利用OCT技术研究脂肪外泌体在血管正性重构与动脉粥样硬化斑块进展中的作用及机制

肥胖是动脉粥样硬化性心血管疾病的独立危险因素。最近脂肪被证实是循环外泌体中miRNAs的主要来源。外泌体(exosome,Exo)与许多重大疾病发病机制关系密切，但脂肪来源Exo能否调节动脉粥样硬化进程？miRNA是否起重要调控作用？具体机制是什么？目前尚不清楚。我们前期研究发现肥胖状态下内脏脂肪组织(VAT)来源Exo显著促进巨噬细胞泡沫化并诱导其向M1型极化，从而促进动脉粥样硬化进展。根据前期测序结果结合临床样本分析，我们推测VAT来源Exo中miR-203对巨噬细胞及动脉粥样硬化具有重要调控作用。本项目拟应用OCT等先进影像模式及多种基因修饰小鼠模型，从细胞到整体水平明确VAT来源Exo中miR-203对动脉粥样硬化及血管正性重构的作用，阐明VAT来源Exo中miR-203下游调控机制，并揭示VAT来源Exo中miR-203含量降低的机制，为动脉粥样硬化性心血管疾病的防治提供新靶点。

Obesity has been demonstrated to be an independent risk factor for arteriosclerotic cardiovascular disease. Recently, adipose tissue has been demonstrated to be a major source of miRNAs in circulating exosomes. Exosomes are closely related to the pathogenesis of many major diseases. However, the mechanisms for the action of adipose tissue derived exosomes on atherosclerosis and whether miRNA will participate in this process remain unknown. Our previous studies have found that visceral adipose tissue (VAT) derived exosomes promoted the macrophage-derived foam cell formation and shifted macrophage polarization toward M1 phenotype, which could promote the progression of atherosclerotic plaques. According to our previous sequencing results and clinical sample analysis, we speculate that miR-203 of VAT-derived exosomes may play a key role in mediating macrophages polarization and promoting atherosclerosis. Our project will use genetic modification technologies and advanced imaging modalities such as optical coherence tomography (OCT) to further investigate and clarify the role of VAT-derived exosomes on atherosclerosis and vascular remodeling, from the level of cell to the general. We will focus on analyzing the potential mechanisms for the decreased expression of miR-203 in VAT-derived exosomes and its role on macrophages, which may provide a better understanding of molecular mechanisms on atherogenesis and novel targets for therapeutic intervention of arteriosclerotic cardiovascular disease.