ESE 1 a novel transcriptional regulator of cartilage remodeling

ESE 1 一种新型软骨重塑转录调节因子

基本信息

  • 批准号:
    8038388
  • 负责人:
  • 金额:
    $ 34.48万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2002
  • 资助国家:
    美国
  • 起止时间:
    2002-08-15 至 2015-02-28
  • 项目状态:
    已结题

项目摘要

DESCRIPTION (provided by applicant): Described originally as Epithelial Specific ETS (ESE)-1 (Elf3 in mouse), we have found that this novel transcription factor suppresses type II collagen gene (COL2A1) expression by binding to the COL2A1 promoter and interacting with Sox9 and CBP and that ESE-1 immunostaining is increased in superficial and midzone regions of cartilage from patients with osteoarthritis (OA). Our preliminary data show that ESE-1 increases the transcription of matrix metalloproteinase (MMP)-13 by binding to ETS/PEA3 sites in the MMP13 promoter and cooperating with Runx2 and AP-1. The absence of MMP-13 protein in the Ese1/Elf3-deficient mouse and the increased Ese1 expression in the articular cartilage of the cho/+ mouse model of OA compared to wild type mice further suggest its pivotal role in de-regulated cartilage remodeling during OA. Thus, we hypothesize that ESE-1 is a critical transcriptional regulator of cartilage remodeling during OA progression. The Specific Aims are: (1) What are the signaling pathways that induce and activate ESE-1 to regulate MMP-13 and other targets? We will use primary mouse and human chondrocytes and cell lines to characterize the signaling and transcriptional mechanisms involved in the induction and action of ESE-1 in the regulation of MMP13 and other gene targets, including the structure/function relationships that determine ESE-1 actions under basal and inflammatory conditions. (2) Does Ese1/Elf3-deficiency protect against or attenuate cartilage loss in surgical and genetic mouse models of OA, and if so, what are its mechanisms of action? We will employ Ese1/Elf3 knockout mice subjected to non-genetic experimentally induced (surgical) OA and the Cho/+ mouse model of age-dependent OA and map gene expression during onset and progression of OA by sensitive, in situ gene expression analysis and other techniques developed in Aim 1. (3) Does ESE-1 over-expression affect the onset or progression of OA in mouse knee joints due to aging or surgical OA? We will generate Tet-Off-inducible Ese1 transgenic mice to examine whether excess ESE-1, by itself, initiates or accelerates surgically induced OA and reveal if ESE-1-dependent mechanisms correlate with the extent of OA progression. By applying insights from in vitro studies to the analysis of early and late events by ex vivo and in situ approaches in the mouse models, we will gain understanding of molecular events underlying initiation and progression that will lead to the development of novel targeted therapies for OA due to trauma or aging. PUBLIC HEALTH RELEVANCE: Our recent findings point to a critical role for a novel transcription factor, ESE-1, in the regulation of cartilage remodeling in osteoarthritis (OA) and have prompted us to examine the mechanisms by which ESE-1 is activated and regulates expression of the cartilage-degrading enzyme, matrix metalloproteinase-13. Thus, we will make use of ESE-1 knockout and conditional transgenic mice to determine its role in non-genetic experimentally-induced (surgical) OA and in genetically based spontaneous OA during aging by applying insights from in vitro studies to the analysis of early and late events by ex vivo and in situ approaches. These studies will provide understanding of molecular events underlying the initiation and progression and lead to the development of novel targeted therapies for OA due to trauma and aging.
描述(由申请人提供):最初被描述为上皮特异性ET(ESE)-1(鼠标中的ELF3),我们发现,这种新型的转录因子通过与COL2A1启动子结合并与SOX9和CBP和CBP的相互作用而与Sox9和CBP相互作用来抑制II型胶原蛋白基因(COL2A1)的表达,并且与Sox9和CBP的相互作用增加了与Spirloic和MISTORIOS在Spriplo Losice sone Insprication symions Insprofice seprions Im carte sore sape sose carterions aste s的carte se。 (OA)。我们的初步数据表明,ESE-1通过与MMP13启动子中的ETS/PEA3位点结合并与RUNX2和AP-1合作,增加了基质金属蛋白酶(MMP)-13的转录。与野生型小鼠相比,在ESE1/ELF3缺陷型小鼠中没有MMP-13蛋白在OA的CHO/+小鼠模型的关节软骨中的ESE1表达增加,这进一步表明其在OA期间在非调控软骨重塑中的关键作用。因此,我们假设ESE-1是OA进展过程中软骨重塑的关键转录调节剂。具体目的是:(1)诱导和激活ESE-1来调节MMP-13和其他目标的信号传导途径是什么?我们将使用原代小鼠和人软骨细胞和细胞系来表征ESE-1在调节MMP13和其他基因靶标中涉及的信号传导和转录机制,包括确定基础和炎症条件下ESE-1作用的结构/功能关系。 (2)ESE1/ELF3缺乏能力是否可以防止OA的手术和遗传小鼠模型中的软骨损失,如果是这样,它的作用机理是什么?我们将采用经受过非遗传实验诱导(手术)OA(手术)OA的ESE1/ELF3敲除小鼠,以及依赖年龄依赖性OA的CHO/+小鼠模型在发​​作过程中和MAP基因表达和通过敏感的OA进展,敏感的原位基因表达分析和在AIM或进表中开发的均匀或进度的均可依次的均可依次依次。哦?我们将生成Tet-Off诱导的ESE1转基因小鼠,以检查过量的ESE-1本身是否会引发或加速手术诱导OA,并揭示ESE-1依赖性机制是否与OA进展程度相关。通过将体外研究中的见解应用到小鼠模型中的早期和晚期事件的分析,我们将了解对由于创伤或成年引起的OA的新型靶向疗法的发展的分子事件的理解。 公共卫生相关性:我们最近的发现表明,新型转录因子ESE-1在调节骨关节炎(OA)中的软骨重塑中的重要作用,并促使我们检查了ESE-1激活ESE-1的机制,并调节软骨促进酶的酶,Matrix Metallopolototeinase-13。因此,我们将利用ESE-1基因敲除和条件转基因小鼠在衰老期间确定其在非遗传实验诱导的(手术)OA和基于遗传的自发OA中的作用,通过将体外研究的见解应用于EX VIVO和现场方法对早期和晚期事件的分析,以分析体外研究的见解。这些研究将提供对起始和进展的基础事件的理解,并导致由于创伤和衰老而发展的新型OA靶向疗法。

