YAP在动脉粥样硬化中的作用研究

Atherosclerosis is a focal disease with the deposition of lesion composed of cholesterol and fat-like substances under the middle and large arteries.One of the mose important features of atherosclerosis is focal distribution. Endothelial cell inflammatory response to shear stress is considered to be one of the early reasons for its occurrence. YAP is a member of the Hippo pathway, and its phosphorylation level and intracellular distribution is significantly changed by cell morphology and physical stressors. Although YAP was found to be directly related with endothelial function,the role of YAP in endothelium under different shear stress is still blank. In this project, our study will focus on the change of YAP phosphorylation level and its nuclear translocation by shear stress. In addition, we will further explore the role of YAP in the regulation of inflammatory factors production and the development of atherosclerosis.To achieve this goal, we will investigate the effect of YAP on the endothelial cells activation under shear stress and inflammation response at cellular level and the underlying mechanism; In addition, we will establish the endothelial cell-specific YAP overexpression atherosclerosis mice models, and observe the lesion area and plaque inflammation reaction in those area. The subject not only to deepen the understanding of atherosclerosis pathophysiological mechanism, but also has great significance for the development of new means of intervention and treatment.

动脉粥样硬化（As）是一种呈局灶性的大、中动脉内膜下出现脂类物质沉积的病变。其的重要特征是呈局灶性分布，内皮细胞的炎症反应被认为是其发生的早期原因之一，血流剪切力参与这一过程的形成。YAP作为Hippo通路的一员，细胞形态结构及物理压力刺激可以显著改变其磷酸化水平及细胞内分布。尽管有研究提示YAP与内皮功能有直接关联，但是对于内皮中YAP在血流动力学中的作用研究尚属空白。为此我们通过研究血流动力学对于YAP的调节，进而改变细胞核内YAP的含量改变其转录活性，从而引起炎症因子的产生，揭示YAP在As早期病理机制中的作用。我们将在细胞水平研究血流动力学对于YAP的调节，以及YAP改变对于内皮细胞激活与炎症反应的影响和机制；此外我们将建立内皮细胞特异性YAP过表达的As模型小鼠，观察期斑块及斑块区域炎症反应情况。本课题不仅加深了对As病理生理机制的理解，对发展新的干预和治疗手段也具有重要意义。

动脉粥样硬化（As）是一种呈局灶性的大、中动脉内膜下出现脂类物质沉积的病变。其的重要特征是呈局灶性分布，内皮细胞的炎症反应被认为是其发生的早期原因之一，血流剪切力参与这一过程的形成。YAP作为Hippo通路的一员，细胞形态结构及物理压力刺激可以显著改变其磷酸化水平及细胞内分布。尽管有研究提示YAP与内皮功能有直接关联，但是对于内皮中YAP在血流动力学中的作用研究尚属空白。为此我们通过研究血流动力学对于YAP的调节，进而改变细胞核内YAP的含量改变其转录活性，从而引起炎症因子的产生，揭示YAP在As早期病理机制中的作用。我们在细胞水平研究血流动力学对于YAP的调节，以及YAP改变对于内皮细胞激活与炎症反应的影响和机制；此外我们建立内皮细胞特异性YAP过表达的As模型小鼠，观察期斑块及斑块区域炎症反应情况。本课题不仅加深了对As病理生理机制的理解，对发展新的干预和治疗手段也具有重要意义。在本项目资助下共发表8篇研究论文。