肺动脉高压中miR-125a-5p调控TGF-β1介导的肺血管重塑的机理研究

肺动脉高压(PAH)发病机制复杂，以肺动脉平滑肌细胞过度增殖和凋亡抵抗导致的肺血管重塑为典型病理特征，已知TGF-β1/STAT3/Bcl-2信号通路激活能加速该进程，但确切的分子机制仍不明确。我们研究发现在野百合碱(MCT)诱导的PAH大鼠肺动脉中miR-125a-5p表达下调，而其靶基因Bcl-2表达上调；miR-125a-5p可抑制STAT3的表达；miR-125a-5p下调后可激活TGF-β1，而生理情况下TGF-β1可促进miR-125a-5p表达。基于此，我们提出科学假说：miR-125a-5p作为负反馈调节分子调控TGF-β1介导的肺血管重塑参与PAH发病。本项目拟首次应用基因敲除小鼠等技术在体研究miR-125a-5p在MCT-PAH中的作用，并从体外明确其调控TGF-β1信号通路的分子机制。预期结果有助于深入理解PAH的发病机理，并为挖掘PAH预防和治疗靶点开拓新视野。

Pulmonary arterial hypertension(PAH) is a devastating disease with complex pathogenesis. Pulmonary vascular remodeling resulted from excessive proliferation and apoptosis resistance of pulmonary artery smooth muscle cells (PASMCs) is the typical pathological features of PAH. It’s known that the activation of TGF-β1/STAT3/Bcl-2 signaling pathway could accelerate this progression, but the exact molecular mechanism is still unknown. Our study found that the expression of miR-125a-5p within pulmonary artery of monocrotaline (MCT) induced PAH rat model was down-regulated, while its target gene Bcl-2 was up-regulated; functionally the activity of STAT3 could be suppressed by miR-125a-5p; the down-regulation of miR-125a-5p could activate TGF-β1, while in normal physiological conditions TGF-β1 could promote the expression of miR-125a-5p. Based on our study, we put forward the following scientific hypothesis: miR-125a-5p, as a negative feedback regulatory factor, is involved in the regulation of TGF-β1 mediated pulmonary vascular remodeling. Our project aims to firstly investigate the functions of miR-125a-5p in MCT induced PAH using the gene knock-out mice, and to elucidate the molecular mechanism of its regulation on TGF-β1 signaling pathway in vitro. The expected results could not only help to understand the pathogenesis of PAH deeply, but also could develop a new vision for mining the preventive and therapeutic targets of PAH.