suPAR and renal fibrosis
suPAR与肾纤维化
基本信息
- 批准号:10220027
- 负责人:
- 金额:$ 45.04万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2020
- 资助国家:美国
- 起止时间:2020-07-20 至 2025-04-30
- 项目状态:未结题
- 来源:
- 关键词:AffectAffinityAnimal ModelBinding ProteinsBiological AssayBloodBone MarrowCD44 geneCRISPR/Cas technologyCell physiologyCellsCellular StructuresChronic Kidney FailureClinicalCultured CellsDevelopmentDiseaseDisease ProgressionEpithelial CellsEventExhibitsFamilyFibrosisFingersFocal Segmental GlomerulosclerosisGrantHK2 geneHealthHealthcareIn VitroIncidenceIndividualInfusion proceduresInjuryInnate Immune ResponseIntegrin alphaVIntegrin alphaVbeta3Integrin beta ChainsIntegrinsKidneyKidney DiseasesKidney FailureKnock-outKnockout MiceMeasuresMediatingMedicalModalityModelingMolecularMyeloid CellsNephronsNeurotoxinsParticipantPathway interactionsPatientsPatternPeptidesPlasmaPlayPrevention strategyProtein IsoformsProteinsPublishingRecurrenceReportingRisk FactorsRoleSignal TransductionSignaling ProteinStreamSurface Plasmon ResonanceTGFBI geneTestingTherapeuticTimeToxinTransgenic MiceTranslatingTubular formationUnited StatesUreteral obstructionUrokinase Plasminogen Activator Receptorbasecell injurycohortcombateffective therapyexperimental studyglomerulosclerosisin vivoinjuredinsightintegrin beta6interstitialkidney fibrosismembermortalitymouse modelnovelnovel therapeuticsoverexpressionperiostinpodocytepost-transplantpreventprogramsprotein protein interactiontreatment strategy
项目摘要
Abstract
Chronic kidney disease (CKD) is a major driver of mortality and a financial challenge for healthcare in
the United States. Treatment options are scarce, indirect and not sufficient, whilst CKD is growing into
one of the largest unmet medical needs of our time.
Once the kidney is injured, progression of the disease is dependent on the degree of fibrosis, which
can differ from patient to patient. We and others have made the unique observation that the soluble
form of urokinase plasminogen activator receptor (uPAR) is a risk factor for incident and prevalent
kidney diseases across the spectrum of CKD. suPAR is a three finger toxin that is produced by
immature myeloid cells in the bone marrow and circulates in the plasma to regulate integrin function
in the kidney. Elevated suPAR levels or the presence of certain suPAR isoforms are causally
involved in CKD by mediating injury to both glomerular podocytes and proximal tubular cells through
specific interactions with β integrins. Building on our published and novel preliminary observations
that suPAR-mediated integrin activation drives fibrotic programs in the kidney, we plan to investigate
the consequences of suPAR interactions with distinct β integrins in different nephron segments and
explore its role in promoting both glomerular and tubulointerstitial fibrosis. Three independent aims
are being proposed: First, we will determine the molecular mechanisms that translate suPAR-αvβ3
integrin signaling into podocyte injuries and glomerular sclerosis using surface plasmon resonance
assays, cultured cell experiments and suPAR transgenic mouse models. Second, we will determine
the molecular mechanisms that drive suPAR-αvβ6 integrin signaling in tubular injuries and
tubulointerstitial fibrosis by genetically modifying the tubular integrin function. Third, we will
investigate therapeutic modalities using peptide based blocking strategies for uPAR and its
associated fibrotic pathways. Experiments outlined in this proposal will allow us to separate different
steps in the suPAR cascade of kidney fibrosis and define best options to intervene. As such, insights
from this grant will provide a basis for preventive and treatment strategies to combat suPAR mediated
fibrosis and CKD.
摘要
项目成果
期刊论文数量(0)
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Jochen Reiser其他文献
Jochen Reiser的其他文献
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{{ truncateString('Jochen Reiser', 18)}}的其他基金
Role of proteolytic suPAR fragment in insulin dependent diabetes and kidney disease
蛋白水解suPAR片段在胰岛素依赖性糖尿病和肾脏疾病中的作用
- 批准号:
10654224 - 财政年份:2023
- 资助金额:
$ 45.04万 - 项目类别:
The KIDCOV Study: Assessment of Kidney Injury and Associated Risk Factors for SARS-CoV-2
KIDCOV 研究:评估 SARS-CoV-2 肾损伤及相关风险因素
- 批准号:
10216618 - 财政年份:2017
- 资助金额:
$ 45.04万 - 项目类别:
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