病理剪切力是致动脉粥样硬化（AS）的重要原因，涉及内皮细胞及细胞间异常。DKK1是一种具有自分泌和旁分泌作用的糖蛋白，是重要的肿瘤治疗靶点，并与AS密切相关，但其机制尚未明了。我们首次证实致AS的震荡剪切力（OSS）上调内皮细胞DKK1表达，引起内皮细胞和平滑肌细胞功能异常，促进AS发生。但OSS上调内皮细胞DKK1表达机制及分泌的DKK1如何影响平滑肌细胞仍不明了。我们提出如下假说：OSS刺激内皮细胞经c-Ets上调DKK1，分泌后被平滑肌细胞表面受体识别，促进AS发生发展。本课题将通过构建内皮细胞DKK1基因条件性敲除小鼠，利用分子生物学、蛋白质组学等技术，在体内外研究验证该假说，明确OSS引起内皮细胞DKK1上调及其介导的内皮-平滑肌细胞间通讯致AS的作用与机制。本研究将拓展对 DKK1生物学功能的新认识，为AS的防治提供新的靶点；同时为明确肿瘤干预治疗潜在的心血管反应提供理论基础。

Pathological shear stress is one of the most important factors leading to atherosclerosis (AS) development, involving endothelial intracellular and intercellular signaling abnormalities. DKK1 is a secreted factor which plays important roles in many physiological and pathological processes in an autocrine and/or paracrine way. Studies have shown that DKK1 is closely related to atherosclerosis (AS), but the underlying mechanism is not clear. Our previous studies firstly confirmed that atheroprone oscillatory shear stress (OSS) upregulated endothelial DKK1 expression and in turn promoted AS; DKK1 mediated the dysfunction of endothelial cells and smooth muscle cells. However, the mechanisms of endothelial DKK1 upregulation by OSS and the roles of endothelial secreted DKK1 in smooth muscle cells need to be further explored. We propose the following hypothesis: OSS increases the expression and secretion of DKK1 in endothelial cells via activating the transcription factor c-Ets, secreted DKK1 are further recognized by surface receptors of smooth muscle cells and then play roles in the development of AS. Our study will construct endothelial DKK1 gene knockout mice model and take advantage of cellular biology and proteomics techniques to fully test our hypothesis both in vitro and in vivo and verify the mechanism of OSS-induced endothelial DKK1 expression and the role of DKK1-mediated endothelial cell-smooth muscle cell communication in the process of AS. This study will expand our information of the biological function of DKK1 and provide new insight into the potential therapeutic targets of AS. Besides, our study might establish theoretical basis for the understanding of cardiovascular response induced by DKK1 intervention in cancers.