2023
Development of neural repair therapy for chronic spinal cord trauma: soluble Nogo receptor decoy from discovery to clinical trial
Howard E, Strittmatter S. Development of neural repair therapy for chronic spinal cord trauma: soluble Nogo receptor decoy from discovery to clinical trial. Current Opinion In Neurology 2023, 36: 516-522. PMID: 37865850, PMCID: PMC10841037, DOI: 10.1097/wco.0000000000001205.Peer-Reviewed Original ResearchConceptsSpinal cord injuryChronic cervical spinal cord injuryCervical spinal cord injuryRecent clinical trialsCentral nervous systemClinical trialsAnimal studiesNeural repairChronic spinal cord injuryIncomplete spinal cord injuryTraumatic spinal cord injuryAdult mammalian central nervous systemContusion spinal cord injuryTreatment-naïve patientsSpinal cord traumaMammalian central nervous systemNeural repair therapiesUpper extremity strengthNonhuman primate studiesReceptor 1 pathwayNeurological recoveryNeurological deficitsCord traumaMedical therapyChronic stageAmino-terminal proteolytic fragment of the axon growth inhibitor Nogo-A (Rtn4A) is upregulated by injury and promotes axon regeneration
Sekine Y, Wang X, Kikkawa K, Honda S, Strittmatter S. Amino-terminal proteolytic fragment of the axon growth inhibitor Nogo-A (Rtn4A) is upregulated by injury and promotes axon regeneration. Journal Of Biological Chemistry 2023, 299: 105232. PMID: 37690690, PMCID: PMC10622843, DOI: 10.1016/j.jbc.2023.105232.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsAxonsFemaleGrowth InhibitorsMammalsMiceMice, Inbred C57BLMyelin ProteinsNerve RegenerationNogo ProteinsProteolysisConceptsAxon regenerationCentral nervous system injuryPersistent neurological deficitsCerebral cortical neuronsNervous system injuryNeurological deficitsSystem injuryCNS injuryCortical neuronsAmino-terminal fragmentInjuryExtracellular actionPhysiological productionNogoInhibitory proteinMiceNeuronsInhibitory domainOverexpression increasesVaried resultsProteolytic fragmentsAxotomyExpressionNogoAGene targeting
2022
Rabphilin3A reduces integrin-dependent growth cone signaling to restrict axon regeneration after trauma
Sekine Y, Kannan R, Wang X, Strittmatter SM. Rabphilin3A reduces integrin-dependent growth cone signaling to restrict axon regeneration after trauma. Experimental Neurology 2022, 353: 114070. PMID: 35398339, PMCID: PMC9555232, DOI: 10.1016/j.expneurol.2022.114070.Peer-Reviewed Original ResearchConceptsAxon regenerationModerate spinal cord contusion injurySpinal cord contusion injuryTraumatic spinal cord injuryAdult mammalian central nervous systemGrowth conesRetinal ganglion cell axonsOptic nerve crushSpinal cord crush injuryGanglion cell axonsSpinal cord injuryMammalian central nervous systemCentral nervous systemCorticospinal axon regenerationContusion injuryAxonal sproutingCrush injuryNerve crushAxonal growth conesCord injuryAxon sproutingCell axonsProximal bodyNervous systemNeural repair
2021
Optic nerve regeneration screen identifies multiple genes restricting adult neural repair
