角质形成细胞表达RIG-I在皮肤创伤愈合过程中的作用及其机制研究

Epidermal keratinocyte proliferation is an essential process of wound repair and diminished keratinocyte proliferation leads to impaired epidermal re-epithelialization, eventually leading to chronic wounds. At present, the mechanisms that regulate epithelial proliferation are incompletely understood. Our previous data show that RIG-I expression is significantly increased in epidermal keratinocyte of skin wounds and upregulated by IFN-γ. Moreover, RIG-I could promote epidermal keratinocyte proliferation and RIG-I-/- mice exhibit delayed wound healing when compared to WT mice. However, the mechanisms by which RIG-I promotes keratinocyte proliferation and wound healing remain largely unknown. In this study, we will identify whether the expression of RIG-I in chronic wounds such as diabetic foot is decreased when compared to normal wounds and explore the underling mechanisms of RIG-I in promoting keratinocyte proliferation and wound healing. What's more, we will also make it clear that whether the agonist of RIG-I could be used in the treatment of chronic wounds. This project will not only clarify the immunomodulatory effect of RIG-I in skin, but also provide evidence for the clinical treatment of chronic wounds.

表皮角质形成细胞分裂增殖是皮肤创伤愈合的关键环节，其增殖能力不足会引起创伤再上皮化受阻，最终导致创伤经久不愈，即慢性创伤。目前，创伤愈合过程中，调控角质形成细胞分裂增殖的机制并不十分清楚。我们前期研究结果证明：RIG-I在皮肤创伤表皮角质形成细胞中的表达增高并受到炎症因子IFN-γ的调控，RIG-I能够促进表皮角质形成细胞分裂增殖且RIG-I基因剔除小鼠皮肤创伤愈合速度显著减慢，但RIG-I促进角质形成细胞分裂增殖以及创伤愈合的分子机制尚不明确。本项目将从临床患者、动物模型及细胞实验着手，以期明确：①慢性创伤如糖尿病足中，RIG-I的表达相对于正常创伤是否降低；②RIG-I促进角质形成细胞分裂增殖以及创伤愈合的具体机制；③RIG-I的激动剂能否用于临床上慢性创伤的治疗。本项目的研究不仅能够明晰RIG-I在皮肤中的免疫调节功能，同时也能为临床上慢性创伤的治疗提供依据。

表皮角质形成细胞增殖即皮肤再上皮化是创伤愈合的关键步骤，异常的再上皮化存在于糖尿病足等多种慢性创伤中。在这项研究中，我们明确了RIG-I能够促进TIMP-1表达而促进创伤愈合，首次证实RIG-I是表皮角质形成细胞增殖的关键调节因子。此外，我们发现RIG-I在正常创伤边缘的角质形成细胞中高表达，而在糖尿病足和STZ诱导的糖尿病小鼠的创伤边缘减少。而RIG-I缺陷小鼠皮肤受到损伤时会出现延迟的创伤愈合表型，RIG-I蛋白能够促进角质形成细胞增殖及创伤愈合。究其机制，RIG-I通过其下游NF-κB信号通路诱导TIMP-1表达而促进创伤愈合。重组TIMP-1蛋白在体外能够促进HaCaT细胞增殖并加速RIG-I基因剔除小鼠及糖尿病小鼠的创伤愈合。综上所述，我们证明RIG-I是介导表皮增殖的关键因子，可能是皮肤损伤严重程度的潜在生物标志物，因此其可能成为治疗糖尿病足等慢性创伤的潜在靶点。

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