基于通路模块标准化的芪参颗粒及其配伍成分治疗冠心病心衰的作用模式研究

Chronic heart failure due to coronary heart disease is a serious and complicated danger to the mankind. Qishenyiqi (QSYQ) is the effective medicine which aims at crucial pathological progresses, especially ventricular remodeling and myocardial fibrosis. However, strategies and methods are still lack for studying mode of action of compound prescription of QSYQ and its compatibility components. In our previous study, a new strategy was developed to evaluate the significance of pathway module based on the priorities of keystone genes, and applied in objectively dissecting the multi-pathways mechanisms of QSYQ. On this basis, our project will combine the recently advanced methods — comparison analysis of gene expression profiles and optimized multiple-templates clustering, and further propose the normalization of pathway modules, to compare the molecular mechanisms of compound prescription and its compatibility components (“compound prescription-single drug”), and thus reveal the mode of action of compound prescription and its compatibility components. Meanwhile, our results of preliminary study demonstrated that both of QSYQ and one of its single drug — Salvia Miltiorrhiza Bunge (‘dan-shen’ in Chinese), significantly regulate ventricular remodeling, fatty acid metabolism and inflammatory infiltration. These preliminary results indicated that as an important component of QSYQ, Salvia Miltiorrhiza Bunge has close associations with QSYQ in pharmacological mechanism, which laid experimental foundation for our project. The achievement of our project will engender new methodology for studying mode of action of compound prescription and its compatibility components from the perspective of Chinese medicine compound. Further, our project will contribute to new strategies for researching and developing monomer and combination drugs, and provide a novel research paradigm for discovering modern component composition drugs.

冠心病慢性心衰是重大复杂疾病，芪参颗粒是目前针对该疾病心室重构和心肌纤维化等关键病理环节确有疗效的药物，但仍缺乏针对该复方及其配伍成分作用模式的研究策略和方法。我们前期构建了基于关键基因的通路模块重要性评估技术，对芪参颗粒的多条作用通路进行了客观分析。本课题在此基础上，结合新发展的表达谱相似性比较和优化的多模板聚类等技术，进一步提出通路模块标准化，实现“复方-单味药”配伍成分的分子机制比较分析，从而揭示芪参颗粒及其配伍成分之间的作用模式。同时，在芪参颗粒和丹参单味药机制比较预实验中，我们发现它们共同调控心室重构、脂质代谢和炎性细胞浸润等病理环节，表明丹参作为组成药物，在药理上紧密参与了芪参颗粒的药效发挥，为本课题奠定了实验基础。本课题的完成将形成从中药复方出发，研究复方及其配伍成分作用模式的新方法，进一步有助于形成研发单体药及成分组合药的新策略，为现代成分组合药的发现提供研发新范式。

冠心病慢性心衰是重大复杂疾病，芪参颗粒是目前针对该疾病心室重构和心肌纤维化等关键病理环节确有疗效的药物，但仍缺乏针对该复方及其配伍成分作用模式的研究策略和方法。我们前期开发了基于关键基因的通路模块重要性评估技术，为芪参颗粒的多条作用通路的客观分析奠定了基础。.本课题在此基础上，开发了通路模块标准化方法，通过构建通路-基因表达谱，保留通路中基因的表达信息，从而对生物学通路定量表示。随后通过置换检验，得到了通路层面的显著性统计量。因此，我们利用了该方法从功能层面和分子机制层面对拆方比较研究，发现芪参颗粒各拆方共同达到对心衰的能量代谢、心室重塑和炎症的治疗效果。此外，我们通过实验验证了通路中基因和蛋白的表达模式，证实了QSYQ复方在通路层面上的功效。本课题实现了“复方-单味药”配伍成分的分子机制比较分析，揭示了芪参颗粒配伍成分治疗冠心病心衰的作用模式，从而显著性提高芪参颗粒配伍成分的优化与组合效率；同时，形成了从中药复方出发，研究复方及其配伍成分作用模式的新方法，进一步有助于形成研发单体药及成分组合药的新策略，为现代成分组合药的发现提供研发新范式。