O-GlcNAc修饰对糖尿病内皮祖细胞功能的影响及microRNA相关机制研究

The functions of EPCs in diabetic patients are severely injured and the specific mechanism has not yet been elucidated. O-GlcNAcylation is one of the main mechanism involved in long-time hyperglycemia-induced toxicity. This project aims to study the effects of hyperglycemia on O-GlcNAcylation, OGT and OGA. Moreover, we will reveal whether the elevated level of O-GlcNAcylation impairs EPC functions and clarify whether OGT or OGA is involved in O-GlcNAcylation-induced EPC dysfunction. EPCs improve neovascularization mainly through paracrine function. This project will demonstrate whether increased O-GlcNAcylation impaires paracrine effect of EPC in vivo angiogenesis in diabetic rat by Matrigel plug model. microRNAs may participate in O- GlcNAcylation-induced EPC dysfunction. This project will study the effects of O- GlcNAcylation on miR-126 and-16, and the mimics or inhibitor of miR-126 and-16 will be applied to test the hypothesis above that microRNAs are downstream pathway of O-GlcNAcylation-induced pathology. This study will provide a deep understanding on how O-GlcNAcylation affects the effects of diabetic EPC and mechanism involved in, and thus provide a theoretical basis. The result will provide new treatment strategies and targets for ischemic complications of diabetes.

内皮祖细胞（EPC）功能在糖尿病患者中受损的具体机制尚未阐明。而O-GlcNAc修饰是导致高糖毒性的主要分子机制之一。本项目拟研究高糖对EPC的糖基转移酶 (OGT)、糖苷酶 (OGA)表达和O-GlcNAc修饰水平的影响，并证实O-GlcNAc修饰上调是否影响糖尿病EPC功能，作用位点是否涉及OGT和OGA。本项目将通过大鼠Matrigel plug模型观察高糖是否通过增加体内O-GlcNAc修饰，从而抑制EPC旁分泌功能及在体血管新生能力。microRNA可能介导O-GlcNAc修饰对糖尿病EPC功能损害作用，本项目通过研究O-GlcNAc修饰对miR-126和-16表达的影响，并利用miR模拟物或抑制剂转染糖尿病EPC探讨O-GlcNAc修饰作用的下游机制。该研究将阐明O-GlcNAc修饰对糖尿病EPC的功能影响及其潜在机制，可以为糖尿病缺血性并发症临床治疗提供新的治疗路径和靶点。

O-GlcNAc修饰是导致高糖毒性的主要分子机制之一。而内皮祖细胞（EPC）功能在糖尿病患者中受损的具体机制尚未阐明。而本项目研究高糖对EPC的糖基转移酶 (OGT)、糖苷酶 (OGA)表达和O-GlcNAc修饰水平的影响，并证实O-GlcNAc修饰上调是影响糖尿病EPC的迁移，增殖以及旁分泌功能，采用OGT siRNA和OGA抑制剂证实作用位点涉及OGT和OGA。此外本项目将进一步通过研究O-GlcNAc修饰对miR-126和-16表达的影响，并利用miR模拟物或抑制剂转染糖尿病EPC探讨O-GlcNAc修饰作用的下游机制。本项目将通过大鼠Matrigel plug模型观察高糖是否通过增加体内O-GlcNAc修饰，从而抑制EPC旁分泌功能及在体血管新生能力。microRNA可能介导O-GlcNAc修饰对糖尿病EPC功能损害作用，该研究将阐明O-GlcNAc修饰对糖尿病EPC的功能影响及其潜在机制，可以为糖尿病缺血性并发症临床治疗提供新的治疗路径和靶点。