AP-1激活miR-940调控胚胎表皮角质形成细胞抑制瘢痕发生的机制研究

增生性瘢痕(HS)已经成为危害人类健康的重要问题，其发病主要是由成纤维细胞(FBs)大量增殖和细胞外基质(ECM)过度沉积所致。前期研究发现，胚胎表皮角质形成细胞(KCs)可抑制FBs增殖和ECM合成，其机制与miR-940表达上调有关，并证实miR-940的靶基因为TGF-β1。通过数据库预测miR-940与上游转录因子激活蛋白-1(AP-1)结合区域，并发现胚胎KCs中AP-1表达上调。据此，我们推测胚胎表皮KCs中AP-1可激活miR-940，通过靶向沉默TGF-β1抑制FBs增殖和ECM合成，减少瘢痕发生。本项目将进一步验证AP-1对miR-940转录调控作用，并以HS来源FBs、AP-1基因敲除小鼠创伤模型为研究对象，通过质粒构建、慢病毒转染等方法，分别从细胞和整体水平展开AP-1激活miR-940调控胚胎KCs抑制瘢痕形成机制的探讨，为有效治疗HS建立新方法。

Hypertrophic scar (HS) has been an important problem threatening human health.Its pathogenesis is mainly caused by overproliferation of fibroblasts (FBs) and excessive deposition of extracellular matrix (ECM).Our preliminary studies have proved that coculturing mid-gestational fetal keratinocytes (KCs) with hypertrophic scar fibroblasts (FBs) significantly reduced proliferation of FBs from HS, and down regulated the expression of collagen.Moreover, we demonstrated that its molecular mechanism is related to the increasing of expression of miR-940. Furthermore, we confirmed that TGF-β1 was a target gene of miR-940.In view of above evidences, we hypothesize that AP-1 activating miR-940 could be involved in inhibition effect of embryonic KCs on scar formation.We intend to identify the role of AP-1 activating miR-940 in function of embryonic KCs in reducing scarring by using FBs from HS, AP-1 knockdown scar animal model, and simultaneously explore the possibilities of signaling pathways in vivo and in vitro by plasmid construction and lentivirus transfection.The confirmation of the above issues would help us to understand the mechanism of embryonic KCs reducing scarring and develop promising stragegies to treat HS.