动脉粥样硬化（As）严重危害人类健康。剪切应力诱导的血管内皮细胞（VEC）损伤是As的早期核心事件，但其确切机制尚未阐明。我们前期研究发现：层流剪切应力上调VEC自噬，低剪切应力以及振荡剪切应力抑制VEC自噬，而自噬具有VEC保护功能。据此，我们推测"剪切应力诱导的VEC自噬不足是VEC功能失调和As发生发展的关键环节"。为证实该假说，本课题拟采用平行平板流动腔系统，结合电镜、免疫印迹、qRT-PCR、激光共聚焦以及荧光示踪等实验技术，探讨剪切应力对VEC自噬的调节以及自噬干预对剪切应力环境中VEC功能的影响；再以DNA甲基化修饰酶TET2为切入点，采用体外培养系统以及整体动物模型，结合生物信息学、siRNA、染色体共沉淀、基因转染等方法，探讨剪切应力调节VEC自噬的分子机制。本研究的完成将从新的视角阐明As的发病机制，为As的有效防治提供新策略和新靶点。

Atherosclerosis is a serious risk to human health. The dysfunction of vascular endothelial cells induced by shear stress is a key event of early atherosclerosis. However, the mechanisms are not fully understood. Our previous studies have shown that vascualr endothelial cells autophagy was upregulated by laminar shear stress, while downregulated by low shear stress and oscillatory shear stress. Therefore, we hypothesized that endothelial cells autophagy dysfunction induced by shear stress is the key step of endothelial cells dysfunction and early atherosclerosis. To test this hypothesis, parallel plate flow chamber system, electron microscopy，western blotting, quantitative reverse transcriptase PCR（qRT-PCR）, laser scanning confocal microscope and fluorescent tracer were used to detect the effect of shear stress on endothelial cells autophagy and autophagy intervention on endothelial cells functon under shear stress. Furthermore, based on Tet methylcytosine dioxygenase 2 (TET2), molecular mechanisms of endothelial cells autophagy regulated by shear stress were explored with in invivo and in vitro modle compling with bioinformatics, siRNA，chromatin immunoprecipitation and gene transfection. The accomplish of this study will further explore the mechnasim of atherosclerosis with a new perspective, which will provide new interventional strategies and targets for the prevention and treatment for atherosclerosis.