miR-200c参与人肺动脉平滑肌细胞异常增殖的调控和分子机制研究

Pulmonary arterial hypertension(PAH) is one of the most important causes of right heart failure.Pulmonary vascular remodeling is the main lesion of PAH. Abnormal proliferation of pulmonary arterial smooth muscle cells (PASMCs) is the major pathophysiological basis in pulmonary vascular remodeling. Our previous studies showed that miR-200c of PASMCs was significantly down-regulated when cell proliferation was induced by ET-1. It was suggested that miR-200c were involved in PASMCs' abnormal proliferation. GATA4 is predicted as the target gene of miR-200c. It is speculated that miR-200c may regulate PASMCs proliferation by GATA4 regulation way. The present study intends to verify the regulation effects of miR-200c on PASMCs proliferation by interfering miR-200c expression using miR-200c mimics and miR-200c inhibitors. Taking GATA4 as the key point, this project will explore the regulation relationships in miR-200c, GATA4 and PASMCs proliferation by interfering GATA4 expression in PASMCs using plasmid and siRNA interference. The role of miR-200c in PASMCs proliferation will also be verified by miR-200c over expression and silent expression on rat model. The molecular roles of miR-200c in PASMCs proliferation will be revealed on cellular level and animal model level. miR-200c regulating PASMCs proliferation has not been reported before. It is an innovatiove project that can further reveal the mechanisms of PAH.

肺动脉高压是右心衰竭的重要病因之一。在肺动脉高压发病的肺血管重构病变中，肺动脉平滑肌细胞的异常增殖是核心因素。本课题组前期研究发现：ET-1诱导人肺动脉平滑肌细胞增殖时，出现miR-200c表达显著下调，提示miR-200c可能参与调控肺动脉平滑肌细胞的异常增殖。生物信息学预测发现GATA4为miR-200c靶基因。推测miR-200c可能通过GATA4对肺动脉平滑肌细胞增殖进行调控。本研究拟通过验证miR-200c高表达和表达沉默对肺动脉平滑肌细胞增殖的影响，以GATA4为切入点,干扰GATA4表达，研究miR-200c与GATA4、肺动脉平滑肌细胞增殖之间的调控关系，揭示miR-200c参与肺动脉平滑肌细胞增殖的调控作用和分子机制。miR-200c参与调控肺动脉平滑肌细胞增殖的研究尚未有报道，具有独特创新性。本研究有助于进一步揭示肺动脉高压的发病机制，为肺动脉高压提供新的研究方向。

在肺动脉高压发病的肺血管重构病变中，肺动脉平滑肌细胞的异常增殖是核心因素。本课题组前期研究发现：ET-1诱导人肺动脉平滑肌细胞增殖时，出现miR-200c表达显著下调，提示miR-200c可能参与调控肺动脉平滑肌细胞的异常增殖。生物信息学预测发现GATA4为miR-200c靶基因并实验验证GATA4在ET-1诱导的肺动脉平滑肌细胞增殖中发生相应表达变化。推测miR-200c可能通过GATA4对肺动脉平滑肌细胞增殖进行调控。本研究拟通过验证miR-200c高表达和表达沉默对肺动脉平滑肌细胞增殖的影响，以GATA4为切入点，干涉GATA4表达，从细胞水平和转基因大鼠模型水平，研究miR-200c与GATA4、肺动脉平滑肌细胞增殖之间的调控关系，揭示miR-200c参与肺动脉平滑肌细胞增殖的调控作用和分子机制。miR-200c参与调控肺动脉平滑肌细胞增殖的研究尚未有报道，具有独特创新性。本研究有助于进一步揭示肺动脉高压的发病机制，为肺动脉高压提供新的研究方向。