Cell Cycle and Metabolism in Chronically Injured Renal Tubules
慢性损伤肾小管的细胞周期和代谢
基本信息
- 批准号:10661066
- 负责人:
- 金额:$ 45.34万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2016
- 资助国家:美国
- 起止时间:2016-06-13 至 2026-06-30
- 项目状态:未结题
- 来源:
- 关键词:5&apos-AMP-activated protein kinaseAffectAmericanApoptosisAutocrine CommunicationCDK4 geneCatalytic DomainCell CycleCell Cycle ProgressionCell Cycle RegulationCell RespirationCellsCellular Metabolic ProcessChronicChronic Kidney FailureCitric Acid CycleCyclin D1Cyclin-Dependent KinasesCyclinsDNA biosynthesisDataDevelopmentDisease modelElectron TransportEnvironmentEnzymesEpithelial CellsEpitheliumFDA approvedFibrosisG2/M ArrestGeneticGenus HippocampusGlucoseGlycolysisHypoxiaInflammationInflammatoryInjuryInjury to KidneyKidneyKidney DiseasesKnockout MiceLactic acidLinkMediatingMetabolicMetabolismMitochondriaMitosisMusMyofibroblastNatural regenerationNutrientParacrine CommunicationPathway interactionsPharmaceutical PreparationsPhenotypePlayProcessProliferatingPyruvateRenal tubule structureResolutionRodentRoleS phaseSignal PathwaySignal TransductionStructureTestingTissuesTubular formationanaerobic glycolysiscardiovascular disorder riskconditional knockoutcytokineepithelial injuryepithelial repairfatty acid oxidationglucose metabolismimprovedin vitro activityin vivoinjuredinnovationkidney fibrosiskidney metabolismmetabolomicsmouse modelnew therapeutic targetnoveloxidationpharmacologicpreclinical studyrepairedresponseresponse to injurystable isotopesuperresolution microscopytool
项目摘要
Chronic kidney disease (CKD) affects almost 15% of Americans, and renal injury often targets the renal tubule
epithelia. How these tubules respond can determine whether the kidney undergoes repair or tubulointerstitial
fibrosis (TIF), the common hallmark of progressive CKD. This proposal focuses on understanding how chronic
renal injury induces changes in the renal tubular cell cycle and metabolism and how these changes affect
tubular survival and the development of TIF. It is well known that cell cycle, metabolism, and mitochondrial
function are all closely coordinated processes, but it is not clear how epithelial G1 to S cell cycle progression
affects metabolism in the CKD kidney. Preliminary data suggests that reducing cell cycle progression from G1
to S phase in renal tubules protects against fibrosis in rodent CKD models and decreases tubular apoptosis. In
addition, reducing G1 to S progression increased glucose oxidation, the metabolism of glucose to pyruvate
which is then oxidized in the mitochondria through the citric acid cycle and electron transport chain. This
proposal will test the hypothesis that reducing epithelial G1 to S phase progression in CKD protects
against epithelial injury and fibrosis through altered metabolism. To test this, Aim 1 will use either a
pharmacologic (palbociclib) or a genetic (conditionally delete cyclin D1 in renal tubules) approach to reduce G1
to S cell cycle progression in mice. We hypothesize that decreasing G1 progression to S phase in epithelial
cells is protective in CKD models by reducing tubular injury and fibrosis. Our preliminary data show that
reducing cell cycle progression in both injured kidney tissue and in isolated tubule cells also suppresses
signaling pathways and inflammatory cytokines associated with kidney injury. This aim investigates how
reducing cell cycle progression may alter these signaling pathways to reduce tubule injury and myofibroblast
activation by autocrine and paracrine signaling, respectively. The second aim investigates the metabolic
changes that occur in injured tubules with reduced G1 to S phase progression using the Seahorse bioflux
analyzer, 14C-pyruvate oxidation studies ex vivo, and stable isotopic metabolomics. We hypothesize that
reducing epithelial cell cycle progression increases glucose oxidation leading to better epithelial survival and
less fibrosis, in part, through the AMP-activated protein kinase pathway. We will also investigate how glucose
oxidation in renal tubules, independent of metabolism, affects the response to chronic injury. The impact of cell
cycle progression on mitochondrial function and structure will also be defined using Oroboros and super-
resolution microscopy. These studies should provide novel information about how changes in epithelial cell
cycle and metabolism affect the response to chronic renal injury with the potential identification of novel
therapeutic targets to treat CKD.
慢性肾脏疾病(CKD)影响了近15%的美国人,肾损伤通常以肾小管为目标
项目成果
期刊论文数量(10)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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Leslie S Gewin其他文献
Leslie S Gewin的其他文献
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{{ truncateString('Leslie S Gewin', 18)}}的其他基金
Epithelial Beta-catenin Signaling Improves Chronic Renal Injury
上皮β-连环蛋白信号传导改善慢性肾损伤
- 批准号:
10266013 - 财政年份:2018
- 资助金额:
$ 45.34万 - 项目类别:
Epithelial Beta-catenin Signaling Improves Chronic Renal Injury
上皮β-连环蛋白信号传导改善慢性肾损伤
- 批准号:
10612208 - 财政年份:2018
- 资助金额:
$ 45.34万 - 项目类别:
Cell Cycle and Metabolism in Chronically Injured Renal Tubules
慢性损伤肾小管的细胞周期和代谢
- 批准号:
10366536 - 财政年份:2016
- 资助金额:
$ 45.34万 - 项目类别:
Cell Cycle and Metabolism in Chronically Injured Renal Tubules
慢性损伤肾小管的细胞周期和代谢
- 批准号:
10493373 - 财政年份:2016
- 资助金额:
$ 45.34万 - 项目类别:
TGF-beta Pathways that Protect Epithelia in Chronic Renal Injury
慢性肾损伤中保护上皮细胞的 TGF-β 通路
- 批准号:
9294119 - 财政年份:2016
- 资助金额:
$ 45.34万 - 项目类别:
TGF-beta Pathways that Protect Epithelia in Chronic Renal Injury
慢性肾损伤中保护上皮细胞的 TGF-β 通路
- 批准号:
9337599 - 财政年份:2016
- 资助金额:
$ 45.34万 - 项目类别:
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