The role of dendrin in glomerular disease progression
树突蛋白在肾小球疾病进展中的作用
基本信息
- 批准号:9344584
- 负责人:
- 金额:$ 38.14万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2015
- 资助国家:美国
- 起止时间:2015-09-10 至 2020-07-31
- 项目状态:已结题
- 来源:
- 关键词:AddressAffectApoptoticArchitectureBindingBiologicalCell NucleusCell SurvivalCellsClinicalCytoplasmDataDepositionDevelopmentDiseaseDisease ProgressionEnd stage renal failureFibronectinsFocal Segmental GlomerulosclerosisGene DeletionGenetic TranscriptionGoalsHumanIn VitroInjuryKidneyKnowledgeMediatingMediator of activation proteinModelingMolecularMusNuclearNuclear TranslocationOutcomePathogenesisPathogenicityPathway interactionsPharmaceutical PreparationsPhosphorylationPhysiologicalProcessProtein InhibitionProtein IsoformsProteinsProteomicsRenal glomerular diseaseResearchRoleSignal PathwaySignal TransductionSignaling MoleculeSteroid ResistanceSystemTechnologyTestingTherapeuticTherapeutic AgentsTherapeutic InterventionTranscription Factor AP-1Transgenic MiceTransgenic OrganismsWorkbasecell injurycostdendringenetic variantglomerulosclerosisimprovedin vivoinhibitor/antagonistinnovationmesangial cellmouse modelmutantnew therapeutic targetnovelnovel therapeutic interventionnovel therapeuticspodocytepublic health relevancetherapeutic target
项目摘要
DESCRIPTION (provided by applicant): A critical barrier to the identification of appropriate therapeutic targets to treat glomerular disease is the limited understanding of signaling cascades that regulate podocyte injury and renal survival. Our long term goal is to enhance the pipeline of putative therapeutic targets available to tackle human glomerular disease by elucidating the details and functional significance of key signaling pathways that regulate podocyte injury and survival. Our preliminary data have identified dendrin as a key pro injury signaling molecule that promotes podocyte depletion and is involved in podocyte mesangial cell crosstalk. We have identified human dendrin gene variants that segregate with familial steroid resistant focal segmental glomerulosclerosis (FSGS) and identified the pro survival Hippo pathway effector Yes associated protein (YAP) as an inhibitor of dendrin function. The overall objective of this application is to define the role of dendrin as a key mediator of pathogenic podocyte mesangial cell crosstalk and subsequent glomerular disease progression.Our central hypothesis is that dendrin is regulated in a phosphorylation dependent manner by YAP, where disease associated dendrin mutants may induce podocyte injury though decreased YAP inhibition. Dendrin regulated soluble factors from podocytes promote mesangial cell fibronectin secretion, leading to mesangial matrix expansion and glomerular disease progression. The rationale for the proposed research is that defining how dendrin function is inhibited by YAP and characterizing its role in glomerular disease progression will advance understanding of glomerular disease progression as well as the quest for novel therapeutic targets available for clinical use. Our hypothesis will be tested by pursuing two specific aims: Aim 1 will explore the inhibition of wild type and FSGS associated dendrin mutants by YAP. We will define the molecular interaction between phosphorylated YAP and the dendrin isoforms and characterize the consequences of binding in the context of cell survival and dendrin subcellular localization and function. We will also test in vivo whether transgenic expression of YAP in podocytes slows murine glomerular disease progression by inhibiting dendrin function. In Aim 2 we will define the role of dendrin in pathogenic podocyte mesangial cell crosstalk using our novel established in vitro cell systems as well as an inducible transgenic mouse model of crosstalk. Our innovative approach utilizes state of the art proteomics technology to identify dendrin regulated soluble factors from podocytes that induce mesangial cell fibronectin secretion. These contributions are significant because they represent the first step in a continuum of research that is expected to advance understanding of glomerular disease progression and identify therapeutic targets and strategies to improve clinical outcomes.
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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Kirk N Campbell其他文献
Kirk N Campbell的其他文献
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{{ truncateString('Kirk N Campbell', 18)}}的其他基金
Mount Sinai Health System Kidney Precision Medicine Project
西奈山卫生系统肾脏精准医学项目
- 批准号:
10703420 - 财政年份:2022
- 资助金额:
$ 38.14万 - 项目类别:
Mount Sinai Health System Kidney Precision Medicine Project
西奈山卫生系统肾脏精准医学项目
- 批准号:
10493649 - 财政年份:2022
- 资助金额:
$ 38.14万 - 项目类别:
Hippo-YAP in podocyte health and disease
Hippo-YAP 在足细胞健康和疾病中的作用
- 批准号:
10618369 - 财政年份:2019
- 资助金额:
$ 38.14万 - 项目类别:
Hippo-YAP in podocyte health and disease
Hippo-YAP 在足细胞健康和疾病中的作用
- 批准号:
9917038 - 财政年份:2019
- 资助金额:
$ 38.14万 - 项目类别:
Hippo-YAP in podocyte health and disease
Hippo-YAP 在足细胞健康和疾病中的作用
- 批准号:
10433862 - 财政年份:2019
- 资助金额:
$ 38.14万 - 项目类别:
Hippo-YAP in podocyte health and disease
Hippo-YAP 在足细胞健康和疾病中的作用
- 批准号:
10188524 - 财政年份:2019
- 资助金额:
$ 38.14万 - 项目类别:
Hippo-YAP in podocyte health and disease
Hippo-YAP 在足细胞健康和疾病中的作用
- 批准号:
10006878 - 财政年份:2019
- 资助金额:
$ 38.14万 - 项目类别:
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