miR-29a/b调控成纤维细胞活化参与低氧性肺血管重建的研究

Activation of pulmonary adventitia fibroblasts (PAFs) is a key point for hypoxia-induced pulmonary vascular remodeling. But what regulates the activation of PAFs is not known. In the preliminary studies, we found that hypoxia upregulated the expression of Smad3 but downregulated the expression of miR-29a/b. Bioinformatics analysis shows that there are suppression elements of Smad3 in the promoter region of miR-29a/b. So we hypothesize that hypoxia release the inhibition of miR-29a/b on the downstream target genes by upregulating the expression of Smad3. In this study we will clarify the role of miR-29a/b in the hypoxia-induced activation of PAFs, and further explore the HIF-Smad3 pathway regulation of expression of miR-29a/b and the regulation of miR-29a/b on TGF-beta. Finally we will explore the role of miR-29a/b on the remodeling of hypoxia pulmonary vasculature in transgene mice. The results will provide new information for the mechanism of hypoxia pulmonary vasculature remodeling and new potential targets for treatment.

肺血管外膜成纤维细胞(PAFs)活化是低氧性肺血管重构的重要发病环节，但其具体机制尚不明确。课题组前期研究发现，低氧上调PAFs中Smad3的表达，同时下调miR-29a/b的表达；生物信息学分析显示，miR-29a/b启动子区含有Smad3抑制性结合元件。据此我们推测："低氧刺激通过Smad3通路下调PAFs中miR-29a/b的表达，从而解除miR-29a/b对下游靶基因的抑制，导致PAFs活化及肺血管重构"。本项目拟先明确miR-29a/b在低氧诱导PAFs活化中的作用，进而用ChIP、EMSA等方法探讨低氧条件下miR-29a/b表达减少的原因(与HIF-Smad3的关系)以及miR-29a/b促血管重构的机制(下游靶基因TGF-β的调控)；最后利用miR-29a/b转基因动物模型探讨其在低氧性肺血管重构中的作用。研究结果将为阐明低氧性肺血管重构的机制、探索其治疗靶点提供新线索。

肺血管外膜成纤维细胞(PAFs)活化是低氧性肺血管重构的重要发病环节，但其具体机制尚不明确。课题组前期研究发现，低氧上调PAFs中Smad3的表达，同时下调miR-29a-3p的表达；生物信息学分析显示，miR-29a启动子区含有Smad3抑制性结合元件。据此我们推测：“低氧刺激通过Smad3通路下调PAFs中miR-29a-3p的表达，从而解除miR-29a-3p对下游靶基因的抑制，导致PAFs活化及肺血管重构”。本项目先明确miR-29a-3p在低氧诱导PAFs活化中的作用，进而用ChIP、EMSA等方法探讨低氧条件下miR-29a-3p表达减少的原因(与HIF-Smad3的关系)以及miR-29a-3p促血管重构的机制(下游靶基因TGF-β的调控)；最后利用miR-29a/b转基因动物模型探讨其在低氧性肺血管重构中的作用。研究结果将为阐明低氧性肺血管重构的机制、探索其治疗靶点提供新线索。