高甘油三酯（TG）血症促进动脉粥样硬化性疾病，是心血管残余风险的关键组成部分。近年来发现针对APOC3调控的反义核酸药物取得降低TG的显著临床效果，APOC3的表观遗传调控也成为研究热点。我们前期通过RNA测序和生物信息学分析发现位于APOA5/A4/C3/A1基因簇的非编码RNA-AP006216.5能特异性调控APOC3基因表达，影响TG代谢；随后预实验发现SRSF5是其结合靶蛋白，但其具体调控机制尚不清楚。本项目将在前期工作基础上利用小鼠高TG血症及动脉粥样硬化模型，通过重组腺相关病毒干预，综合运用EMSA、CHIP、RNA-pulldown、RIP和报告基因等转录调控研究手段，充分阐明AP006216.5募集SRSF5蛋白调控APOC3基因影响TG代谢的分子机制，并探讨其作为高TG血症和动脉粥样硬化治疗靶点可能性。本项目开展将为血脂治疗靶点开发和心血管残余风险的管控奠定理论基础。

High triglyceride (TG) promote atherosclerotic cardiovascular disease, and as a component of residual cardiovascular risk plays an importantly role in controlling cardiovascular events. More recently, it was found that the anti-sense nucleic acids of APOC3 had significantly decreased TG level in human beings, and regulation of APOC3 by epigenetic mechanisms has become a hot topic issue. In the early experiments, RNA-seq technology and bioinformatics analysis were used to detect a novel long chain non coding RNA (LncRNA) -AP006216.5, locating at the APOA5/A4/C3/A1 gene cluster, and specifically regulating the gene expression of APOC3 and TG metabolism. Subsequently, we found that SRSF5 is its binding target protein, but its specific regulatory mechanism is not yet clear. To explore the potential underline mechanism, we will make a comprehensive study by using HTG and atherosclerotic cardiovascular disease mice model along with rAAV package technology, as well as EMSA,CHIP,RNA pull down, RIP and dul report method, to systematically determinate the potential mechanism of regulating APOC3 expression and TG metabolism by recruitment of SRSF5 from AP006216.5, and as a novel therapy target for reducing HTG and arteriosclerosis. Our research may lead to innovative lipid target therapies for reducing cardiovascular residual risk.