糖尿病个体内皮祖细胞（EPC）数量减少且功能下降但机制不明，限制了活化内源性EPC治疗糖尿病血管并发症的前景。低氧诱导因子-1α（HIF-1α）是体内活化EPC的关键转录因子，稳定HIF-1α对EPC活性至关重要，但糖尿病时HIF-1α表达下降。课题组发现Rnd3表达下降可导致HIF-1α泛素化降解增多而影响损伤组织的血管新生，而糖尿病EPC中Rnd3表达下降；进一步生物学信息分析显示Rnd3启动子上具有HIF-1α的结合位点。由此，本项目假设糖尿病情况下EPC中Rnd3表达不足将引起HIF-1α/Rnd3信号反馈环路功能缺陷，这可能是导致糖尿病EPC生物学功能障碍的新机制。本项目拟从体内、体外两个层面研究Rnd3影响EPC功能及其在修复糖尿病血管损伤中的作用并探讨其分子机制，明确靶向干预HIF-1α/Rnd3信号反馈环路对EPC生物学功能的影响，为糖尿病伤口愈合治疗提供新靶点与新策略。

To date, it is still unclear about the mechanisms regarding the decrease in number and dysfunction of the endothelial progenitor cell (EPC) in diabetic patients, which limited the prospects in application of activated endogenous EPC for treatment of diabetic vascular complications. Hypoxia inducible factor-1α (HIF-1α) is a key transcriptional factor that involves in activating the EPC, and stabilization of HIF-1α is essential for EPC activity. However, the expression and activity of HIF-1α were decreased in diabetes mellitus. Our previous studies have showed that downregulation of Rnd3 would result in an increase in HIF-1α hydroxylation and a subsequent HIF-1α degradation through ubiquitin proteasomal system (UPS), in turn following an impaired response to angiogenesis post tissue injured. Interestingly, we found that the decreased Rnd3 was occurred in diabetic EPC; besides, bioinformatics analysis further showed that there existed the binding sites of HIF-1α in the promoter of Rnd3. In this proposal, we hypothesize that the deficiency of Rnd3 may compromise the HIF-1α/Rnd3 signal feedback loop in diabetic EPC, which may be a new mechanism involved in the diabetic EPC dysfunction. In this project, we aim to explore the effects of dysregulation of Rnd3 on the biofunction of diabetic EPC as well as the molecular mechanism related to the diabetic vascular injury repair combining in vitro experiments and diabetic hindlimb ischemia mice models, and to demonstrate the effect of targeting HIF-1α/Rnd3 signal feedback loop on the biological function of EPC. The findings of this project would provide a potentially new target and strategy for treatment of diabetic wound healing based on EPC infusion.