RIPK1在银屑病发生发展中的调控机制及其抑制剂临床转化研究

基于本团队前期开发原创性RIPK1小分子抑制剂NHWD-1062能显著改善咪喹莫特诱导的银屑病样皮炎，并显著下调IL-23、IL-17、IL-1β等多种炎症因子表达，但其调控机制尚不清楚。本项目提出“RIPK1可能通过角质形成细胞或免疫细胞调控银屑病疾病进展，新抑制剂NHWD-1062在银屑病转归中有着潜在临床转化价值”的科学假说。拟综合利用抑制剂阻断、RIPK1敲除或过表达等技术及多种银屑病样皮炎小鼠模型进一步确证RIPK1可能调控角质形成细胞或T细胞增殖、分化及细胞因子分泌等疾病进展的关键环节，继而构建RIPK1在银屑病发病机制中的调控网络，进一步明确抑制剂NHWD-1062潜在的临床应用价值。本研究将系统阐述RIPK1作为银屑病治疗新靶点的调控机理，为RIPK1抑制剂临床转化奠定基础。

Based on the previous research, the original RIPK1 small molecule inhibitor NHWD-1062 can significantly improve the imiquimod-induced mouse model of psoriasis and decrease the expression of inflammatory factors like IL-23、IL-17 and IL-1β in skin lesions. However, the regulatory mechanism of RIPK1 in psoriasis is still unclear. This project proposes the hypothesis that RIPK1 may regulate the development of psoriasis through keratinocytes or immune cells, and new inhibitor NHWD-1062 has potential clinical transformation value in the treatment of psoriasis. Therefore, this project intends to further confirm that RIPK1 may play a key role in regulating the proliferation, differentiation and cytokine secretion of keratinocytes or T cells by using inhibitor blocking, RIPK1 knockout or over-expression techniques and various mouse models of psoriasis. Moreover, this project intends to construct the RIPK1 regulatory network in the pathogenesis of psoriasis, and identifies the potential of clinical application value of its inhibitor NHWD-1062. This study will systematically elaborate the regulatory mechanism of RIPK1 as a new target for psoriasis treatment, and provide evidence for clinical transformation of RIPK1 inhibitors.