转录因子E2F1在内皮祖细胞介导的创伤愈合中的作用及机制

The E2F1 transcription factor is traditionally considered a cell-cycle regulator. However, in this study we found that E2F1 also plays an important role in wound healing. Wound healing is a common and important clinical situation that is associated with many disease processes (e.g., diabetes) and surgical procedures. But how to accelerate the function recovery of wound healing is still largely unknown. Previously we and others have shown that E2F1 regulates infarct sizes in both myocardial infarction and stroke models in mice, and oncogene p53-mediated repression of VEGF expression and neovascularization. Interestingly, a number of studies suggest that mobilization of progenitor cells from bone marrow into blood circulation is associated with a downregulation of E2F1 expression. We recently found that E2F1 knockout mice have faster wound healing function recovery; and knock-out E2F1 gene in endothelial-progenitor-cell (EPC) increases its migration capability. In this study, we will extend our novel preliminary findings by investigating the functional significance of E2F1 in the process of skin wound healing; the specific role of E2F1 in the regulation of EPC function under ischemia/hypoxia and its contribution to the wound healing; and lastly, genetically engineering the expression of a small peptide in EPCs to interfere the E2F1:p53 interaction, thereby augmenting intracellular VEGF expression and enhancing EPC-mediated wound healing.

外伤、手术或糖尿病等引起的伤口长期不愈严重影响患者生活质量，而新生血管不足是影响创伤部位组织修复和再生的重要因素。E2F1是转录因子E2F家族成员之一，传统观点认为E2F1是"转录激活子"，其主要生物学功能为调节细胞周期促进肿瘤发生。但我们前期研究却发现，组织缺血缺氧后E2F1从"转录激活子"转变成为"转录抑制子"， 对血管生成和内皮祖细胞（EPC）功能有极强的抑制作用；缺氧时E2F1与p53相互作用，调节血管内皮生长因子（VEGF）的表达抑制血管生成。我们最新研究提示，E2F1基因敲除小鼠皮肤创伤愈合进程明显加快，伴随EPC迁移能力增强。本项目将在前期研究基础上，进一步确定E2F1在创伤愈合过程中的作用；探究缺氧时E2F1对EPC功能的调节；阐明E2F1影响创伤愈合的细胞机理及分子机理；并利用基因工程手段，靶向干预EPC细胞内E2F1与p53的相互作用，开辟皮肤创伤愈合细胞治疗的新方向。

外伤、手术或糖尿病等引起的伤口长期不愈严重影响患者生活质量，而新生血管不足是影响创伤部位组织修复和再生的重要因素。E2F1是转录因子E2F家族成员之一，传统观点认为E2F1是“转录激活子”，其主要生物学功能为调节细胞周期促进肿瘤发生。但我们前期研究却发现，组织缺血缺氧后E2F1从“转录激活子”转变成为“转录抑制子”， 对血管生成和内皮祖细胞（EPC）功能有极强的抑制作用；缺氧时E2F1与p53相互作用，调节血管内皮生长因子（VEGF）的表达抑制血管生成。本项目将在前期研究基础上，进一步确定E2F1在创伤愈合过程中的作用；探究缺氧时E2F1对EPC功能的调节；阐明E2F1影响创伤愈合的细胞机理及分子机理。本研究发现，E2F1-/-小鼠不仅创面愈合速度更快，且E2F1-/-小鼠创面真皮厚度较WT小鼠厚、胶原沉积较WT小鼠多、创面周围血管较WT小鼠丰富，我们进一步发现E2F1-/-小鼠创面巨噬细胞数比WT小鼠多，但创面组织中的中性粒细胞及T细胞数无明显差异，可是E2F1-/-小鼠创面VEGF表达比WT小鼠增高。我们期望未来能利用基因工程手段，靶向干预创面中E2F1的表达，开辟皮肤创伤愈合治疗的新方向。