高糖所致内皮细胞急性功能障碍与慢性结构损伤是糖尿病心血管病的重要始动因素。脂联素通过APPL1保护血管内皮急性功能障碍，但脂联素对糖尿病血管内皮慢性结构损伤的保护机理尚未阐明。申请者前期体外研究原创结果提示，APPL1与窖蛋白-1信号复合体在脂联素抗高糖所致内皮细胞凋亡保护中具有关键作用，且这一作用可能与窖蛋白运载的APPL1入核诱导多种细胞保护基因表达上调有关。本课题拟利用APPL1基因敲除小鼠加高糖高脂喂养构建2型糖尿病模型，明确APPL1在脂联素保护糖尿病血管慢性结构损伤中的作用；利用高通量测序技术与基因干预手段，寻找并确认APPL1介导的脂联素血管保护关键基因，并进一步阐明脂联素：APPL1通路调控血管内皮保护基因表达的核内分子机制。本项目的完成将不但进一步丰富脂联素调控基因的分子机制，而且有助于以脂联素：窖蛋白：APPL1信号轴为切入点寻求新的有效的糖尿病血管保护措施。

Acute endothelial dysfunction and chronic structural damage caused by diabetes are important initiating factors of diabetic cardiovascular disease. Adiponectin protects the acute dysfunction of vascular endothelium via the adaptor protein APPL1. However, the protective mechanism of adiponectin on chronic structural damage in diabetic vascular endothelium has not yet been elucidated. Our previous original results showed that APPL1 and Caveolin-1 signaling complexes play key roles in the protection of endothelial cells against apoptosis induced by high glucose, which may be related to a variety of cytoprotective genes up-regulation mediated by Caveolin-1-dependent APPL1 nuclear translocation. This study intends to establish type 2 diabetic models in APPL1 knockout mice to confirm the role of APPL1 in adiponectin-repaired diabetic chronic structural damage. High-pass sequencing technique and gene intervention means will be used to find the vascular protective genes regulated by adiponectin/APPL1 pathway, and further clarify the nuclear molecular mechanisms underlying vascular protective gene expression. The completion of this project will not only further enrich the molecular mechanisms underlying adiponectin-regulated genes, but also help to find new and effective measures in diabetic vascular endothelial protection.