Mesangial cell matrix deposition in high glucose as a model of glomerulosclerosis
高糖条件下系膜细胞基质沉积作为肾小球硬化模型
基本信息
- 批准号:8313109
- 负责人:
- 金额:$ 4.22万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2012
- 资助国家:美国
- 起止时间:2012-03-01 至 2017-02-28
- 项目状态:已结题
- 来源:
- 关键词:AccountingAffectBindingBinding SitesBlood GlucoseCell Culture TechniquesCell LineCellsCicatrixCollagenDefectDepositionDetergentsDevelopmentDiabetes MellitusDiabetic NephropathyDiseaseDisease ProgressionEnd stage renal failureEnvironmentEventExhibitsExtracellular MatrixExtracellular Matrix ProteinsFeedbackFibroblastsFibronectinsFibrosisFiltrationFlow CytometryFutureGenerationsGlomerular CapillaryGlucoseHumanImmunofluorescence ImmunologicIntegrin BindingIntegrinsKidneyKineticsKnock-outLeadMeasuresMediatingMesenchymalModelingMolecularNatureNewly DiagnosedPathway interactionsPlayPost-Translational Protein ProcessingProcessProductionPropertyProteinsProteinuriaRenal glomerular diseaseRoleStructure of glomerular mesangiumSurfaceTestingTherapeuticTimeTissuesUnited Statescell assemblycell typedensitydeoxycholatedimerfibrillogenesisglomerular basement membraneglomerular filtrationglomerulosclerosisglycationglycosylated fibronectininsightkidney cellmesangial cellneutralizing antibodynew therapeutic targetreceptorresearch studysugar
项目摘要
DESCRIPTION (provided by applicant): Diabetic nephropathy is among the most devastating long-term consequences of diabetes mellitus and is now the leading cause of end-stage renal disease (ESRD) in the United States. The effects of the disease are predominantly focused in the glomerulus and are characterized by increased levels of extracellular matrix (ECM) proteins that disrupt the function of the glomerular filtration apparatus. Mesangial cells, which support th glomerular capillary network, are the primary matrix-producing cells of the glomerulus. Fibronectin (FN), a major component of the ECM throughout the body, is found in the normal glomerulus and at significantly elevated levels in diabetic nephropathy. FN is an important player in cell-matrix interactions and FN matrix precedes and in part dictates the deposition of other ECM proteins. Consequently, perturbations in FN matrix assembly have profound effects on the overall integrity of tissue-appropriate ECM. Cells mediate FN matrix assembly via integrin receptors, notably ¿5¿1, binding to RGD cell-binding domains of FN dimers. This binding induces FN-FN interactions and formation of short fibrils that then mature into a stable insoluble matrix through continued addition of FN dimers. High glucose conditions have been shown to increase mesangial cell expression of various ECM proteins, including FN. The effects of high glucose on mesangial cell-mediated assembly of a mature matrix are as yet undetermined. Non-enzymatic glycation of matrix proteins represents another mode of glucose-mediated ECM disruption. Glycated FN, which exhibits altered binding properties, is found at elevated levels in diabetes. We propose that defects in mesangial cell matrix assembly represent a final common pathway in glomerulosclerosis, which marks diabetic nephropathy and other fibrotic diseases. The influence of high glucose on the kinetics of matrix assembly will first be determined by a time course of FN accumulation under normal and high glucose conditions by measuring deoxycholate (DOC) detergent-insoluble FN, an established marker for FN matrix maturity. Fibril density will be quantified to determine any glucose- mediated changes in ECM organization. Similar experiments will be performed in the presence of glycated FN. Since the 3D nature of a cell's environment stimulates matrix production, the effects of 3D matrix on the dynamics of mesangial cell-mediated FN fibrillogenesis will be examined to determine if a positive feedback loop exists, in which accumulation of insoluble matrix stimulates further matrix deposition. Since integrin receptors initiate the final common pathway, the roles of ¿5¿1 and ¿v¿3 integrins in high glucose-induced matrix deposition will be examined using neutralizing antibodies and knockout cells. Further insight into the mechanisms of increased matrix assembly in diabetic nephropathy may pave the way for the development of a new generation of therapeutics, which target this process in hopes of reversing the progression towards ESRD.
PUBLIC HEALTH RELEVANCE: Chronically high blood sugar levels in diabetes mellitus can have devastating effects on the kidney's filtration apparatus. This apparatus depends on proper organization of a network of proteins called the extracellular matrix, which accumulate in excess and block filtration when exposed to high sugar levels. Using a kidney cell culture model, we plan to clarify the effects of high sugar levels on the filtration matrix in hopes of revealing new
targets for future therapies aimed at reversing the progression of this increasingly common and potentially deadly disease.
