Protective Unfolded Protein Response in Human Pancreatic Beta Cells Transplanted into Mice 英文参考文献.docVIP

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Protective Unfolded Protein Response in Human Pancreatic Beta Cells Transplanted into Mice 英文参考文献.doc

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Protective Unfolded Protein Response in Human Pancreatic Beta Cells Transplanted into Mice 英文参考文献

ProtectiveUnfoldedProteinResponseinHuman PancreaticBetaCellsTransplantedintoMice JeffreyKennedy1,HitoshiKatsuta1,Min-HoJung1,LorellaMarselli1,AllisonB.Goldfine1, UlyssesJ.Balis2,DennisSgroi2,SusanBonner-Weir1,GordonC.Weir1* 1SectiononIsletCellBiologyandRegenerativeMedicine,ResearchDivision,JoslinDiabetesCenter,andtheDepartmentofMedicine,HarvardMedicalSchool,Boston, Massachusetts,UnitedStatesofAmerica,2MolecularPathologyUnit,MassachusettsGeneralHospital,HarvardMedicalSchool,Boston,Massachusetts,UnitedStatesof America Abstract Background:ThereisgreatinterestaboutthepossiblecontributionofERstresstotheapoptosisofpancreaticbetacellsin thediabeticstateandwithislettransplantation. MethodsandFindings:ExpressionofgenesinvolvedinERstresswereexaminedinbetacellenrichedtissueobtainedwith lasercapturemicrodissection(LCM)fromfrozensectionsofpancreasesobtainedfromnon-diabeticsubjectsatsurgeryand fromhumanislets transplanted intoICR-SCIDmice for4wk.Becausemice havehigher glucoselevelsthanhumans,the transplantedbetacellswereexposedtomildhyperglycemiaandtheabnormalenvironmentofthetransplantsite.RNAwas extractedfromtheLCMspecimens,amplifiedandthensubjectedtomicroarrayanalysis.Thetransplantedbetacellsshowed an unfolded protein response (UPR). There was activation of many genes of the IRE-1 pathway that provide protection against the deleterious effects of ER stress, increased expression of ER chaperones and ERAD (ER-associated protein degradation)proteins.TheothertwoarmsofERstress,PERKandATF-6,hadmanydownregulatedgenes.Downregulation ofEIF2Acouldprotectbyinhibitingproteinsynthesis.Twogenesknowntocontributetoapoptosis,CHOPandJNK,were downregulated. Conclusions: Human beta cells in a transplant site had UPR changes in gene expression that protect against the proapoptoticeffectsofunfoldedproteins. Citation:KennedyJ,KatsutaH,JungM-H,MarselliL,GoldfineAB,etal.(2010)ProtectiveUnfoldedProteinResponseinHumanPancreaticBetaCellsTransplanted intoMice.PLoSONE5(6):e11211.doi:10.1371/journal.pon