Molecular Mechanisms of Mesangial Sclerosis
系膜硬化的分子机制
基本信息
- 批准号:7369741
- 负责人:
- 金额:$ 32.38万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2006
- 资助国家:美国
- 起止时间:2006-03-01 至 2010-02-28
- 项目状态:已结题
- 来源:
- 关键词:Actin-Binding ProteinActinsAftercareAppearanceBindingC-terminalCell NucleusCell physiologyCellsCleaved cellComplexDataDevelopmentDiabetic NephropathyDiseaseFHL2 geneFigs - dietaryFocal AdhesionsGene ExpressionGene TargetingGenerationsGenesGenetic TranscriptionGoalsHyperglycemiaIndiumInsulin-Like Growth Factor Binding Protein 5IntegrinsKidney DiseasesLIM Domain ProteinLamininMediatingMolecularNuclearNuclear ProteinNuclear ProteinsPhenotypePhosphorylationPlayProcessProgress ReportsProtein IsoformsRecruitment ActivityRenal glomerular diseaseResearch PersonnelRoleSclerosisStimulusStress FibersTranscriptional Regulationbasecrosslinkfilamininsightlaminin-9mesangial cellnephrogenesisnovelprogramspromoterrho GTP-Binding Proteinstranscription factor
项目摘要
Temporal and spatial expression of laminin (LN)isoforms is critical to glomerular development and
contributes to altered cell function in diabetic nephropathy and other progressive renal diseases. Yet, little is
known about the mechanisms that regulate LN isoform expression. We propose that insulin-like growth
factor binding protein-5 (IGFBP-5) leads to formation of a filamin-based nuclear shuttle that binds
transcription factors (e.g.sox9, GKLF, Sp1, Smad) and transcriptional co-activators (e.g., IGFBP-5 and LIM
domain proteins such as FHL2) and regulates laminin (LN)isoform expression in mesangial cells (MC). This
hypothesis suggests a novel mechanism whereby perturbations in the cell-matrix interface regulate gene
expression. This hypothesis will be examined by:
Specific Aim 1: To characterize the generation and composition of the filamin nuclear shuttle following
treatment of MC with IGFBP-5. First, we will demonstrate that a fragment of filamin forms and translocates to
the nucleus. Second, we will characterize the transcription factors that are recruited to the complex; and
finally, we will evaluate the role of transcriptional co-activators, LIM domain protein FHL2 and IGFBP-5, in
the complex.
Specific Aim 2: To demonstrate that nuclear accumulation of filamin is required for IGFBP-5-mediated
changes in LN gene expression. First, we will demonstrate that filamin is required for IGFBP-5-mediated
effects on LN gene expression. Second, we will show that the filamin shuttle is recruited to LN gene loci
where it specifically midifies LN gene transcription.
Specific Aim 3: To define the mechanisms whereby the filamin nuclear shuttle activates LN gene
transcription. First, we will determine if FLN interacts directly with the LN promoter and if it drives
transcription. Second, we will define the elements in the shuttle that are required for transcriptional control.
These studies will define the role of a filamin-based nuclear shuttle in mediating the effects of IGFBP-5 on
laminin gene expresison. Understanding transcriptional control of LN isoform expression will add new
insights into the role that LN plays in normal glomerulogenesis and that becomes disordered in glomerular
disease.
层粘连蛋白 (LN) 亚型的时间和空间表达对于肾小球的发育和发育至关重要
导致糖尿病肾病和其他进行性肾脏疾病的细胞功能改变。然而,很少的是
了解调节 LN 亚型表达的机制。我们建议胰岛素样生长
因子结合蛋白 5 (IGFBP-5) 导致形成基于细丝蛋白的核梭,该核梭结合
转录因子(例如 sox9、GKLF、Sp1、Smad)和转录共激活因子(例如 IGFBP-5 和 LIM)
结构域蛋白(例如 FHL2)并调节系膜细胞 (MC) 中的层粘连蛋白 (LN) 亚型表达。这
假设提出了一种新的机制,通过细胞-基质界面的扰动调节基因
表达。该假设将通过以下方式进行检验:
具体目标 1:表征细丝核梭的生成和组成
用 IGFBP-5 治疗 MC。首先,我们将证明细丝蛋白片段形成并易位到
核。其次,我们将表征被招募到复合物中的转录因子;和
最后,我们将评估转录共激活因子 LIM 结构域蛋白 FHL2 和 IGFBP-5 在
复杂的。
具体目标 2:证明细丝蛋白的核积累是 IGFBP-5 介导所必需的
LN 基因表达的变化。首先,我们将证明细丝蛋白是 IGFBP-5 介导所必需的
LN 基因表达的影响。其次,我们将证明细丝蛋白穿梭被招募到 LN 基因位点
它特异性地介导 LN 基因转录。
具体目标 3:确定细丝蛋白核穿梭激活 LN 基因的机制
转录。首先,我们将确定 FLN 是否直接与 LN 启动子相互作用以及它是否驱动
转录。其次,我们将定义穿梭中转录控制所需的元件。
这些研究将确定基于细丝蛋白的核梭在介导 IGFBP-5 对细胞的影响中的作用。
层粘连蛋白基因表达。了解 LN 亚型表达的转录控制将增加新的内容
深入了解 LN 在正常肾小球生成中的作用以及肾小球中的紊乱
疾病。
项目成果
期刊论文数量(0)
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会议论文数量(0)
专利数量(0)
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