同型半胱氨酸水解酶对树突状细胞功能的调控作用及机制研究

树突状细胞（DC）在免疫反应中起着决定性的重要作用，直接参与自身免疫性疾病的病理进程。我们运用同型半胱氨酸水解酶（SAHH）靶向抑制剂DZ2002，证明抑制SAHH产生免疫抑制效应，改善系统性红斑狼疮（SLE）小鼠和实验性自身免疫性脑脊髓炎（EAE）小鼠的病理进程及相关症状，影响DC的分化及功能，改变初始T细胞的选择性分化；发现SAHH反应产物同型半胱氨酸（Hcy）在SLE模型小鼠中随着疾病进展有升高趋势，随着治疗后症状的缓解，Hcy水平随之降低。基于上述发现，本项目深入开展SAHH对DC的功能调控及作用机制研究（包括固有免疫和获得性免疫），同时基于自身免疫疾病模型，研究Hcy作为自身免疫性疾病进展的生物标志物的可能性。研究结果不仅阐明SAHH调控DC的作用机制，为SAHH抑制剂的后续研究提供理论基础，并且促进自身免疫病治疗新靶点的研究，为疾病生物标志物的研究提供新线索。

Dendritic cells (DCs), as a bridge between innate and adaptive immunity, play a key role in autoimmune diseases. We proved that targeted in S-Adenosyl-L-Homocysteine Hydrolase (SAHH) exerted therapeutic activity in autoimmune diseases such as experimental autoimmune encephalomyelitis (EAE) and systemic lupus erythematosus (SLE), affected the differentiation and function of DCs, resulted in the altered microenvironment for na?ve T cell differentiation. We also found that the level of homocysteine (Hcy), the product of SAHH reaction, correlated with disease severity in lupus mice. Bases on these results, further studies would be carried out to explore the underlying mechanism of SAHH in DCs function, both in innate and adaptive immunity, and evaluate the potential value of Hcy as a biomarker in autoimmune disease. This project will push forward the frontiers of drug discovery. And the research of drug target and biomarker will also bring forth new ideas in drug discovery and development.