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
慢性肾脏疾病(CKD)是死亡率的主要驱动因素,也是美国医疗保健面临的财务挑战。
美国的治疗选择是稀缺的,间接的,不充分的,而CKD正在成长为
我们这个时代最大的未满足的医疗需求之一。
一旦肾脏受损,疾病的进展取决于纤维化的程度,
可能因患者而异。我们和其他人已经做出了独特的观察,
尿激酶型纤溶酶原激活物受体(uPAR)是一种危险因素,
所有CKD的肾脏疾病。suPAR是一种三指毒素,
骨髓中的未成熟髓样细胞并在血浆中循环以调节整合素功能
在肾脏中。suPAR水平升高或某些suPAR亚型的存在是因果关系
通过介导肾小球足细胞和近端肾小管细胞的损伤参与CKD,
与β整联蛋白的特异性相互作用。根据我们发表的新的初步观察
suPAR介导的整合素激活驱动肾脏纤维化程序,我们计划调查
suPAR与不同肾单位中不同β整合素相互作用的结果,
探讨其促进肾小球和肾小管间质纤维化的作用。三个独立目标
正在提出:首先,我们将确定翻译suPAR-αvβ3的分子机制
利用表面等离子体共振技术研究整合素在足细胞损伤和肾小球硬化中的信号传导
测定、培养细胞实验和suPAR转基因小鼠模型。第二,我们将确定
在肾小管损伤中驱动suPAR-αvβ6整合素信号传导的分子机制,
肾小管间质纤维化通过遗传修饰肾小管整合素功能。三是
研究使用基于肽的uPAR阻断策略的治疗方式及其
相关的纤维化途径。本提案中概述的实验将使我们能够将不同的
在肾纤维化的suPAR级联中的步骤,并定义最佳干预方案。因此,洞察力
这笔赠款将为预防和治疗策略提供基础,以对抗suPAR介导的
纤维化和CKD。
项目成果
期刊论文数量(0)
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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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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