細胞凋亡華子春課件

細胞凋亡與雙語教學(xué)華子春醫(yī)藥生物技術(shù)國家重點實驗室

南京大學(xué)《細胞生物學(xué)》課程雙語課程介紹《細胞生物學(xué)》：專業(yè)必修課，2學(xué)時，本科生2年級《細胞生物學(xué)實驗》：專業(yè)必修課，3學(xué)時，本科生2年級

《分子細胞生物學(xué)》：研究生選修課，4學(xué)時，研究生1年級

授課對象：生命科學(xué)學(xué)院、醫(yī)學(xué)院、環(huán)境學(xué)院、強化部、物理系、生物制藥（合辦）專業(yè)

課程情況1．基礎(chǔ)知識與學(xué)科發(fā)展相結(jié)合；2．細胞層次與其它微/宏觀層次相結(jié)合；3.

細胞的結(jié)構(gòu)與其功能相結(jié)合；4.

與普通生物學(xué)、生理學(xué)、分子生物學(xué)相結(jié)合、與生理和病理過程相結(jié)合；5．本專業(yè)知識與其它學(xué)科相結(jié)合：教學(xué)要點整體及生理、病理過程中的細胞結(jié)構(gòu)與功能將基礎(chǔ)理論知識與學(xué)科前沿發(fā)展相結(jié)合將分子細胞層次與病理生理過程相結(jié)合將夯實基本概念與培養(yǎng)創(chuàng)新意識相結(jié)合將國內(nèi)教師主講與外聘教師授課相結(jié)合教學(xué)理念寓學(xué)科前沿于基本理論之中寓實驗原理于基本概念之中寓科學(xué)思維于基本概念之中中英文教學(xué)英文教學(xué)國內(nèi)教師主講外聘教師短期授課循序漸進、國際化和多元化的雙語教學(xué)第1章：細胞概述（2學(xué)時）；第3章：細胞質(zhì)膜與跨膜運輸（3學(xué)時）；第4章：細胞環(huán)境與互作（3學(xué)時）；第5章：細胞通訊（6學(xué)時）；第6章：核糖體與核酶（2學(xué)時）；第7章：線粒體與過氧化物酶體（4學(xué)時）；第9章：內(nèi)膜系統(tǒng)與蛋白質(zhì)分選和膜運輸（6學(xué)時）；第10章：細胞骨架與細胞運動（4學(xué)時）；第11章：細胞核與染色體（2學(xué)時）；第12章：細胞周期與細胞分裂（4學(xué)時）；第13和:細胞死亡（2學(xué)時）。課時安排第十三章細胞死亡

—基礎(chǔ)概念與實際應(yīng)用

ApoptosisvsnecrosisApoptosisNecrosisDeathbyapoptosisisaneat,orderlyprocessNecrosis

?Deathbyaccident?Associatedwithnonphysiologicalcircumstancesthatdisruptcellularhomeostasis(eg.,ischemia,hypoxiaandpoisoning)?Necrosisiscausedbymembranedissolution(osmoticlysis,shearstress,pore-formingproteins,lossofATP)?Necrosisisbadbecausecellularmaterial(includingdegradativeenzymes)isreleasedintosurroundingtissue?Affectscontiguousgroupsofcell?NecrosisusuallycausesinflammatoryreactionCytologicalcharacteristicsofnecrosis?Initialswellingofthecell?Ruptureoftheplasmamembrane?CytoplasmisspilledtotheextracellularenvironmentApoptosis

?Deathbydesign–geneticallyprogrammedcelldeath?Inducedbynewgenesynthesis,primarilyinresponsetodevelopmentalcues?RequiresnewRNAandproteinsynthesis–Inhibitorsoftranscriptionortranslationpreventapoptosis?Importantfordevelopment,homeostasisandeliminationofpathogensandtumorcells?Causesdeletionofindividualcellsinthemidstofothers–Butitcanbeinvolvedindeletionofentirestructures?Apoptosisisfollowedbyfastphagocytosis–Anti-inflammatory(housekeeping)Morphologicchangesduringapoptosis

?Membranesbecomeirregular?Chromatinbecomescondensedandsegregated?Condensationofcytoplasm?DNAisfragmented?CellisfragmentedandphagocytosedBiochemicalcharacteristicsofapoptosis:ApoptosisinducedbyCytoCLane1．0h2．1h3．2h4．3h5．4h6．Control7．Marker

