miR-223在腹主动脉瘤发展和干预中的作用及机制研究

项目名称： miR-223在腹主动脉瘤发展和干预中的作用及机制研究

项目编号： No.91539121

项目类型： 重大研究计划

立项/批准年度： 2016

项目学科： 医药、卫生

项目作者： 李玉琳

作者单位： 首都医科大学

项目金额： 80万元

中文摘要： 腹主动脉瘤是血管结构/功能稳态失衡导致重构异常的血管疾病，破裂致死率高，缺乏药物干预手段。miRNA在血管稳态和疾病中发挥重要作用。我们前期利用腹主动脉瘤临床标本、疾病动物模型进行miRNA测序，发现mir-223表达升高。mir-223过表达抑制腹主动脉瘤，反之缺失加剧其发展；mRNA测序发现mir-223过表达促进AKT通路上调；但腹主动脉瘤中mir-223表达如何升高，进而通过何种机制抑制腹主动脉瘤的发展等科学问题尚不清楚。本课题将应用基因操作及生物信息等技术，探讨：1）腹主动脉瘤高危因素调节mir-223表达的机制；2）mir-223通过靶基因调控AKT等信号影响平滑肌细胞功能抑制腹主动脉瘤的机制；3）腹主动脉瘤靶向基因载体输送mir-223对其的干预作用。本课题将阐明mir-223在腹主动脉瘤中维持血管稳态、抑制血管损伤/重构异常的保护机制，为其防治提供新的靶点和理论依据。

中文关键词： 腹主动脉瘤；微小RNA-223；分子机制；基因治疗

英文摘要： The abdominal aortic aneurysms（AAA）caused by the imbalance of vascular structure/function and the abnormal vascular reconstruction. Mortality following rupture of AAA is high. Current therapeutic options to prevent AAA are restricted to surgical repair, as there remains a lack of validated pharmaceutical approaches. miRNA plays an important role in vascular homeostasis and disease. We performed miRNA-sequencing in abdominal aortic tissue from AAA patients or two AAA mouse models. mir-223 agomir treatment inhibits the development of AAA whereas mir-223 deficiency promotes AAA. mir-223 overexpression promote AKT signals activation in AAA utilizing mRNA-sequencing technology. However, the underlying mechanism is unclear. Using gene overexpression/knockdown and bioinformatics technology, our specific aims are: 1) to determine how the high risk factors of AAA induce increased mir-223 expression; 2) to explore the molecular mechanisms by which mir-223 affects targets genes to regulate AKT signaling, then regulating the function of smooth muscle cells and progression of AAA; and 3) to elucidate the intervention effects of new synthesized AAA-targeting gene vector delivery mir-223 on AAA. The present study will demonstrate the important role of mir-223 in the maintenance of vascular homeostasis and resistance of vascular injury and abnormal remodeling and provide novel gene vector for therapeutic approaches in AAA.

英文关键词： abdominal aortic aneurysms;mir-223;molecular mechanisms;genetic therapy