PDGF通过下调miR-1281诱发肺动脉高压形成的分子机制

肺动脉高压（PAH）发病机制复杂，死亡率高。肺动脉平滑肌细胞(PASMC)增殖和肺血管结构重建是PAH的重要特征，PDGF是参与这一过程强有力的有丝分裂原，阻断PDGF通路已成为PAH治疗的有效途径。前期研究发现，PDGF-BB下调miR-1281及EP300；miR-1281靶基因则是与EP300功能拮抗的HDAC4；过表达miR-1281能抑制PASMC增殖。推测miR-1281参与调控PDGF-BB诱发的PAH。本项目拟从分子水平揭示PDGF-BB如何调控miR-1281；研究miR-1281下调的功能及机制；以PAH大鼠为模型，探讨导入miR-1281对PAH症状的改善作用；明确miR-1281与PAH在临床上的相关性。研究将从表观遗传学角度，包括miRNA、甲基化、组蛋白乙酰化和去乙酰化等改变阐述PDGF-BB诱发PAH的新机制，也为开发基于miRNA的治疗和早期诊断提供新思路。

Pulmonary arterial hypertension (PAH), a complex vascular disease with a dreadful survival rate, is characterized by abnormal proliferation of pulmonary artery smooth muscle cells (PASMCs) and progressive structural remolding of pulmonary arteries. Platelet-derived growth factor (PDGF), a potent mitogen, has been implicated in these processes. Inhibition of the PDGF signaling pathway is consideraed as a potential target for the treatment of pulmonary hypertension. Our preliminary data showed that PDGF-BB down-regulated miR-1281 and EP300 expression. HDAC4, a functional antagonism of EP300, is a direct target of miR-1281. Functionally, miR-1281 inhibits the proliferation of PASMCs. Based on the results above, we propose that PDGF-reduced miR-1281 might contribute to the development of PAH. In this proposal, we will explore the molecular mechenism of miR-1281 downregulation induced by PDGF-BB and the potential biological function of miR-1281. The impact of synthetic miR-1281 agomir on pulmonary vascular remodeling and PAH symtoms will be evaluated by using hypoxia induced PAH rat model. Finally, the clinical relationship between miR-1281 level and PAH disease will be evaluated. A new molecular mechanism of PDGF-induced PAH will be elucidated by epigenetic studies including miRNA, methylation, histone acetylation and deacetylation. This project will also provide a new clue for the development of miRNA-based treatment and early diagnosis means for PAH.