IKK-beta的SUMO化修饰在糖尿病创伤愈合中的作用与机制研究

Inflammatory disorders is an important feature of diabetic wound healing, and the inflammatory response is closely related to the regulation of macrophage. Many studies have shown that macrophage polarization plays a key role in regulating macrophage function. .SUMOylation is a widespread and important post-translational modification. Our previous study has showed that IKK-beta could be SUMOylated, and SUMOylation can promote IKK-beta activity and NF-kappaB activation. It was widely known that activation of NF-kappaB signaling pathway linked to macrophage polarization and wound inflammatory response. Therefore, we proposed that Inflammatory disorders in diabetic wound healing due to the dysfunction of macrophage infiltration and macrophage polarization, SUMOylation of IKK-beta regulates the activation of itself and NF-kappaB signaling pathway, which involved in the regulation of macrophage polarization and the ultimate impact of diabetic wound healing. We plan to use biochemistry、molecular cell biology techniques and other means to test this hypothesis, and this study will help to elucidate the pathological/physiological molecular-mechanism of diabetic wound healing and provide a theoretical basis for the treatment of diabetic wound healing.

炎症反应紊乱是糖尿病创面难愈的重要特征，而机体的炎症反应与巨噬细胞的调控密切相关。大量研究证实，在对巨噬细胞功能的调控方面，巨噬细胞的极化具有重要作用。.SUMO化修饰是细胞内普遍存在且具有重要功能的一种蛋白质翻译后修饰。我们的前期研究结果发现，NF-kappaB信号通路活化的关键激酶IKK-beta能够发生SUMO化修饰，且SUMO化修饰可以促进IKK-beta的活化以及NF-kappaB信号通路的活化。鉴于NF-kappaB的活化与巨噬细胞极化以及创伤炎症反应之间的紧密联系，我们推测糖尿病创伤愈合过程中炎症反应的紊乱是由于巨噬细胞浸润和巨噬细胞极化失常所致，IKK-beta可通过SUMO化修饰来调节自身以及NF-kappaB信号通路的活化，从而参与巨噬细胞极化的调控，最终影响糖尿病创面的愈合。我们拟通过生物化学、分子细胞生物学等手段来验证这一假设，该研究将有助于阐明糖尿病创伤难愈的病理生理分子机制，为日后治疗糖尿病创伤愈合提供理论基础。

弱激光治疗（又被称为光生物调节作用）作为一种无创无痛的治疗方法一直以来饱受争议，缘于其在促进一些特殊性创面（如慢性/难愈性创面）的愈合上虽具有良好的临床疗效，但对其功效背后所暗含的确切分子机制却知之甚少。在本研究中，我们发现弱激光治疗可以促进慢性/难愈性创面的愈合，原因是弱激光作用可以加速角质形成细胞的迁移，而该步骤对于伤口表皮化以及皮肤创面愈合必不可少。进一步，我们揭示了弱激光调节角质形成细胞迁移的分子机制，即弱激光可特异性下调SENP2导致NDR1/STK38的SUMO化修饰水平增加，而发生于Lys-465位的SUMO化修饰通过破坏NDR1与MEKK1/2之间的相互作用，从而减弱其对p38/ERK1/2-MAPK信号通路的抑制作用，最终导致弱激光介导的角质形成细胞迁移加快以及伤口再表皮化。我们的研究填补了针对弱激光治疗分子机制研究的空白，为弱激光治疗在创伤修复方面的临床应用提供了重要的理论支持。