MicroRNA及其靶基因在多发性肌炎发病中的作用及分子机制研究

Polymyositis (PM) is a systemic disease characterized by chronic inflammation in muscle tissue, and presents muscle weakness as a common clinical feature. Induction of a robust type I interferon (IFN) response plays an important role in PM. MircoRNAs regulate a wide range of developmental and physiological cellular processes including differentiation, proliferation, growth and apoptosis. Our preliminary work showed that the level of miR-23a-3p, miR-146a-5p and miR-150-5p was significantly down-regulated in PM, and the predicted target gene of the differentially expressed miRNA was RNA binding protein, HuR, which specific interacting with and regulating the stability of mRNA of IFN-β and MyoD. On the basis of the previous study, we estabilsh the hypotheses that the differentially expressed miRNAs and HuR are involved in the pathogenesis of PM by activating type I interferon system and inhibiting the expression of myogenic regulatory factors. MicroRNAs transgenic mice will be used to verify the molecular mechanism, to provide experimental results for new biomarkers and immune therapy in PM.

多发性肌炎（PM）是一类以侵害骨骼肌为主的系统性自身免疫性疾病。在PM的免疫调节过程中，I型干扰素系统的激活是发病的重要环节。MicroRNAs广泛参与调控细胞增殖、分化、凋亡和组织器官发育等生物学过程。我们的前期工作显示miR-23a-3p、miR-146a-5p及miR-150-5p在PM患者中表达水平显著下调，RNA结合蛋白HuR为其预测靶基因。HuR可与IFN-β及MyoD mRNA结合并调控mRNA的稳定性。在此基础上，我们推测差异表达的miRNA及HuR通过活化I型干扰素系统及下调成肌调节因子表达参与PM的发病。本研究将从分子、细胞、动物不同层面对上述机制进行深入探讨，为PM新的生物学标记物的发现及免疫治疗提供实验依据。

免疫介导坏死性肌病（IMNM）是一类以侵害骨骼肌为主的系统性自身免疫性疾病，临床上可出现严重肌无力。MicroRNAs广泛参与调控细胞增殖、分化、凋亡和组织器官发育等生物学过程。本研究拟探讨IMNM差异表达的microRNAs及其靶基因对肌肉组织再生分化的调控作用。本研究揭示1）miR-18a在IMNM患者肌肉组织中表达较正常对照显著上调。2）通过生物信息学预测及验证试验，发现miR-18a靶向调节RNA结合蛋白HuR。3）IMNM患者肌肉组织中HuR mRNA及蛋白水平均较正常对照显著下降。4）在人naïve myoblast中，HuR表达在细胞核内。myoblast分化早期，HuR可在细胞质内表达。分化晚期，HuR回归至细胞核内。5）成肌细胞中敲减HuR可引起成肌调节因子myogenin及肌球蛋白重链MYH表达显著下调。研究成果提示miR-18a及其靶基因HuR参与成肌细胞分化过程，IMNM患者肌肉组织HuR表达下调可能参与病理过程。通过本研究成果初步揭示miR-18a与HuR共同参与了IMNM的发病机制，有助于寻求IMNM的治疗新靶点。