Horvath TL, Rakic P. Metabolic regulation and glucose sensitivity of cortical radial glial cells. Proceedings Of The National Academy Of Sciences Of The United States Of America 2018, 115: 10142-10147. PMID: 30224493, PMCID: PMC6176632, DOI: 10.1073/pnas.1808066115.Peer-Reviewed Original ResearchConceptsRadial glial cellsGlial cellsRGC fibersCortical radial glial cellsEmbryonic cortical slicesGestational obesityCerebral cortexCortical slicesMetabolic disturbancesCortical neurogenesisMetabolic supportBrain disordersAcute lossMitochondrial transportBrain developmentIntracellular CaPotential mechanismsHyperglycemiaMitochondrial functionGlucose sensitivityMiceStem cellsPrimary stem cellsPhysiological mechanismsCells
2017
Erythrocyte efferocytosis modulates macrophages towards recovery after intracerebral hemorrhage
Chang CF, Goods BA, Askenase MH, Hammond MD, Renfroe SC, Steinschneider AF, Landreneau MJ, Ai Y, Beatty HE, da Costa LHA, Mack M, Sheth KN, Greer DM, Huttner A, Coman D, Hyder F, Ghosh S, Rothlin CV, Love JC, Sansing LH. Erythrocyte efferocytosis modulates macrophages towards recovery after intracerebral hemorrhage. Journal Of Clinical Investigation 2017, 128: 607-624. PMID: 29251628, PMCID: PMC5785262, DOI: 10.1172/jci95612.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsApoptosisAxl Receptor Tyrosine KinaseBrain InjuriesCerebral HemorrhageC-Mer Tyrosine KinaseErythrocytesHematomaHumansImmunity, InnateInflammationMacrophagesMaleMiceMice, Inbred C57BLMice, TransgenicPhagocytosisPhenotypeProto-Oncogene ProteinsReceptor Protein-Tyrosine KinasesSolubilityTreatment OutcomeConceptsMonocyte-derived macrophagesIntracerebral hemorrhageEryptotic erythrocytesNeurological recoveryHematoma clearanceExperimental intracerebral hemorrhageReceptor tyrosine kinase AXLHuman monocyte-derived macrophagesTyrosine kinase AXLICH onsetFunctional outcomeBrain injuryTissue injurySoluble AxlDynamic phenotypic changesAlternative activationPhenotypic changesMacrophage phenotypeIron depositionMurine brainMacrophage responseRestorative functionEfferocytosisMacrophagesEngulfment of erythrocytesAntiviral CD8 T cells induce Zika-virus-associated paralysis in mice
Jurado KA, Yockey LJ, Wong PW, Lee S, Huttner AJ, Iwasaki A. Antiviral CD8 T cells induce Zika-virus-associated paralysis in mice. Nature Microbiology 2017, 3: 141-147. PMID: 29158604, PMCID: PMC5780207, DOI: 10.1038/s41564-017-0060-z.Peer-Reviewed Original ResearchConceptsCentral nervous systemZIKV infectionZika virusT cellsNeurological complicationsNervous systemBlood-brain barrier breakdownAntiviral CD8 T cellsHigh viral burdenIFNAR knockout miceCD8 T cellsEffector T cellsSusceptible mouse modelBlood-brain barrierNon-haematopoietic cellsSite of infectionIFNAR1 deficiencyViral burdenNeurological manifestationsGuillain-BarréBarrier breakdownMouse modelKnockout miceAstrocytes resultsAntiviral activitySurface chemistry governs cellular tropism of nanoparticles in the brain
Song E, Gaudin A, King AR, Seo YE, Suh HW, Deng Y, Cui J, Tietjen GT, Huttner A, Saltzman WM. Surface chemistry governs cellular tropism of nanoparticles in the brain. Nature Communications 2017, 8: 15322. PMID: 28524852, PMCID: PMC5454541, DOI: 10.1038/ncomms15322.Peer-Reviewed Original ResearchConceptsSurface chemistryDifferent surface chemistriesDrug deliveryNanoparticlesNanoparticle designChemistryTherapeutic efficacyAssociation rateFunctionalizationCentral nervous systemConvection-enhanced deliverySignificant uptakeBrain interstitiumOrthotopic modelNervous systemNeurological diseasesAdverse toxicityCellular tropismExtent of internalizationCellular depositionBrainCell populationsDepositionPropertiesGlioblastoma
2012
A Neuron-Specific Role for Autophagy in Antiviral Defense against Herpes Simplex Virus
Yordy B, Iijima N, Huttner A, Leib D, Iwasaki A. A Neuron-Specific Role for Autophagy in Antiviral Defense against Herpes Simplex Virus. Cell Host & Microbe 2012, 12: 334-345. PMID: 22980330, PMCID: PMC3454454, DOI: 10.1016/j.chom.2012.07.013.Peer-Reviewed Original ResearchConceptsI interferonHSV-1 replicationDorsal root ganglionic neuronsType I IFN treatmentHerpes simplex type 1I IFN treatmentI IFNsHSV-1 infectionHerpes simplex virusNeuron-specific rolesSimplex type 1Type I interferonMucosal epithelial cellsDRG neuronsGanglionic neuronsNeurotropic virusesIFN treatmentSimplex virusViral infectionAntiviral pathwaysViral replicationType 1Antiviral strategiesLittle type INeurons