基于大数据以食用性状为育种目标的水果类中药材药效的记忆与变异规律研究

In case of the Chinese materials whose original plants are fruits, such as persicae semen, citrireticulatae pericarpium, citri exocarpium bubrum, and chanenomelis chaenomelis fructus, their breeding has been being carried out mainly for the their edible characters. However, it was ignored for their pharmaceutical function heredity and variation. The breeding variations of plants to adapt the environments will result in the changes of their macro-molecules and secondary metabolites. We have collected some varieties of persicae semen and chanenomelis chaenomelis fructus and we found the chemical and pharmaceutical function varied among different samples. In this project, four fruit Chinese materials were chosen including persicae semen, citrireticulatae pericarpium, citri exocarpium bubrum, and chanenomelis chaenomelis fructus. After the investigation of their breeding background, the systems biological study would be developed, including genomic analysis, chemical analysis and pharmaceutical function analysis. Metabonomics and serum pharmacochemistry, as well as pharmaceutical functional targets, would be also conducted. Finally, the inherent relationships of heredity and variation among the above research would be investigated by huge data analysis on computer. The results produced by this project would guide the breeding of fruit Chinese materials to develop mainly focus on the pharmaceutical function characters rather than edible characters, it would become pharmaceutical breeding rather than edible breeding in future for the fruit Chinese materials. In a word, the project would provide the theoretical basis for the cultivation and clinical utilization of fruit Chinese materials.

桃仁、陈皮、橘红和木瓜等水果类基源植物的中药材，其新品种的选育多年来一直主要针对其果实的食用性状来开展，而其药用部位的药效性状的保持与变异一直被忽视。植物适应不同生态环境的品种变异必然导致其内在大小分子成分的改变，我们在木瓜和桃仁上的前期实验已经初步证实了水果类药材药效的变异。本项目选择桃仁等代表性水果类中药材，在调研其品种选育遗传和变异背景的基础上，从分子生物学角度，揭示水果类中药材遗传与变异的规律；从成分分析、代谢组学和血清药物化学角度，揭示水果类中药材作用物质基础的稳定与变异规律；从传统药效和分子靶标角度，揭示水果类中药材药效性状的记忆与变异规律。最后通过大数据揭示水果类中药材从基因到成分再到药效组学的系统生物学记忆与变异规律。这些研究结果将指引水果类中药材的育种走向以药效学性状为核心，开展针对医药使用目标的药学育种而不是农学育种，为该类药材的种植及指导医生临床用药奠定理论基础。

本项目按要求完成，针对水果类基源植物的中药材药效性状的保持与变异一直被忽视而开展,对陈皮、木瓜等4种水果类中药材从小分子成分、大分子成分、转录组学、蛋白组学、药效学研究等方面进行了遗传与变异规律的研究。（1）性状:不同产地、不同品种的水果类中药材存在形态变异现象，性状差异越显著，成分含量差异越大。（2）小分子成分:对3种药材分别建立专属多成分定量方法，系统比较了小分子化学成分的差异，并在此基础上，通过非靶向代谢组学，鉴定出陈皮的59个化合物，其中龙葵素和木犀草素-6,8-2-C-葡萄糖苷两种橘皮成分差异显著。鉴定出木瓜98个化合物，以有机酸类为主；鉴定出桃仁共51种化合物，其化学成分相似，但化合物含量存在一定差异，发现不同产地、不同品种的水果类中药材药用价值与成分含量在一定程度呈正相关。（3）大分子成分:发现不同品种、不同生长环境的柑桔果皮果胶的理化性质、结构和抗氧化活性存在显著差异，分子量较低的果胶比其他分子量较高的果胶具有更强的ABTS清除能力和羟基自由基的活性，证明果胶的结构对其功能性质和生物活性起着重要作用。（4）分子生物学:转录组学与蛋白组学结果显示不同品种的木瓜中基因与蛋白水平存在显著差异性，其在生长成熟基因方面，皱皮木瓜上调基因个数明显多于光皮木瓜。桃仁和山桃仁的转录组学进一步完善其生物合成途径相关基因的表达特征，共存在1679个差异表达基因，碳代谢、氨基酸的生物合成等被显著富集。（5）药效学:通过对比桃仁和山桃仁的抗凝血功能，发现桃仁具有优良的抗凝血活性，且较高浓度的抗凝效果更好，针对木瓜肝损伤肠道菌群进行分析，发现皱皮治疗效果更优，且光皮由于其有机酸含量较少，不易降低菌群中有害菌占比。本研究为指引水果类中药材的育种走向以药效学性状为核心，从成分-基因-药效角度开展针对医药使用目标的药学育种而不是农学育种提供了理论依据，为该类药材的种植及指导医生临床用药奠定理论基础。