动脉粥样硬化（Atherosclerosis , AS）是脂质代谢异常导致的血管壁的慢性炎症、影响血管稳态和重构，是多种心血管疾病的病理基础。免疫细胞，特别是巨噬细胞在这一病理过程中发挥重要作用。自噬作为调控细胞代谢和自稳的重要方式，可调节巨噬细胞的脂质代谢，进而影响AS斑块的稳定性，已成为药物研发的靶点，但其内源性调控机制尚不清楚。我们前期研究发现，蛋白质翻译抑制因子PDCD4具有抑制巨噬细胞脂自噬及脂质代谢的作用。它不仅影响自噬小体的形成，而且参与自噬溶酶体的重构；但其作用的分子机制及其在AS斑块稳定性中的作用尚不清楚。本课题拟从Atg12-Atg5-Atg16L1复合体和AP2-网蛋白通路入手，研究PDCD4抑制自噬小体的形成和自噬溶酶体重构的分子机制，探讨PDCD4介导的自噬对巨噬细胞胆固醇转运和泡沫化的影响及其在AS斑块稳定性中的作用，为AS相关疾病的防治提供新的策略和靶点。

Atherosclerosis (AS), an abnormal lipid metabolism-induced chronic inflammation of vascular wall, affects the homstasis and remodeling of blood vessel and is the pathological basis of the multiple cardiovascular diseases. Immune cells, especially macrophages, play an important role in it. Recent reseaches reveal that autophagy, an evolutionarily conserved process which controls cellular metabolism and homestasis, regulates the lipid metabolism in macrophage and impact on the instability of plaque. However, the endogenous mechanism that macrophage autophagy is regulated remains unclear. In the previous studies, we have found that programmed cell death 4 (PDCD4) can inhibit lipophagy of macrophage and lipid metabolism. Preliminary exploration of mechanism suggests that PDCD4 not only inhibits the formation of autophagosome but also participates in the reformation of autolysosome. However, the exact molecular mechanism and its role in plaque stability remain to be investigated. This project will explore the molecular mechanism by which PDCD4 inhibits the formation of autophagosome and the reformation of autolysosome from Atg12-Atg5-Atg16L1 complex and AP2-clatherin axis on the basis of previous research and further determine the effect of autophagy mediated by PDCD4 on cholesterol efflux from macrophage and foam cell formation as well as its role in the instability of atherosclerotic plaque. Our research will provide new strategies and intervention targets for the prevention and therapy of cardiovascular diseases related to atherosclerosis.

动脉粥样硬化（Atherosclerosis , AS）是脂质代谢异常导致的血管壁的慢性炎症、影响血管稳态和重构，是多种心血管疾病的病理基础。免疫细胞，特别是巨噬细胞在这一病理过程中发挥重要作用。自噬作为调控细胞代谢和自稳的重要方式，可调节巨噬细胞的脂质代谢，进而影响AS斑块的稳定性，已成为药物研发的靶点，但其内源性调控机制尚不清楚。本课题利用体内外实验、基因敲除小鼠及高脂诱导的动脉粥样硬化模型，系统研究了一种新的蛋白质翻译抑制因子-PDCD4对巨噬细胞脂自噬的调控及其在血管稳态中的作用并探讨了其作用机制。研究发现PDCD4缺失改善Ox-LDL对巨噬细胞自噬流的损伤、促进脂自噬介导的脂滴降解，进而抑制巨噬细胞泡沫化；小鼠体内实验证明PDCD4敲除增强动脉粥样硬化斑块局部巨噬细胞的自噬流、减少脂质在斑块的积累和炎症反应，进而抑制动脉粥样硬化的发生。通过骨髓移植进一步证明巨噬细胞中PDCD4的表达对动脉粥样硬化斑块的形成发挥更重要的作用。这些结果说明内源性PDCD4具有抑制巨噬细胞自噬流及促进动脉粥样硬化的作用。从机制上，我们发现PDCD4不仅可抑制自噬相关蛋白Atg5表达抑制自噬小体的形成，而且可通过抑制溶酶体重要转录因子TFEB表达，进而抑制自噬流及自噬介导的溶酶体再生。另外，基于我们发现PDCD4敲除的巨噬细胞可通过增强自噬抑制动脉粥样硬化斑块的形成，故进一步发现了一种小鼠体内可促进促进巨噬细胞自噬进而抑制动脉粥样硬化的制剂-3-MA，为动脉粥样硬化的治疗提供了新的方法。本研究在Cellular and molecular immunology、Cell death disease 及Journal of Clinical Investigation等杂志发表SCI论文7篇，申请国家发明专利2项，申请国际PCT1项。研究结果不仅为PDCD4的功能研究提供新的思路，而且对揭示动脉粥样硬化的发病机制、寻找新的治疗靶点具有重大的理论价值和潜在的应用价值。