Sufu对TGF-β信号通路及纤维化调控的研究

Dermal and organ fibrosis are main pathologic features of systemic scleroderma, and mesenchymal responses are important for fibrosis. Mesenchymal responses are an essential aspect of tissue repair. Failure to terminate this repair process correctly, however, results in fibrosis and organ dysfunction. TGF-β signaling pathway is the main pathway that inducing fibrosis in systemic scleroderma. Therapies that block fibrosis and restore tissue homeostasis are not yet available for clinical use. Our previous research have identified that overexpression of Suppressor of fused (Sufu) decreased the expression of myofibroblast markers in dermal fibroblast, and reduced dermal fibrosis. But the mechanism is not clear. In this project, we will investigate the role of Sufu in controlling TGF-β signaling and fibrogenesis in vitro and in vivo. It’s an in-depth further continuation of our previous study. The results would contribute to our in-depth understanding of the role of Sufu in fibrosis and provide new molecular targets for the development of methods in fibrosis prevention through Sufu.

皮肤及多系统内脏组织纤维化是系统性硬皮病的主要病理学特点，其中纤维化的关键步骤是间充质转化。间充质转化亦是组织修复的重要环节，若不能正确终止这一修复过程将造成器官功能障碍。其中，TGF-β信号通路是促进系统性硬皮病纤维化发生发展主要信号通路。目前尚无阻断纤维化以及重建组织稳态的临床治疗方法。我们的前期研究结果证实Sufu过表达能降低成纤维细胞中肌成纤维细胞标志物的表达，减轻纤维化程度，但对更为深入的机制仍缺乏了解。本课题拟采用Sufu-KO及Sufu-TG小鼠，在小鼠中建立纤维化模型，并且体外培养Sufu-KO及Sufu-TG小鼠的真皮成纤维细胞，研究Sufu在系统性硬皮病纤维化发病中的作用，并探索Sufu与TGF-β信号转导通路的相互作用。该项目是前期研究的进一步延续和深入。结果不但有助于对Sufu调控纤维化的机制有更为清晰的认识，也有可能为今后以Sufu为靶标的纤维化治疗提供新的思路。

本研究通过体外实验进一步证实了Sufu在BLM诱导的小鼠真皮成纤维细胞中表达是下调的，并且Sufu在表皮中的过表达影响了真皮，BLM诱导后表皮特异性hSufu转基因小鼠真皮厚度显著小于WT小鼠，并且其中胶原蛋白含量和α-SMA的表达均显著降低。另外，通过细胞实验证明，Sufu影响皮肤伤口愈合的机制主要与β-catenin、Gli1以及MMP-3相关。故本研究进一步丰富了系统性硬皮病发病中Sufu参与的分子机制，为今后寻找以Sufu为靶标的纤维化治疗新方案提供了可能的分子靶点。