Cytoprotection of Beta Cells Through Modulation of Ire1Alpha Function
Cytoprotection of Beta Cells Through Modulation of Ire1Alpha Function
批准号:
9065686
负责人:
Feroz R Papa
金额:
$33.29万
依托单位国家:
美国
项目类别:
财政年份:
2009
资助国家:
美国
项目状态:
已结题
起止时间:
2009-07-01 至 2018-05-31
关键词:
AffectAmericanApoptosisApoptoticAttenuatedBeta CellCell DeathCell Fate ControlCell SurvivalCell physiologyCellsCessation of lifeCollectionCytoprotectionDegenerative DisorderDevelopmentDiabetes MellitusDiseaseDisease ProgressionEndoplasmic ReticulumEndoribonucleasesEukaryotaEventFeedbackFunctional disorderGenesGlucoseGoalsGrowthHealthHealthcareHomeostasisHumanInbred NOD MiceIndividualInsulinInsulin ResistanceInsulin-Dependent Diabetes MellitusIntegral Membrane ProteinIslet CellIslets of LangerhansKnowledgeLearningLinkMeasuresMediatingMediator of activation proteinMembraneMessenger RNAMicroRNAsMolecularMusNon-Insulin-Dependent Diabetes MellitusNucleotidesOrthologous GeneOutcomeOutputPathway interactionsPeripheralPhosphotransferasesPhysiologicalProcessProductivityProteinsRNARNA SplicingResearchResolutionRibonucleasesRiskSaccharomyces cerevisiaeSecond Messenger SystemsSignal PathwaySignal TransductionSignaling ProteinSiteSomatic MutationStressSystemTestingTranslationsWorkassaultbasecostendoplasmic reticulum stressfeedinginhibitor/antagonistinsightinsulin secretionisletkinase inhibitormonomernovelpreventprogramsprotein foldingresponsesecond messengersecretory proteinsmall moleculetherapy developmenttooltranscription factor
中文摘要
描述(由申请人提供):许多最近的研究将糖尿病的发展与内质网(ER)应激联系起来,内质网应激是一种在分泌途径中蛋白质折叠需求压倒蛋白质折叠能力时发生的病症。值得注意的是,越来越多的证据表明ER应激导致β细胞中葡萄糖响应性胰岛素分泌减少、β细胞凋亡以及一般外周胰岛素抵抗,这些都是2型糖尿病的标志;此外,ER应激在1型糖尿病中也很明显。ER应激触发未折叠蛋白反应(UPR)途径,其减慢翻译并转录上调增强ER蛋白折叠能力的基因。如果体内平衡没有通过这些输出恢复,UPR反而触发细胞凋亡。我们假设UPR的关键成分在稳态和凋亡输出之间起着切换开关的作用,最终控制着β细胞的命运。我们的项目目标是在分子水平上研究这些开关,使用介入方法。
英文摘要
DESCRIPTION (provided by applicant): Numerous recent studies link development of diabetes to endoplasmic reticulum (ER) stress, a condition that occurs whenever protein-folding requirements overwhelm protein-folding capacity in the secretory pathway. Notably, there is mounting evidence that ER stress contributes to diminished glucose-responsive insulin secretion in �-cells, to �-cell apoptosis, and to general peripheral insulin resistance, all hallmarks of type 2 diabetes; additionally ER stress is evident in type 1 diabetes. ER stress triggers the unfolded protein response (UPR) pathway, which slows translation and transcriptionally upregulates genes that enhance ER protein-folding capabilities. If homeostasis is not restored through these outputs, the UPR triggers apoptosis instead. We hypothesize that key components of the UPR, act as toggling switches between homeostatic and apoptotic outputs, ultimately controlling �-cell fate. Our project goal is to study these switches at the molecular level, using interventional approaches.
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