Lindborg JA, Tran NM, Chenette DM, DeLuca K, Foli Y, Kannan R, Sekine Y, Wang X, Wollan M, Kim IJ, Sanes JR, Strittmatter SM. Optic nerve regeneration screen identifies multiple genes restricting adult neural repair. Cell Reports 2021, 34: 108777. PMID: 33657370, PMCID: PMC8009559, DOI: 10.1016/j.celrep.2021.108777.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsAxonsCRISPR-Cas SystemsDependovirusFemaleGene EditingGene Expression RegulationGenetic Association StudiesHEK293 CellsHumansInterleukinsMaleMAP Kinase Kinase KinasesMice, Inbred C57BLMice, TransgenicNerve RegenerationNeurogenesisOptic NerveOptic Nerve InjuriesRetinal Ganglion CellsSignal TransductionSTAT3 Transcription FactorConceptsOptic nerve crushRetinal ganglion cellsRegeneration-associated genesShort hairpin RNAIL-22Neural repairCentral nervous system traumaNeurological deficits persistNervous system traumaNerve crushAxonal damageAxonal regenerationGanglion cellsSystem traumaInflammatory responseCNS regenerationDeficits persistAxonal growthHairpin RNAConcurrent activationTranscription 3Cell-autonomous factorsKinase pathwaySignal transducerRepair
2020
Nogo receptor decoy promotes recovery and corticospinal growth in non-human primate spinal cord injury
Wang X, Zhou T, Maynard GD, Terse PS, Cafferty WB, Kocsis JD, Strittmatter SM. Nogo receptor decoy promotes recovery and corticospinal growth in non-human primate spinal cord injury. Brain 2020, 143: 1697-1713. PMID: 32375169, PMCID: PMC7850069, DOI: 10.1093/brain/awaa116.Peer-Reviewed Original ResearchConceptsPrimate spinal cord injurySpinal cord injuryCord injuryFemale African green monkeysTreatment-related adverse eventsChronic neurological deficitsNogo receptor 1Left motor cortexRecovery of functionPreclinical rodent modelsSpinal cord injury animalsAfrican green monkeysRaphespinal fibersAdverse eventsCervical cordNeurological deficitsSurgical complicationsCNS traumaTreatment cessationCorticospinal axonsLumbar catheterInjury animalsNeural recoverySpontaneous feedingLateral hemisection
2019
A proteolytic C-terminal fragment of Nogo-A (reticulon-4A) is released in exosomes and potently inhibits axon regeneration
Sekine Y, Lindborg JA, Strittmatter SM. A proteolytic C-terminal fragment of Nogo-A (reticulon-4A) is released in exosomes and potently inhibits axon regeneration. Journal Of Biological Chemistry 2019, 295: 2175-2183. PMID: 31748413, PMCID: PMC7039549, DOI: 10.1074/jbc.ra119.009896.Peer-Reviewed Original ResearchConceptsMembrane-associated proteinsRecombinant protein expressionMatrix-associated proteinOligodendrocyte plasma membraneProteolytic C-terminal fragmentsRegeneration assaysC-terminal fragmentPlasma membraneNeurite outgrowth inhibitor NogoAxonal regenerationExosomal releaseDiffusible inhibitorC-terminalSiRNA knockdownCleavage siteCultured cellsLong fragmentPrimary cortical neuron culturesCentral nervous system traumaExosomesEnzyme inhibitor treatmentExosomal fractionSpinal cord crush injuryCerebral cortex neuronsProteinPlexina2 and CRMP2 Signaling Complex Is Activated by Nogo-A-Liganded Ngr1 to Restrict Corticospinal Axon Sprouting after Trauma
Sekine Y, Algarate PT, Cafferty WBJ, Strittmatter SM. Plexina2 and CRMP2 Signaling Complex Is Activated by Nogo-A-Liganded Ngr1 to Restrict Corticospinal Axon Sprouting after Trauma. Journal Of Neuroscience 2019, 39: 3204-3216. PMID: 30804090, PMCID: PMC6788813, DOI: 10.1523/jneurosci.2996-18.2019.Peer-Reviewed Original ResearchConceptsCNS traumaNeural repairMouse cervical spinal cordSpinal cord traumaCervical spinal cordNon-neuronal cellsInteraction of NogoAxon growth inhibitionAxonal guidance mechanismsNeurological recoveryAxonal sproutingCNS pathwaysCord traumaFunctional recoveryAxon sproutingSpinal cordNgR1 functionUnilateral pyramidotomyAxon regenerationAdult traumaNgR1TraumaAxon growthNogoCytoplasmic mediators
2018
Diltiazem Promotes Regenerative Axon Growth
