LPA-LPAR1信号通路调控放射性肺损伤的机制研究

项目名称： LPA-LPAR1信号通路调控放射性肺损伤的机制研究

项目编号： No.81472196

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： 卢铀

作者单位： 四川大学

项目金额： 72万元

中文摘要： 放射性肺损伤（RILI）是肺癌放疗常见及严重并发症，目前尚缺乏有效治疗手段。上皮细胞及成纤维细胞是RILI的主要效应细胞。LPA是一种磷脂类小分子物质，通过其受体发挥广泛的作用。我们前期工作证实：发生放射性肺炎的患者，血浆中LPA明显升高；小鼠全肺照射后，肺组织LPA升高；动物实验证实抑制LPA受体1 (LPAR1)可以显著减轻RILI，提高小鼠生存。基于文献报道及我们的前期工作，提示：LPA-LPAR1信号通路具有促使上皮细胞及成纤维细胞稳态失衡的作用，一方面可以促进上皮细胞凋亡和上皮间质转化，另一方面促进成纤维细胞凋亡抵抗和迁移。本课题将通过分子生物学手段及转基因小鼠杂交模型，深入研究LPA-LPAR1信号通路调控RILI的分子机制。本课题组的研究有利于从新的视角揭示RILI的分子病理过程，为RILI的防治提供新的思路和方法。

中文关键词： C05_气管；支气管；肺肿瘤；放射性肺损伤；溶血磷脂酸；溶血磷脂酸受体1；上皮间质转化

英文摘要： Radiation-induced lung injury (RILI) is a common and serious complication in the radiation therapy of lung cancer. The prevention and treatment of RILI have long been a clinical challenge. The epithelial cells and fibroblasts are the main target cells in RILI. Lysophosphatidic acid (LPA) is a small bioactive phospholipid known to regulate several cellular processes via binding to its receptors (LPAR). In our previous studies, we confirmed that LPA concentration was increased significantly in the plasma of lung cancer patients at the onset of radiation pneumonitis; the level of LPA in the lung was increased in RILI mice model; LPAR1 inhibitor effectively alleviated the lung injury and prolonged animal survival. Current research and our previous works indicate that LPA-LPAR1 signaling pathway may play the paradoxical role between epithelial cells and fibroblasts: LPA-LPAR1 may promote the apoptosis and epithelial-to-mesenchymal transition (EMT) of the epithelial cells; LPA-LPAR1 may also promote the apoptotic resistance and migration of the fibroblasts. In the further study, we will complete the preliminary studies and determine the exact molecular mechanism of LPA-LPAR1 signaling in the regulation of RILI. Our study may provide new insight and avenue for the prevention and treatment of RILI in clinic.

英文关键词： Lung cancer;Radiation-induced lung injury;Lysophosphatidic acid (LPA);Lysophosphatidic acid receptor 1 (LPAR1);Epithelial-to-mesenchymal transition