miR-29调控PDGF通路在肺动脉高压肺血管重塑中的作用及机制研究

Pulmonary hypertension (PH) is a haemodynamic and pathophysiological condition characterized as pulmonary vascular remodeling and further increased pulmonary artery pressure. PDGF signal pathways are associated with abnormal proliferation and migration of smooth muscle cells (SMCs), and play a pivotal role in the pathogenesis of vascular remodeling of PH. The results of microarray indicate downregulated of miR-29 was present with the development of PH, further, we found the PDGF is a potential target of miR-29. Thus, we hypothesize that downregulation of miR-29 and further increased expression of PDGF with its signal pathway activation are the major pathway to promote SMCs proliferation and migration, and induce the development of vascular remodeling of PH. Restoring the expression of miR-29 may have a potential therapeutic effects in the PH models. To test our hypothesis, we first investigate the change of miR-29 level and PDGF expression in different rodent models. Second, using gain and loss functional study and luciferase reporter assay, we will further investigate the mechanism of miR-29 regulating vescular remodeling in vitro. Finally, we will evaluate the therapeutic potential of miR-29 in PH by delivering miR-29 through Sleeping Beauty transposon system. We predict that our study will get a new mechanism of the pathegenesis of PH and further establish a new and effective therapeutic strategy for PH.

肺动脉高压是一种表现为肺血管重塑而导致肺动脉压力异常升高的疾病或病理生理综合征。PDGF 通路调节肺血管平滑肌增殖迁徙，是肺动脉高压治疗的重要靶点。近期miRNA 微阵列分析提示肺动脉高压中miR-29水平降低，本课题组亦发现PDGF 是miR-29 的潜在靶点。因此，我们假设miR-29 表达下调导致的PDGF 通路活化是肺动脉高压发病的重要环节，恢复miR-29 水平能够抑制PDGF通路并改善肺血管重塑及肺动脉高压。为验证此假说，我们利用不同肺动脉高压动物模型，通过功能获得缺失及萤光素酶报告基因检测方法，明确miR-29 调控PDGF通路在肺动脉高压血管重塑中的作用机制，进而采用国内外首创的利用睡美人转座子系统介导miRNA基因治疗技术，进一步证实miR-29 调控PDGF通路在肺血管重塑的作用及机制。本研究利用miRNA调控肺动脉高压发病的重要通路，为肺动脉高压的治疗提供新型策略。