A Detailed Modular Analysis of Heat-Shock Protein Dynamics under Acute and Chronic Stress and Its Implication in Anxiety Disorders 英文参考文献.docVIP

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A Detailed Modular Analysis of Heat-Shock Protein Dynamics under Acute and Chronic Stress and Its Implication in Anxiety Disorders 英文参考文献.doc

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A Detailed Modular Analysis of Heat-Shock Protein Dynamics under Acute and Chronic Stress and Its Implication in Anxiety Disorders 英文参考文献

ADetailedModularAnalysisofHeat-ShockProtein DynamicsunderAcuteandChronicStressandIts ImplicationinAnxietyDisorders K.Sriram1,2,3,MariaRodriguez-Fernandez1,2,FrancisJ.Doyle,III1,2 * 1Institute of Collaborative Biotechnologies, University of California Santa Barbara, Santa Barbara, California, United States of America, 2Department of Chemical Engineering,UniversityofCaliforniaSantaBarbara,SantaBarbara,California,UnitedStatesofAmerica,3IndraprasthaInstituteofInformationTechnology(IIIT),Delhi,India Abstract Physiological and psychological stresses cause anxiety disorders such as depression and post-traumatic stress disorder (PTSD)andinducedrasticchangesatamolecularlevelinthebrain.Tocounteractthisstress,theheat-shockprotein(HSP) networkplaysavitalroleinrestoringthehomeostasisofthesystem.Tostudythestress-induceddynamicsofheat-shock network, we analyzed three modules of the HSP90 network—namely trimerization reactions, phosphorylation– dephosphorylation reactions, and the conversion of HSP90 from an open to a closed conformation—and constructed a corresponding nonlinear differential equation model based on mass action kinetics laws. The kinetic parameters of the modelwereobtainedthroughglobaloptimization,andsensitivityanalysesrevealedthatthemostsensitiveparametersare thekinaseandphosphatasethatdrivethephosphorylation–dephosphorylationreactions.Bifurcationanalysiscarriedout with the estimated kinetic parameters of the model with stress as bifurcation parameter revealed the occurrence of ‘‘mushroom’’,atypeofcomplexdynamicsinwhichS-shapedandZ-shapedhystereticbistableformsarepresenttogether. We mapped the molecular events responsible for generating the mushroom dynamics under stress and interpreted the occurrenceoftheS-shapedhysteresistoanormallevelofstress,andtheZ-shapedhysteresistotheHSP90variationsunder acuteandchronicstressinthefearconditionedsystem,andfurther,wehypothesizedthatthiscanbeextendedtostress- related disorders such as depression and PTSD in humans. Finally,