Mechanism of Renal Cell Injury
肾细胞损伤机制
基本信息
- 批准号:8696794
- 负责人:
- 金额:--
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2011
- 资助国家:美国
- 起止时间:2011-07-01 至 2015-06-30
- 项目状态:已结题
- 来源:
- 关键词:1-Phosphatidylinositol 3-Kinase2-tyrosine5&apos Flanking RegionAddressAdenovirusesAlbuminsAntibodiesBiological AssayCell ProliferationCell physiologyCellsCreatinineCreatinine clearance measurementDNADNA biosynthesisDataDiseaseDisease ProgressionDominant-Negative MutationDrug DesignElectrophoretic Mobility Shift AssayElementsEnd stage renal failureEnzymesExcretory functionExperimental ModelsFirefly LuciferasesGene TransferGenesGenetic TranscriptionGlomerulonephritisGrowth FactorGuanosine Triphosphate PhosphohydrolasesHourHumanIkappaB kinaseImmunoblot AnalysisImmunoblottingImmunofluorescence ImmunologicImmunohistochemistryImmunoprecipitationIsoenzymesKidneyMediatingMessenger RNAModalityModelingMolecularMolecular Mechanisms of ActionMonomeric GTP-Binding ProteinsPathogenesisPathologyPhosphorylationPhosphotransferasesPlasmidsPlatelet-Derived Growth FactorPlatelet-Derived Growth Factor ReceptorPlatelet-Derived Growth Factor beta ReceptorPlayPopulationProcessProliferating Cell Nuclear AntigenProliferative GlomerulonephritisProtein Tyrosine KinaseProteinsRas homolog enriched in brainRattusRegulationRenal functionReporterRoleSRC geneSU 6656Sequence AnalysisSignal PathwaySignal TransductionSignal Transduction PathwayStaining methodStainsStructure of glomerular mesangiumTechniquesTestingTherapeuticTherapeutic EffectTranscription Initiation SiteTransfectionVeteransanti-Thy-1cell injurycell motilitychromatin immunoprecipitationcytokinedesignin vivoinhibitor/antagonistkidney cellmesangial cellmigrationmutantp65promoterprotein expressionprotein-tyrosine kinase c-srcreceptor upregulationresearch studyresponsesmall hairpin RNAurinary
项目摘要
DESCRIPTION (provided by applicant):
A major manifestation of mesangioproliferative glomerulonephritis in human and experimental model is increased expression of platelet-derived growth factor receptor-2 (PDGFR) in mesangial cells with concomitant proliferation and migration. The mechanism by which increased PDGFR results in the activation of mesangial cells is poorly understood. Our results provide first evidence that in mesangial cells PDGFR-activated phosphatidylinositol (PI) 3 kinase/Akt kinase regulates proliferation and migration. Furthermore, we demonstrate an increase in PDGFR tyrosine kinase activity, resulting in PI 3 kinase and Akt kinase activities in anti-Thy-1-induced mesangioproliferative glomerulonephritis in the rat. Moreover, the non-receptor tyrosine kinase c-Src regulates Ras-GTPase and associates with PI 3 kinase, which regulates Akt kinase activity. In this proposal, using mesangial cells in culture and glomeruli from rats with anti-Thy-1-induced glomerulonephritis, we will test the hypothesis that signal relay from c-Src to PI 3 kinase/Akt through Ras regulates the state of mesangial cell activation. In the preliminary data, we show that PDGF-stimulated Akt kinase activates I:B kinases 1 and 2, resulting in NF:B activation. Importantly, we provide the first evidence that PDGF increases expression of Akt kinase effector Rheb (Ras homolog enriched in brain). We hypothesize that Akt-dependent NF:B-mediated expression of Rheb regulates mesangial cell activation. In the first specific aim, we plan to investigate the molecular mechanisms of action of c-Src and Ras on PDGFR-stimulated PI 3 kinase/Akt signaling in mesangial cells and in glomeruli of rats with mesangioproliferative glomerulonephritis. Also a cross-talk between c-Src and Ras will be studied in mesangial cell activation. In the second specific aim, the roles of I:B kinases 1 and 2 and NF:B in mesangial cell proliferation and migration will be studied. Phosphorylation of I:B kinase isotypes and phosphorylation of their substrates in anti-Thy-1-induced glomerulonephritis will be investigated. In the specific aim 3, role of PI 3 kinase/Akt signaling and its upstream regulators Ras and c-Src in expression of Rheb will be examined. Contribution of NF:B to the Rheb expression will be investigated. To address these specific aims, techniques including immunohistochemistry/immunofluorescence, immunoprecipitation, immunoblotting, reporter transfection assays, electrophoretic mobility shift assays, chromatin immunoprecipitation asays, adenovirus-mediated gene transfer of mutant enzymes, si/shRNA expression and conditional expression of proteins will be used.
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GOUTAM GHOSH CHOUDHURY其他文献
GOUTAM GHOSH CHOUDHURY的其他文献
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{{ truncateString('GOUTAM GHOSH CHOUDHURY', 18)}}的其他基金
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