项目成果

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MARY B GOLDRING其他文献

MARY B GOLDRING的其他文献

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{{ truncateString('MARY B GOLDRING', 18)}}的其他基金

Defining Common Molecular Parameters For Onset and Progression of Osteoarthritis
定义骨关节炎发病和进展的常见分子参数
  • 批准号:
    8046767
  • 财政年份:
    2010
  • 资助金额:
    $ 34.48万
  • 项目类别:
Epigenetic Regulation of MMP-13
MMP-13 的表观遗传调控
  • 批准号:
    7385654
  • 财政年份:
    2007
  • 资助金额:
    $ 34.48万
  • 项目类别:
Epigenetic Regulation of MMP-13
MMP-13 的表观遗传调控
  • 批准号:
    7495610
  • 财政年份:
    2007
  • 资助金额:
    $ 34.48万
  • 项目类别:
Role of ESE1 Regulation of Type II Collagen in Cartilage
ESE1 对软骨中 II 型胶原蛋白的调节作用
  • 批准号:
    6801386
  • 财政年份:
    2002
  • 资助金额:
    $ 34.48万
  • 项目类别:
Role of ESE1 Regulation of Type II Collagen in Cartilage
ESE1 对软骨中 II 型胶原蛋白的调节作用
  • 批准号:
    7097916
  • 财政年份:
    2002
  • 资助金额:
    $ 34.48万
  • 项目类别:
ESE 1 a novel transcriptional regulator of cartilage remodeling
ESE 1 一种新型软骨重塑转录调节因子
  • 批准号:
    8432029
  • 财政年份:
    2002
  • 资助金额:
    $ 34.48万
  • 项目类别:
Role of ESE1 Regulation of Type II Collagen in Cartilage
ESE1 对软骨中 II 型胶原蛋白的调节作用
  • 批准号:
    6513736
  • 财政年份:
    2002
  • 资助金额:
    $ 34.48万
  • 项目类别:
Role of ESE1 Regulation of Type II Collagen in Cartilage
ESE1 对软骨中 II 型胶原蛋白的调节作用
  • 批准号:
    7390978
  • 财政年份:
    2002
  • 资助金额:
    $ 34.48万
  • 项目类别:
ESE 1 a novel transcriptional regulator of cartilage remodeling
ESE 1 一种新型软骨重塑转录调节因子
  • 批准号:
    8644768
  • 财政年份:
    2002
  • 资助金额:
    $ 34.48万
  • 项目类别:
ESE 1 a novel transcriptional regulator of cartilage remodeling
ESE 1 一种新型软骨重塑转录调节因子
  • 批准号:
    8223260
  • 财政年份:
    2002
  • 资助金额:
    $ 34.48万
  • 项目类别:

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