ATF3在皮肤创伤愈合中促进真皮组织重塑和减少疤痕形成的作用研究

Scarless healing has been a big challenge for studying skin wounds. It has been reported that cytokine expression and inflammation response in the dermis are crucial for the scar formation, however the molecular mechanisms of scar formation is still not completely known, and one of main reasons is due to no ideal animal model for studying skin wound healing. ATF3 is a key stress-response transcription factor, and was shown to play a protection role in tissue injury through controlling different cytokine expression including inhibition of inflammation response, however the function of ATF3 in skin wound healing needs to be clarified. We established a new mouse model containing a regenerated human full-thickness skin, and found that the regenerated human skin could heal after wounding, and its healing procedure was similar to that of normal human skin. Moreover, our preliminary data showed the expression of ATF3 in dermal cells was induced by the scratch assay, and overexpression of ATF3 could promote wound closure in the dermal fibroblast cells, therefore we hypothesize that ATF3 can play a crucial role in skin wound healing。 In order to confirm the hypothesis, the present study will use our established new mouse model to study the role of ATF3 in the human skin wound healing, especially in the dermal remodeling and scar formation, and the underlying molecular mechanisms will be explored as well. Finally, we will identify new chemical compounds, which can enhance ATF3 expression and inhibit inflammatory cytokine expression in the dermal fibroblast, and will validate them to promote skin healing after wound. This study will provide a basis to develop new drugs for treatment of skin wounds by promoting scarless healing.

无疤痕愈合是研究皮肤创伤的一大挑战。研究表明真皮组织中细胞因子表达和炎症反应对疤痕的形成起关键作用，然而疤痕形成具体机理目前尚未清楚，而且其研究缺乏理想的动物模型。 ATF3是一重要压力反应性转录因子, 它可通过抑制不同细胞因子表达包括拮抗炎症反应，对机体组织损伤起保护作用，然而ATF3在皮肤创伤中的作用未见报道。申请者创建了再生人皮肤动物模型，该再生皮肤创伤后愈合和人正常皮肤相似。前期工作发现体外创伤可诱导皮肤细胞ATF3表达，而且高表达ATF3可促进真皮细胞划痕后的愈合，提示ATF3在皮肤创伤中起重要作用。本研究将用再生人皮肤创伤愈合的新型小鼠模型来探讨ATF3在人皮肤创伤愈合中的作用，特别是在真皮组织重塑和瘢痕形成中的作用及相应的分子机理，筛选和验证真皮细胞中调控ATF3及相应细胞因子表达促进愈合的化合物,为今后临床转化用于治疗创伤促进无疤痕愈合提供基础。

无疤痕愈合是研究皮肤创伤的一大挑战。研究表明真皮组织中细胞因子表达和炎症反应对疤痕的形成起关键作用，然而疤痕形成具体机理目前尚未清楚，而且其研究缺乏理想的动物模型。 ATF3是一重要压力反应性转录因子, 它可通过抑制不同细胞因子表达包括拮抗炎症反应，对机体组织损伤起保护作用，然而ATF3在皮肤创伤中的作用未见报道。申请者创建了再生人皮肤动物模型，该再生皮肤创伤后愈合和人正常皮肤相似。前期工作发现体外创伤可诱导皮肤细胞ATF3表达，而且高表达ATF3可促进真皮细胞划痕后的愈合，提示ATF3在皮肤创伤中起重要作用。本研究用再生人皮肤创伤愈合的新型小鼠模型来探讨ATF3在人皮肤创伤愈合中的作用，特别是在真皮组织重塑和瘢痕形成中的作用及相应的分子机理。项目研究结果表明，高表达的 ATF3 可促进皮肤创伤愈合，特别是真皮组织的愈合和减少疤痕形成，而低表达ATF3结果正好相反；机理上研究显示ATF3主要通过调控不同细胞因子来促进真皮组织的重塑；本研究鉴定了创伤愈合中 ATF3 新的作用靶因子并验证了再生人皮肤小鼠模型为研究人皮肤创伤愈合的理想模型。此外，本研究筛选和验证了真皮细胞中调控ATF3及相应细胞因子表达促进愈合的化合物，为今后临床转化用于治疗创伤促进无疤痕愈合提供了基础。