心力衰竭的细胞分子生物学基础pkc激活和心力衰竭英文课件

WeiDUANSchoolofMedicineDeakinUniversityMelbourne Australia MolecularMedicineforHeartFailureIsozyme specificModulationofPKC HeartFailureinAustralia TheprevalenceofheartfailureinAustraliais 6 3 Theheartfailureprevalenceis 10 inpeopleagedover65years thispopulationwilldoubleoverthenext50yearsinAustralia StagesofheartfailurefromGoldman CecilMedicine 23rded EffusionfromcongestiveheartfailurefromMason Murray Nadel sTextbookofRespiratoryMedicine 4thed MolecularCellBiologyunderlyingheartfailure PKCActivationandHeartFailure CirculationResearch 2007 101 195 J Clin Invest 115 527 2005 ActivationofPKC andHeartFailurePKC isactivatedbyGq G11 PLC IP3 SR releasedCa andDAG SarcoplasmicReticulum wo NatureMedicine 10 239 2004 ProteinPhosphatase 1 PhospholambanPca uptake increasedCa release contractileforce Sarcoplasmicreticularcalciumuptakeprotein PKCa Ca cycling Reduced1 contractionstrength2 ralaxation3 Cardiacreserve PKCaisactivatedbyCa stressagonists pressureload myocardialinfarction angiotensin TransitioninfailingheartsfromadequatecompensationToadvancedfailure ProteinPhosphataseInhibitor 1 Calciumhandlingproteins PLB SERCA 2a DomainStructureofPKC MostavailablekinaseinhibitorsareATP bindingsiteanalogues Lackofspecificity Nat Biotechnol 23 329 336 2005Biochem J 351 95 105 2000 Staurosporine originallydevelopedasaPKCinhibitor Istheresuchathingasa Specific kinaseinhibitor 3 DstructureofPKA DIFFICULTIESinstructuraldeterminationofC tail RoleoftheveryC terminiofPKCs N Lobe C Lobe StudyofthefunctionofC terminusofPKC alpha Thelast10aminoacidresiduesareessentialforthecatalyticcompetenceofPKC alpha Intrinsicactivity protaminesulfateassubstrate DAG activationHistoneH1assubstrate S S Yeong etal J Biol Chem 281 30768 2006 ThecriticalroleoftheveryC terminusofPKC aintheactivationofMAPK S S Yeong etal J Biol Chem 281 30768 2006 ThecriticalroleoftheveryC terminusofPKC ainAugmentingMelatonin stimulatedNeuriteOutgrowthinNeuronalCells S S Yeong etal J Biol Chem 281 30768 2006 Targeting intrinsicallydisorderedsegment insteadof druggablepocket Proof of principledata S S Yeong etal J Biol Chem 2006 Aptamers fromLatinaptus means fitting SyntheticRNA DNAorpeptidethatbindstoproteintargetswithhighspecificityandaffinity Foldintowell defined3 Dstructure Bindbycomplementaryshapeinteractions Nottoxicorimmunogenic Effectivelyinhibitthefunctionoftargetprotein Nopriorknowledgeofthe3 Dstructureofthetargetisrequired thrombin CurrentOpinioninChemicalBiology 9 336 342 2005 NucleicAcidsBasePairing tRNA SELEX SystemicEvolutionofLigandsbyExponentialenrichment DevelopAptamersTargetingtheveryC terminusofPKC C terminusofPKCisexposed accessible fromIPexperiments FromAptamertoSmallMoleculeDrugs Aptamer guidedHTS FluorescencePolarization basedscreening Homogenousassaysystem FluorescenceIntensity basedscreening Prof MichaelFamulokLaboratoryofChemicalBiologyUniversityofBonn SourceofChemicalLibraries Commercialsources freeofroyalty NCI http dtp nci nih gov docs misc available samples dtp indsamples html StructuralDiversitySet version1 1 991compounds StructuralDiversitySet version2 1 986compounds MechanisticDiversitySet 879compounds OpenCollection1 90 000compounds OpenCollection2 10 000compounds ChemDiv ChemBridgeCorporation SourcesofCurrentorOff patientmedications PrestwickChemicalCo 1120off patientdrugs Microsources TheSpectrumCollection 2000 Sequoia alargecollection NIHBrainBioactiveCompoundcollection Aptamer guidedHeart SpecificDelivery MolecularMedicineforHeartDiseases EngineeringnanoparticlesDrugloadingTargetingControlledRelease heat magneticfield pH engineeringthenanoparticlesystemsuchthattheintracellulardrug releasekineti