Characterization of a novel protein required for glomerular podocyte function
肾小球足细胞功能所需的新型蛋白质的表征
基本信息
- 批准号:7808507
- 负责人:
- 金额:$ 4.76万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2010
- 资助国家:美国
- 起止时间:2010-04-16 至 2011-04-15
- 项目状态:已结题
- 来源:
- 关键词:AdhesionsAreaBindingBiochemicalBiological AssayBloodCalciumCalcium SignalingCalpainCell AdhesionCell Adhesion MoleculesCellsCysteine ProteaseDataDefectDiabetes MellitusDiabetic NephropathyDiseaseDystroglycanElectron MicroscopyEmbryoEventFactor AnalysisFoot ProcessGene ExpressionGenesGoalsHealthHumanImmunofluorescence ImmunologicImmunoprecipitationIn VitroIntegrinsIon Channel ProteinKidneyKidney DiseasesKidney FailureKidney GlomerulusLeadMaintenanceMammalsMessenger RNAMethodsMissionMusMutant Strains MiceMutationNephroblastomaNephronsNephrotic SyndromePhysiologicalProteinsProteinuriaPublic HealthRNA InterferenceRenal functionRenal glomerular diseaseResearchRoleSpecialized Epithelial CellStructureSymptomsSystemTalinTechniquesTestingTumor Suppressor ProteinsUtrophinWaste ProductsZebrafishbaseblood filtrationcalpain inhibitorcell motilitydesigngene functiongenetic analysisglomerular basement membraneglomerular filtrationglomerular functionglomerulosclerosisimprovedin vivoin vivo Modelinsightkidney celllink proteinloss of functionmouse modelmutantnew therapeutic targetnoveloverexpressionpodocytepreventrelease of sequestered calcium ion into cytoplasmresearch studytranscription factorwasting
项目摘要
DESCRIPTION (provided by applicant): Podocytes are specialized cells of the kidney involved in filtering waste products from the blood. However, in various nephrotic syndromes, these cells become compromised and their foot processes detach from the underlying glomerular basement membrane (GBM). This detachment is thought to be the major cause of disease symptoms such as proteinuria and will eventually lead to kidney failure in many cases. Understanding how the podocytes form and retain their foot process attachments to the GBM is therefore an important area of research. The experiments in this proposal are designed to characterize molecules involved in maintaining these attachments, and may lead to novel therapeutic targets for various kidney diseases. These goals directly relate to the mission of the NIH/NIDDK to improve human health through novel research, in this case specifically related to renal function and disease. Podocyte-GBM attachment factor (PGAF) is a novel protein required for the attachment of podocyte foot processes to the GBM. It is a downstream target of Wilms' tumor suppressor-1 (WT1) and binds capnsi, the small subunit of the cysteine protease calpain. As active calpains promote detachment of cellular adhesions, the current hypothesis is that PGAF inhibits calpain activity in podocytes to prevent foot process detachment. The aims of this proposal are to use a combination of in vitro and in vivo techniques to investigate the role of PGAF and calpains in the maintenance of podocyte attachments to the GBM. In vivo studies will be conducted on a combination of zebrafish and mouse models. As the embryonic zebrafish kidney provides a simple, rapid and easily manipulatable system in which to study podocyte function, our primary in vivo analysis of PGAF and calpain function will be carried out in this system. Techniques including morpholino-based gene knockdown and mRNA over-expression will be used to perturb gene function in embryos. Electron microscopy analysis of podocytes and assessment of glomerular filtration ability will be used to analyze the resulting mutant embryos. In addition, PGAF loss-of-function mice will be generated and assessed using similar techniques. In vitro analysis will involve biochemical characterization of protein interactions and knockdown/overexpression of PGAF in cultured murine podocyte cells. Relevance to public health: The kidney filters waste from the blood by using specialized cells called podocytes. However, these cells can become damaged by conditions such as diabetes or various kidney diseases. Our research will examine how podocytes form and are maintained, which will facilitate our understanding of what happens to them during disease, and potentially lead to new therapies.
