LAMININ GENE EXPRESSION IN GLOMERULAR CELLS

肾小球细胞中的层粘连蛋白基因表达

基本信息

批准号：
7921107
负责人：
KAROL BOMSZTYK
金额：
$ 9.59万
依托单位：
UNIVERSITY OF WASHINGTON
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-09-21 至 2011-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7921107
关键词：
Address Be++ element Beryllium Binding Binding Sites CREB-binding protein Cells Complex DNA Development EP300 gene Elements Enhancers Extracellular Matrix Gene Expression Genes Genetic Transcription Glomerular Mesangial Cell Goals Growth Factor HMGA1a Protein Human Kidney Diseases Laminin Mediating Messenger RNA Modeling Molecular Phosphorylation Play Property Proteins RNA Polymerase II Renal glomerular disease Research Personnel Rodent Role Series Signal Pathway Signal Transduction Smad Proteins Smad protein Testing Transcription Coactivator Transcriptional Activation Transforming Growth Factors Work activating transcription factor base dC-Stretch-Binding Protein design glomerular basement membrane glomerulosclerosis human CREBBP protein insight mesangial cell overexpression programs promoter protein K response synergism transcription factor

Address Be++ element Beryllium Binding Binding Sites CREB-binding protein Cells Complex DNA Development EP300 gene Elements Enhancers Extracellular Matrix Gene Expression Genes Genetic Transcription Glomerular Mesangial Cell Goals Growth Factor HMGA1a Protein Human Kidney Diseases Laminin Mediating Messenger RNA Modeling Molecular Phosphorylation Play Property Proteins RNA Polymerase II Renal glomerular disease Research Personnel Rodent Role Series Signal Pathway Signal Transduction Smad Proteins Smad protein Testing Transcription Coactivator Transcriptional Activation Transforming Growth Factors Work activating transcription factor base dC-Stretch-Binding Protein design glomerular basement membrane glomerulosclerosis human CREBBP protein insight mesangial cell overexpression programs promoter protein K response synergism transcription factor

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项目摘要

Glomerulosclerosis is the most serious sequela of progressive renal disease. Glomerulosclerosis results from an abnormal accumulation of proteins, some of which, that normal]y make up the glomerular basement membrane (GBM) and mesangial matrix (MM). Laminin is one of the components of GBM and MM that accumulates within glomeruti during the progression of glomerular disease. A number of growth factors including transforming growth factor-[_ (TGF-_), activate glomerular cells resulting in abnormal accumulation of laminin. Although laminin is known to play a key role in the development of glomerulosclerosis, the mechanisms that regulate expression of laminin chains are incompletely understood. Treatment of glomerular cells with TGF-[3 and other growth factors increases mRNA levels of laminin 71 chain. The human and rodent larrdnin y1 chain (LAMCt) gene promoters contain the critical ben-1 element that is activated by transcription factor #E3 (TFE3). In glomerular mesangial cells, the TFE3-mediated activation of the bcn-1 element is greatly augmented by Smad proteins, acting through the LAMC1 promoter's Smad- binding elements (SBE), and by the TGF-[3-signaling pathways. The bcn-l-element-dependent activation of the LAMC1 promoter by the synergistic action of TFE3 and Smad proteins provides insight into how TGF-_ mediates activation of the endogenous LAMC1 gene in these cells Expression of the transcriptional co-activator, CREB- binding protein (CBP), increased the activity of the LAMC1 promoter in mesangial cells. The goal of the current proposal is to define the molecular mechanisms responsible for the TFE3- and Smad-dependent activation of LAMC 1 gene transcription that is induced by TGF-[3 in glomerular cells. The following specific aims are proposed to explore these mechanisms. We will define the role of CBP and other co-activators in mediating the TFE3-Smad-dependent TGF-_-induced LAMC1 gene expression. We will identify components of the basal transcriptional machinery that interact with TFE3 protein and define their role in mediating TGF-fl-induced gene expression. We will define the molecular mechanisms responsible for the TFE3-Smad3 synergistic activation of the LAMC1 gene in response to TGF-_. These studies will provide insight into transcriptional mechanisms utilized by TGF-[_ to direct TFE3- and Smad- dependent LAMC1 gene transcription in glomerular cells. The results of these studies are anticipated to have a broad impact on understanding the basic mechanisms by which TGF-[3 triggers transcription of genes encoding components of extracellular matrix and of other genes expressed in glomerular cells.

肾小球硬化是进行性肾脏疾病的最严重的后遗症。肾小球硬化是由蛋白质的异常积累，其中一些正常构成肾小球基底膜（GBM）和介子矩阵（mm）。层粘连蛋白是在glomeruti中积聚的GBM和MM的成分之一在肾小球疾病的进展过程中。许多生长因素，包括转化生长因子 - [_ （TGF-_），激活肾小球细胞，导致层粘连蛋白的异常积累。虽然已知层粘连蛋白会发挥在肾小球硬化的发展中的关键作用，调节层粘连蛋白链表达的机制是不完全理解。用TGF-治疗肾小球细胞[3和其他生长因子增加mRNA水平层粘连蛋白71链。人和啮齿动物larrdnin Y1链（LAMCT）基因启动子包含关键的BEN-1 由转录因子＃E3（TFE3）激活的元素。在肾小球肾小球细胞中，TFE3介导 Smad蛋白会大大增加BCN-1元素的激活，该蛋白通过LAMC1启动子的Smad-作用结合元素（SBE）和TGF- [3-信号途径。 BCN-L元素依赖性激活 LAMC1启动子通过TFE3和SMAD蛋白的协同作用提供了有关TGF-_介导的见解在这些细胞表达转录共激活剂CREB-的这些细胞表达中，内源性LAMC1基因的激活结合蛋白（CBP）增加了在膜细胞中LAMC1启动子的活性。电流的目标建议是定义负责LAMC 1的TFE3和SMAD依赖性激活的分子机制 TGF- [3在肾小球细胞中诱导的基因转录。提出了以下特定目标来探索这些机制。我们将定义CBP和其他共激活因子在介导TFE3-SMAD依赖性TGF -_-诱导中的作用 LAMC1基因表达。我们将确定与TFE3蛋白相互作用的基础转录机械的组件并定义它们在介导TGF-FL诱导的基因表达中的作用。我们将定义负责LAMC1的TFE3-SMAD3协同激活的分子机制响应TGF-_的基因。这些研究将提供对TGF使用的转录机制的见解 - [_指导TFE3-和SMAD- 肾小球细胞中的依赖性LAMC1基因转录。这些研究的结果预计会有广泛对理解TGF-的基本机制的影响 - [3触发编码组件的基因转录细胞外基质和其他在肾小球细胞中表达的基因