描述(申请人提供):糖尿病肾病是糖尿病最具破坏性的长期后果之一,现在是美国终末期肾病(ESRD)的主要原因。该病的影响主要集中在肾小球,其特点是细胞外基质(ECM)蛋白水平升高,扰乱肾小球滤过装置的功能。肾小球系膜细胞是肾小球的主要基质生成细胞,支持肾小球毛细血管网络。纤维连接蛋白(FN)是全身细胞外基质的主要成分,在正常肾小球中发现,在糖尿病肾病中水平显著升高。FN是细胞-基质相互作用的重要参与者,FN基质先于细胞外基质,并在一定程度上决定其他ECM蛋白的沉积。因此,FN基质组装中的扰动对适合组织的ECM的整体完整性有深远的影响。细胞通过整合素受体,特别是与FN二聚体的RGD细胞结合域结合的整合素受体,介导FN基质的组装。这种结合诱导Fn-Fn相互作用并形成短纤维,然后通过继续添加Fn二聚体成熟为稳定的不溶基质。高糖环境可增加系膜细胞各种ECM蛋白的表达,包括FN。高糖对系膜细胞介导的成熟基质组装的影响尚不确定。基质蛋白的非酶糖基化是葡萄糖介导的细胞外基质破坏的另一种方式。糖化的FN表现出结合特性的改变,在糖尿病患者中发现水平升高。我们认为,系膜细胞基质组装缺陷是肾小球硬化的最终共同途径,它标志着糖尿病肾病和其他纤维化疾病。高糖对基质组装动力学的影响将首先通过测定脱氧胆酸盐(DOC)洗涤剂不溶于FN来确定FN在正常和高糖条件下积聚的时间进程,脱氧胆酸盐(DOC)是FN基质成熟度的既定标志。纤维密度将被量化,以确定任何葡萄糖介导的细胞外基质组织的变化。在糖化FN存在的情况下,将进行类似的实验。由于细胞环境的3D特性刺激基质的产生,因此将研究3D基质对系膜细胞介导的FN纤维形成动力学的影响,以确定是否存在正反馈回路,在该回路中,不溶性基质的积累刺激进一步的基质沉积。由于整合素受体启动了最终的共同途径,因此将使用中和抗体和基因敲除细胞来研究整合素在高糖诱导的基质沉积中的作用。对糖尿病肾病中基质聚集增加的机制的进一步了解可能为新一代疗法的开发铺平道路,该疗法以这一过程为目标,希望逆转向终末期肾病的进展。
公共卫生相关性:糖尿病患者的长期高血糖水平可能会对肾脏的过滤装置产生毁灭性的影响。这一装置依赖于一种称为细胞外基质的蛋白质网络的适当组织,当暴露在高糖水平下时,细胞外基质会过量积累并阻止过滤。利用肾脏细胞培养模型,我们计划阐明高糖水平对滤过基质的影响,以期揭示新的
未来治疗的目标是扭转这种日益常见和可能致命的疾病的发展。
项目成果
期刊论文数量(0)
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Charles Grabel Miller其他文献
Charles Grabel Miller的其他文献
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{{ truncateString('Charles Grabel Miller', 18)}}的其他基金
Mesangial cell matrix deposition in high glucose as a model of glomerulosclerosis
高糖条件下系膜细胞基质沉积作为肾小球硬化模型
- 批准号:
8625747 - 财政年份:2012
- 资助金额:
$ 4.22万 - 项目类别:
Mesangial cell matrix deposition in high glucose as a model of glomerulosclerosis
高糖条件下系膜细胞基质沉积作为肾小球硬化模型
- 批准号:
8813561 - 财政年份:2012
- 资助金额:
$ 4.22万 - 项目类别:
Mesangial cell matrix deposition in high glucose as a model of glomerulosclerosis
高糖条件下系膜细胞基质沉积作为肾小球硬化模型
- 批准号:
8427586 - 财政年份:2012
- 资助金额:
$ 4.22万 - 项目类别:
Mesangial cell matrix deposition in high glucose as a model of glomerulosclerosis
高糖条件下系膜细胞基质沉积作为肾小球硬化模型
- 批准号:
9052756 - 财政年份:2012
- 资助金额:
$ 4.22万 - 项目类别:
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