Molecular Mechanism of PARC-Mediated Lung Fibrosis

PARC介导的肺纤维化的分子机制

• 批准号: 6920643
• 负责人: Sergei P. Atamas
• 金额: $ 25.2万
• 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/6920643
• 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经常结果。几种细胞因子有助于肺部和其他器官的纤维化。众多实验室的先前报告表明，仅针对这些因素中的一个可以改善动物模型的纤维化，这表明纤维化的发展是一个高度整合的过程，而单一细胞因子的靶向可能成为重要的治疗选择。靶向器官特异性的纤维化因子可能会导致副作用更少，而靶向无处不在的细胞因子。 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.理解PARC直接纤维化作用的机制是本研究的主题。这项研究的特定假设是，PARC通过与特定的细胞表面受体结合，通过ERK途径信号传导，激活转录因子SP1，激活胶原蛋白的转录并最终引起肺纤维化，激活人肺成纤维细胞中的胶原蛋白产生。为了检验这一假设，将解决以下特定目标： 1。在肺成纤维细胞上确定PARC特异性受体，确定其他分子是否参与PARC结合，并表征PARC与其受体的结合动力学。 2。表征通过PARC在肺成纤维细胞中ERK途径和SP1的激活，并确定SP1的PARC依赖性激活是否由ERK途径介导。确定ERK和SP1激活在肺成纤维细胞中PARC刺激的胶原蛋白产生中的作用。 3。使用胶原蛋白启动子的缺失构建体，定位了通过PARC对胶原蛋白转录调控的响应元件。确定mRNA稳定性提高是否也有助于胶原蛋白产生的PARC刺激上调。 4。分析PARC肺腺压介导的基因转移对完整小鼠肺和博来霉素治疗的小鼠肺中肺纤维化的影响。