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
基本信息
- 批准号:6801386
- 负责人:
- 金额:$ 34万
- 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 2007-07-31
- 项目状态:已结题
- 来源:
- 关键词:JAK kinaseJUN kinasebiological signal transductioncartilage developmentcell linechondrocytescollagengel mobility shift assaygene expressiongene induction /repressionimmunoprecipitationinterleukin 1microarray technologymitogen activated protein kinasephosphatidylinositol 3 kinaseprotein protein interactiontissue /cell culturetranscription factortransfectiontumor necrosis factor alphayeast two hybrid system
项目摘要
DESCRIPTION (provided by applicant): The catabolic and proinflammatory cytokines, interleukin-1beta (IL-1beta) and tumor necrosis factor-alpha (TNF-alpha) produced in the joint tissues, not only contribute to the destruction of cartilage matrix in osteoarthntis and rheumatoid arthritis, but also decrease the synthesis of cartilage-specific matrix proteins, including type II collagen and aggrecan. We have shown in published and preliminary studies that IL-1beta suppresses expression of the type II collagen gene (COL2A1) in chondrocytes at the transcriptional level via multiple signaling pathways. Furthermore, we have found that a novel ETS factor, ESE-1, which is induced by ILi1beta and TNF-alpha, binds to the COL2A1 promoter and directly suppresses its activity, indicating a pivotal role for this transcription factor in regulating COL2A1 gene expression. Our hypothesis is that IL-1beta-induced suppression of COL2A1 gene expression is mediated by ESE-1 as the primary transcriptional regulator and involves multiple signaling pathways and transcription factors that interact directly or indirectly with ESE-1. For these studies, we have developed immortalized human chondrocyte cell lines, which retain chondrocyte-specific phenotype and responses to cytokines. The Specific Aims will test the hypotheses that: (1) ESE-1 is the primary transcription factor involved in IL-1beta-mediated suppression of the COL2A 1 gene; (2) multiple signaling pathways involving p38 MAPK, JNK, Jak3, IKK/IkappaB and P13K/Akt kinase cascades transduce IL-1beta-induced suppression of COL2A1 gene expression, both directly and indirectly, via ESE-1; (3) ESE-1 serves its repressor function on COL2A1 expression via specific protein-DNA and protein-protein interactions involving other IL-1beta-induced transcription factors and constitutive factors; and (4) ESE-1 suppression of COL2A1 expression results in chondrocyte-dependent inhibition of cartilage matrix synthesis. These studies will permit dissection of the specific signaling pathways and molecular regulatory systems involved in transcriptional regulation of the COL2A1 gene by IL-1beta. These results may also lead to the development of more specific and effective therapeutic approaches for blocking the adverse effects of IL-1beta on cartilage matrix genes and their products in disorders such as OA and RA.
描述(申请人提供):关节组织中产生的分解代谢和促炎细胞因子白细胞介素-1β(IL-1β)和肿瘤坏死因子-α(TNF-α)不仅有助于骨关节炎和类风湿性关节炎中软骨基质的破坏,而且还减少软骨特异性的合成 基质蛋白,包括 II 型胶原蛋白和聚集蛋白聚糖。我们在已发表的初步研究中表明,IL-1β 通过多种信号通路在转录水平抑制软骨细胞中 II 型胶原蛋白基因 (COL2A1) 的表达。此外,我们发现一种新的ETS因子ESE-1,由ILi1beta和TNF-α诱导,与COL2A1启动子结合并直接抑制其活性,表明该转录因子在调节COL2A1基因表达中发挥着关键作用。我们的假设是,IL-1β 诱导的 COL2A1 基因表达抑制是由 ESE-1 作为主要转录调节因子介导的,并涉及与 ESE-1 直接或间接相互作用的多种信号传导途径和转录因子。在这些研究中,我们开发了永生化的人类软骨细胞系,该细胞系保留了软骨细胞特异性表型和对细胞因子的反应。具体目标将检验以下假设: (1) ESE-1 是参与 IL-1beta 介导的 COL2A 1 基因抑制的主要转录因子; (2) 涉及 p38 MAPK、JNK、Jak3、IKK/IkappaB 和 P13K/Akt 激酶级联的多个信号通路通过 ESE-1 直接或间接转导 IL-1beta 诱导的 COL2A1 基因表达抑制; (3) ESE-1通过涉及其他IL-1β诱导的转录因子和组成因子的特定蛋白质-DNA和蛋白质-蛋白质相互作用来发挥其对COL2A1表达的抑制功能; (4) ESE-1对COL2A1表达的抑制导致软骨细胞依赖性软骨基质合成的抑制。这些研究将有助于剖析参与 IL-1beta 对 COL2A1 基因转录调节的特定信号传导途径和分子调节系统。这些结果还可能导致开发更特异和有效的治疗方法,以阻断 IL-1β 对软骨基质基因及其产物在 OA 和 RA 等疾病中的不利影响。
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)
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MARY B GOLDRING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:
7784750 - 财政年份:2002
- 资助金额:
$ 34万 - 项目类别:
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