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(由申请人提供):关节组织中产生的分解代谢和促炎细胞因子,白细胞介素-1 β(IL-1 β)和肿瘤坏死因子-α(TNF-α)不仅导致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基质蛋白(包括II型胶原和聚集蛋白聚糖)的合成。我们在已发表的和初步的研究中表明,IL-1 β通过多种信号通路在转录水平上抑制软骨细胞中II型胶原基因(COL 2A 1)的表达。此外,我们发现一种新的ETS因子ESE-1,它是由ILi 1 β和TNF-α诱导的,与COL 2A 1启动子结合并直接抑制其活性,表明这种转录因子在调节COL 2A 1基因表达中起关键作用。我们的假设是,IL-1 β诱导的COL 2A 1基因表达抑制是由ESE-1作为主要的转录调节因子介导的,并涉及多种信号通路和转录因子,直接或间接地与ESE-1相互作用。对于这些研究,我们已经开发了永生化的人软骨细胞系,其保留软骨细胞特异性表型和对细胞因子的反应。具体目的将检验以下假设:(1)ESE-1是参与IL-1 β介导的COL 2A 1基因抑制的主要转录因子;(2)涉及p38 MAPK、JNK、Jak 3、IKK/IkappaB和P13 K/Akt激酶级联的多种信号通路直接或间接地通过ESE-1抑制IL-1 β诱导的COL 2A 1基因表达;(3)ESE-1通过涉及其它IL-1 β诱导的转录因子和组成性因子的特异性蛋白-DNA和蛋白-蛋白相互作用对COL 2A 1表达发挥其阻遏物功能;(4)ESE-1对COL 2A 1表达的抑制导致软骨细胞依赖性的软骨基质合成抑制。这些研究将允许解剖参与IL-1 β对COL 2A 1基因转录调控的特异性信号通路和分子调控系统。这些结果也可能导致开发更特异和有效的治疗方法,用于阻断IL-1 β对OA和RA等疾病中软骨基质基因及其产物的不良影响。
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)
专利数量(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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