Differential Mitochondrial Toxicity Screening and Multi-Parametric Data Analysis 英文参考文献.docVIP

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Differential Mitochondrial Toxicity Screening and Multi-Parametric Data Analysis 英文参考文献.doc

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Differential Mitochondrial Toxicity Screening and Multi-Parametric Data Analysis 英文参考文献

DifferentialMitochondrialToxicityScreeningandMulti- ParametricDataAnalysis MariaV.Tsiper1,JenniferSturgis3,LarisaV.Avramova1,ShilpaParakh1,RaymondFatig2,AnaJuan- Garc?′a3,NianyuLi5,BartekRajwa1,PadmaNarayanan5,C.W.Qualls,Jr.5,J.PaulRobinson3,4 ,V. JoDavisson2* 1BindleyBioscienceCenteratPurdueUniversityDiscoveryPark,WestLafayette,Indiana,UnitedStatesofAmerica,2DepartmentofMedicinalChemistryandMolecular Pharmacology,PurdueUniversity,WestLafayette,Indiana,UnitedStatesofAmerica,3DepartmentofBasicMedicalSciences,PurdueUniversity,WestLafayette,Indiana, UnitedStatesofAmerica,4WeldonSchoolofBiomedicalEngineering,PurdueUniversity,WestLafayette,Indiana,UnitedStatesofAmerica,5ComparativeBiologyand SafetySciences,AmgenInc,Seattle,Washington,UnitedStatesofAmerica Abstract Earlyevaluationofnewdrugentitiesfortheirpotentialtocausemitochondrialdysfunctionisbecominganimportanttask fordrugdevelopment.Multi-parametrichigh-contentscreening(mp-HCS)ofmitochondrialtoxicityholdspromiseasalead in-vitrostrategyfordrugtestingandsafetyevaluations.Inthisstudy,wehavedevelopedamp-HCSandmulti-parametric dataanalysisschemeforassessingcellresponsestoinducedmitochondrialperturbation.Themp-HCSmeasurementsare showntoberobustenoughtoallowforquantitativecomparisonofbiologicalsystemswithdifferentmetabolicpathways simulatedbyalterationofgrowthmedia.Substitutionofmediumglucoseforgalactosesensitizedcellstodrugactionand revealed novel response parameters. Each compound was quantitatively characterized according to induced phenotypic changes of cell morphology and functionality measured by fluorescent biomarkers for mitochondrial activity, plasma membranepermeability,andnuclearmorphology.DescriptorsofdrugeffectswereestablishedbygenerationofaSCRIT (Specialized-Cell-Response-to-Induced-Toxicity) vector,consistingofnormalizedstatisticalmeasuresofeachparameter at eachdoseandgrowthcondition.ThedimensionalityofSCRITvectorsdependsonthenumberofparameterschosen,which in turn depends on the hypothesis being tested.