信号转导及其异常.ppt

AberrantCellSignalingandtheRelatedDisorders,Disordersofsignaltransductionsystems,CausesGenemutation-FunctionlossorgainChangeofquantityofsignalproteinsChangeofactivityofsignalproteinsAutoimmunediseasesSecondarychanges,Abnormality:Ligands,Receptors,Post-receptorpathways,EffectorsDown-regulation/interruptionofsignalingSignalInsufficiencyReceptorsdown-regulation/desensitization:decreasedquantity,bindingaffinity,inhibitoryAb,cofactordisorders,functionloss,etc.DefectsinAdaptors,Signaltransducers,Effectors(Enzymes,Transcriptionfactors,etc)Up-regulation/over-activationofsignalingSignalExcessReceptorup-regulation,hypersensitivity,stimulatoryAb,etcSignaltransducers,TFs:over-expression,persistentactivationOthers,Pathogenesisanddiseases,1.AberrantSignal,Viralinfectionsorotherdamagestopancreatic-cellinsulinproductionhyperglycemiaDiabetes(TypeI),(1)AberrantSignal(SignalInsufficiency),Insulinreceptor(IR):heterotetramer(2,2)InsulinbindingleadstochangeinconformationActivatesIR-subunitPTKactivity-subunitphosphorylatesTyrresiduesoncytoplasmicdomainsaswellasdownstreamsubstrates(IRS),ischemia,epilepsy,neurodegenerativediseasesextracellularglutamate/asparticacidNMDARactivation(N-methyl-D-aspartatereceptor,IonChannelLinkedReceptor)Ca2+influxCa2+i,activationofenzymesexcitatoryintoxication,(2)AberrantSignal(SignalExcess),2.AberrantReceptorinCellSignaling,Disturbanceofreceptorscanoccurin:genelevel,processesofproteinsynthesis,post-translationalmodification,conformation,oligomerization,translocation,endocytosis,andetc.Receptoralterationsinnumber,structure,function,andregulation:down-regulation:decreaseinnumberofreceptorsdesensitization:decreasedresponsetoligandstimulationupregulation:increaseinnumberofreceptorshypersensitivity:increasedresponsetoligandstimulation,orself-activationwithoutligandsReceptordiseases:receptoralterations-changesofligand-receptorsignaling-abnormalcellulareffects-diseases,（1）ReceptorGeneMutationGeneticinsulin-resistantdiabetes,IRgenemutationsDisturbancesinsynthesistransfertothemembraneaffinitytoinsulinPTKactivityproteolysis,TypeIIDiabetes,BindingofTSHtoR,hypothyroidism,(2)Autoimmunediseases-thyropathy,BlockingAbTSH-R295302385395residues,Graves病（弥漫性毒性甲状腺肿）刺激性抗体模拟TSH的作用促进甲状腺素分泌和甲状腺腺体生长女性男性甲亢、甲状腺弥漫性肿大、突眼,桥本病(Hashimotosthyroditis,慢性淋巴细胞性甲状腺炎)阻断性抗体与TSH受体结合减弱或消除了TSH的作用抑制甲状腺素分泌甲状腺功能减退、黏液性水肿,(3)SecondaryAbnormalityinReceptors,受体异常疾病,3.AberrantG-proteininCellSignaling,Gsgenemutation,GTPaseactivity,PersistentactivationofGs,PersistentactivationofAC,cAMP,Pituitaryproliferationandsecretion,GHRHPituitaryGHRH-RGsAc,cAMPGH,AcromegalyorGigantism,(1)G-proteingenemutationpituitarytumor,(2)G-proteinmodificationcholeraCholeratoxinGsribosylationatArg201InactivationofGTPasePersistentactivationofGsandAc,cAMPConformationalalterationofintestinalepitheliaCl-andH2OtolumenofintestineDiarrheaanddehydrationCirculationfailure,Theintracellularsignalinginvolvesvariousmessengers,transducers,andtranscriptionfactors.Disorderscanoccurinanyofthesesettings.-Calciumoverloadisageneralpathologicalprocessinvariousdiseases;-ThelevelofNOispositivelycorrelatedwithischemicinjury;-StimulationofNF-Bisseeninvariousinflammatoryresponses,4.AberrantintracellularSignaling,AberrantintracellularSignaling,佛波酯型促癌物,5.MultipleAbnormalitiesinSignalingPathway,Cancer,asetofdiseasescharacterizedbyuncontrolledorinappropriatecellgrowth,isstronglyassociatedwithdefectsinsignal-transductionproteins.Ligands(GFs):e.g.EGFReceptors(overexpression,activationofTPK):e.g.EGFRIntracellularsignaltransducers：RasgenemutationRas-GTPaseRasactivationRafMEKERKProliferationTUMOR,MultifactorAberranciesandCancer-Enhancementofproliferatingsignals,MultifactorAberranciesandCancer-Deficitsinproliferation-inhibitingsignal,6.SameStimulantInducesDifferentResponses(thesamestimulicanactondifferentreceptors),7.DifferentSignalsInducestheSamePathologicResponse(differentreceptorsusethesamepathwayorbycross-talk),DifferentreceptorsusesamepathwaysGPCR,RTK,CytokinesRsPLCRasPI-3KPKCRafPKBMEKERK,Crosstalkhowhypertensionleadstomyocardialhypertrophy?,NE,AT-II,PLC,Ca2+/PKC,Mechanicstimuli,Na+,Ca2+influxNa+-H+exchange,MAPK,Transcriptionfactors,targetgenesTargetproteins,MyocardialHypertrophy,GFTGF-,TPKPSTK,Raf,RasSmad-P,Alkalization,8.PrinciplesforTreatmentofAberrantSignaling-relatedDiseases,Stratagy:ToregulatethelevelofextracellularmoleculesToregulatethestructureandthefunctionofreceptorsToregulatethelevelandmodificationsofintracellularmessengers,sign