Pathology-specificGeneDiscoveryProgram.ppt

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1、BiomolecularProcessesasConcurrentComputation:ModelingMolecularProcessesinthep-calculusProcessAlgebraIntracellularbiochemicalprocessesMetabolicpathwaysSignaltransductionTranscriptionalregulation2Signaltransduction(ST)pathwaysPathwaysofmolecularinteractionsthatprovidecommunicationbetweenthe

2、cellmembraneandintracellularend-points,leadingtosomechangeinthecell.3Modularatdomain,componentandpathwaylevelMAPKKKMAPKKMAPKMultipleconnections:feedback,crosstalkGproteinreceptorsCytokinereceptorsDNAdamage,stresssensorsRTKRTKRhoAGCKRABPAKRAC/Cdc42?JNK1/2/3MKK4/7MEKK1,2,3,4MAPKKK5C-ABLHPKP

3、38a/b/g/dMKK3/6MLK/DLKASK1GgGbGaCa+2PYK2Celldivision,DifferentiationRsk,MAPKAP’sKinases,TFsInflammation,ApoptosisTFs,cytoskeletalproteinsPP2AMOSTLP2PKAGAPGRB2SHCSOSRASERK1/2MKK1/2RAF4Whatismissingfromthepicture?InformationaboutDynamicsMolecularstructureBiochemicaldetailofinteractionThePowe

4、rtosimulateanalyzecompareFormalsemanticsScript:Characters+PlotMovie5OurGoalAformalrepresentationlanguageformolecularprocessesPowerfulandessentialDynamicandexecutable(simulation)Analyzable(comparativeandfunctionalstudies)6ThemoleculeasacomputationalprocessRepresentastructurebyitspotentialbe

5、havior:bytheprocessinwhichitcanparticipateExample:Anenzymeastheenzymaticreactionprocess,inwhichitmayparticipate7Example:ERK1Ser/ThrkinaseBindingMP1moleculesRegulatoryT-loop:ChangeconformationKinasesite:PhosphorylateSer/Thrresidues(PXT/SPmotifs)ATPbindingsite:BindATP,anduseitforphsophoryla

6、tionBindingtosubstratesStructureProcessCOOHNtlobeCatalyticcoreCtlobeNH2p-Yp-T8Thecorrespondencebetweenmolecularandcomputationalprocesses9Thep-calculusAprogramspecifiesanetworkofinteractingprocessesProcessesaredefinedbytheirpotentialcommunicationactivitiesCommunicationoccursviachannels,defi

7、nedbynamesCommunicationcontent:Changeofchannelnames(mobility)(Milner,WalkerandParrow)10Thep-calculus:FormalstructureSyntaxHowtoformallywriteaspecification?CongruencelawsWhenaretwospecificationsthesame?ReactionrulesHowdoescommunicationoccur?11Syntax:ChannelsAll