Regulation and function of AMPK in endothelial cells

AMP激活的蛋白激酶(AMPK)在内皮细胞的能量供应、应激保护以及维持抗炎和抗动脉粥样硬化表型方面起着重要作用。目前关于AMPK在内皮细胞中的调节和功能的研究将集中于两个目标。我们将证明这一假设，即AMPK包含一个抑制性磷酸化位点，靶向该位点可能是影响AMPK活性的一种途径。我们将进一步研究AMPK是否以及如何参与内皮细胞屏障功能的调节，以及它如何控制内皮细胞迁移。我们假设在低能状态下激活的AMPK将保护内皮结构和连接。相反，通过受体依赖的信号通路激活的AMPK可能支持屏障的破坏和细胞的运动。为了验证这一假设，我们将研究不同的AMPK刺激途径的作用，表征与调节内皮结构相关的AMPK靶点，并在体外和带有AMPK A1亚单位(通透性、迁移、血管生成)基因去除的小鼠中进行功能分析。我们期望在这个项目中获得的数据将有助于开发针对内皮功能障碍的药理学策略。

The AMP-activated protein kinase (AMPK) plays a role in endothelial cell energy supply, stress protection and maintaining an antiinflammatory and antiatherogenic phenotype. The present project on AMPK regulation and function in endothelial cells will focus on two goals. We will prove the hypothesis that AMPK contains an inhibitory phosphorylation site and that targeting this site may be an approach to affect AMPK activity. We will further investigate whether and how AMPK is involved in the regulation of endothelial barrier function and how it controls endothelial cell migration. We hypothesize that AMPK activated at low energy state will preserve endothelial structure and junctions. In contrast, AMPK activated via receptor-dependent signalling pathways may support barrier disruption and cell movement. To verify this hypothesis, we will investigate the role of different pathways of AMPK stimulation, characterize AMPK targets related to the regulation of endothelial structure and perform functional assays in vitro and in mice with genetically ablated AMPK a1 subunit (permeability, migration, angiogenesis). We expect that the data obtained in this project will contribute to the development of pharmacological strategies targeting endothelial dysfunction.