CTGF Stimulation of Collagen Production in Scleroderma

CTGF 刺激硬皮病中胶原蛋白的产生

• 批准号: 6659646
• 负责人: JOEL ROSENBLOOM
• 金额: $ 10万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-09-20 至 2004-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6659646
• 关键词: cell line; clinical research; collagen; fibroblasts; fibrogenesis; genetic regulatory element; growth factor; pathologic process; scleroderma; transcription factor; transforming growth factors

One of the cardinal manifestations of Scleroderma or Systemic Sclerosis (SSc) is excessive production of connective tissue matrix which impairs function in the skin and multiple internal organs. While the pathogenic mechanisms underlying this disease are complex and incompletely understood, it is likely that many of the harmful aspects with respect to connective tissue are mediated by the manifold effects of TGF-beta acting as a final common pathway. Strong evidence suggests that many of the effects of TGF-beta on fibroblast extracellular matrix may be mediated by connective tissue growth factor (CTGF) Our preliminary data demonstrate that CTGF expression by cultured SSC and normal fibroblasts is greatly stimulated by TGF-beta1 aqnd we have confirmed the presence of excess CTGF in the dermis of SSc patients by immunolocalization. We pose the following hypotheses: (1) TGF-beta stimulation of CTGF expression requires the activity of prenylated protein(s) and protein kinase C (PKC) in addition to the Smads. (2) CTGF is a major mediator of the fibroproliferative response, exerting its activity through binding to integrin cell surface receptor(s). (3) Alteration in the regulation of CTGF expression and/or its activity is a significant feature of the pathogenic fibrotic response found in SSc. In order to test these hypotheses, we propose the following aims: (1) To identify and characterize the molecular mechanisms whereby TGF-beta stimulates expression of CTGF in normal and SSC fibroblasts. (2) To define the signaling pathways whereby CTGF increases expression of collagen in normal and SSC fibroblasts. (3) To identify and characterize CTGF cis- responsive elements in the promoter of the COLIA1 gene and their cognate transacting factors. Identification of the mechanisms of action of CTGF and the pathways regulating its expression are of considerable importance, since CTGF may play a key role in the pathogenesis of SSC and blocking its abnormal production may ameliorate the most harmful features of the fibrotic response.

硬皮病或系统性硬化症（SSC）的主要表现之一是过度产生结缔组织基质，会损害皮肤和多个内部器官的功能。尽管该疾病背后的致病机制是复杂且未完全理解的，但相对于结缔组织的许多有害方面可能是由TGF-beta的歧管介导的，它是最终的公共途径。有力的证据表明，TGF-β对成纤维细胞外基质的许多影响可能是通过结缔组织生长因子（CTGF）介导的，我们的初步数据表明，培养的SSC和正常成纤维细胞的CTGF表达受到TGF-BETA1 AQND的极大刺激。通过免疫定位证实了SSC患者真皮中过量的CTGF。我们提出以下假设：（1）TGF-β刺激CTGF表达需要除SMADS之外，还需要蛋白质激酶C（PKC）的蛋白质激酶C（PKC）的活性。 （2）CTGF是纤维增生反应的主要介体，通过与整联蛋白细胞表面受体（S）结合发挥其活性。 （3）改变CTGF表达和/或其活性的改变是SSC中发现的致病性纤维化反应的重要特征。为了检验这些假设，我们提出了以下目的：（1）识别和表征分子机制，从而在正常和SSC成纤维细胞中刺激CTGF的表达。 （2）定义信号通路，从而在正常和SSC成纤维细胞中增加胶原蛋白的表达。 （3）识别和表征COLIA1基因启动子及其同源交易因子的CTGF顺序响应元素。识别CTGF的作用机理和调节其表达的途径非常重要，因为CTGF可能在SSC的发病机理和阻止其异常产生中起关键作用，这可能会改善纤维化反应的最有害特征。