Huebner EA, Budel S, Jiang Z, Omura T, Ho TS, Barrett L, Merkel JS, Pereira LM, Andrews NA, Wang X, Singh B, Kapur K, Costigan M, Strittmatter SM, Woolf CJ. Diltiazem Promotes Regenerative Axon Growth. Molecular Neurobiology 2018, 56: 3948-3957. PMID: 30232777, PMCID: PMC6424671, DOI: 10.1007/s12035-018-1349-5.Peer-Reviewed Original ResearchConceptsL-type calcium channel blockerDorsal root gangliaCentral nervous systemChondroitin sulfate proteoglycanAxon regenerationMouse dorsal root gangliaAdult central nervous systemHuman sensory neuronsCalcium channel blockersSpinal cord injuryRat cortical culturesCord injuryAxonal regrowthRoot gangliaCortical culturesChannel blockersRegenerative propensityRegenerative axon growthSensory neuronsNervous systemPharmacological enhancersAxon growthPermanent lossSulfate proteoglycanAxotomyThe nociceptin receptor inhibits axonal regeneration and recovery from spinal cord injury
Sekine Y, Siegel CS, Sekine-Konno T, Cafferty WBJ, Strittmatter SM. The nociceptin receptor inhibits axonal regeneration and recovery from spinal cord injury. Science Signaling 2018, 11 PMID: 29615517, PMCID: PMC6179440, DOI: 10.1126/scisignal.aao4180.Peer-Reviewed Original ResearchConceptsSpinal cord injuryCord injuryAxonal regenerationMid-thoracic spinal cordTraumatic spinal cord injuryPartial neurological recoveryTraumatic CNS injuryDorsal hemisectionNeurological recoveryPeptide nociceptinCNS injuryAxon sproutingORL1 agonistSelective blockadeSpinal cordLocomotor functionNociceptin receptorAxon regenerationNeural repairPrimary neuronsNgR1 proteinAxonal growthNull miceMRNA expressionORL1Functional Genome-wide Screen Identifies Pathways Restricting Central Nervous System Axonal Regeneration
Sekine Y, Lin-Moore A, Chenette DM, Wang X, Jiang Z, Cafferty WB, Hammarlund M, Strittmatter SM. Functional Genome-wide Screen Identifies Pathways Restricting Central Nervous System Axonal Regeneration. Cell Reports 2018, 23: 415-428. PMID: 29642001, PMCID: PMC5937716, DOI: 10.1016/j.celrep.2018.03.058.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsAxonsCaenorhabditis elegansCaenorhabditis elegans ProteinsCentral Nervous SystemFemaleGene Regulatory NetworksGenomeMiceMice, Inbred C57BLMice, KnockoutNerve RegenerationOptic NerveRab GTP-Binding ProteinsRecovery of FunctionRetinal Ganglion CellsRNA InterferenceRNA, Small InterferingSpinal Cord InjuriesSuppressor of Cytokine Signaling ProteinsConceptsAxonal regenerationCentral nervous system axonal regenerationRetinal ganglion cell axon regenerationGreater motor functionOptic nerve crushCerebral cortical neuronsSpinal cord traumaNeurological recoveryCord traumaNerve crushCNS injuryAxonal regrowthCortical neuronsMotor functionAxon regenerationReceptor bindingComprehensive functional screenAdult mammalsInjuryMultiple pathwaysExpression profilesIdentifies pathwaysSignificant overlapPathwayFunction screen
2017
Regulation of axonal regeneration by the level of function of the endogenous Nogo receptor antagonist LOTUS
Hirokawa T, Zou Y, Kurihara Y, Jiang Z, Sakakibara Y, Ito H, Funakoshi K, Kawahara N, Goshima Y, Strittmatter SM, Takei K. Regulation of axonal regeneration by the level of function of the endogenous Nogo receptor antagonist LOTUS. Scientific Reports 2017, 7: 12119. PMID: 28935984, PMCID: PMC5608707, DOI: 10.1038/s41598-017-12449-6.Peer-Reviewed Original ResearchConceptsSpinal cord injuryOptic nerve crushAxonal regenerationMotor recoveryNerve crushNeural repairRetinal ganglion cell axonal regenerationAdult mammalian central nervous systemIntrinsic motor recoverySpontaneous neural repairAxonal growth inhibitorsMammalian central nervous systemCentral nervous systemNon-permissive environmentLevel of functionUntreated miceFunctional recoveryCord injuryReceptor antagonistNeuronal overexpressionNervous systemGenetic deletionViral overexpressionCrushInhibitors
