磷酸酶SHP2促进IL-23转录加剧银屑病发病的分子机制及潜在药靶研究

银屑病是一种累及皮肤的慢性自身免疫性疾病，详细发病机制仍不清楚。前期研究发现，磷酸酶SHP2可促进银屑病发病过程中关键性细胞因子IL-23的转录，加剧小鼠银屑病发病。本项目拟进一步解析不同发病时期小鼠皮损组织巨噬细胞、树突状细胞及T细胞中SHP2的变化特征，探讨SHP2活化与皮肤炎性因子动态改变的内在关联；分别运用巨噬细胞、树突状细胞以及T细胞上SHP2条件性敲除鼠，考察不同细胞上敲除是否改善小鼠银屑病发病；进一步阐明SHP2调控IL-23转录的详细机制，结合磷酸化蛋白质组学手段寻找SHP2直接或间接影响的转录因子，挖掘SHP2新的调控模式；借助临床银屑病患者血液和皮损样本，明确SHP2与银屑病发生发展的相关性；利用SHP2小分子抑制剂进一步确证体内改善小鼠银屑病的疗效，为SHP2作为银屑病新型药物治疗靶标奠定基础。本项目的成功实施将为阐明银屑病的病理机制以及发现新的潜在药靶提供实验依据。

Psoriasis is a chronic skin autoimmune disease, and the detailed pathomechanism remains unclear. Our previous studies showed that phosphatase SHP2 aggravated psoriasis in mice through promoting the transcription of IL-23. This project is to investigate the critical role of SHP2 in the pathogenesis of psoriasis. To explore the dynamic relationship between SHP2 activation and skin inflammation, macrophages, dendritic cells and T cells from mice at different stages of imiquimod-induced psoriasis were separated and analyzed; Using macrophage, dendritic cell or T cell SHP2 conditional knockout mice, the effect and mechanism of SHP2 deficiency on imiquimod-induced murine psoriasis model was investigated; To explore the detailed mechanism of SHP2's up-regulating IL-23 transcription in imiquimod-induced murine psoriasis model, the new partners of SHP2 were identified using phosphoproteomics and Co-IP-MS; Using psoriasis patients' blood and skin pathological samples, the correlation between SHP2 and its downstream related signaling pathways and the occurrence and development of psoriasis was further clarified. Using various SHP2 small molecule inhibitors, the effect of SHP2 inhibition on imiquimod-induced murine psoriasis model was examined. The successful implementation of this project will provide an experimental basis for elucidating the pathological mechanism of psoriasis and the discovery of new potential drug targets.