Molecular Mechanism of PARC-Mediated Lung Fibrosis

PARC介导的肺纤维化的分子机制

• 批准号: 7084620
• 负责人: Sergei P. Atamas
• 金额: $ 21.53万
• 依托单位: UNIVERSITY OF MARYLAND BALTIMORE
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-07-10 至 2008-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7084620
• 关键词: binding sites; biological signal transduction; chemical stability; chemokine; chemokine receptor; chromatin immunoprecipitation; collagen; diagnostic respiratory lavage; fibroblasts; genetic regulation; genetic regulatory element; genetic transcription; immunocytochemistry; inflammation; laboratory mouse; messenger RNA; mitogen activated protein kinase; molecular pathology; protein biosynthesis; pulmonary fibrosis /granuloma; receptor binding

DESCRIPTION (provided by applicant): Lung fibrosis is a frequent consequence of chronic inflammatory processes and environmental exposures. Several cytokines contribute to fibrosis in the lungs and other organs. Previous reports from numerous laboratories indicate that targeting only one of these factors may ameliorate fibrosis in animal models, suggesting that development of fibrosis is a highly integrated process, and that targeting of a single cytokine may become an important therapeutic option. Targeting organ-specific profibrotic factors may lead to fewer side effects than targeting ubiquitous cytokines. Available data suggest that pulmonary and activation-regulated chemokine, PARC, a recently discovered lung-specific CC chemokine, may be an independent lung-specific key factor contributing to lung fibrosis through its dual action - 1) indirectly by attracting T cells and stimulating production of profibrotic cytokines from these T cells, and 2) directly by activating collagen production from lung fibroblasts. Understanding mechanisms of the direct profibrotic effect of PARC is the subject of this study. The specific hypothesis of this study is that PARC activates collagen production in human lung fibroblasts by binding to a specific cell surface receptor, signaling through the ERK pathway, activating transcription factor Sp1, activating transcription of collagen, and finally causing lung fibrosis. To test this hypothesis, the following Specific Objectives will be addressed: 1. Identify the PARC-specific receptor(s) on lung fibroblasts, determine whether other molecules are involved in PARC binding, and characterize the binding kinetics of PARC to its receptor(s). 2. Characterize activation of the ERK pathway and Sp1 in lung fibroblasts by PARC and establish whether PARC-dependent activation of Sp1 is mediated by the ERK pathway. Determine the role of ERK and SP1 activation in PARC-stimulated collagen production in lung fibroblasts. 3. Using deletion constructs of the collagen promoter, locate response elements involved in transcriptional regulation of collagen by PARC. Determine whether increased mRNA stability also contributes to PARC-stimulated upregulation of collagen production. 4. Analyze the effects of pulmonary adenovector-mediated gene transfer of PARC on lung fibrosis in intact mouse lung and bleomycin-treated mouse lung.

描述（由申请人提供）：肺纤维化是慢性炎症过程和环境暴露的常见后果。几种细胞因子导致肺和其他器官的纤维化。先前来自许多实验室的报告表明，仅靶向其中一种因子可能改善动物模型中的纤维化，这表明纤维化的发展是一个高度整合的过程，靶向单一细胞因子可能成为一种重要的治疗选择。靶向器官特异性促纤维化因子可能比靶向无处不在的细胞因子导致更少的副作用。现有数据表明，肺和激活调节趋化因子PARC是最近发现的肺特异性CC趋化因子，可能是一个独立的肺特异性关键因子，通过其双重作用促进肺纤维化- 1)间接吸引T细胞并刺激这些T细胞产生促纤维化细胞因子，2)直接激活肺成纤维细胞产生胶原。了解PARC直接促纤维化作用的机制是本研究的主题。本研究的具体假设是PARC通过与特定的细胞表面受体结合，通过ERK通路发出信号，激活转录因子Sp1，激活胶原转录，最终引起肺纤维化，从而激活人肺成纤维细胞的胶原生成。为了验证这一假设，将解决以下具体目标：