转录因子c-myc高表达参与糖尿病难愈创面的再上皮化障碍的机制

Dysfunction of diabetic keratinocytes has been found in diabetic chronic wounds. Transcript factor c-myc and its upstream regulative molecule β-catenin, which is involved in the regulation of cell function is over expressed in diabetic chronic wounds. Increased O-GlcNAc modification, a specific post-translational modification manner of protein was observed in diabetic individuals. We assume that the over expression of c-myc in diabetic chronic wounds is due to the activation of Wnt/β-catenin signaling induced over production, and O-GlcNAc modification induced less-degradation of c-myc. This project integrates, for the first time, the findings that the abnormal expression of c-myc in diabetic chronic wounds with the abnormal proliferation, migration and differentiation of diabetic keratinocyte. The study will explore the effect of high glucose on the expression of c-myc in keratinocyte and the role of c-myc in the impairment of re-epithelialization, as well as explore the reason of increased c-myc expression in diabetic chronic wounds. An experimental approach to rescure the impairment of re-epithelialization of diabetic wound healing will be tested through the manipulation on c-myc expression. The results might make c-myc a new therapeutic target for diabetic impaired healing

糖尿病慢性创面表皮细胞功能异常，参与调节细胞行为的转录因子c-myc及其调控信号β-catenin在糖尿病溃疡创面表皮细胞内表达明显增加。糖尿病体内蛋白的翻译后修饰方式O-GlcNAc修饰水平增加。我们推测糖尿病创面可能存在Wnt/β-catenin信号激活致c-myc产生增加，以及因蛋白的O-GlcNAc修饰增加导致的c-myc降解减少，从而使c-myc在表皮细胞内高表达。课题首次将c-myc在糖尿病慢性创面组织的异常表达与糖尿病表皮角质形成细胞的高增殖、低迁移和分化异常联系起来。研究将从高糖对糖尿病表皮角质形成细胞c-myc表达的影响及其在糖尿病再上皮化障碍中的作用，以及c-myc高表达的原因两方面入手，研究糖尿病创面难愈机制。并力图通过调控c-myc水平而改善糖尿病创面再上皮化障碍。研究结果将有可能使c-myc成为糖尿病难愈创面治疗的新靶点

正常的创面愈合是高度有序的动态过程，再上皮化是创面愈合极为重要的一个环节。再上皮化是指创缘或基底残存的表皮角质形成细胞通过增殖、迁移及分化等行为，完成表皮结构与功能重建的过程，对恢复皮肤屏障功能、抵御外界病原体有重要作用。再上皮化障碍是糖尿病慢性创面最明显的特征之一，糖尿病创面进入持续炎症、甚至永久性不可愈合状态，其特征是慢性病程及频繁复发。糖尿病创面表皮角质形成细胞功能受损，表现为增殖异常、迁移及分化障碍。本研究探索c-Myc及其靶基因S100A6在介导糖尿病创面再上皮化障碍中的作用。主要研究了糖尿病状态下表皮角质形成细胞c-Myc表达增多的机制；探索异常表达的c-Myc对糖尿病创面再上皮化的影响；探索c-Myc及其靶基因S100A6对HaCaT细胞分化功能的影响。. 我们研究发现高糖可激活表皮角质形成细胞WNT/β-catenin通路，β-catenin表达增多，入核后引起下游靶基因c-Myc增多。此外，高糖可通过增加c-Myc蛋白的O-GlcNAc修饰增强其稳定性，间接引起c-Myc蛋白表达增加；糖尿病创缘高表达的c-Myc促进表皮角质形成细胞增殖、抑制其迁移及分化，引起再上皮化障碍。抑制c-Myc及c-Myc蛋白的O-GlcNAc修饰可改善糖尿病创面再上皮化障碍；c-Myc可通过直接转录调控靶基因S100A6介导角质形成细胞分化障碍，抑制c-Myc转录活性或敲减S100A6可改善高糖引起的角质形成细胞分化障碍；c-Myc及S100A6可作为改善糖尿病创面再上皮化障碍的潜在治疗靶点。未来可设计c-Myc及S100A6小分子抑制剂，与创面新材料相结合，应用于创面愈合。成果应用转化是我们下一步的重点研究方向之一。