2.0kbp1.00.50.2180~200bpDNAladder,AccumulationoftTG,PSflip-flop體內(nèi)細胞凋亡檢測紫杉醇治療小鼠肺癌腫瘤ApoptosisDoesNotDamageNeighboringCellsMorphologicalfeaturesofapoptosis:CytoskeletoncollapsesNuclearenvelopedisassemblesNuclearDNAbreaksupintofragmentsCellsurfacechangessothatthecellcanberapidlyphagocytosedTheconsequenceisneatdeath---nodamagetotheneighboringcellsDeathbycellnecrosis;cellcontentsspilledallovertheneighborsCellapoptosis,inculturedishCellapoptosis,intissue.ShowingphagocytosisFormsofcelldeathNecrosisApoptosisPassiveActivePathologicalPhysiologicalor pathologicalSwelling,lysis Condensation,cross-linkingDissipatesPhagocytosedInflammation NoinflammationExternallyinduced Internallyor externallyinducedAPOPTOSISProgrammedcelldeathOrderlycellularselfdestructionProcess:ascrucialforsurvivalofmulti-cellularorganismsascelldivisionMULTIPLEFORMS???ApoptosispathwaysAPOPTOSIS:importantinembryogenesis?Intrinsic/MitochondrialApoptosis–RegulatedbyMitochondria–Cytochromecrelease?Extrinsic/DeathReceptorApoptosis–ActivatedbyligationofDeathReceptors–Fas,TNFalpha?ThesepathwaysintersectattheeffectorcaspasesTwoPathwaysthatInitiateApoptosis

APOPTOSIS:controlReceptorpathway(physiological):Deathreceptors:(FAS,TNF-R,etc)FASligandTNFDeathdomainsAdaptorproteinsPro-caspase8(inactive)Caspase8(active)Pro-executioncaspase(inactive)Executioncaspase(active)DeathMITOCHONDRIAAPOPTOSIS:control

PhysiologicalIntrinsicreceptorpathwaydamagepathwayMITOCHONDRIALSIGNALSCaspasecleavagecascadeOrderlycleavageofproteinsandDNACROSSLINKINGOFCELLCORPSES;ENGULFMENT(noinflammation)ApoptosisIsMediatedbyaCaspasesApoptosisdependsonagroupofproteases---Caspases(胱冬蛋白酶)Havea

cysteine

(半胱氨酸)intheactivesiteCleavethetargetproteinsatspecificasparticacid

(天冬氨酸)residuesCaspasesaresynthesizedasinactiveprocursor,“procaspase”.Othercaspasesactivateitbycleavingit:Aapoptoticproteolyticsystem—caspase

Whycalledcaspase?Activesite:CysteineCleavagesite:Asparaticacid

CysteineAsparaticacidspecificproteaseAps-Xxx天冬氨酸特異性的半胱氨酸蛋白水解酶CaspasesTriggeraProteolysisCascadeCleavesinhibitorsofDNaseDNAfragmentationAPOPTOSIS:RoleinDiseaseCancerApoptosiseliminatesdamagedcells(damage=>mutations=>cancer)Tumorsuppressorp53controlssenescenceandapoptosisresponsestodamageMostcancercellsaredefectiveinapoptoticresponse(damaged,mutantcellssurvive)Highlevelsofanti-apoptoticproteinsorLowlevelsofpro-apoptoticproteins===>CANCERTRAIL:

一種細胞凋亡誘導(dǎo)蛋白質(zhì)TRAIL:腫瘤壞死因子相關(guān)的凋亡誘導(dǎo)配體TRAIL腫瘤選擇性:不同TRAIL受體表達的結(jié)果死亡受體(DR4，DR5):

介導(dǎo)細胞凋亡信號誘騙受體(DcR1，DcR2):不傳導(dǎo)細胞凋亡信號DcRs與DRs

競爭結(jié)合TRAIL，賦予正常組織TRAIL抗性TRAIL變體具有更好的細胞凋亡活性

Adaptorproteinsbringmanycopiesofinitiatorprocaspase

togetherInitiatorcaspasehaslowactivity,butwhentheyformaggregates,theycancross-activateeachother.AggregationcausesconformationalchangesApoptosisIsActivatedbyBindingtoAdaptorProteinstoFormAggregatesFasFasLFADDCaspase

8APOPTOSISActivationofApoptosisfromOutsidetheCellDeathreceptorsKillerlymphocytesproduceFas

ligandtobindtoFasprotein(deathreceptor)ontargetcellsAdaptorproteinsaggregate

caspase8,whichcross-activateSomedamagedcellsproducebothFasligandandFasproteinforself-destructionExtrinsicpathwayAPOPTOSIS:controlIntrinsicpathway(damage):MitochondriaCytochromecreleasePro-caspase9cleavagePro-executioncaspase(3)cleavageCaspase(3)cleavageofcellularproteins,nucleaseactivation,etc.DeathBAXBAKBOKBCL-XsBADBIDBIKBIMNIP3BNIP3BCL-2BCL-XLBCL-WMCL1BFL1DIVANR-13SeveralviralproteinsActivationofApoptosisfromInsidetheCellIntrinsicpathwayWhencellsaredamaged:Mitochondriareleasecytochromec

Incytosol,cytochromecbindstoApaf-1

(adaptorprot