PGC-1α转基因兔抗动脉粥样硬化机制中miRNA调控作用的研究

微小RNA（miRNA）是一种小的非编码RNA，它通过转录后修饰在多种病理生理过程中调控相关基因的表达。近期研究在细胞水平证明，转录共激活因子 PGC-1α具有抗动脉粥样硬化的作用。最近我们已基本成功构建了在血管平滑肌细胞中特异性表达高水平 PGC-1α的转基因兔子，该种转基因兔能够显著抵抗高脂诱导的动脉粥样硬化斑块形成。通过对人动脉硬化手术样本检测，我们发现 PGC-1α的mRNA升高，而蛋白表达却明显降低，基于miRNA对基因广泛的转录后调控作用，我们预测他们很可能参与了此过程。首先，我们将使用生物芯片以及生物信息方法预测可能参与这一过程的miRNA；第二，检测筛选出的miRNA是否能在细胞水平调控的PGC-1α的表达；第三，在转基因兔中验证miRNA对 PGC-1α抗动脉粥样硬化功能的影响。我们希望通过筛选转录后水平上调节 PGC-1α的miRNA对动脉粥样硬化的防治提供新的策略。

MicroRNAs (miRNAs) are small noncoding RNAs post-transcripionally control gene expression in many pathogenic and physiological processes. In our previous study, the nuclear hormone receptor peroxisome proliferator-activated receptor-gamma (PPARγ) coactivator-1alpha (PGC-1α), which is a transcriptional co-activator involved in the regulation of cellular energy metabolism, showed atheroprotective effect. Recently, the transgenic rabbit which specifically express high level of PGC-1α in vascular smooth muscles has been successfully constructed. Consist with our expectation, this transgenic rabbit is resistant to high fat induced atherosclerotic lesion formation. By testing human atherosclerotic lesion, we surprisingly found that the expression of PGC-1α was increased, however, the protein level of PGC-1α was down-regulated, suggesting that miRNAs may involve in this process in terms of their function of posttranscriptional gene regulation. According to our plan, first, we are going to predict the miRNAs which may participate this process by microarray and bioinformatics analysis; secondly, the predicted miRNAs will be used on endothelial and vascular smooth muscle cells to identify whether they regulate the protein level of PGC-1α or not; last but not least, the confirmed miRNAs will be tested on PGC-1α transgenic rabbit to further investigate their function in atherosclerotic process. Here, we aim to identify miRNAs which could regulate PGC-1α in post-transcriptional level and this may comprise a promising strategy to combat atherosclerosis.