2016
Inhibition of Poly-ADP-Ribosylation Fails to Increase Axonal Regeneration or Improve Functional Recovery after Adult Mammalian CNS Injury
Wang X, Sekine Y, Byrne AB, Cafferty WB, Hammarlund M, Strittmatter SM. Inhibition of Poly-ADP-Ribosylation Fails to Increase Axonal Regeneration or Improve Functional Recovery after Adult Mammalian CNS Injury. ENeuro 2016, 3: eneuro.0270-16.2016. PMID: 28032120, PMCID: PMC5187389, DOI: 10.1523/eneuro.0270-16.2016.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsAxonsBenzimidazolesCells, CulturedCerebral CortexDisease Models, AnimalFemaleIsoenzymesMaleMice, 129 StrainMice, Inbred C57BLMice, TransgenicMotor ActivityNerve RegenerationOptic Nerve InjuriesPoly (ADP-Ribose) Polymerase-1Poly(ADP-ribose) Polymerase InhibitorsRecovery of FunctionSpinal Cord InjuriesThoracic VertebraeConceptsOptic nerve crush injuryNerve crush injuryThoracic spinal cordAxonal regenerationSpinal cordDorsal hemisectionCrush injuryFunctional recoveryPARP inhibitorsMotor function recoveryRecovery of functionPoly (ADP-ribose) polymeraseClinical PARP inhibitorsNeurological recoveryShort hairpin RNACNS traumaCNS injuryFunction recoveryAxonal regrowthSystemic administrationPharmacodynamic actionAxon regenerationTraumatic damageTherapeutic efficacyNeurological trauma
2015
Comprehensive Corticospinal Labeling with mu-crystallin Transgene Reveals Axon Regeneration after Spinal Cord Trauma in ngr1−/− Mice
Fink KL, Strittmatter SM, Cafferty WB. Comprehensive Corticospinal Labeling with mu-crystallin Transgene Reveals Axon Regeneration after Spinal Cord Trauma in ngr1−/− Mice. Journal Of Neuroscience 2015, 35: 15403-15418. PMID: 26586827, PMCID: PMC4649010, DOI: 10.1523/jneurosci.3165-15.2015.Peer-Reviewed Original ResearchMeSH KeywordsAmidinesAnalysis of VarianceAnimalsAxonsBiotinCrystallinsDextransDisease Models, AnimalFunctional LateralityGene Expression RegulationGlial Fibrillary Acidic ProteinGPI-Linked ProteinsLuminescent ProteinsMiceMice, Inbred C57BLMice, TransgenicMu-CrystallinsMyelin ProteinsNerve RegenerationNogo Receptor 1Pyramidal TractsReceptors, Cell SurfaceRecovery of FunctionSpinal Cord InjuriesConceptsCorticospinal tractCST axonsTransgenic miceMotor tractsDextran amineFunctional deficitsSpinal cordAxon regenerationSpinal Cord Injury StudySpontaneous axon regenerationSpinal cord traumaNogo receptor 1Permanent functional deficitsPersistent functional deficitsBilateral pyramidotomyDorsal hemisectionMidthoracic cordCord traumaMotor pathwaysAdult CNSCST regenerationInjury studiesLesion siteRegenerating fibersNeural repairGene-Silencing Screen for Mammalian Axon Regeneration Identifies Inpp5f (Sac2) as an Endogenous Suppressor of Repair after Spinal Cord Injury
