Functional Characterisation of insect nicotinic Acetylcholine Receptors

据估计，到2050年，全球人口将增加三分之一。维持这一人口的热量需求将需要增加50%，并且随着对肉类消费的日益偏好，还需要额外提供原料。据估计，到2050年，这将需要粮食产量增加70%。因此，为实现高效、可靠和可持续的粮食生产，对现有农业用地的需求将不断增加。杀虫剂是确保作物有效产量的重要工具。需要定期研制新的杀虫剂，以克服害虫种群的抗药性，并提供更良性的环境影响和人类安全概况。特别是，新杀虫剂需要对非目标物种，特别是蜜蜂等主要传粉媒介表现出低毒性，同时保持对“咀嚼”和“吸吮”害虫的有效性，这些害虫可以摧毁许多主要作物。最重要的商业杀虫剂的目标是神经元乙酰胆碱信号通路，在这类杀虫剂中，最安全、最有效的是作用于烟碱乙酰胆碱受体（nAChR）的分子（新烟碱类和spinosyns）。nAChR实际上是由五个蛋白质亚基组成的复合物。在已经建立的模式昆虫果蝇黑腹果蝇中，有10种不同的基因编码nAChR亚基蛋白，这些基因可以组合形成许多不同种类的nAChR，每种nAChR都有可能与不同的杀虫化合物相互作用。迄今为止，对于这些亚基是如何结合的，哪些其他蛋白质作为辅助分子与受体亚基相互作用，或者每种复合物的“部分列表”对其药理学特性有什么影响，我们知之甚少。该项目的目的是表征果蝇中功能不同的nachr类别，这是一种遗传和生化易于处理的昆虫模型系统，将产生广泛适用于其他昆虫物种的见解。对果蝇nachr功能分类的了解将为未来更有针对性的害虫研究铺平道路，这些害虫对主要作物造成严重破坏，目前很少有遗传学工具。在这个应用程序中，我们将应用Kathryn Lilley创建的尖端空间蛋白质组学方法，结合Steve Russell提供的昆虫基因编辑和先进遗传学技术，推进世界领先的农用化学品公司之一先正达（Syngenta）建立的昆虫受体生化和药理学方法。总之，拟议的研究计划将导致对不同原生nAChR类别的彻底描述，并大大提高我们对一类对保护全球农业至关重要的杀虫剂目标的理解。设计安全且对环境影响小的有效新型杀虫剂的能力，对于继续推动提高农业产量和更好地养活不断增长的全球人口至关重要。

By 2050 it is estimated that the global population will have increased by a third. The calorific requirements to sustain this population will need to increase by 50% and, with a growing preference for meat consumption, additional provision of feedstocks will also be needed. It has been estimated that this will require a 70% increase in crop yields by 2050. Thus increasing demands will be placed on available agricultural land to deliver efficient, reliable and sustainable food production. Insecticides are important tools for ensuring efficient crop yields. New insecticides need to be created on a regular basis to overcome resistance in pest populations as well as providing more benign environmental impacts and human safety profiles. In particular, new insecticides need to exhibit low toxicity to non-target species, particularly the major pollinators such as bees, while retaining efficacy against both the 'chewing' and 'sucking' pests that can devastate many major crops. The target of the most commercially important insecticides is the neuronal acetylcholine signalling pathway and of this class of insecticides, the safest and most effective are molecules (neonicotinoids and spinosyns) that act at the nicotinic acetylcholine receptor (nAChR). The nAChR is in fact composed of five protein subunits that form a complex. In the well established model insect, the fruit fly Drosophila melanogaster, there are ten different genes encoding nAChR subunit proteins, and these can combine to form many different classes of nAChRs, each with the potential to interact differently with insecticidal compounds. To date, very little is known about how these subunits combine, what other proteins act as accessory molecules interacting with receptor subunits, or what impact the 'parts list' of each complex has on its pharmacological properties. The aim of this project is to characterise functionally distinct classes of nAChRs in Drosophila melanogaster, a genetically and biochemically tractable insect model system that will generate insights broadly applicable to other insect species. Knowledge of the functional classes of nAChRs in Drosophila will pave the way for more targeted future research in the pest insects that cause havoc to major crops and for which there are currently very few genetics tools. In this application we will apply cutting edge spatial proteomics methods created by Kathryn Lilley with insect gene editing and advanced genetics techniques available from Steve Russell to advance the insect receptor biochemical and pharmacological approaches established at Syngenta, one of the world's leading agrochemical companies. Together, the proposed research programme will lead to a thorough characterisation of different native nAChR classes and substantially advance our understanding of a class of insecticide targets that are crucial for protecting global agriculture. The ability to design effective new insecticides that are safe and have low environmental impact will be essential to the continuing drive to increase agricultural yields and better feed the growing global population.