PTPN14在血流剪切力介导的内皮激活以及动脉粥样硬化中的作用与机制研究

血流剪切力造成的内皮激活是动脉粥样硬化斑块局灶性分布的重要原因，申请人近期研究发现YAP酪氨酸357位点的磷酸化介导血流剪切力导致的内皮激活，但YAPY357具体分子调控机制尚不清楚。预实验蛋白组学以及细胞实验首次发现内皮细胞中PTPN14可与YAP结合并减少YAPY357磷酸化；动物实验发现PTPN14抑制血流剪切力介导的小鼠内皮细胞激活以及动脉粥样硬化斑块的形成。因此我们提出假说，即PTPN14是新的内皮稳态调控的关键分子，通过抑制YAP活性在血流剪切力介导的内皮激活和动脉粥样硬化中发挥关键作用。拟通过运用蛋白组学及基因工程小鼠等多种手段在内皮中重点研究：1、PTPN14 调控YAP的分子机制；2、PTPN14在血流剪切力诱导的内皮激活以及动脉粥样硬化中的作用；3、以PTPN14-YAP通路为靶点的抗动脉粥样硬化小分子化合物的筛选验证。以期为动脉粥样硬化的防治提供研究基础。

Oscillatory shear stress (OSS) plays a critical role in plaque location and progression of atherosclerosis. Recently, we found that phosphorylation of YAP at tyrosine 357 site mediated OSS-induced endothelial activation, but the underlying mechanism remained unclear. Preliminary results from proteomics and in vitro experiments showed that PTPN14 bound with YAP and reduced p-YAPY357. Also, PTPN14 alleviated disturbed flow-induced endothelial activation and atherosclerotic plaque formation in ApoE-/- mice. Thus, we hypothesize that PTPN14 is a novel regulator of endothelial homeostasis, and plays a vital role in OSS-induced endothelial activation and atherosclerosis via inhibiting YAP activity. With PTPN14/YAP cascade as a central, using proteomics and genetically engineered mice, we’ll investigate 1) The underlying mechanism of YAP regulated by PTPN14; 2) The role of PTPN14 in OSS-induced endothelial activation and atherosclerosis; 3) Screening and verification of small molecule compounds targeting the PTPN14/YAP pathway. Our study will provide theoretical and experimental evidence for the intervention of atherosclerosis.