Zou Y, Stagi M, Wang X, Yigitkanli K, Siegel CS, Nakatsu F, Cafferty WB, Strittmatter SM. Gene-Silencing Screen for Mammalian Axon Regeneration Identifies Inpp5f (Sac2) as an Endogenous Suppressor of Repair after Spinal Cord Injury. Journal Of Neuroscience 2015, 35: 10429-10439. PMID: 26203138, PMCID: PMC4510284, DOI: 10.1523/jneurosci.1718-15.2015.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsAxonsDisease Models, AnimalGene Knockdown TechniquesImmunohistochemistryInositol Polyphosphate 5-PhosphatasesMiceMice, Inbred C57BLMice, KnockoutNerve RegenerationPhosphoric Monoester HydrolasesRecovery of FunctionReverse Transcriptase Polymerase Chain ReactionSpinal Cord InjuriesConceptsSpinal cord injuryCord injuryEndogenous suppressorAxon regenerationNonoverlapping substrate specificityGenome-wide scaleHigh-throughput functional screensFunctional recoveryAxonal regenerationCNS axon repairSpinal cord injury researchDorsal hemisection injuryMammalian genesPI3K/AKT/mTOR pathwayCNS axon growthAKT/mTOR pathwayLipid phosphataseCorticospinal tract axonsCNS axon regenerationAdult mammalian CNSFunctional screenSubstrate specificityNovel suppressorShRNA resultsINPP5FIntravitreal Delivery of Human NgR-Fc Decoy Protein Regenerates Axons After Optic Nerve Crush and Protects Ganglion Cells in Glaucoma ModelsNgR-Fc Rescues Ganglion Cells in Glaucoma
Wang X, Lin J, Arzeno A, Choi JY, Boccio J, Frieden E, Bhargava A, Maynard G, Tsai JC, Strittmatter SM. Intravitreal Delivery of Human NgR-Fc Decoy Protein Regenerates Axons After Optic Nerve Crush and Protects Ganglion Cells in Glaucoma ModelsNgR-Fc Rescues Ganglion Cells in Glaucoma. Investigative Ophthalmology & Visual Science 2015, 56: 1357-1366. PMID: 25655801, PMCID: PMC4338631, DOI: 10.1167/iovs.14-15472.Peer-Reviewed Original ResearchConceptsOptic nerve crushFluro-GoldNerve crushAxonal regenerationGanglion cellsOptic nerve crush injuryRetinal ganglion cell degenerationRGC axonal regenerationNerve crush injuryDisease-modifying therapiesGanglion cell degenerationDecoy proteinMicrobead modelVitreal spaceIntravitreal treatmentRGC densityAxonal sproutingCrush injuryGlaucoma modelNeuroprotective effectsAnterior chamberControl ratsVision lossAnterograde labelingBolus administration
2012
PlexinA2 limits recovery from corticospinal axotomy by mediating oligodendrocyte-derived Sema6A growth inhibition
Shim SO, Cafferty WB, Schmidt EC, Kim BG, Fujisawa H, Strittmatter SM. PlexinA2 limits recovery from corticospinal axotomy by mediating oligodendrocyte-derived Sema6A growth inhibition. Molecular And Cellular Neuroscience 2012, 50: 193-200. PMID: 22564823, PMCID: PMC3383336, DOI: 10.1016/j.mcn.2012.04.007.Peer-Reviewed Original ResearchConceptsAxonal growthSpinal cordPellet retrieval taskCervical spinal cordWild-type miceContralateral gray matterAxon guidance cuesSevered fibersSprouted fibersAxonal sproutingCorticofugal projectionsFunctional recoveryBehavioral recoveryCNS injuryImpaired forelimbClass 3 semaphorinsCorticospinal fibersCorticospinal tractMedullary pyramidsSynaptic punctaInhibitor receptorsType miceUnilateral pyramidotomyNeuron inhibitionAdult traumaMyelin-derived ephrinB3 restricts axonal regeneration and recovery after adult CNS injury
Duffy P, Wang X, Siegel CS, Tu N, Henkemeyer M, Cafferty WB, Strittmatter SM. Myelin-derived ephrinB3 restricts axonal regeneration and recovery after adult CNS injury. Proceedings Of The National Academy Of Sciences Of The United States Of America 2012, 109: 5063-5068. PMID: 22411787, PMCID: PMC3323955, DOI: 10.1073/pnas.1113953109.Peer-Reviewed Original ResearchConceptsAxonal regenerationAxonal growthAdult mammalian central nervous systemAdult CNS injuryDorsal hemisection injurySpinal cord injuryMammalian central nervous systemWild-type miceCentral nervous systemCaudal spinal cordAxonal guidance cuesAxonal growth inhibitionLater time pointsGreater spasticityCNS traumaHemisection injuryCrush siteOptic nerveNeurological functionCNS injuryCord injuryTransection modelGrowth restrictionSpinal cordTraumatic injury
