D-甘露糖通过调控TSC2/mTOR信号通路抑制角质形成细胞增殖对抗银屑病发生发展的作用及机制研究

Psoriasis is a common chronic inflammatory skin disease. The over- proliferation of keratinocytes (KCs) plays an important role in the pathogenesis of psoriasis. Based on the previous studies on the metabolomics of psoriasis, we found that the decrease of plasma level of D-mannose in psoriasis patients was related to the pathogenesis of psoriasis. Further studies have shown that D-Mannose can activate AMPK and TSC2 activity, and preliminarily confirmed the function of TSC2 in the pathogenesis of psoriasis. We proposed a novel hypothesis that D-mannose inhibit over-proliferation and inflammatory reaction of KCs by regulating the TSC2/mTOR signaling pathway through activates AMPK activity, and reduce exacerbation of psoriasis. We will study the function of D-mannose and TSC2 (new target molecule) in the pathogenesis of psoriasis from clinical samples, animal models and cell biology, and combine the changes in cellular energy metabolism caused by D-mannose with over-proliferation of KCs in psoriasis through AMPK, to determine the mechanism of D-mannose inhibit KCs proliferation by regulation of the TSC2/mTOR signaling pathway in the occurrence and development of psoriasis. This study is expected to discover the new methods and target molecule for the treatment of psoriasis.

银屑病是一种常见的慢性炎症性皮肤疾病，角质形成细胞（KCs）的过度增殖在银屑病发病过程中起着重要作用。基于前期银屑病代谢组学的研究结果，我们发现银屑病患者体内血浆D-甘露糖水平降低与银屑病发病相关。进一步机制研究发现，D-甘露糖可以激活AMPK及后者下游重要分子TSC2，并初步明确了TSC2在银屑病发病过程中的作用。本项目科学假说：D-甘露糖通过AMPK调控TSC2/mTOR信号通路抑制KCs过度增殖及炎症因子释放对抗银屑病的发生发展。本项目拟从临床样本、动物模型及细胞生物学三个层面验证并深入研究D-甘露糖、新靶分子TSC2与银屑病发病之间的关系。以AMPK为桥梁，将D-甘露糖代谢所造成的细胞能量代谢变化与银屑病KCs过度增殖结合，阐明D-甘露糖通过调控TSC2/mTOR信号通路抑制KCs增殖对抗银屑病发生发展的作用机制。本项目有望探寻出银屑病治疗新方法和新靶分子。

银屑病是一种常见的慢性炎症性皮肤疾病，角质形成细胞（KCs）与多种免疫细胞相互作用形成的恶性循环在银屑病发病过程中起着重要作用。首先，基因表达数据库（GEO）数据集分析显示银屑病患者皮损组织中D-甘露糖代谢关键酶甘露糖磷酸异构酶（MPI）表达水平高于正常皮肤组织，且在临床样本中发现银屑病患者和正常人血浆D-甘露糖水平存在显著性差异，这提示D-甘露糖的代谢可能在银屑病的发生发展中发挥了重要作用。通过动物模型研究发现，D-甘露糖下调缺氧诱导因子1α（HIF-1α），抑制角质形成细胞中趋化因子CCL20的表达，从而抑制Th17细胞的局部浸润。因此，D-甘露糖通过抑制HIF-1α/CCL20/Th17细胞轴，阻断角质形成细胞-Th17细胞的恶性循环，抑制炎症反应，对抗银屑病的发展。其次，TSC2在银屑病患者体内低表达，而D-甘露糖可以增强TSC2基因的表达水平。TSC2基因敲降小鼠的血浆代谢组学和皮肤转录组学的研究表明，TSC2调控甘氨酸-丝氨酸-苏氨酸这一代谢通路的关键调控基因GNMT表达，进而影响皮肤组织中DNA甲基化水平，从而对抗银屑病的发展。本项目阐明了D-甘露糖及TSC2分子对抗银屑病发生发展的作用机制，并探寻了局部外用D-甘露糖治疗银屑病的新方法。