炎症反应参与动脉粥样硬化（AS）易损斑块进展和脂质沉积过程。五聚素家族蛋白PTX3是具有心血管疾病相关性的炎症因子，与胆固醇逆转运（RCT）相关。明确PTX3与易损斑块巨噬细胞RCT的关系，为从炎症角度干预胆固醇流出提供具有双重作用的治疗靶点。本课题组前期研究提示AKT信号因子参与单核巨噬细胞分泌PTX3的过程，而且PTX3可抑制巨噬细胞自噬。据此，我们提出如下假说：巨噬细胞中PTX3通过AKT-mTOR-JNK信号通路抑制巨噬细胞自噬，减少胆固醇流出而改变斑块稳定性。为证实假说，本项目拟以PTX3与巨噬细胞RCT的关系为主线，利用体外巨噬细胞和本课题组成功建立的易损斑块动物模型，阐明自噬在PTX3干预巨噬细胞RCT过程中的作用及AKT-mTOR-JNK信号通路相关的分子机制，以期发现AS炎症反应与脂质沉积之间新的交叉点，为寻找改善斑块稳定性干预靶点提出新的理论依据。

Inflammation plays pivotal roles in advanced atherosclerotic plaque formation and lipid deposition. Pentraxin-related protein PTX3 is an acute phase inflammatory factor essential for pathogenesis of cardiovascular diseases partially through regulation of cholesterol reverse transport. Dissecting molecular mechanism of PTX3 and the reverse cholesterol transport in macrophage of vulnerable plaque will provide fundamental basis for targeting the cholesterol efflux from the aspect of inflammation. Our preliminary results demonstrated that: 1) PTX3 is highly expressed in resident macrophages; 2) PTX3 functionally inhibits macrophage autophagy; 3) AKT is an important factor of the signal pathway during PTX3 secretion by monocyte. We hypothesize here that PTX3 directly regulates macrophage autophagy contributing to reverse cholesterol transport and plaque stabilization via AKT-mTOR-JNK signaling pathway as key downstream molecular events. To extend mechanistic study to translational potentials, targeting PTX3- AKT-mTOR-JNK axis to modulate plaque stability will be further pursued in this proposal using in vitro primary macrophage culture method and in vivo animal models established by our program team. Taken together, modulating atherosclerotic inflammation and lipid metabolism by targeting PTX3 to improve plaque stability proposed in current study will provide proof-of-concept for novel treatment of advanced atherosclerotic diseases.