控制性释放EGFR的抑制剂吉非替尼阻缓骨关节炎的效应及机制研究

项目名称： 控制性释放EGFR的抑制剂吉非替尼阻缓骨关节炎的效应及机制研究

项目编号： No.81472115

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： 章淑芳

作者单位： 浙江大学

项目金额： 72万元

中文摘要： 骨关节炎（OA）是最常见骨科疾病,药物治疗多为消炎镇痛的对症处理，而阻缓其病理进程的有效药物缺乏。近年研究表明在生长板发育早期EGFR信号激活能使软骨厚度增加，而发育晚期EGFR的持续激活引起软骨基质降解酶的释放，提示EGFR也可能参与关节软骨生理病理活动。我们前期结果发现EGFR在人OA关节软骨组织中的活性升高。所以，我们假说控制性释放吉非替尼抑制EGFR能调控关节软骨细胞的合成、分解，从而阻缓OA的关节软骨退变。本课题组将1）体外研究OA组织和细胞水平中EGFR信号活性成分水平的改变；2）应用siRNA及EGFR激活剂和抑制剂研究EGFR信号活性成分水平对软骨细胞功能的影响及其分子机理；3）以动物软骨修复模型研究壳聚糖微球关节内控制性释放吉非替尼在骨关节炎发病过程中所起到的作用及其体内作用机理。本研究发现将阐明EFGR在骨关节炎中的病理作用及其机制，为骨关节炎的治疗提供新知识和新手段。

中文关键词： 骨关节炎；吉非替尼；控制性释放；EGFR信号

英文摘要： Osteoarthritis (OA) is the most often happened worldwide orthopedic disorder, current drugs are applied for inflammation inhibition and pain release, while no drugs can effectively prevent or even slow down its pathological process. Recent study showed that EGFR activation during early growth plate development resulted in thicker cartilage while during its late development induced higher secretion of matrix metallopeptidase, indicating that EGFR may also involve in the physiological and pathological process of articular cartilage. We found from our preliminary study that phosphorylated EGFR was higher in articular cartilage tissue from OA patient. So we hypothesize that controlled release of gefitinib which is an EGFR inhibitor can regulate the synthesis/decomposition of articular chondrocyte ECM, thus prevent OA cartilage from degeneration. So in this proposal, we will 1) first study the change of total and phosphylated EGFR in OA tissue and cells in vitro; 2) apply siRNA, EGFR inhibitor and activator to investigate its effect on chondrocyte and underlying mechanism; 3) examine whether controlled release of gefitinib in cartilage by chitosan microsphere will slow down OA process and its possible mechanism in animal model. The findings will help to understand the role of EGFR in OA and shed light on involved signaling pathway, thus provide some new knowledge and method for OA treatment.

英文关键词： osteochritiris;gefitinib;controlled release;EGFR signaling