基于mTORC1/S6K1介导的自噬-溶酶体途径调控表皮分化探讨芍苓方治疗银屑病的作用机制

银屑病是以表皮分化异常为特征的慢性增生性皮肤病，调控表皮正常分化是银屑病的重要治疗策略。自噬-溶酶体途径是表皮分化必需的早期信号传递过程，通过抑制mTORC1/S6K1信号通路，能够活化角质形成细胞自噬-溶酶体途径，促进表皮正常分化。芍苓方是由国医大师禤国维教授所创制银屑灵方化裁而来，临床疗效确切，其作用机制亟需阐明。课题组前期研究发现，芍苓方能够上调银屑病动物和细胞模型中自噬水平，且能够抑制mTOR分子磷酸化。因此，提出“芍苓方通过抑制mTORC1/S6K1信号通路活化自噬-溶酶体途径，进而调控表皮分化治疗银屑病”的科学假说。本研究通过分离银屑病患者皮损组织成分制备3D全层银屑病皮肤模型，并结合银屑病动物和细胞模型，研究芍苓方对mTORC1/S6K1介导的自噬-溶酶体途径调控表皮分化的作用机制。本课题将阐明芍苓方治疗银屑病的作用机制，同时将为芍苓方临床开发为安全有效的现代制剂提供基础。

Psoriasis is a chronic proliferative skin disease characterized by abnormal epidermal differentiation. Regulating normal epidermal differentiation is an important treatment strategy for psoriasis. The autophagy-lysosome pathway is an early signaling process which is necessary for epidermal differentiation. Inhibiting the mTORC1/S6K1 signaling pathway can activate the autophagy-lysosome pathway of keratinocytes to promote normal epidermal differentiation. PSORI-CM02 is the formula simplified and optimized from Yin Xie Ling, which is created by National Medical Master, Professor Guowei Xuan. PSORI-CM02 has specific clinical efficacy for the treatment of psoriasis, which is urgently needed to elaborate the mechanism. Recently, our team found that PSORI-CM02 could induce a massive flux of autophagy and inhibit the phosphorylation of mTOR in IMQ-induced mice and TNF-α induced keratinocytes. Therefore, we make the scientific hypothesis that "PSORI-CM02 can inhibit the mTORC1/S6K1 signaling pathway to activate the autophagy-lysosome pathway, thereby regulating epidermal differentiation for the treatment of psoriasis". In this study, a 3D full-thickness human skin model of psoriasis was prepared by separating skin tissue components from psoriatic patients, combined with IMQ-induced mice and multiple cytokines induced keratinocytes, to explore the mechanism of PSORI-CM02 on epidermal differentiation which is regulated by mTORC1/S6K1 mediated autophagy-lysosome pathway. This study wil elucidate the potential mechanism of PSORI-CM02 on the treatment of psoriasis and provide the basis for the clinical application.