FIBROSIS--MOLECULAR BASIS FOR FIBROBLAST ACTIVATION

纤维化——成纤维细胞激活的分子基础

• 批准号: 6374973
• 负责人: MARIA TROJANOWSKA
• 金额: $ 19.72万
• 依托单位: MEDICAL UNIVERSITY OF SOUTH CAROLINA
• 依托单位国家: 美国
• 财政年份: 1994
• 资助国家: 美国
• 起止时间: 1994-08-10 至 2003-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6374973
• 关键词: cell growth regulation; clinical research; collagen; cytokine; extracellular matrix; fibroblasts; fibrosis; gene expression; gene induction /repression; genetic regulation; genetic regulatory element; genetic transcription; human subject; integrins; molecular cloning; molecular pathology; scleroderma; transcription factor; transforming growth factors

DESCRIPTION: (Adapted from the applicant's abstract) - The principal investigator's long-term objective is to understand the regulation of ECM production by human fibroblasts and its dysregulation in fibrotic diseases such as scleroderma (SSc). Substantial evidence has accumulated in recent years that implicates transcriptional activation of collagen genes as a key component in development of fibrosis in SSc and other fibrotic diseases. Lesional SSc fibroblasts maintain an activated phenotype during propagation in culture, thus providing an accessible system to study the molecular mechanisms responsible for the elevated expression of collagen genes. Data generated during the last funding period together with work by others reveal that SSc and normal fibroblasts respond differently to exogenous signals transmitted by cytokines as well as integrins. In addition, the principal investigator has recently identified transcription factors Sp1 and Sp3 as central regulators of the COL1A2 gene transcription. More importantly, the principal investigator has shown that Sp1 and Sp3 not only contribute to the basal expression level but can elicit inductive responses to serum and at least one cytokine, Oncostatin M. These results enable the principal investigator to propose a much more complete model for collagen gene regulation, in which intersecting cytokine and integrin signaling pathways exert induction or repression effects through a limited number of transcription factors. Dysregulated response to these signaling pathways likely underlies the elevated levels of collagen gene expression in SSc. This model thus provides the basis for unraveling the complex molecular mechanism responsible for abnormal regulation of collagen genes in SSc fibroblast. Four specific aims are proposed: 1) To identify the cis-regulatory elements and to characterize levels and activities of the cognate transcription factors in the COL1A2 promoter responsible for the different regulation of basal and cytokine (TGF-beta, OSM) stimulated collagen gene transcription in SSc and normal fibroblasts; 2) to characterize cis-regulatory elements in the human COL1A2 promoter mediating integrin modulation of the collagen gene transcription in SSc and normal fibroblasts; 3) to identify and characterize additional trans-acting factors involved in regulation of the human COL1A2 promoter activity, and 4) to characterize intracellular signaling pathways mediating cytokine and integrin regulation of collagen production in SSc and normal fibroblasts.

描述：（改编自申请人的摘要）- 校长 研究者的长期目标是了解 ECM 的监管 人类成纤维细胞的产生及其在纤维化疾病中的失调 例如硬皮病（SSc）。 近年来积累了大量证据 多年以来，胶原蛋白基因的转录激活是关键 SSc 和其他纤维化疾病中纤维化发展的组成部分。 病变 SSc 成纤维细胞在繁殖过程中维持激活表型 在文化中，从而提供了一个可访问的系统来研究分子 负责胶原蛋白基因表达升高的机制。 数据 上一个资助期间产生的成果以及其他人的工作揭示了 SSc 和正常成纤维细胞对外源信号的反应不同 通过细胞因子和整合素传播。 此外，校长 研究人员最近鉴定出转录因子 Sp1 和 Sp3 COL1A2 基因转录的中央调节因子。 更重要的是， 首席研究员表明 Sp1 和 Sp3 不仅有助于 基础表达水平，但可以引发对血清和 at 的诱导反应 至少一种细胞因子，制瘤素 M。这些结果使主要 研究人员提出一个更完整的胶原蛋白基因模型 调节，其中细胞因子和整合素信号通路交叉 通过有限的数量发挥诱导或抑制作用 转录因子。 对这些信号通路的反应失调 可能是 SSc 中胶原蛋白基因表达水平升高的原因。 因此，该模型为解开复杂的分子提供了基础 SSc 中胶原蛋白基因异常调节的机制 成纤维细胞。 提出了四个具体目标： 1) 确定 顺式监管要素并描述其水平和活动 COL1A2 启动子中的同源转录因子负责 刺激基础和细胞因子（TGF-β、OSM）的不同调节 SSc 和正常成纤维细胞中胶原蛋白基因的转录； 2）到 表征人类 COL1A2 启动子介导的顺式调控元件 整合素对 SSc 和正常人胶原蛋白基因转录的调节 成纤维细胞； 3) 识别和表征其他反式作用因子 参与人类 COL1A2 启动子活性的调节，以及 4) 表征介导细胞因子的细胞内信号传导途径和 整合素对 SSc 和正常成纤维细胞胶原蛋白产生的调节。