超声造影动态监测Renalase基因调控斑块稳定性的研究

Acute cardiocerebrovascular event is an important disease, which lead to death and disability. And plaque instability is the main reason why it happened. At present, how to convenient, quick and noninvasive screening of unstable plaque and make it tending to be stable is one of the current medical hot problem to be solved. . Applicants according to the pathological signs of plaque instability: inflammation, intraplaque neovasculature, big lipid core and thin fibrous cap are related to new blood vessel growth. Using neovascularization in atherosclerotic plaque and adventitial vasa vasorum could quantificationally analyse by ultrasound imaging, and first discovered renalase gene has protective effect on the stability of plaque. We try to take advantage of ultrasound imaging quantitiative distinction between stable and unstable plaques, and dynamic monitoring renalase gene regulation on the stability of plaque. From the relationship between renalase and diseased tissue cell necrosis and apoptosis, we further explore renalase gene effect on the stability of atherosclerotic plaque and its mechanism. Not seen similar reports at home and abroad, the implementation of this project opens a new research direction for regulatory mechanism of atherosclerosis and plaque stability research, and provides a new gene targets for clinical diagnosis and treatment of unstable plaque, as well as provides a new platform for molecular imaging.

急性心脑血管事件是全球致死、致残的重要原因，斑块不稳定性是其发生的主要因素。目前，如何方便快捷、无创筛查不稳定斑块及使其趋于稳定是当前亟待解决的医学热点问题之一。.申请者根据斑块不稳定性的病理标志：炎症、斑块内出血、大的脂质核心及薄的纤维帽，都与新生血管增生有关。利用前期工作超声造影可以定量分析动脉粥样硬化斑块内新生血管和外膜滋养血管增殖情况，和首次发现Renalase基因对斑块稳定性具有保护作用。试图利用超声造影定量区分稳定和不稳定斑块，并动态监测Renalase基因对斑块稳定性的调控，从Renalase与病变组织细胞坏死和凋亡的关系出发，进一步探讨Renalase基因对动脉粥样硬化斑块稳定性的作用及机制，目前国内外未见类似报道，本项目的实施为动脉粥样硬化及斑块稳定性调控机制研究开辟了新研究方向，为临床诊断和治疗不稳定斑块提供了一个新的基因靶点，也为分子影像学的研究提供了一个新的平台。

动脉粥样硬化是一种多因素相关的慢性炎症性疾病，与心脑血管疾病密切相关。许多研究者试图阐明动脉粥样硬化的发病机制，但仍然很难制定出有效针对该疾病的临床治疗策略。 circRNA和lncRNA可以作为mRNA的竞争性内源性RNA（ceRNA）在各种疾病中起作用。然而，关于circRNA及lncRNA在动脉粥样硬化中的作用知之甚少。在本项目中，课题组通过高脂肪饮食诱导兔颈动脉粥样硬化模型，对circRNA及lncRNA在动脉粥样硬化中的生物学功能进行探究，使用RNA-seq技术分析了lncRNA、circRNA、miRNA和mRNA的表达谱。结果显示，多个miRNA、mRNA、circRNA和lncRNA在动脉粥样硬化中有差异表达，但是renalase基因差异不显著。我们采用miRanda软件预测miRNA的靶向相互作用，并构建了差异表达的circRNA/lncRNA-miRNA-mRNA三维互作网络。功能富集分析表明，circRNA-miRNA-mRNA网络中的基因参与了细胞粘附、细胞活化和免疫应答的作用过程。lncRNA-miRNA-mRNA三维互作网络中的基因参与血管生成和炎症等作用过程，此外，我们还构建了差异表达的circRNA及lncRNA相关的ceRNAs网络，发现7个circRNAs（ocu-cirR-novel-18038，-18298，-15993，-17934，-17879，-18036和-14389）和6个lncRNA（MSTRG.10603.16, 5258.4, 12799.3, 5352.1, 12022.1和 12250.4)与动脉粥样硬化有关。这些结果表明，circRNA及lncRNA与其竞争性mRNA之间的相互作用可能在动脉粥样硬化的发展中起关键作用。