色素上皮衍生因子（PEDF）及其受体家族调控COPD肺结构细胞异常凋亡与炎性损伤的机制研究

项目名称： 色素上皮衍生因子（PEDF）及其受体家族调控COPD肺结构细胞异常凋亡与炎性损伤的机制研究

项目编号： No.81470236

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： 文富强

作者单位： 四川大学

项目金额： 75万元

中文摘要： 肺结构细胞异常凋亡所致的肺实质损伤是形成慢性阻塞性肺疾病（COPD）的重要机制。色素上皮衍生因子(PEDF）是一种分泌型糖蛋白，通过作用于PEDF受体家族发挥多种生物学活性。最新研究显示PEDF及其受体在调控细胞凋亡过程中发挥关键作用，但在COPD中的作用尚未知。我们前期研究发现COPD患者循环PEDF水平明显升高，并与凋亡及炎性因子水平密切相关；通过SILAC（稳定同位素标记技术）蛋白组学研究还发现香烟烟雾提取物能显著增加人气道上皮细胞PEDF的表达，并在熏烟动物气道炎症模型中得以验证。因此我们推测PEDF及其受体家族可能是调控COPD肺组织结构细胞异常凋亡与炎症反应的重要机制。本项目拟通过构建体内外COPD疾病模型，采用PEDF腺病毒表达载体、PEDFR基因敲除鼠等技术，明确PEDF及其受体家族在COPD肺实质损伤过程中的作用与分子机制，以期为临床治疗提供新的思路。

中文关键词： 慢性阻塞性肺病；肺气肿；色素上皮衍生因子；细胞凋亡；炎性损伤

英文摘要： Aberrant apoptosis of lung structure cells could induce lung destruction, leading to Chronic Obstructive Pulmonary Diseases (COPD). Pigment epithelium-derived factor (PEDF) belongs to secreting glycoprotein and perform multiple functions via PEDF receptors family. Recent studies indicated that PEDF and its receptors played an essential role in modulating cell apoptosis. However, the role of PEDF in pathogenesis of COPD remains unclear. Our pioneer study demonstrated that the levels of PEDF in serum of COPD patients increased significantly, which was also positively correlated with apoptosis and inflammatory indicators. Furthermore, the expression of PEDF in human airway epithelial cells was found to be induced by cigarette smoke extract (CSE) by using differential proteomics SILAC in vitro and in vivo. Therefore, we assume that PEDF and its receptor family may play an important role in regulating abnormal apoptosis of lung structure cells and mediating inflammatory response in COPD. Our goal in this proposal is to elucidate the molecular mechanisms of PEDF and its receptors involved in lung injury of COPD, via constructing AVV expressed PEDF plasmid, PEDFR knockout mice, and COPD models in vivo and ex vivo. The study may find novel target for the treatment of COPD.

英文关键词： COPD;emphysema;PEDF;cell apoptosis;inflammatory injury