ZEB1通过介导TGF-β1/Smad信号通路诱导增生性瘢痕形成的机制研究

ZEB1 is a transcription factor highly expressed in hypertrophic scarring according to our previous discoveries. It is related to fibrosis in multiple tissues. However, the function of ZEB1 in skin tissue remains unclear. In our previous investigation, ZEB1 could up-regulate the expression of α-SMA and extra cellular matrix proteins. It could also enhance the transcription of FKBP10, which severs as a crucial role in hypertrophic scarring based on our previous results. ZEB1 over-expression was also observed in fibroblasts treated with TGF-β1. According to these results, we hypothesize that ZEB1, as an essential transcription factor, could mediate TGF-β1 induced hypertrophic scarring through enhancing the transcription of α-SMA and FKBP10, therefore, promoting the acquisition of myofibroblast phenotype and ECM protein deposition. To validate these proposals, experimental methods such as small interfering RNA, adenovirus, CHIP, Western blot, q-PCR will be applied in vivo or in vitro. Our findings will provide novel insights into prevention and treatment of hypertrophic scarring.

ZEB1是我们发现高表达于增生性瘢痕的一种转录因子，与多种组织纤维化有关，但其在皮肤中的功能知之甚少。预实验提示，ZEB1与细胞外基质（ECM）、纤维化标记物α-SMA及我们先前研究的瘢痕增生相关基因FKBP10的表达呈正相关，且其受经典的TGF-β1/Smad通路正向调控，但ZEB1在增生性瘢痕中的作用及机制仍有待进一步探讨。为此我们提出以下假说：创伤愈合中，高表达的TGF-β1通过激活Smad信号通路促进成纤维细胞中ZEB1的表达，ZEB1通过转录调控功能上调α-SMA和FKBP10，诱导大量成纤维细胞向肌成纤维细胞转化，并通过FKBP10加剧ECM的沉积，最终导致瘢痕增生。为验证假说，我们通过成纤维细胞、小鼠增生性瘢痕模型，采用RNA干扰、腺病毒转染、CHIP、Western blot、q-PCR等手段，从分子、细胞、组织和动物整体水平探讨ZEB1在瘢痕增生过程中的重要作用及机制。

增生性瘢痕与损伤后皮肤过度纤维化相关，影响组织功能并导致审美缺陷，虽然压力疗法、激光治疗、手术切除以及局部注射类固醇等已被报道用于瘢痕治疗，但仍缺乏特异性，需要探索新型治疗靶点。ZEB1是与多种脏器纤维化有关的转录因子，我们发现其在增生性瘢痕组织中高表达，并与细胞外基质（ECM）蛋白、纤维化标记物α-SMA及瘢痕增生相关基因FKBP10的表达呈正相关，且能够调控人增生性瘢痕成纤维细胞（HHSF）的活性。进一步研究发现TGF-β1激活成纤维细胞中Smad信号通路，使Smad3入核结合ZEB1启动子促进其转录。而ZEB1又通过转录调控功能上调FKBP10，诱导成纤维细胞向肌成纤维细胞转化，加剧ECM的沉积，促进增生性瘢痕的形成。通过在小鼠增生性瘢痕模型的体内实验，我们验证了下调ZEB1可以抑制胶原沉积，减轻皮肤纤维化。总的来说，我们探索了TGF-β1/Smad3/ZEB1/FKBP10通路在增生性瘢痕发生发展中的作用，这些结果有望为增生性瘢痕的治疗提供潜在的靶点。