皮肤区域免疫特性及银屑病靶向治疗新策略

Psoriasis is an autoimmune skin disease, one of the world's top ten chronic disorders.The incidence of psoriasis is 0.5%, and approximately 800 million patients in China. We found that cell cycle negative regulator Protein Phosphatase (Ppp6c) was markedly down-regulated in lesional skin of patients with psoriasis, and it was a consequence of up-regulated IL-17. To study the efficient strategy to cure psoriasis via inhibiting Th17 differentiation, our group developed a new method for the isolation of novel skin-derived mesenchymal stem cells (S-MSCs). We found that S-MSCs displayed a faster growth rate than bone marrow-derived MSCs (BM-MSCs), and effectively suppressed Th17 cell differentiation. A part of results was published in STEM CELLs in 2014. Meanwhile, we have constructed Ppp6cfl/fl-K5Cre mouse model to study the Ppp6-mediated cross-talk between Th17 and KC. The current project intends to use a psoriasis mouse model, perform the following studies. 1) Signaling pathway(s) and molecules involved in hyperproliferation of KC in psoriasis; 2) Mechanisms of S-MSCs in the regulation of Th17 differentiation. Our work will possibly provide a valuable scientific theory and basis for clinical utility of S-MSCs in the treatment of psoriasis.

银屑病（Psoriasis）是皮肤免疫性疾病，世界十大顽症之一，我国发病率为0.5%，患者约800万。课题组前期发现：细胞增殖负调节子蛋白磷酸酶6（Ppp6c）在银屑病表皮细胞中低表达，原因是皮损处高表达IL-17所致。为了探索抑制Th17细胞分化治疗银屑病的新策略，课题组确立了快捷、高效分离新型皮肤间充质干细胞（S-MSCs）的方法。与骨髓MSCs相比，S-MSCs易获得，且有效抑制Th17分化。部分成果2014年被干细胞权威杂志Stem Cells发表。同时，课题组首次构建了皮肤角质形成细胞（KC）Ppp6c条件性基因剔除小鼠，用于研究KC与Th17间cross-talk。该项目拟进一步求证：1、银屑病皮损中T细胞免疫特性调控KC分裂、增殖的信号及关键因子；2、银屑病中S-MSCs对Th17分化的作用机制。项目的完成可为临床上理解银屑病发病机制及有效治疗提供有价值的科学理论和依据。

本项目以严重危害我国人民健康的自身免疫性疾病：银屑病为核心，以干细胞与免疫细胞的互作与表观调控和自身免疫性疾病发生发展之间关系为基点，深入研究S-MSCs通过影响Th17细胞的分化来抑制角质形成细胞增殖的假设并进一步研究其免疫调节机理。项目负责人在自身免疫性疾病免疫学机理和治疗新靶点领域取得了系列创新成果：（一）发现病毒感染激发了自身免疫性疾病的发生发展（EMBO MM 2017），提出寻常型银屑病是由病毒感染激发，抗病毒免疫应答中易感基因促进表皮细胞与免疫细胞互作异常而导致疾病发生发展的病因学假说，为银屑病等自身免疫性疾病诊治提供了新思路；（二）首次阐明银屑病病人角质形成细胞单碳循环异常，提示单碳循环或MAT2A蛋白有可能成为干预银屑病的新靶点和新机制（ EBioMed 2018；ZL 2013106233142）；（三）发现靶向KC代谢重编程改善小鼠与非人灵长类的类银屑病表型 这些研究发表通讯作者论文11篇，合计IF：77.7，授权专利3项。同时在本项目的资助下，发现NOHA或成为银屑病新型治疗药物。项目负责人2017年获得国家杰出青年基金的支持，获吴孟超医学青年基金奖。本项目中免疫学新机制的阐明和新靶点的发现有利于增强对负调控分子和负调控细胞表观调控的理解，为自身免疫性疾病的诊治提供新思路新方法。