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1、Page1of591OriginalResearchCommunicationPharmacodynamicsofDimethylFumarateareTissue-specificandInvolveNRF2-dependentand-independentMechanisms1a,21a1b1b1bMelanieSBrennan,HiralPatel,NormAllaire,AliceThai,PatrickCullen,Sarah1c1c1c1d1aRyan,MatveyLukashev,PradeepBista,RonHuang,KennethJ.Rhodes,RobertH.1
2、aScannevin1aNeurologyResearch,BiogenInc.,Cambridge,MA,021421bComputationalBiology,BiogenInc.,Cambridge,MA,021421cImmunologyResearch,BiogenInc.,Cambridge,MA,021421dDMPK,BiogenInc.,Cambridge,MA021422GPN,BostonUniversitySchoolofMedicine,Boston,MA02118AbbreviatedTitle:InvivoDMFpharmacodynamicresponse
3、sAntioxidants&RedoxSignalingCorrespondingauthor:MelanieSBrennan250BinneyStreetCambridge,MA02142Tel:617-914-4743Fax:617-914-5819E-mail:melanie.brennan@biogen.comWordcount:5,948References:58GreyscaleIllustrations:9(3supplementary)PharmacodynamicsofDimethylFumarateareTissue-specificandInvolveNRF2-de
4、pendentand-independentMechanisms(doi:10.1089/ars.2015.6622)ColorIllustrations:3Brennan1Thisarticlehasbeenpeer-reviewedandacceptedforpublication,buthasyettoundergocopyeditingandproofcorrection.Thefinalpublishedversionmaydifferfromthisproof.Page2of592AbstractAims:Gastro-resistantdimethylfumarate(DM
5、F)isanoraltherapeuticindicatedforthetreatmentofrelapsingmultiplesclerosis.RecentdatasuggestthataprimarypharmacodynamicresponsetoDMFtreatmentisactivationofthenuclearfactor(erythroid-derived2)-like2(NRF2)pathway;however,thegenetargetsmodulateddownstreamofNRF2thatcontributetoDMF-dependenteffectsarep
6、oorlyunderstood.Results:UsingwildtypeandNRF2knockoutmice,wecharacterizedDMFtranscriptionalresponsesthroughoutthebrainandperipherytounderstandDMFeffectsinvivoandexplorethenecessityofNRF2inthisprocess.Ourfindingsidentifiedtissue-specificexpressionofNRF2targetgenesaswellasNRF2-dependentand-independe
7、ntgeneregulationfollowingDMFadministration.Furthermore,usinggeneontology,weidentifiedcommonbiologicalpathwaysthatmayberegulatedbyDMFandcontributetoinvivofunctionaleffects.Innovation:Together,thesedatasuggestDMFmodulate
