Harnessing hypoxia responses to treat postischemic kidney injury and inflammation
利用缺氧反应治疗缺血后肾损伤和炎症
基本信息
- 批准号:10676938
- 负责人:
- 金额:$ 24万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2022
- 资助国家:美国
- 起止时间:2022-08-15 至 2025-05-31
- 项目状态:未结题
- 来源:
- 关键词:Acute Renal Failure with Renal Papillary NecrosisAddressAffectAnti-Inflammatory AgentsAreaAttenuatedCell ProliferationCell RespirationCellsCellular Metabolic ProcessCytoprotectionDataDialysis procedureEnvironmentErythropoiesisFinancial costGenesGeneticGenetic ModelsGlycolysisGoalsHospitalizationHumanHypoxiaHypoxia Inducible FactorIncidenceInflammationInjuryInjury to KidneyIntensive Care UnitsInvestigationInvestigational TherapiesIschemiaKidneyKnowledgeKynurenic AcidKynurenineMediatingMetabolicMetabolic PathwayMetabolismMorbidity - disease rateN&apos-formylkynurenineOxidative PhosphorylationOxygenPathway interactionsPatientsProcessProcollagen-Proline DioxygenaseProtein IsoformsPublic HealthPublishingRecoveryReperfusion InjuryResearchRoleSerumSignal TransductionTertiary Protein StructureTestingTherapeutic InterventionTissuesTryptophanTryptophan 2,3 DioxygenaseTryptophan Metabolism Pathwayanaerobic glycolysisangiogenesisbHLH-PAS factor HLFeffective therapyhypoxia inducible factor 1improvedinjury and repairinjury preventioninnovationinsightkidney repairmetabolomicsmortalitynew therapeutic targetnovelnovel therapeuticspharmacologicpreventpromote resilienceprotective effectpublic health relevancerenal ischemiarepairedresponsesensortissue injurytissue repairtranscription factortranscriptomicstranslational applicationsuptake
项目摘要
Modified Project Summary/Abstract Section
Ischemia is a major cause of human acute kidney injury (AKI), a common condition in hospitalized patients with high morbidity and mortality. In ischemic AKI, hypoxic adaptation is mediated by Hypoxia-Inducible-Factors (HIF), transcriptional factors whose activity is negatively regulated by prolyl-hydroxylase domain proteins 1 to 3 (PHD1 to PHD3). HIF activation by pharmacologic PHD inhibition prior to renal IRI attenuates postischemic kidney injury and inflammation. The shift of cell metabolism from oxidative phosphorylation to anaerobic glycolysis has emerged as a critical factor by which PHD/HIF signaling promotes resilience to ischemia. Despite this fundamental concept, the mechanisms by which HIF affects different metabolic pathways beyond glycolysis remain unclear. Our long-term goal is to understand how hypoxic metabolic adaptation affects postischemic renal injury and repair. We recently discovered a non-canonical role for HIF signaling on tryptophan metabolism, a pathway that generates several bioactive metabolites with profound protective effects on tissues. Among them, kynurenine and kynurenic acid have emerged as metabolites that exert cytoprotective and anti-inflammatory actions but their role in AKI remains unclear. The objective of this proposal is to understand how alterations in tryptophan metabolism induced by HIF-2 affect postischemic renal injury and repair. The central hypothesis is that HIF-2 activation protects against postischemic renal injury and promotes repair through alterations in tryptophan derived metabolites kynurenine and kynurenic acid. Our rationale is that identification of the mechanism by which HIF-2 induced alterations in tryptophan metabolism provide renoprotection will create urgently needed new targeted therapeutic opportunities in the field of AKI. Our specific aim will test the following hypothesis: Activation of HIF-2 protects against AKI and promotes repair by increasing kynurenine levels systemically and in the kidney tissue in either Slc7a5- or IDO1-dependent manner. Completion of this aim will define a new paradigm in postischemic kidney injury and repair by HIF-2 activation through tryptophan metabolism and will stimulate new areas for experimental therapeutics in AKI. The proposed research is innovative because we investigate the role of hypoxic signaling in tryptophan metabolism in the context of ischemic AKI, an unexplored metabolic axis with exciting translational applications
修改的项目摘要/摘要部分
项目成果
期刊论文数量(0)
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Pinelopi P. Kapitsinou其他文献
Pinelopi P. Kapitsinou的其他文献
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{{ truncateString('Pinelopi P. Kapitsinou', 18)}}的其他基金
Endothelial PHD2/HIF Axis in Ischemic Kidney Injury and Inflammation
缺血性肾损伤和炎症中的内皮 PHD2/HIF 轴
- 批准号:
10600614 - 财政年份:2017
- 资助金额:
$ 24万 - 项目类别:
Endothelial PHD2/HIF Axis in Ischemic Kidney Injury and Inflammation
缺血性肾损伤和炎症中的内皮 PHD2/HIF 轴
- 批准号:
10301012 - 财政年份:2017
- 资助金额:
$ 24万 - 项目类别:
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