核仁素通过SREBP1/FASN信号通路调控血管平滑肌细胞泡沫化促动脉粥样硬化

动脉粥样硬化（AS）是引起多种心脑血管疾病发生发展的病理生理基础之一，明确血管平滑肌细胞泡沫化的形成机制具有非常重要的意义。核仁素是一种多功能的rRNA结合蛋白。申请者前期工作发现冠心病患者血清核仁素表达上调，其表达与甘油三酯、高密度脂蛋白胆固醇相关；人及小鼠AS斑块血管平滑肌细胞核仁素表达上调；生信学分析发现SREBP1/FASN信号通路中关键基因mRNA含有核仁素结合元件；核仁素过表达或干扰导致细胞中SREBP1表达上调或下调。由此提出科学假说：“核仁素与SREBP1/FASN信号通路关键基因mRNA结合，调控血管平滑肌细胞泡沫化，促动脉粥样硬化发生。”本项目拟采用核仁素慢病毒干扰apoE-/-小鼠模型、核仁素过表达及siRNA干扰细胞模型，采用RNA pull-down、免疫共沉淀等技术阐释核仁素对血管平滑肌细胞泡沫化的影响及其机制，为AS的防治提供新思路和药物作用新靶点。

Atherosclerosis is a common pathological basis for the development of various cardiovascular and cerebrovascular diseases. Vascular smooth muscle cells -derived foam cells are key regulators of atherogenesis. Nucleolin is a multifunctional RNA-binding protein can regulate rRNA metabolism. However, whether nucleolin plays a role in vascular smooth muscle cells -derived foam cells of atherosclerosis remains unclear. Our previous studies showed that serum nucleolin significantly increased in patients with coronary heart disease; Pearson or Spearman correlation analysis between the nucleolin level and the patient's biochemical indicators found that the patient's serum nucleolin level is positively correlated with triglycerides, and negatively correlated with high-density lipoprotein cholesterol; nucleolin expression was up-regulated in atherosclerotic plaques of human or apoE-/- mice. The applicant found that the mRNAs of SREBP1, FASN in the SREBP1/FASN signaling pathway which contained complete nucleolin binding elements, indicating that the mRNA stability may be directly regulated by nucleolin. We hypothesized that nucleolin might binds to the mRNA of key genes in the SREBP1/FASN signaling pathway, regulate the foaming of vascular smooth muscle cells and promote the occurrence of atherosclerosis. This project intends to use nucleolin lentiviral interference apoE-/- mice model, nucleolin overexpression and siRNA interference cell model, using RNA pull-down assay, immunoprecipitation, etc. to explain the effect of nucleolin on the foaming of VSMCs and its mechanism, and Provide new ideas and new targets of drug action for the prevention and treatment of atherosclerosis.