HOXA5通过p53信号通路抑制病理性疤痕形成的研究

Pathological scarring is induced mainly by impaired apoptosis. Studies have proved that p53 signal dysregulation is strongly indicated to the pathological scarring, thus presenting a potential target for the control of scar formation. However, no effective method has been found to target this apoptotic pathway till now. In our previous study, we demonstrated that HOXA5 was significantly upregulated during the process of scarless skin regeneration. In addition, HOXA5 promoted keratinocytes apoptosis, and it has been confirmed that p53 is an important downstream factor of HOXA5. These results underlined the importance of HOXA5 in regulation of scarless wound healing through the activation of p53 signal pathway. As a result, we prepare to study the HOXA5 function in transcriptionally modulating p53 gene expression and activating p53 pathway in fibroblasts derived from hypertrophic scars (HSFb) and keloids (KFb). Next, we will inspect the cell apoptosis and cell behavior regulated by HOXA5. Furthermore, we intend to construct a scarring model by p53 knock-out heterozygotic mice and transfected into the wound the mouse HoxA5 cDNA. By doing that, we expect to activate p53 signaling, thus inhibiting wound fibrosis and promoting scarless wound healing. Through our research, we aim to explore the role of HOXA5 in scar inhibition in order to create a new approach to the regulation of wound healing.

细胞凋亡机制受损是病理性疤痕形成的重要原因。研究已证实凋亡刺激蛋白p53的失活对疤痕形成具有显著的推动作用，这提示p53凋亡通路可能成为对抗疤痕增殖的潜在调控靶点。然而如何靶向性激活该通路以抑制疤痕生成，目前尚不明确。本项目前期研究发现，HOXA5在皮肤再生过程中显著激活，并且能诱导皮肤角朊细胞凋亡。并且p53通路已被证实为HOXA5诱导凋亡的下游通路。故推测HOXA5能通过激活p53通路抑制疤痕形成。为验证此假设，本项目拟首先研究HOXA5对疤痕成纤维细胞内p53基因转录激活和p53蛋白通路活化的调控；进而探讨HOXA5对细胞凋亡和细胞行为的影响；然后通过p53+/-小鼠疤痕性创面愈合模型的构建和HOXA5基因的导入，明确HOXA5是否能靶向激活p53通路，进而抑制疤痕的增殖，实现创面的无疤痕修复。通过本研究，探索HOXA5通过p53通路抑制疤痕增殖的可行性，为创伤修复寻找新的调控靶点。

p53 的失活对疤痕形成具有显著的推动作用，而其同时也是HOXA5 诱导凋亡的下游通路。HOXA5已被证实能诱导皮肤角朊细胞凋亡。因而推测HOXA5激活的p53通路对于诱导疤痕细胞凋亡、抑制瘢痕增殖具有重要意义。本项目主要研究HOXA5对瘢痕成纤维细胞凋亡和细胞行为的影响，以及HOXA5对疤痕成纤维细胞内p53基因转录激活和p53蛋白通路活化的调控，并进一步通过p53+/-小鼠创面内hoxa5基因的导入，明确hoxa5是否能靶向性激活p53通路，进而抑制疤痕的增殖，实现创面无疤痕的修复。目前已证实HOXA5可以抑制增生性瘢痕和瘢痕疙瘩成纤维细胞HSFb和KFb的增殖活性，并且促进细胞凋亡，并且HOXA5可以显著降低HSFb和KFb细胞的迁移能力。进一步通过ChIP PCR检测，项目组阐明了HOXA5通过与p53启动子区富含ATTA的HOX核心结合序列结合调控p53的表达。通过western blot 检测证实HOXA5还可以促进p53下游靶基因p21和MDm2的表达。此外，项目组还发现HOXA5能促进含成纤维细胞的胶原网架（FPCL）的收缩，抑制大鼠创面的愈合，抑制胶原增殖和创面的血管化反应。部分研究结果发表在“Brit J Dermatol”和“Ann Plas Surg”上。