胶原受体DDR2通过YAP/TAZ和JAK/STAT3通路正反馈调控增生性瘢痕形成的作用及机制研究

Hypertrophic scar is caused by excessive fibrosis during wound healing. There is no effective drug target for the treatment of hypertrophic scar. Collagen receptor DDR2 plays an important role in fibrosis. DDR2 regulates fibrosis in the form of phosphorylation and non-phosphorylation, but the mechanism of DDR2 in hypertrophic scar formation is still unclear. TGF-1 and collagen I of hypertrophic scar environment can promote the expression and phosphorylation of DDR2. Our previous studies showed that the expression of DDR2 was significantly increased in hypertrophic scar than normal skin, and the expression DDR2 is closely related to YAP/TAZ and JAK/STAT3 pathway. It has been reported that YAP/TAZ and JAK/STAT3 pathway can regulate the expression of TGF-1 and collagen I. This study planned to study the effect of DDR2 expression and phosphorylation on hypertrophic scar formation， and to elucidate the molecular mechanism of ositive feedback regulation of collagen receptor DDR2 on formation of hypertrophic scar through YAP/TAZ and JAK/STAT3 pathway. Our study will provide a theoretical basis for the targeted prevention and treatment of hypertrophic scar and the development of DDR2 phosphorylation inhibitors.

增生性瘢痕是创面过度纤维化的产物，目前仍缺乏有效的治疗靶点。胶原受体DDR2和纤维化关系密切，磷酸化和非磷酸化的DDR2均能够调控纤维化过程，但在增生性瘢痕形成中的作用机制仍不明确。增生性瘢痕环境中的TGF-β1和I型胶原是促进DDR2表达和磷酸化的重要因素。申请人的预实验研究发现增生性瘢痕中成纤维细胞DDR2的表达显著高于正常皮肤，并且DDR2的表达和YAP/TAZ、JAK/STAT3通路有关。文献报道YAP/TAZ和JAK/STAT3通路能够调控TGF-β1和I型胶原的表达。本课题在此基础上，深入研究DDR2的表达和磷酸化对增生性瘢痕形成的调控作用，阐明DDR2通过YAP/TAZ和JAK/STAT3通路正反馈调控纤维化的分子机制，为DDR2靶向防治增生性瘢痕以及DDR2磷酸化抑制剂的研发提供理论依据。

研究背景：增生性瘢痕是创面过度纤维化的产物，目前对增生性瘢痕的靶向治疗仍缺乏有效的分子靶点。研究增生性瘢痕的形成机制对减少病理性瘢痕的产生，促进创面愈合具有重要价值。盘状结构受体2（Discoidin domain receptor 2，DDR2）是位于细胞膜表面的受体型酪氨酸蛋白激酶，在纤维化疾病中发挥重要的作用。依据前期基础我们推断：推测DDR2能够通过YAP/TAZ和JAK/STAT3通路调控增生性瘢痕的纤维化过程。本基金研究了胶原受体DDR2的表达和磷酸化对增生性瘢痕纤维化过程的调控作用，探索DDR2调控皮肤纤维化可能的分子机制。研究内容：项目研究主要从以下几个方面进行开展：1. 通过荧光探针、western等方法，验证了DDR2在增生性瘢痕纤维化的组织和细胞中的表达显著提高；2.通过DDR2成纤维细胞条件敲除小鼠和野生型小鼠皮肤纤维化模型的比较，明确了DDR2对增生性瘢痕纤维化的作用；3. 在细胞层面，进一步明确DDR2的表达和磷酸化对YAP/TAZ和JAK/STAT3通路的机制。科学意义：为DDR2靶向防治增生性瘢痕以及DDR2小分子磷酸化抑制剂的研发提供理论依据。