'Omics'-based approaches and synthetic biology platform to investigate valuable plant natural products.

自史前时代以来，植物天然产物（PNPs）就被用于治疗人类疾病，并且仍然是当今大多数药物的最重要来源。世界上约90%的人口依赖传统药用植物，不仅是为了满足他们的初级保健需求，也是为了创收。虽然有大量的药用植物，但很少有人大规模种植，世界上大部分的供应都是从野外采集的。因此，某些药用植物在商业上的成功可能导致它们被过度采集，从而使这些植物的种植和它们宝贵的pnp的生产成为必要。近年来，由amaryllid科药用植物（如Amaryllis、Galanthus和Narcissus）产生的生物碱类pnp因其多种药理活性而受到越来越多的关注。苋菜科生物碱具有镇痛、抗癌、抗菌作用，并对心血管和呼吸系统有一定的作用。例如，水仙素显示出强大的抗有丝分裂活性，犯罪胺以其精神活性而闻名，而加兰他明是一种乙酰胆碱酯酶抑制剂，用于治疗阿尔茨海默病的症状。大多数原子吸收剂的商业开发受到其在植物中的低浓度所造成的有限可利用性的限制。只有加兰他敏是商业生产的。尽管在作物改良和药物开发方面对AA的工程生产有明显的兴趣，但缺乏关于AA生物合成途径及其调控的信息使得这项任务非常具有挑战性。最近，基于系统生物学的方法通过整合多个“组学”（基因组学、转录组学、蛋白质组学和代谢组学）数据集，促进了其他植物家族中参与PNP代谢途径的生物合成基因的发现。到目前为止，还没有开发出用于Amaryllidaceae的“组学”资源。因此，一些AA途径仍然是假设的，酶和代谢中间体有待发现。该研究的总体目标是通过应用创新的现代基因组学和集成系统生物学策略来增加对植物中AAs代谢的了解。具体目标是：(i)建立“组学”数据库，以促进发现新的AA生物合成基因；（ii）生化基因组学，以表征新基因；（iii）开发可持续的“绿色”微藻合成生物学平台，以功能验证基因并生产具有前景的药用价值的AA。提高对AA生物合成的分子理解是开发具有有价值AA谱的Amaryllidaceae新品种的必要前提，并将为合成生物学等生物技术创造工程微藻菌株以生产与加拿大农业和制药工业多样化相关的高价值AA铺平道路。

Plant natural products (PNPs) have been used for treating human ailments since prehistoric times and are still the most important source for the majority of today's medicines. About 90% of the world's population relies on traditional medicinal plants, not only to meet their primary care needs but also for income generation. Although there are a vast number of medicinal plants, few are cultivated on a large scale and the majority of the world's supply is collected from the wild. Consequently, the commercial success of certain medicinal plants may lead to their over-collection, making the cultivation of these plants and production of their valuable PNPs necessary. Recently, PNPs of the alkaloid group produced by medicinal plants of the Amaryllidaceae family (e.g. Amaryllis, Galanthus and Narcissus), have been attracting increasing interest due to their multiple pharmacological activities. The properties of Amaryllidaceae alkaloids (AAs) include analgesic, anticancer and antimicrobial activities, and effects on cardiovascular and respiratory system. For example, narciclasine displays potent antimitotic activity, crinamine is reputed for its psychoactive properties whereas galanthamine, an acetylcholinesterase inhibitor, is used to treat symptoms of Alzheimer's disease. The commercial development of most AAs is restricted by their limited availabilities due to their low concentrations in planta. Only galanthamine is produced commercially. Although there are obvious interests in engineering AA production for crop improvement and development of pharmaceuticals, the lack of information on AA biosynthetic pathways and their regulation make this task very challenging. Recently, systems biology-based approaches have facilitated the discovery of biosynthetic genes involved in PNP metabolic pathways in other plant families through the integration of multiple `omics' (genomic, transcriptomic, proteomic and metabolomic) datasets. To date, no `omics' resources have been developed for the Amaryllidaceae. Consequently, several AA pathways remain hypothetical and enzymes and metabolic intermediates await discovery. The overall goal of the proposed research is to increase knowledge on the metabolism of AAs in plants through the application of innovative and modern genomics and integrated systems biology strategies. Specific aims are (i) the establishment of `omic' databases to facilitate discovery of novel AA biosynthetic genes, (ii) biochemical genomics to characterize novel genes and (iii) the development of a sustainable `green' microalgal synthetic biology platform to functionally validate genes and to produce AAs with promising medicinal value. An improved molecular understanding of AA biosynthesis is a necessary prerequisite to develop novel Amaryllidaceae cultivars with valuable AA profiles, and will pave the way for biotechnologies, such as synthetic biology, to create engineered microalgae strains for the production of high-value AAs relevant to diversifying Canadian agricultural and pharmaceutical industries.