2009
Rho-Associated Kinase II (ROCKII) Limits Axonal Growth after Trauma within the Adult Mouse Spinal Cord
Duffy P, Schmandke A, Schmandke A, Sigworth J, Narumiya S, Cafferty WB, Strittmatter SM. Rho-Associated Kinase II (ROCKII) Limits Axonal Growth after Trauma within the Adult Mouse Spinal Cord. Journal Of Neuroscience 2009, 29: 15266-15276. PMID: 19955379, PMCID: PMC2855556, DOI: 10.1523/jneurosci.4650-09.2009.Peer-Reviewed Original ResearchMeSH KeywordsAmidesAnalysis of VarianceAnimalsAxonsBehavior, AnimalBrain InjuriesCA1 Region, HippocampalCells, CulturedCholera ToxinEnzyme InhibitorsGanglia, SpinalGene Expression RegulationMedian NeuropathyMiceMice, Inbred C57BLMice, KnockoutMyelin ProteinsNerve RegenerationNeuronsNogo ProteinsPyridinesReceptors, Calcitonin Gene-Related PeptideRhizotomyRho-Associated KinasesSpinal Cord InjuriesTime FactorsVersicansConceptsSpinal cordCNS traumaFunctional recoveryBasso Mouse Scale scoresSpinal Cord Injury StudyAxonal growthDorsal root entry zoneDorsal root ganglion neuronsAdult mouse spinal cordAxonal growth inhibitorsSpinal cord hemisectionRoot entry zoneSpinal cord injuryCaudal spinal cordMouse spinal cordDorsal hemisectionRaphespinal axonsDorsal rhizotomyCrush injuryCord hemisectionCorticospinal axonsChondroitin sulfate proteoglycanCord injuryGanglion neuronsInjury paradigmsAxon Regeneration in the Peripheral and Central Nervous Systems
Huebner EA, Strittmatter SM. Axon Regeneration in the Peripheral and Central Nervous Systems. Results And Problems In Cell Differentiation 2009, 48: 305-360. PMID: 19582408, PMCID: PMC2846285, DOI: 10.1007/400_2009_19.Peer-Reviewed Original ResearchConceptsCentral nervous systemPeripheral nervous systemSpinal cord injuryNervous systemAxon regenerationLong-distance axon regenerationMature mammalian central nervous systemMammalian peripheral nervous systemSubstantial functional recoveryMammalian central nervous systemTraumatic brain injuryIntrinsic growth capacityFunctional recoveryCord injuryAxonal disconnectionFunctional deficitsBrain injuryRelated conditionsInjuryRegenerative successExtracellular moleculesGrowth capacityStrokeIbuprofen Enhances Recovery from Spinal Cord Injury by Limiting Tissue Loss and Stimulating Axonal Growth
Wang X, Budel S, Baughman K, Gould G, Song KH, Strittmatter SM. Ibuprofen Enhances Recovery from Spinal Cord Injury by Limiting Tissue Loss and Stimulating Axonal Growth. Journal Of Neurotrauma 2009, 26: 81-95. PMID: 19125588, PMCID: PMC2913782, DOI: 10.1089/neu.2007.0464.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsAnti-Inflammatory Agents, Non-SteroidalAxotomyChick EmbryoDisease Models, AnimalEfferent PathwaysFemaleGrowth ConesGrowth InhibitorsIbuprofenMiceNerve RegenerationNIH 3T3 CellsPyramidal TractsRaphe NucleiRatsRats, Sprague-DawleyRhoA GTP-Binding ProteinSpinal CordSpinal Cord InjuriesConceptsSpinal cord injuryAxonal sproutingCord injuryAxonal regenerationAxon regenerationNonsteroidal anti-inflammatory drugsComplete spinal cord transectionWeight-bearing statusSpinal cord contusionRecovery of ratsSpinal cord traumaTreatment of miceAdministration of ibuprofenSpinal cord transectionAnti-inflammatory drugsCorticospinal axon regenerationAction of ibuprofenRaphespinal axonsSpinal contusionCord contusionCord traumaMicroglial reactionChondroitin sulfate proteoglycanCord transectionCorticospinal fibers