系统解析microRNA参与狼疮免疫病理损伤的细胞和分子机理

miRNA, an important mediator of gene post-transcriptional regulation and epigenetic pathways, plays a significant role in maintaining normal physiological functions and the development of disease. However, so far, the studies of the function of miRNA have been mostly limited to single cell system in vitro, lacking the integral dissection in vivo, especially in the dynamic process of a certain disease. Recently, our group focused on dissection the function of miRNAs in immune regulation and immune injury, involving in the systemic lupus erythematosus, as a prototypical model of autoimmune diseases. We have published a series of work, revealing that the genetic and epigenetic factors can lead to the abnormal expression of a set of miRNA associated with the recognized phenotype of lupus .We also further described that miRNAs can singly or synergistically participate in the abnormal activation of immune and inflammatory pathways related to organ damage of lupus. More importantly, we demonstrated that specific intervening disease-related miRNA can restore the abnormal immune cell phenotype of the patients in vitro. On this basis, we select the pristane-induced lupus mouse model that has similar disease pathway with human lupus, use gene knockout, transgenic and bone marrow chimeric mice, as well as chemically synthesized miRNA mimics and inhibitors, to study the role of miR-146a and miR-155 in pathological tissue damage of lupus in vivo system, and combine with systemic biology, a comprehensive system, to elucidate the exact function of miRNA in the cell level and the corresponding signaling pathways and molecular regulatory networks.Expected outcome of our study will provide a theoretical basis for further clarifying the cellular and molecular mechanism of miRNAs involving in the development of autoimmune diseases, and novel approach to immune intervention for lupus in the future.

miRNA作为表观遗传调控网络中的重要组分，参与维持人体生理功能和疾病病理过程。目前对miRNA的功能研究大多局限于体外单一细胞系统，缺乏在特定疾病发生的动态过程中的体内功能研究。本课题组近年来以红斑狼疮这一重要自身免疫病为研究模型，聚焦于研究miRNA在免疫调节和免疫损伤中的功能。我们已发表的系列工作揭示了多个miRNA分别或协同参与狼疮脏器受累相关的免疫炎症通路的异常活化。更为重要的是，体外靶向干预这些miRNA可以改变病人细胞的异常免疫表型。在此基础上，本课题选择经典的降植烷诱导狼疮小鼠模型，利用基因敲除、转基因、骨髓嵌合小鼠以及化学合成的miRNA模拟物和抑制物，从体内整体水平研究miR-146a和miR-155在狼疮重要脏器病理损伤过程中的作用，并结合系统生物学手段，系统阐明miRNA发挥作用所涉及的关键细胞亚群以及相应的分子调控网络，为今后发展miRNA靶向治疗提供理论基础。

miRNA 作为表观遗传调控网络中的重要组分，参与维持人体生理功能和疾病病理过程。目前对miRNA 的功能研究大多局限于体外单一细胞系统，缺乏在特定疾病发生的动态过程中的体内功能研究。本项目选择狼疮小鼠模型，利用基因敲除、转基因、骨髓嵌合小鼠以及化学合成的miRNA 模拟物和抑制物，从体内整体水平研究miRNA在狼疮重要脏器病理损伤过程中的作用，并结合系统生物学手段，系统阐明miRNA 发挥作用所涉及的关键细胞亚群以及相应的分子调控网络，取得了以下主要研究进展：.1）发现了miR-146a在疾病干预中的作用以及异常表达的新机制：狼疮患者的外周血中，干扰素信号通路的活化促进了MCPIP1的表达，而上调的MCPIP1抑制了炎症通路关键负调因子miR-146a的表达。重要的是，通过尾静脉注射miR-146a的antagomir系统干预miR-146a的功能，能显著影响狼疮小鼠的肺损伤、自身抗体以及蛋白尿等临床表型，这提示miR-146a可以作为一个有效的干预靶点。.2）发现了miR-155和miR-125a在炎症损伤中的作用：在pristane诱导的狼疮急性肺损伤小鼠模型中，异常高表达的miR-155抑制了负调节分子PPARα的 表达水平，从而促进了炎症因子的表达。miR-155 antagomir 能够有效地抑制炎症因子的产生，阻断免疫细胞向肺组织地侵润，从而有效地缓解了急性肺损伤。这提示，定向干预miR-155的表达水平可发展为狼疮急性肺损伤新的治疗手段。同时，我们发现miR-125a通过调节Treg和中性粒细胞的功能从而参与自身免疫病的炎症损伤过程。.3） 发现了调节干扰素及炎症通路的新分子：最近我们发现狼疮肾炎肾脏中低表达的miR-130b和高表达的CDK1参与调控I型干扰素通路，可以作为狼疮组织损伤新的药物干预靶点。我们同时也发现长链非编码RNA NEAT1异常高表达是狼疮IL-6、CCL2、CXCL10等炎症因子过度分泌的原因之一。