基于RORγt靶点的雷公藤内生真菌免疫抑制活性成分及其作用机制研究

针对Th17及相关细胞因子的免疫抑制药物研究是自身免疫性疾病治疗的发展方向。以转录因子RORγt为靶点的Th17抑制剂极有望成为最安全、有效的自身免疫性疾病治疗药物。本研究以IL-17表达抑制和RORγt受体结合实验为活性筛选方法，选择雷公藤内生真菌发酵液中具有IL-17表达抑制活性的菌株为研究对象，通过活性追踪，应用各种色谱分离技术分离其中能够抑制IL-17表达且与RORγt受体具有较强结合作用的化合物，并对其进行RORγt转录活性、mRNA表达水平，Th17细胞分化，核受体及T细胞抑制专属性等免疫抑制活性评价。阐明活性化合物的免疫抑制作用机制及构效关系，发现新型的RORγt受体抑制剂。本项目有助于从雷公藤内生真菌中发现作用机制明确的具有免疫抑制活性的先导化合物，进而为发现治疗自身免疫性疾病的药物奠定科学基础。

It is the developing direction of autoimmune disease treatment to study the immunosuppressive drug aimming at Th17 and its cytokines. The inhibitors, of which are Th17 targeted to RORγt, are promising to be the most safe and effective therapeutic drugs. In our research, to isolate IL-17-suppressed and RORγt binding chemical constituents from the fermentation broth of endophytic fungi in Tripterygium wilfordii Hook. f. (TWHf), several column chromatographic techiques are used by bioactivity-guided fractionation. The separation process are directed by RORγt receptors binding and IL-17-suppressed assays. Then, the studies, of which are the transcriptional activity and mRNA expression level of RORγt, the differentiation of Th17, the inhibitive specificity to T cells and nuclear hormone receptors, are carried out in order to clarify the mechanisms of action and structure-activity relationships, and discover new inhibitors of RORγt receptors. This study are contributed to the discovery of immunosuppressive leading compounds from endophytic fungi in TWHf, and to establishing scientific foundation for the discovery of therapeutic agents which can attenuate autoimmune diseases.