基于周细胞功能探究过山枫活性成分抗类风湿关节炎滑膜血管新生的作用

类风湿关节炎（RA）是高致残的多发病，停止药物干预后RA容易复发、甚至加重，抗滑膜血管新生是治疗RA的有效策略。中药过山枫在临床上常用于治疗风湿痹痛且疗效显著。我们的前期研究发现过山枫活性成分扁蒴藤素靶向于血管内皮细胞以抑制RA滑膜血管新生；但停药后滑膜血管产生重塑而引起疾病的复发，周细胞可能是参与调控该进程的关键因素。据此，我们以周细胞为体外模型从过山枫中筛选获得的活性成分Nimbidiol（Nim）能够选择性抑制周细胞功能，初步的机制研究证实Nim可能是通过下调DLL4的表达以调控周细胞的功能。本项目拟从细胞与动物模型证实扁蒴藤素干预后周细胞介导的内皮祖细胞分化调控血管重塑的作用及其机制，且揭示Nim靶向周细胞抑制RA滑膜血管新生的分子机理；旨在阐明过山枫抗RA的药效物质基础及作用机制，为临床上过山枫治疗RA提供现代药理学依据，也为将靶向于周细胞发展成为抗RA的策略提供实验基础。

Rheumatoid arthritis (RA) is a disorder with high rate of incidence and disability, which is prone to relapse or even worsen after withdrawing the drug therapy. However, inhibition of angiogenesis on synovium may be an effective potential strategy for the treatment of RA. Celastrus aculeatus Merr., a traditional Chinese herbal medicine, has been used in China to treat various rheumatoid diseases with remarkable curative effect. Our recent results found that pristimerin, a bioactive component from Celastrus aculeatus Merr., inhibited synovial angiogenesis in adjuvant-induced arthritic rats by targeting vascular endothelial cells, but revascularization occurred on synovium resulting in recurrence of the disease after withdrawal of interference with pristimerin. In vivo experiments had shown that synovial revascularization in adjuvant-induced arthritic rats was mainly regulated by pericytes. We screened and obtained Nimbidiol (Nim), a different bioactive component from Celastrus aculeatus Merr., which selectively inhibited the function of pericytes; and the initial mechanistic studies suggested that Nim may regulated the function of pericytes by decreasing the expression levels of DLL4. In this project, we intend to further confirm that the regulation of revascularization mechanisms is controlled by the pericytes-mediated differentiation of endothelial progenitor cells after withdrawal of interference with pristimerin in vitro and vivo; and reveal the underlying molecular mechanisms of Nim inhibiting synovial angiogenesis in RA. This project aims to illustrate the effective substances and the underlying mechanisms of Celastrus aculeatus Merr., which will lead to providing modern pharmacology basis for clinical usage, and also supplying the evidence for the development of targeting pericytes as a strategy for the treatment of RA.