应用新型类人化仓鼠模型研究载脂蛋白C3在冠心病发病机制中的作用

冠心病是严重危害人类健康的疾病。新近临床研究发现载脂蛋白C3（ApoC3）突变与高甘油三酯血症（HTG）和冠心病有明显的相关性，且针对ApoC3的反义核酸临床试验在HTG患者取得了理想的疗效。这些临床研究在新英格兰医学杂志的连续发表提出了一个重要科学问题：ApoC3通过什么机制影响冠心病的发生发展。为回答这个问题，我们前期以小鼠模型进行了研究，发现ApoC3转基因可以促进动脉硬化（As），但ApoC3敲除却无保护作用，与临床发现不符，说明小鼠不是研究ApoC3与As的适当模型。因此我们自主研发了类人化基因工程仓鼠模型，包括能够诱发冠心病的LDL受体敲除及ApoC3双敲模型。应用这两种模型并结合AAV介导的ApoC3高表达技术，本项目将得以验证ApoC3缺陷对冠心病的保护作用，并探索ApoC3是否通过炎症及氧化应激途径导致As的发生，为ApoC3作为新的冠心病治疗靶点奠定理论基础。

Coronary heart disease (CAD) is one of the biggest threats to human health. In recent years, large-scale clinical survey confirmed that Apolipoprotein C3 (ApoC3) mutations and hypertriglyceridemia are closely associated with CAD. The clinical trials of antisense against ApoC3 in two groups of severe HTG patients achieved satisfactory results. The publications of the above clinical studies in the New England Journal of Medicine have attracted great attention to ApoC3. However, in our own experimental study we only found pro-atherosclerotic effect in transgenic mice overexpression human ApoC3 but not anti-atherosclerotic effect in ApoC3 knockout mouse models, indicating that mice are not appropriate animal model for human atherosclerosis. .Recently, we have developed brand-new genetically engineered human-like hamster models including LDL receptor KO and ApoC3-LDL receptor double KO, in which CAD can be induced with dietary manipulations. We will first verify the protective role of ApoC3 deficiency in CAD using these 2 hamster models, in combination with AAV mediated gene delivery of ApoC3. We’ll then explore whether ApoC3 leads to CAD via inflammatory and oxidative stress pathways. Our results will provide novel insights into the mechanisms of coronary artery disease and lay theoretical foundation for clinical application of ApoC3 as a therapeutic target.