Podocyte Secreted Proteins
足细胞分泌蛋白
基本信息
- 批准号:8545169
- 负责人:
- 金额:$ 30.75万
- 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:2011-09-20 至 2016-08-31
- 项目状态:已结题
- 来源:
- 关键词:Adipose tissueAffectAffinityAgrinAlbuminuriaAnabolismAngiopoietinsBindingBinding SitesBiological AssayChargeD-mannosamineDNA BindingDevelopmentDiffuseDiseaseDissociationDominant-Negative MutationElectron TransportEnzymesFoot ProcessGenesGlomerular CapillaryGlucocorticoidsGlycoproteinsGoalsHeparan Sulfate ProteoglycanHomeoboxHumanImmune SeraIn VitroIncubatedIsoelectric PointKidneyLaboratoriesLigationLipopolysaccharidesMass Spectrum AnalysisMedicineMembrane ProteinsModelingMonosaccharidesMusNatureNephrosisNephrotic SyndromeNuclearPathogenesisPathway interactionsPermeabilityPolysaccharidesProcessProductionProtein SecretionProteinsProteinuriaPublishingPuromycinPuromycin AminonucleosideRattusRecombinantsRegulationRelative (related person)Renal glomerular diseaseRoleSialic AcidsSignal TransductionSiteSite-Directed MutagenesisTestingTherapeuticTissuesTransgenic OrganismsUp-RegulationZinc Fingersbasedesignfeedingglomerular basement membraneglomerular filtrationglycosylationheparin proteoglycaninhibitor/antagonistknock-downoverexpressionpodocalyxinpodocytepromoterprotein protein interactionresearch studysialylation
项目摘要
DESCRIPTION (provided by applicant): Recent studies published from the PI's laboratory show increased expression of Angiopoietin-like 4 (Angptl4) in podocytes in human and experimental glucocorticoid sensitive nephrotic syndrome. Secretion of this protein into the glomerular capillary loop leads to binding to the glomerular basement membrane (GBM), and results in the development of nephrotic range selective proteinuria, diffuse effacement of foot processes, and loss of GBM charge. Angptl4 secreted from podocytes in experimental minimal change disease (MCD) is deficient in sialic acid residues that would normally be incorporated at glycosylation sites. This hypo-salivated state, caused either by a relative deficiency of substrate or concomitant changes in the sialic acid biosynthetic pathway, influences the interaction of Angptl4 with GBM proteins. Feeding sialic acid precursor ManNAc to rats with transgenic expression of Angptl4 from podocytes over a period of 12 day results in over 40% reduction in albuminuria, and significantly increases sialylation of Angptl4. We hypothesize that podocyte secreted Angptl4 interacts with GBM proteins to induce proteinuria, and this process is strongly influenced by the state of Angptl4 sialylation. In Specific Aim 1, we characterize the sialylation of podocyte secreted Angptl4 by studying its incorporation into N-glycans and / or O-glycans, and looking for changes in the sialic acid synthesis and incorporation pathway in experimental MCD. In Specific Aim 2, we study the interaction of sialylated and hypo-sialylated Angptl4 with heparin sulfate proteoglycans using in vitro plate assays, and with all GBM proteins in tissue sections using the Proximity Ligation Assay. In Specific Aim 3, we investigate the upregulation of podocyte Angptl4 expression in experimental MCD by transcriptional factor ZHX1, and propose experiments to study whether dominant negative ZHX1 constructs can be used to reduce Angptl4 expression in disease states. The experiments proposed in this application will help in the design of therapeutic strategies for the reduction of proteinuria.
描述(由申请人提供):PI 实验室发表的最新研究表明,人类和实验性糖皮质激素敏感肾病综合征的足细胞中血管生成素样 4 (Angptl4) 的表达增加。该蛋白分泌到肾小球毛细血管袢中,导致与肾小球基底膜 (GBM) 结合,并导致肾病范围选择性蛋白尿、足突弥漫性消失和 GBM 电荷损失。实验性微小病变病 (MCD) 足细胞分泌的 Angptl4 缺乏通常会掺入糖基化位点的唾液酸残基。这种低唾液酸状态是由底物相对缺乏或唾液酸生物合成途径的伴随变化引起的,影响 Angptl4 与 GBM 蛋白的相互作用。给足细胞转基因表达 Angptl4 的大鼠喂食唾液酸前体 ManNAc 12 天,可导致白蛋白尿减少 40% 以上,并显着增加 Angptl4 的唾液酸化。我们假设足细胞分泌的Angptl4与GBM蛋白相互作用诱导蛋白尿,并且该过程受到Angptl4唾液酸化状态的强烈影响。在具体目标 1 中,我们通过研究足细胞分泌的 Angptl4 掺入 N-聚糖和/或 O-聚糖,并寻找实验 MCD 中唾液酸合成和掺入途径的变化来表征足细胞分泌的 Angptl4 的唾液酸化。在具体目标 2 中,我们使用体外平板测定法研究唾液酸化和低唾液酸化 Angptl4 与硫酸肝素蛋白聚糖的相互作用,并使用邻近连接测定法研究组织切片中 Angptl4 与组织切片中所有 GBM 蛋白的相互作用。在具体目标 3 中,我们研究了转录因子 ZHX1 对实验性 MCD 足细胞 Angptl4 表达的上调,并提出实验来研究显性失活 ZHX1 构建体是否可用于减少疾病状态下的 Angptl4 表达。本申请中提出的实验将有助于设计减少蛋白尿的治疗策略。
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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Sumant Singh Chugh其他文献
Sumant Singh Chugh的其他文献
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Investigation of non-HIV Collapsing Glomerulopathy
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$ 30.75万 - 项目类别:
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8816097 - 财政年份:2014
- 资助金额:
$ 30.75万 - 项目类别:
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