国家1类候选新药钩吻素子治疗类风湿关节炎作用机制的研究

Koumine is expected to be developed as a novel drug with independent intellectual property rights against rheumatoid arthritis (RA) for its good characteristics of patent medicine. And our previous series of studies have preferentially domenstrated its therapeutic effect on RA, as well as its regulation effect on the imbalance of Th cells in RA animal models. However, the underlying mechanism including the target, the pathway and the action mode of koumine is still needed to be explored by further systematical studies. Our previous work has also found that the mitochondrial translocation protein (TSPO), which participates in immunomodulation, is an important target of koumine. Therefore, this project intends to use Th-cell polarization as a breakthrough point in which the regulation effect of koumine will be further clarified firstly at the cellular level on the basis of the previous work to elucidate the action mode of koumine in the treatment of RA. And secondly, the molecular mechanism of the effect of koumine against RA will be disscussed from the viewpoint of the three signals in T cell activation. Finally, the role of TSPO as a target to mediate the effect of koumine against RA will be confirmed to elucidate the mechanism of its therapeutic effect on RA. This study will lay a theoretical foundation for the development of koumine as a novel drug with independent intellectual property rights, and provide a new kind of drug target, pathway and action mode for the development of novel drugs against RA, and also help to further understand the pathogenesis of RA.

钩吻素子具有良好的成药性特征，有望开发成为拥有自主知识产权的抗类风湿关节炎（RA）新型药物。我们前期系列研究优先发现钩吻素子具有显著的治疗RA功效，可调节RA动物模型Th细胞平衡的偏移，但其作用机制包括作用靶点、作用途径和作用方式亟待深入系统探索。TSPO可参与免疫调节，我们前期工作还表明，TSPO是钩吻素子的重要作用靶点。鉴此，本项目以Th细胞极化为切入点，在前期工作基础上，首先在细胞水平进一步确证钩吻素子对Th细胞极化偏移的调节作用，明确其抗RA的作用方式；进而从Th细胞活化的3种信号入手，探讨钩吻素子抗RA作用的分子机制；最后证实TSPO可作为药物作用靶点介导钩吻素子抗RA作用，以期较为全面阐释钩吻素子治疗RA作用机制。本研究将为发展拥有自主知识产权创新药物钩吻素子奠定理论基础，为防治RA新药研发提供新的药物靶点、作用途径和作用方式，并有助深化理解RA的发病机制。

钩吻素子具有良好的成药性特征，可能开发为拥有自主知识产权的抗类风湿关节炎（RA）新型药物。我们前期工作已证实钩吻素子的抗RA效应，其调节Th细胞极化偏移的作用方式还需进一步研究确证，作用靶点、作用途径还有待阐释。线粒体转位蛋白（TSPO）可参与免疫调节，是课题组前期工作发现的钩吻素子重要作用靶点，但其是否介导钩吻素子的抗RA效应尚不明确。为此，本项目以Th细胞极化为切入点，首先在细胞水平进一步确证了钩吻素子对Th细胞极化偏移的调节作用以明确其作用方式，进而从Th细胞活化的3种信号入手探讨钩吻素子抗RA效应的作用途径和分子机制，最后证实TSPO可作为药物作用靶点介导钩吻素子抗RA的效应，以全面阐释钩吻素子治疗RA的作用机制。结果发现，钩吻素子作为别构调节剂，可选择性作用于参与RA发病的巨噬细胞等免疫细胞内TSPO，调节内源性配体的效应，减少ROS表达从而调节恢复免疫微环境的生理状态，并通过巨噬细胞对RA发病时免疫细胞间相互作用产生连锁性效应。钩吻素子抑制巨噬细胞的异常活化，调节M1/M2巨噬细胞的极化，减少TNF-α等细胞因子的产生，从而抑制FLSs的异常增殖、减弱其迁移与侵袭功能，缓解了滑膜病变。巨噬细胞是RA抗原依赖性Th细胞活化的重要APCs，钩吻素子对其调节作用可进一步抑制Th细胞的活化，在免疫微环境调节效应的协同作用下使Th细胞极化偏移得以恢复，并进一步减弱了Th细胞对B淋巴细胞的“辅助”作用，从而减少自身抗体的产生，减轻自身抗体对关节结构中胶原等成分的破坏，抑制RA的进展。此外，钩吻素子可通过TSPO-ROS作用抑制NLRP3炎症小体的异常活化，在Th细胞极化调节等效应的共同作用下，减少IL-1β等致炎细胞因子的分泌，从而缓解RA的炎症状态。本研究为发展拥有自主知识产权创新药物钩吻素子奠定了理论基础，为防治RA新药研发提供新的药物靶点与作用方式，也有助深化理解RA的发病机制。

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