个体化医疗的现状与未来-生物标志物.ppt

个体化医疗的现状与未来四.生物标志物研究,吕林莉M.D.,Ph.D.,Outline,生物标志物的概念如何评价生物标志物？生物标志物的研究方法？,生物标志物的概念,什么是生物标志物(biomarker)？,“measurableandquantifiablebiologicalparameters”-aMedicalSubjectHeading(MeSH)term,1989“Acharacteristicthatisobjectivelymeasuredandevaluatedasanindicatorofnormalbiologicalprocesses,pathogenicprocessesorpharmacologicalresponsestoatherapeuticintervention.”-BiomarkerDefinitionsWorkingGroup,2001,NIH,FeaturesofaUsefulBiomarker,HighsensitivityandspecificityEasyaccessiblesampleCorrelationwithhistologicalscoringChangeinadvanceofclinicalsignsTranslationalfromresearchtoclinicaluse,不同水平生物标志物,DNA,Primarytranscript,mRNA,Transcription,protein,Translation,RNAprocessing,Nucleus,BiomarkerExamples,Cholesterolisoneofthemostwell-knownbiomarkersofcardiovascularhealthPhysicalmeasurements:bodytemperature(fever);bloodpressure(strokerisk)Otherbiomarkers:bloodsugarlevel(diabetes)antigens(hepatitis)proteins(heartattack)geneticvariations(Huntingtonsdisease),生物标志物的临床应用,LudwigJAetal.Naturereviews2005,5:845-856,目前临床很多疾病的诊断依赖病理诊断，但不能作为常规筛查、监测手段众多疾病缺乏早期、特异性生物标志物治疗缺乏个体化方案,生物标志物应用现状,ClinJAmSocNephrol3:18951901,2008.,Biomarkersforchronickidneydisease,Arewetreatingsub-populations?,FromKalow,Tyndale113:2335-2362.,TheAgendiaMammaPrintTest首个FDA批准的基因组检测试验-Feb.2007,Howtheygotthere？,2002Discoveryof70genesignature(117patients)2002Duplicationofresults(inanothersampleset:295patients)2006Assayperformance2006Optimizedarrayformat:reproducibility;backtooriginalsampleset2006Externalconfirmation(307patients,5hospitals)2007ApprovalbyFDA,生物标志物研究技术,传统研究方法：PCR,Westernblotting,ELISA,etal新型研究方法：基因组学技术蛋白质组学技术：2-DIGE/MS,蛋白质芯片,生物标志物研究方法,Question1.Whathumansamplesshouldbecollected,andhowshouldtheybeused?Doesthisvarybetweendiscovery,validationandimplementation?,Answer1.,AllbiologicalsamplesareeligibleforcollectionCollectedbiologicalmaterialdependsonanalyteandtissuesourceExamplesBiologicalfluidsSerum,plasma,urine,csfSecretionsSaliva,seminalfluidBodycavityfluidsPleuralfluid,peritonealfluid,etcSpecifictissuematerialSpecializedcellsreproductivecellsNon-cellular,IdealBiomarkerdiscoverysamplesshouldbeidenticaltotheprojectedtestingsituation(e.g.Donotstudyplasmafordiscovery,andthenvalidateorimplementassayusingserum)Practicalsetupstudywithsamplesthatareasclosetothetestingsituationaspossible,Question2.,Whatistheroleofroutinelyaccessiblebiofluidssuchasplasma,serum,andurine?Whatistheroleof“proximal”fluidslikeCSF,synovialfluid,ascites,pancreaticductalfluid,etc?Whatistheroleofsolidtissues?,Roleofroutinelyaccessiblebiofluids,Veryimportantinthediscoveryofbiomarkersofdiseases(anspecific/local)Importantfor:earlydetectiondiseaseseveritytumorburdenprognosismonitoringofresponsetotherapy,“Proximalfluids”CanreflectdiseaseperturbationsintheorgansortissuesfromwhichtheyaresecretedSolidtissuesVeryimportantforthedevelopmentofnovelinsitubiomarkersImmunofluorescence,immunocytochemistryImagingmassspectrometry,Question3.,Musthumansamplecollectionbeprospective,orcanexistingrepositoriesbeused?Whatconsiderationsareimportantindeterminingtheadequacyofrepositorysamples?,Answer3:,UltimateconfirmationofthevalidityofabiomarkerhastobeproveninaprospectivestudyNevertheless,welldesignedretrospectivestudiesusingwellcharacterizedsamplesinrepositoriescanbeperformedandfrequentlyyieldviablecandidates,生物标志物研究面临的挑战,The