膜受体一直被认为只在细胞膜上激活传递信号，内化是受体降解终止下游信号的过程。课题组前期发现提示HIP-55能够介导Clathrin依赖的血管紧张素II1型（AT1）受体内化，调节AT1下游信号内化减敏（如p38 MAPK），但同时发现一个受体内化的新作用——内化激活AT1下游AKT信号。即HIP-55具有调节AT1受体内化减敏和内化激活双向功能。进一步功能研究提示HIP-55明显改善血管紧张素II诱导的高血压小鼠主动脉内皮依赖性舒张功能障碍。因此，提出科学假说：HIP-55调控Clathrin依赖的AT1受体内化，通过内化双向调节下游信号，内化减敏p38 MAPK、清除ROS，内化激活AKT/eNOS、促进NO生成，发挥血管内皮保护作用。本课题将利用活细胞单分子荧光成像等交叉学科技术证实上述假说。

It is canonically accepted that Membrane receptors are activated and then transmit signaling only at the plasma membrane, and that the internalization of receptors lead to their degradation and the termination of signaling transduction. Our previous research revealed that HIP-55 can interact with angiotensin type 1 receptors (AT1) and clathrin, which mediate the internalization of AT1. The knockdown of HIP55 distinctly decreased AT1 internalization. Further research on receptor signaling indicates that HIP-55 can bidirectionally mediate both internalization dependent desesensitizaiton (p38 MAPK) and activation (AKT) of signaling. Functional research suggests HIP-55 can distinctly ameliorate the endothelium-dependent diastolic dysfunction of aorta in angiotensin II induced hypertension mice. The hypothesis is therefore proposed as that HIP-55 can regulate clathrin dependent internalization of AT1, and exert the endothelium protecting effect through bidirectionally mediate the internalization dependent desesensitizaiton of p38 MAPK/ROS and activation of AKT/eNOS/NO. This hypothesis will be testified in this project by multiple cross-displine technologies such as single molecule fluorescence imaging of live cell.