研究证实高同型半胱氨酸血症（HHcy）是动脉粥样硬化发病的独立危险因子。前期发现HHcy 导致动脉粥样硬化发生和发展，单核巨噬细胞介导了炎症免疫激活是十分重要的发病机制，预实验发现Hcy引起线粒体的重编程介导的磷脂代谢途径失衡,据此提出释放磷脂生物活性小分子和形成了细胞膜磷脂结合蛋白复合物可能放大了内毒素受体（TLR4）及其下游信号，介导了HHcy促进巨噬细胞过度炎性活化。本项目将采用代谢组和细胞原子力显微术等新技术，重点研究： 1. 通过整体水平TLR4-/- ApoE -/-小鼠和离体巨噬细胞培养揭示动脉粥样硬化发病过程中Hcy是否引起线粒体依赖的磷脂代谢失衡；2. 是否通过释放磷脂生物活性小分子；和3. 通过细胞膜上结合的磷脂结合蛋白复合物从而放大了TLR4受体致炎作用，介导Hcy加速动脉粥样硬化的代谢免疫新机制，从而可能为寻找动脉粥样硬化早期免疫诊断新靶标提供线索。

Hyperhomocysteinmia (HHcy) is a novel independent risk factor of atherosclerosis pathogenesis. Mono-macrophages mediate immune inflammation is very critical in the development of hyperhomocysteinmia-accelareted atherosclerosis. Our previous study have showed that metabolic reprogramming in the mitochondria is involved in imbalance of phospholipids' metabolism in macrophages. We hypothesis that hyperhomocystein promotes excess proinflammation through the release of small bioactive molecules of phospholipids or binding of antiphospholipid antibodies, particularly against phospholipid binding protein beta-2 glycoprotein 1 (β2GP1) to toll-like receptor 4(TLR4) in macrophages. By performing high throughput lipidomics technique and TLR4-/- atherosclerosis mouse model in vivo, we will clarify 1. whether or not metabolic reprogramming in the mitochondria is involved in imbalance of phospholipids' metabolism in macrophages; 2. reveal the mechanisms of HHcy-amplified early pathogenesis of atherosclerosis via the release of biologic active small molecules of phospholipids; 3. or via the binding of antiphospholipid antibodies to toll-like receptor 4 (TLR4) in macrophages. Our results will uncover a novel mechanism of HHcy-amplified metabolic inflammation during atherosclerosis and might provide a new target for early immune diagnosis for the atherosclerosis pathogenesis.