治疗矽肺炎性反应及肺纤维化的新靶点-MCPIP1 (ZC3H12A）的作用机制研究

项目名称： 治疗矽肺炎性反应及肺纤维化的新靶点-MCPIP1 (ZC3H12A）的作用机制研究

项目编号： No.81473263

项目类型： 面上项目

立项/批准年度： 2015

项目学科： 医药、卫生

项目作者： 巢杰

作者单位： 东南大学

项目金额： 73万元

中文摘要： 矽肺是由长期吸入二氧化硅粉尘引起的以肺组织持续慢性炎症、进行性肺纤维化为主，并伴有全身系统性炎症为特征的全身性疾病。由于对矽肺发生发展机制不明，目前主要面临：1）早期缺少筛检诊断方法，2）后期肺纤维化缺乏特效治疗措施。因此发现矽肺早期诊断标志物及干预肺纤维化进程靶标成为迫切需要解决的问题。申请者前期研究表明，粉尘吸入引起肺部炎症，涉及单核细胞趋化蛋白-1（MCP-1）及其下游分子MCP-1诱导蛋白1（MCPIP1，ZC3CH12A)。进一步研究表明，MCPIP1还参与成纤维细胞增殖与迁移的调控。基于以上结果，申请者提出MCPIP1是治疗矽肺炎症反应和肺纤维化的有效和关键靶点这一假设，在原有研究基础上，应用分子生物学手段，结合经典药理学方法，从整体、细胞和分子水平系统揭示MCPIP1在矽肺炎症和肺纤维化中的功能和作用机制，研究成果将为临床治疗策略的选择和治疗药物靶标的遴选提供重要线索。

中文关键词： 矽肺；肺纤维化；炎症反应；信号通路；三维细胞模型

英文摘要： Silicosis is a systemic disease caused by inhalation of free crystalline silicon dioxide or silica. Phagocytosis of crystalline silica in the lung causes inflammatory cascade with subsequent fibrosis, resulting in systemic inflammatory response. Although more and more studies were undertaken to dissect the pathological mechanisms underlying the process of silicosis, the primary cause of this often devastaing dissease remains elusive. Diagnosis of silicosis could easily be missed, since which needs carefully documented records of occupational exposure and radiological features, with exclusion of other competing diagnoses. As yet, no curative treatment exists, but comprehensive management strategies help to improve quality of life and slow deterioration. Thus, further efforts are needed to find early molecular marker of diagnosis, new target to control the fibrosis induced by silica. Clinical evidence indicated that activation of alveolar macrophage induced by silica produces a rapid and sustained inflammation characterized by generation of monocyte chemotactic protein 1 (MCP-1) and MCP-1 induced protein 1 (MCPIP1, ZC3H12A). Our previous studies also suggested that MCPIP1 played a critical role in fibroblast proliferation and migration. However, the detailed cellular and molecular mechanisms underlying inflammation and the subsequent fibrosis in response to silica remain unknown. Therefore, we hypothesized that MCPIP1 will be the potential target of curative treatment for silicosis involving in regulation of inflammation and fibrosis. The proposed studies will be initiated in human sample followed by study in intact animals as well as primary cell cultures. Studies using classic pharmacological methods will be combined with molecular biological techniques as well as and immunological methods, all of which are currently well established in our laboratory. This proposal is both novel and innovative in that the efficacy of regulation of MCPIP1 expression can be of value to prevent or halt progression of silicosis in people. Our study will decipher the link between MCPIP1 and inflammation with subsequent fibrosis, induced by silica providing a novel insight into the potential of MCPIP1 in terms of opening up novel therapeutic avenues for silicosis.

英文关键词： silicosis;pulmonary fibrosis;inflammation;signaling pathway;3D matrix model