青藤碱靶向胆碱能抗炎通路中α7nAChR治疗RA的机制研究

青藤碱（SIN）是中药青风藤的主要有效成分，是治疗类风湿性关节炎（RA）的常用药。但其作用于靶细胞时确切结合或作用的靶分子尚未明确。我们最新研究发现SIN的抗炎作用和抑制NF-κB活化依赖于烟碱型乙酰胆碱受体α7（α7nAChR，简称α7）。α7是机体胆碱能抗炎通路（CAP）中的关键受体，并参与细胞活化、增殖。据此我们提出SIN通过作用于α7抑制炎症及滑膜组织的异常增生、α7是SIN治疗RA的关键靶点的假设。本项目应用体外巨噬细胞和α7基因敲除小鼠进一步明确SIN靶向α7的抗炎作用和胞内信号机制，体外实验观察SIN抑制成纤维样滑膜细胞的炎症、增殖与靶向α7的关系，采用RA动物模型观察SIN的治疗作用与靶向α7的关系。本研究从神经-免疫、CAP角度探讨SIN治疗RA的作用机制，为阐释SIN治疗RA、青风藤祛风通络功能的现代药理学内涵提供依据，也为靶向α7抗关节炎的新治疗策略提供实验依据。

Sinomenine (SIN) is a major effective component of the Chinese materia medica Sinomenium acutum for treatment of rheumatoid arthritis (RA). Our team had elucidated some anti-inflammatory mechanism of SIN before, but the exact binding sites or proteins on target cells remain unclear. We found recently the anti-inflammation effects and the inhibition of activation of NF-κB of SIN were mediated by nicotinic acetylcholine receptor alpha 7 (α7nAChR). α7nAChR is the key receptor in cholinergic anti-inflammatory pathway (CAP), and is involved in cell activation and proliferation. So we forward hypothesis that SIN inhibition effects on inflammation and synovial hyperplasia depend on α7nAChR, which is the major target of SIN in treatment of RA. The anti-inflammation mechanism of SIN targeting α7nAChR will be revealed by analysis SIN effect on macrophages and α7-deficient mice. The correlation between α7nAChR and SIN effect on inflammation and proliferation of fibroblast-like synoviocytes cells will be detected in vitro. The therapeutic effects of SIN on RA rat model by acting on α7nAChR will be investigated. From the angle of neuro-immune to study the mechanism of sinomenine acting on α7nAChR of cholinergic anti-inflammatory pathway will provide theoretical basis on treatment of RA, and be helpful to explain Qu-Feng-Tong-Luo function of Sinomenium acutum. The study will also provide a new target and a new strategy to study treatment of RA.