描述(由申请人提供):足细胞是肾脏的特化细胞,参与从血液中过滤废物。然而,在各种肾病综合征中,这些细胞变得受损,并且它们的足突与下面的肾小球基底膜(GBM)分离。这种脱离被认为是引起蛋白尿等疾病症状的主要原因,在许多情况下最终会导致肾衰竭。因此,了解足细胞如何形成并保持其对GBM的足突附着是一个重要的研究领域。该提案中的实验旨在表征参与维持这些连接的分子,并可能导致各种肾脏疾病的新治疗靶点。这些目标直接关系到NIH/NIDDK的使命,即通过新的研究改善人类健康,在这种情况下,特别是与肾功能和疾病有关。足细胞-GBM附着因子(PGAF)是一种新的足细胞足突与GBM附着所需的蛋白质。它是Wilms肿瘤抑制因子-1(WT 1)的下游靶标,并结合capnsi,半胱氨酸蛋白酶钙蛋白酶的小亚基。由于活性钙蛋白酶促进细胞粘附的脱离,目前的假设是PGAF抑制足细胞中的钙蛋白酶活性以防止足突脱离。本提案的目的是使用体外和体内技术相结合的研究PGAF和钙蛋白酶在维持足细胞附着GBM的作用。将在斑马鱼和小鼠模型的组合上进行体内研究。由于胚胎斑马鱼肾脏提供了一个简单,快速和易于操作的系统,在其中研究足细胞的功能,我们的主要在体内分析PGAF和钙蛋白酶功能将在这个系统中进行。包括基于吗啉代的基因敲低和mRNA过表达的技术将用于干扰胚胎中的基因功能。将使用足细胞的电子显微镜分析和肾小球滤过能力的评估来分析所得突变胚胎。此外,将使用类似的技术产生和评估PGAF功能丧失小鼠。体外分析将涉及蛋白质相互作用的生物化学表征和培养的鼠足细胞中PGAF的敲低/过表达。与公共卫生的相关性:肾脏通过使用称为足细胞的专门细胞过滤血液中的废物。然而,这些细胞可能会受到糖尿病或各种肾脏疾病等疾病的损害。我们的研究将研究足细胞如何形成和维持,这将有助于我们了解疾病期间它们发生了什么,并可能导致新的治疗方法。
项目成果
期刊论文数量(0)
专著数量(0)
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Lori L O'Brien其他文献
What's so Bor(a)ing about Aurora-A activation?
Aurora-A 激活有何无聊之处?
- DOI:
10.1016/j.devcel.2006.07.011 - 发表时间:
2006 - 期刊:
- 影响因子:11.8
- 作者:
C. Wiese;Lori L O'Brien - 通讯作者:
Lori L O'Brien
Lori L O'Brien的其他文献
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{{ truncateString('Lori L O'Brien', 18)}}的其他基金
Trophic interactions directing proper kidney development
营养相互作用指导肾脏的正常发育
- 批准号:
10312135 - 财政年份:2020
- 资助金额:
$ 4.76万 - 项目类别:
Trophic interactions directing proper kidney development
营养相互作用指导肾脏的正常发育
- 批准号:
10112900 - 财政年份:2020
- 资助金额:
$ 4.76万 - 项目类别:
Trophic interactions directing proper kidney development
营养相互作用指导肾脏的正常发育
- 批准号:
10540685 - 财政年份:2020
- 资助金额:
$ 4.76万 - 项目类别:
Characterization of a novel protein required for glomerular podocyte function
肾小球足细胞功能所需的新型蛋白质的表征
- 批准号:
8071159 - 财政年份:2010
- 资助金额:
$ 4.76万 - 项目类别:
Characterization of a novel protein required for glomerular podocyte function
肾小球足细胞功能所需的新型蛋白质的表征
- 批准号:
8265666 - 财政年份:2010
- 资助金额:
$ 4.76万 - 项目类别:
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