动脉粥样硬化常见于发生湍流的动脉血管分叉或弯曲处，其分子机制不清。前期研究表明在血管内皮细胞湍流促使整合素α5（α5）向细胞膜脂筏转位并激活；同时活化Hippo通路的效应分子YAP，激活内皮，但二者关系尚未阐明。本研究旨在揭示湍流激活α5-YAP通路的机制及其在动脉粥样硬化发生中的作用。提出假说：湍流促使α5脂筏内转位，通过与GPCR相互作用而激活；通过RhoA通路和/或氨酸激酶活化YAP，进而调控下游基因转录，导致内皮的激活。拟将以湍流激活α5-YAP通路为中心，运用组学、生化、细胞及分子生物学手段和基因工程小鼠，重点研究在内皮细胞中：1）洄流引起α5脂筏转位并激活的分子机制；2）α5与GPCR相互作用对下游通路激活的机制；3）湍流诱导α5促进YAP活化的分子机制及其意义；4）以α5-YAP通路为靶点进行小分子化合物的筛选验证。以期为干预动脉粥样硬化早期病变的药物筛选提供理论及实验依据。

Atherosclerotic lesions often happen in bifurcations and curved regions of artery vessel, which suggests that local variations in hemodynamic forces play a significant role in atherogenesis. However, the molecular mechanism is still unclear. Our previous study demonstrated that disturbed flow induced translocation of integrin α5 (α5) to the cell membrane lipid rafts and activated, an important effector of Hippo pathway, YAP was also activated in vascular endothelial cells, but their relationship has not yet been elucidated. The purpose of this study is to explore the molecular mechanism of disturbed flow activation of α5-YAP cascade and its role in atherogenesis. We hypothesize that disturbed flow promotes α5 lipid raft translocation, and be activated via an interaction with GPCR, in turn, activates YAP through RhoA and/or tyrosine kinase pathway(s), thus regulates the transcription of downstream genes, leading to endothelial activation. With disturbed flow activation of α5-YAP cascade as a central, using proteomics, biochemistry, cell and molecular biology tools and genetically engineered mice, we will systematically investigate 1) the molecular mechanism of disturbed flow induced α5 lipid raft transposition and activation in endothelial cells; 2) the mechanism of downstream pathway activation via the interaction between α5 and GPCR; 3) the molecular mechanism of disturbed flow promotes α5-induced YAP activation, and 4) α5-YAP pathway as targets, drug screening and verification of small molecule compounds to provide theoretical and experimental evidence for early intervention of atherogenesis.