miR-23a在动脉粥样硬化炎症反应中的作用及机制研究

Nuclear transcription factor kappa B (NF-κB) is closely related to the atherosclerosis (AS) throughout it's occurrence and development. At present,many studies have shown that the activity of IκB kinase (IKK)complex and NF-κB needs the involvement of heat shock protein 90 (HSP90). 1) In the tissue of atherosclerosis, the expression of miR-23a was significantly decreased by miRNAs array and Real-time PCR detected. Meanwhile the expression of forecast target gene (HSP90) by cDNA array and Western blot detected highly increased. 2) The activity of NF-kB increased significantly in atherosclerosis. But when we used HSP90 inhibitor, it's activity decreased obviously. It maybe indicate miR23 can regulate NF-kB by HSP90 to involved in the formation of atherosclerotic plaque. This project is planned to observe miR23 how to affect the inflammation of atherosclerotic plaque in AS animal models on the cellular level. On the basis that we can make sure miR23 regulate inflammation reaction by interrupting NF-kB signaling pathway, then we will certify the target genes of miR23a. This will clear the inflammation reaction mechanism which is controlled by miR23. It can provide a new theoretical foundation and experimental basis for atherosclerosis by target gene therapy.

动脉粥样硬化(AS)整个过程中核转录因子κB(NF-κB)与AS的发生，发展具有密切相关。研究证明IκB激酶（IKK）复合物及NF-kB的活性需要热休克蛋白90(HSP90)的参与。1) miRNAs array及Real-time PCR检测发现AS组织中miR-23a表达显著下降，而预测靶基因HSP90表达在cDNA芯片及Western blot检测均显著增高2) AS组织中NF-kB活性显著增高，而用HSP90抑制剂发现NF-kB活性显著降低。提示miR-23a可能通过HSP90调控NF-kB转录因子参与粥样斑块的形成。本项目拟通过细胞水平及AS动物模型观察miR-23a对于粥样斑块炎症反应的影响，在确证miR-23a通过干扰NF-kB信号途径，促进炎症反应的基础上，验证miR-23a调控的靶基因，明确miR-23a调控炎症反应的机制，为AS炎症的靶向治疗提供新的理论基础和实验依据。

动脉粥样硬化(atherosclerosis, AS) 是一种常见的慢性病，是栓塞血栓性疾病、脑血管病和冠心病等缺血性心脑血管慢性疾病的重要病因。众多发病机制学说当中，炎症发病机理已经吸引了广大研究者的广泛兴趣，相关学者进行了大量的基础研究，现在正逐渐的得到了认可。本项目利用细胞模型对miR-23a在动脉粥样硬化中的作用进行探讨，并揭示在动脉粥样硬化发生发展过程中，miR-23a可降低巨噬细胞及泡沫细胞中炎症反应因子IL-6及MCP-1的释放，同时，miR-23a可抑制巨噬细胞及泡沫细胞的细胞凋亡，减轻动脉粥样硬化硬化的发生发展。通过基因表达检测及荧光素酶报告基因实验，揭示了miR-23a在动脉粥样硬化发生发展这一过程中通过调节下游基因hsp90及其所在通路NF-KB发挥其作用。本项目主要针对miRNA在动脉粥样硬化过程中巨噬细胞及泡沫细胞中的作用展开研究，成果发表多篇论文，培养博士生、硕士生多名。通过本项目的实施我们对miRNA在动脉粥样硬化疾病中的认识有了进一步的积累。