eIF4F复合物活性下调导致糖尿病创面难愈的分子成因及病理意义

eIF4F复合物能通过调控多种促修复分子的翻译起始过程影响创面愈合，已知其上游Akt-mTOR-4EBP1信号通路的异常失活与糖尿病创面难愈密切相关，但机理不明。我们前期研究首次发现：①糖尿病小鼠皮肤组织中4EBP1的O-GlcNAc修饰增强；②持续高糖培养成纤维细胞能够下调eIF4F复合物活性；③限制O-GlcNAc修饰或上调eIF4F复合物活性均能逆转高糖对成纤维细胞增殖的抑制作用；④上调eIF4F复合物活性能加速小鼠皮肤创面愈合。据此我们推测：高糖上调4EBP1和Akt 的O-GlcNAc修饰引发eIF4F复合物活性下调是糖尿病创面难愈的新机制。本项目拟系统探讨高糖对4EBP1和Akt的翻译后修饰方式及水平、eIF4F复合物的活性及其下游分子的表达水平以及细胞生物学行为的影响，为建立以eIF4F复合物为靶点、能高效促进糖尿病创面愈合的治疗新策略提供科学依据。

eIF4F complex can promote wound healing by stimulating the translation initiation process of a variety of molecules. Akt-mTOR-4EBP1 signaling pathway regulates the activity of eIF4F complex and its dysfunction has been found to be closely related to the impaired wound healing of diabetic mellitus ulcers (DMU), but its molecular mechanism remains uncovered. In our previous research, we demonstrated that: ① The O-GlcNAc modification of 4EBP1 was enhanced in the skin tissues of diabetic mice; ② The activity of eIF4F complex was reduced in fibroblasts cultured in sustained high glucose condition; ③ The inhibitory effect of high glucose on the proliferation of fibroblasts can be reversed either by restricting the O-GlcNAc modification or by increasing the activity of eIF4F complex; ④ Up-regulation of the activity of eIF4F complex significantly accelerates the skin wound healing in mice. Accordingly, we speculated that high glucose up-regulate the O-GlcNAc modifications of 4EBP1 and Akt, and thereby down-regulate the activity of eIF4F complex, is a new molecular mechanism of the impaired wound healing of DMU. In this project, we intended to systematically explore the effects of high glucose on the post-translation modifications and expression levels of 4EBP1 and Akt, the activity of eIF4F complex and the expression levels of its downstream molecules and the biological behavior of the fibroblasts, therefore provides a scientific basis for a new strategy to use the eIF4F complex as a molecular target for efficiently promoting wound healing of DMU.