血管内皮损伤是众多心血管疾病的共同病理基础，内皮祖细胞（EPCs）是内皮修复的主要参与者。然而EPCs在动脉粥样硬化（AS）环境下生存能力低，增殖能力弱，限制了血管内皮的修复；改善其在应激环境下生存能力是目前亟待解决的问题。申请人新近报道了CAMKKII介导的细胞自噬能够促进EPCs生存、维持增殖，但何种自噬途径及其分子机制尚待明确。结合既往文献及预实验我们推测：在AS环境下EPCs生物学功能和线粒体自噬受损，而增强线粒体-内质网膜偶联结构（MAM）介导的内质网-线粒体单向跨膜钙流，激活CAMKKII通路，上调线粒体自噬水平，促进EPCs生存，提高AS环境下血管内皮修复。本项目拟运用蛋白组学、基因转染、电生理等分子生物学技术，明确MAM介导的单向跨膜钙流激活CAMKKII-CAMKI-PINK1线粒体自噬途径，提高EPCs生物学功能和促进血管内皮修复的新分子机制，为血管内皮再生提供新方向。

The impairment of vascular endothelium is a general pathological process in most cardiovascular diseases. Endothelial progenitor cells (EPCs) play a major role in the maintenance of endothelial integrity and contribute to re-endothelialization of injured vessels. However, the poor viability and proliferation limit the repairment of EPCs in atherosclerotic environment. Therefore, improving the survival of EPCs is crucial to delaying or blocking the development of atherosclerosis. Recently, we have confirmed that CAMKKII-mediated autophagy promoted EPCs survival and proliferation in atherosclerotic environment, but the type of autophagy as well as the exact mechanism remained unclear. Interestingly, our preliminary experiment revealed that PINK1-PARK2-mediated mitophagy was inhibited in EPCs from atherosclerosis model mice. Furthermore, both the autophagic marker LC3II and calcium signaling protein CAMKKII localized less on mitochondria-associated endoplasmic reticulum membrane (MAM) of EPCs from atherosclerosis model mice. Combining with our previous study, we speculate that atherosclerotic environment leads EPCs bio-function and mitophagy impaired, enhancement of MAM-mediated calcium flux from endoplasmic reticulum to mitochondrion reverses EPCs mitophagy through activating CAMKKII that localized on MAM, which will be able to promote EPCs survival and bio-function as well as accelerate vascular endothelium repairment in atherosclerotic environment. As a consequence, we plan to employ proteomics, gene transfection, electrophysiology and other molecular biological techniques to explore the mechanism of CAMKKII-CAMKI-PINK1 signaling pathway in MAM-mediated mitophagy as well as the role of mitophagy in EPC function and endothelium repairment. This study will provide new theoretical basis and intervention targets for the prevention and treatment of atherosclerosis.