以循环microRNAs为手段的急性冠脉综合征早期预警方法研究

Acute coronary syndrome (ACS) which are the most intensive manifestation of coronary artery disease (CAD), are a major cause of mortality and morbidity, and most are caused by rupture and thrombosis of vulnerable atherosclerotic plaques.Identification of such high-risk vulnerable patients with new/established screening tools (traditional risk factors, biomarkers and vascular imaging tools) is improving although still imperfect. MicroRNAs (miRNAs) are approximately 20- to 25-nt-long noncoding RNAs that negatively regulate gene expression by binding to sites in the 3' untranslated region (UTRs) of targeted messenger RNAs. The recent discovery that miRNAs are present in the circulation and miRNAs are very likely involved in the pathogenesis of vulnerable plaque sparked interest in their use as potential prewarning biomarkers of ACS.In this study, on the basis of previous work,we will perform an miRNA arrays analysis between ACS patients and controls to obtain differential expressing miRNAs in the circulation.The association between circulating differential expressing miRNAs and clinical assessment index on vulnerable plaque (image results, traditional risk factors, etc.) , and the diagnostic value of circulating miRNAs on vulnerable plaque with the application of receiver operating characteristic curve would be further evaluated.In addition, the source, secretion mechanisms and regulatory factors of these differential expressing miRNAs would be studied in atherosclerotic tissues and cells.The objective of our study is to identify a unique signature of circulating miRNAs for early diagnosis of vulnerable plaque, and to provide a sensitive , specific and simple new technology for prewarning of ACS and the basis for the translation of circulating miRNAs to clinical application.

易损斑块作为急性冠脉综合征(ACS)的病理基础,可导致急性心血管事件。但临床上缺乏早期诊断易损斑块的有效手段。microRNA(miRNA)是一类非编码小分子RNA,具有疾病特定表达模式,可在血中检出。最新研究提示miRNA与心血管疾病关系密切,可能成为预测ACS的新型生物标志物。本研究在既往工作基础上,应用高通量miRNA芯片筛查ACS患者和对照者循环miRNA表达谱,获得循环差异miRNAs；进而分析循环差异miRNAs与易损斑块临床评估指标(影像指标、传统危险因素等)的相关性,并应用受试者工作特征曲线评价循环差异miRNA诊断易损斑块的临床价值；此外在动脉粥样硬化组织和细胞中,研究循环差异miRNAs的细胞来源、分泌机制和调控因素。旨在鉴定出一组循环miRNAs,并阐明其存在形式及释放机制,为易损斑块的早期诊断提供一种敏感、特异和简单的新技术,为miRNAs向临床应用转化提供依据。

针对急性冠脉综合征这一严重心血管疾病缺乏早期预警生物标志物的临床问题，本项目以循环microRNAs为切入点，根据新型心血管生物标志物发展的标准研究步骤，通过临床、细胞以及分子层面的一系列研究，确定了可用于急性冠脉综合征患者早期预警的一组循环microRNAs，为临床急性冠脉综合征的早期预警和监测提供新型生物标志物，并为临床高危胸痛的早期鉴别诊断提供新型手段；同时探讨了急性冠脉综合征患者循环microRNAs的分泌来源，为研究其功能奠定基础和提供理论依据；此外，对发现的多个关键循环microRNAs的功能进行探讨，明确其抗血栓形成和抗炎等作用，为动脉粥样硬化的防治提供新型靶点；最后，通过生物信息学分析，研究了他汀类药物对急性冠脉综合征患者循环microRNAs的网络调控，为他汀类药物的抗动脉粥样硬化多效性提供新的机制解释。.通过这一系列研究，本项目共发表论文16篇，其中SCI论文8篇，中文期刊论文8篇；协助培养博士研究生6人、晋升高级职称2人、中级职称4人；获得2014年第八届药明康德生命化学研究奖1项。