术后认知功能障碍炎症机制调控的新靶点：miR-124

Nowadays, Post-operative cognitive dysfunction (POCD) attracted increasing attention in the field of Anesthesiology and Neuroscience. Recently,it is recognized that POCD is related to neuroinflammation and activation of the immune system,which are caused by surgical trauma . MicroRNA modulators of both neuronal and immune processes (here termed NeurimmiRs) are associated with neuroinflammatory diseases. Microglia/macrophage(MG/MΦ)activation is pivotal for POCD related neuroinflammation. In addition ,the function of NeurimmiRs miR-124 as the key regulator of MG/MΦ activation in the brain has been reported. Accordingly ,we hypothesized that miR-124 would play an important role in the pathogensis of POCD, considering the close relationship between miR-124 expression and MG/MΦ activation . We adopted disease related miRNA research strategy to test the hypothesis,using bioinformatics and molecular biology technology. The main contents are summarized as follows: 1.To investigate the changes of MG/MΦ miR-124 expression in the hippocampus and prefrontal cortex of POCD mice; 2.To observe the effects of miR-124 on the expression of predicted target gene(NF-κBp65); 3. To validate the effects and mechanisms of miR-124 on MG/MΦ activation, cognitive function , neuroinflammation, neuronal apoptosis and neurogenesis by gain - of - function and loss-of-function experiments , in vitro and in vivo . Our research may elucidate the key role of miR-124 in POCD related neuroinflammation and offer a new therapeutic target to POCD.

术后认知功能障碍（POCD）是目前麻醉学与神经科学研究的热点。现认为POCD与手术创伤所致脑内免疫炎症反应有关。神经免疫微RNA（NeurimmiRs）是一类同时参与神经及免疫系统功能调节的miRNAs，与脑内炎症反应疾病密切相关。研究表明，脑内小胶质细胞（MG）/巨噬细胞（MΦ）过度激活为POCD炎症机制的中心环节，而NeurimmiRs成员miR－124是脑内MG/MΦ活化状态的关键调控者。因此，我们推测miR－124可能参与POCD炎症机制调控。为验证此假说，我们采用生物信息学及分子生物学方法，观察POCD小鼠脑内MG/MΦ内miR－124表达的变化；探讨miR－124对预测靶基因NF-κBp65表达的影响；在细胞和POCD模型动物水平，观察过表达和抑制miR－124表达对MG/MΦ激活，学习记忆能力，脑内炎症反应，神经元凋亡与再生的影响，分析其分子机制，为POCD防治提供新靶点。

术后认知功能障碍（POCD）是目前麻醉学与神经科学研究的热点，现认为POCD与手术创伤所致脑内免疫炎症反应有关。神经免疫微小RNA（NeurimmiRs）是一类同时参与神经及免疫系统功能调节的miRNAs，与脑内炎症反应疾病密切相关。. 本研究结合miRNA微流体芯片，生物信息学分析和文献报道，选取miR-181c和miR-146a作为候选基因，研究 NeurimmiRs与POCD炎症机制之间的关系。结果发现：①POCD小鼠海马miR-181b表达明显降低；miR-181b通过与TNF-αmRNA的3’-UTR特异性互补结合从而靶向调控TNF-α的表达及影响下游炎症因子，如IL-1β及MCP-1的表达，及小胶质细胞炎症反应；过表达miR-181b（海马立体定位注射miR-181b agomir）可明显减轻术后小鼠海马TNF-α及其下游炎症因子表达，抑制小胶质细胞炎症反应，明显改善POCD；②POCD小鼠血清、海马及前额叶皮质中miR-146a表达升高；miR-146a通过与IRAK1mRNA3’-UTR特异性互补结合从而靶向调控IRAK1及影响NF-κB 上游的重要接头蛋白编码基因IRAK2，TRAF6的表达，调控NF-κB 通路,从而调节小胶质细胞炎症反应；过表达miR-146a（海马立体定位注射miR-146a agomir）可明显抑制POCD小鼠海马IRAK1，IRAK2，TRAF6 mRNA和蛋白表达，负反馈调节NF-κB通路，抑制海马炎症反应，明显改善POCD；反之，下调miR-146a表达（海马脑立体定位注射miR-146a Antagomir），则上调POCD小鼠海马IRAK1，IRAK2，TRAF6 mRNA和蛋白表达，激活NF-κB通路，促发海马炎症反应，加重POCD症状。上述研究结果表明，NeurimmiRs：miR-181b和miR-146a参与POCD的炎症机制，可能在POCD的发病机制中发挥重要作用。. 此外，课题组研究了行髋膝关节置换术老年患者术后谵妄（Postoperative delirium,POD）与术前脑脊液和血清中NeurimmiRs ：miR-146a,miR-125b和miR-181c表达水平的关系。结果发现，老龄髋膝关节置换术患者术前脑脊液和血浆中miR-146a和miR-181c表达水平的异常可能与POD的