新型小分子化合物SKLB-Y023抗肺纤维化的作用机制研究

项目名称： 新型小分子化合物SKLB-Y023抗肺纤维化的作用机制研究

项目编号： No.81500054

项目类型： 青年科学基金项目

立项/批准年度： 2016

项目学科： 医药、卫生

项目作者： 叶庭洪

作者单位： 四川大学

项目金额： 18万元

中文摘要： 肺纤维化在临床上可由肿瘤放疗与药物等引起、也包括病因不明的特发性肺纤维化，但治疗效果不理想。已知成纤维细胞生长因子受体FGFRs在成纤维细胞中高表达，而我们前期研究也发现FGFRs不仅在成纤维细胞中高表达，也在肺纤维化前期的CD11b+Gr-1+炎性细胞中高表达。由此我们推测FGFRs可能为肺纤维化的治疗靶点。我们前期经设计、合成及体外筛选得到的新型小分子化合物SKLB-Y023能有效抑制FGFRs酪氨酸激酶活性、并能抑制成纤维细胞增殖，还可以减少肺纤维化前期的CD11b+Gr-1+炎性细胞数量。本研究拟在前期基础上，进一步研究SKLB-Y023在动物体内治疗肺纤维化作用及其安全性，特别深入研究SKLB-Y023作用于肺纤维化前期CD11b+Gr-1+炎性细胞及通过抑制FGF/FGFR信号通路抗肺纤维化的潜在机制。本课题将为基于FGF/FGFR信号通路抗肺纤维化作用及机制研究提供新思路。

中文关键词： 肺纤维化；成纤维细胞；炎性细胞；FGF/FGFR；信号通路；博莱霉素

英文摘要： Pulmonary fibrosis is clinically associated with radiotherapy and drug adverse reaction, as well as unknown reasons, which termed idiopathic pulmonary fibrosis. Nowadays, there is no ideal therapeutics for pulmonary fibrosis. Our previous works showed that FGFRs were highly expressed in fibroblasts, which was consistent with other reports. We also found that CD11b+Gr-1+ inflammatory cells ahead of fibrosis expressed FGFRs. Thus, we postulate that FGFRs may be a therapeutic target for pulmonary fibrosis. After our previous design, synthesis and in vitro screening, we found the compound SKLB-Y023 could inhibit effectively the activities of FGFRs kinase and the proliferation of fibroblasts. SKLB-Y023 also reduced the numbers of CD11b+Gr-1+ inflammatory cells in the early stage of pulmonary fibrosis. Base on the preliminary study, this study will further investigate the effect of SKLB-Y023 on pulmonary fibrosis and assess its safety in vivo. We will investigate the effect of SKLB-Y023 on CD11b+Gr-1+ inflammatory cells and clarify the underlying mechanism of anti-pulmonary fibrosis through FGF/FGFR signaling pathway inhibition. This study will provide a novel therapeutical idea for pulmonary fibrosis.

英文关键词： Pulmonary Fibrosis;Fibroblast;Inflammatory Cells;FGF/FGFR Signaling Pathway;Bleomycin