磷脂转运蛋白调控巨噬细胞炎症活性和动脉壁胆固醇代谢稳态的分子机制

动脉内膜巨噬细胞和胆固醇聚集是粥样硬化（AS）及易损斑块形成的重要病理特征。我们前期工作证明磷脂转运蛋白（PLTP）通过影响脂蛋白代谢和斑块稳定性（发表在“自然医学”等杂志）参与血管稳态和重构，但其作用机制尚不清楚。在已结题项目中我们发现PLTP可影响动脉巨噬细胞炎性反应和胆固醇外流，故提出PLTP通过调控巨噬细胞炎症活性和动脉壁胆固醇代谢影响血管稳态的假说。为此拟观察（1）；PLTP不同表达对炎症诱导动脉壁和相关脏器炎性改变、胆固醇聚集和胞膜脂质组学的影响；（2）巨噬细胞不同表达PLTP对炎性因子刺激下细胞表面受体、内质网应激蛋白、细胞信号通路、胞膜脂筏区脂质组学的影响；（3）外源PLTP蛋白和活性结构域对巨噬细胞炎性因子诱导上述改变量效关系和胆固醇代谢的影响。最终确定PLTP相关作用关键生物分子和调控血管壁胆固醇代谢的信号通路机制，期待为血管稳态调控提供新思路和新靶点。

The pathological lesion of atherosclerosis (AS) is characterized by the arterial intimal macrophage and cholesterol accumulation. We have proved previously that phospholipid transfer protein (PLTP) participates the vessel homeostasis maintenance and remodeling via alternating the lipoprotein metabolism and lesion stability (published in the journals including Nature Medicine), whereas the mechanism remains unknown. We also found that PLTP influences inflammatory response and cholesterol efflux in macrophage in the accomplished grant. Therefore we hypothesize that PLTP may modulate the vascular homeostasis via affecting macrophage inflammation and cholesterol metabolism of arterial wall. In this grant, we will investigate 1) the inflammation in artery wall and relative organs mediated by macrophage, cholesterol accumulation, and lipidomics alternation induced by inflammatory factor in mouse model with different PLTP expressing level; 2) cellular surface receptor, endoplasmic reticulum stress protein, signaling pathway, lipidomics alternation in lipid raft, and cholesterol efflux in inflammatory factor stimulated macrophage which expressing different PLTP level; 3) role of exogenous PLTP or its active domains in dose-effect relationship and cholesterol metabolism in macrophage stimulated by inflammatory factor. The accomplishment of this grant may provide the new strategy and target of vessel homeostasis modulation via PLTP.