动脉粥样硬化（AS）是单核巨噬细胞系统对抗“入侵”动脉壁的“病原性”脂蛋白产生的过度免疫应答损伤。AS进程中，血管壁单核巨噬细胞溶酶体脂质代谢紊乱，导致巨噬细胞表型转化障碍，成为AS免疫炎症发生和演进的重要病理机制之一。因此，从溶酶体功能研究入手，阐明巨噬细胞表型转化的调控机制，将有可能为AS血管重构提供新思路。本研究选择申请者最新研究发现的溶酶体稳态调控分子CREG为靶向分子，建立巨噬细胞特异性CREG基因过表达和表达缺失的ApoE-/-小鼠AS模型，从在体水平揭示CREG能否通过调控巨噬细胞极化分型，发挥对AS的保护作用。并通过原代培养技术建立CREG过表达和表达缺失的小鼠脾脏单核巨噬细胞模型，从分子水平深入阐明CREG调控巨噬细胞表型转化的分子机制，尝试为临床AS研究找到新的治疗靶点。

Atherosclerosis is a chronic excessive immune response of monocyte-macrophage system to pathogenic lipoprotein invading arterial wall. Dysfunction of macrophage polarization manifests with abnormal switch from M2 to M1 phenotype, which may be an essential factor contributing to onset and progress of atherosclerosis. However, mechanism underlying macrophage polarization remains unclear. In this study, we aim to elucidate role and mechanism of cellular repressor of E1A stimulated genes (CREG), a novel homeostatic regulating factor, in atherosclerosis from view of macrophage polarization. Role of CREG in regulating macrophage polarization in vivo will be determined in atherosclerosis models by using different mice, i.e. CREG transgenic/heterozygote mice with ApoE-/- background and macrophage specific CREG transgenic/knockout mice with ApoE-/- background. Moreover, by using the primary macrophage isolated from CREG transgenic or knockout mice, mechanism of CREG in regulating macrophage polarization will be further elucidated at molecular level in vitro. Implementation of this study will provide novel therapeutic target for prevention and treatment of atherosclerosis.