Beyond the Connectome: Unravelling Neuropeptide Signalling in Parasitic Nematodes to Inform Drug Discovery Pipelines

线虫或蛔虫是非常成功的无脊椎动物。有大约2.5万种生物，它们可以是自由生活的，也可以是人类、动物和植物的寄生虫，是常见的疾病来源。人类寄生虫在经济不太发达的国家尤其普遍，在这些国家，贫困、医疗保健供应不足和恶劣的生活条件司空见惯，有利于线虫的持续存在。许多人类寄生线虫生活在胃肠道系统、淋巴系统或身体组织中，在那里它们会给宿主带来严重的健康问题。儿童感染会影响他们的身体和智力发育，而成人感染线虫病会导致无法工作和养家糊口。在全球范围内，线虫感染在农业牲畜中也很常见，对动物生产力（包括肉类和牛奶生产）和英国农业食品工业随后的经济可持续性产生负面影响。不幸的是，目前可用于治疗寄生虫感染的药物（驱虫药）不再有效。事实上，线虫寄生虫的抗虫性是一个主要的地方性和全球性问题。在世界上的一些地区（例如，苏格兰和新西兰），由于线虫寄生虫控制问题，羊和牛无法养殖。因此，英国和全球都迫切需要开发新药来治疗这种耐药线虫寄生虫。新药对未来粮食生产的畜牧业的长期可持续性至关重要。线虫的神经肌肉系统（神经肌肉系统）是一个已证实的药物靶点来源。事实上，大多数用于控制线虫感染的驱虫药都对这一系统起作用。线虫的神经肌肉系统协调行为，控制诸如运动、进食和繁殖等重要过程。如果这些过程能够有效地中断，那么线虫寄生虫的生存和传播将大大减少。神经肌肉系统继续受到学术界和制药公司寻找新的药物靶点的关注。事实上，线虫的神经肌肉系统目前尚未被充分开发为药物靶点来源，许多新的耐药靶点正在等待发现。为了开发针对寄生虫神经肌肉系统的新药，我们需要更好地了解线虫神经系统的结构和功能。线虫的神经系统是复杂的，我们目前对其结构的了解是基于一种叫做秀丽隐杆线虫的自由生活模式。我们有秀丽隐杆线虫每一个神经细胞（神经元）的详细图谱，以及它们之间所有的联系。我们称之为连接体。然而，我们对连接体之外通过充满液体的体腔发生的交流一无所知。这一点很重要，因为连接组之外的信号（通过体腔液传递的突触外信号）被认为是线虫通信系统的关键部分，但我们对此知之甚少。对线虫突触外信号的更全面的了解将使我们能够更好地利用神经肌肉系统作为药物靶点资源。本项目利用各种复杂的技术和工具，通过利用大型胃肠道线虫寄生虫Ascaris suum作为模型系统，研究线虫中突触外信号传导的程度和意义。蛔虫的体型使我们能够很容易地收集它的体腔液体并分析它所含的信号分子——这在以前没有做过，在其他线虫物种中也非常困难。该项目产生的信息将有助于我们更好地了解线虫生物学，并将为制药行业的药物发现提供有价值的数据。

Nematodes, or roundworms, are highly successful invertebrates. There are >25,000 species which can be either free-living or parasites of humans, animals and plants, acting as a common source of disease. Human parasites are particularly prevalent in less economically developed countries where poverty, inadequate healthcare provision, and poor living conditions are commonplace and favour nematode persistence. Many human parasitic nematodes live in the gastrointestinal system, lymphatic system, or body tissues, where they cause serious health problems to the host. Infections in children impact on their physical and intellectual development, while nematode disease in adults can result in an inability to work and provide for their families. Globally, nematode infections are also common in agricultural livestock negatively impacting animal productivity (including meat and milk production) and the subsequent economic sustainability of the UK agri-food industry.Unfortunately, the drugs currently available to treat parasitic nematode infections (anthelmintics) no longer work effectively. Indeed, anthelmintic resistance in nematode parasites is a major local and global problem. In some areas of the world (for example, Scotland and New Zealand), sheep and cattle cannot be farmed due to nematode parasite control problems. Therefore, the development of new drugs to treat such resistant nematode parasites is urgently needed both in the UK and globally. New drugs are critical to the long-term sustainability of livestock farming for future food production.The nematode nerve-muscle system (neuromuscular system) is a proven source of drug targets. Indeed, the majority of anthelmintic drugs used to control nematode infectionhave exerted their effects on this system. The neuromuscular system of nematodes coordinates behaviour, controlling vital processes such as movement, feeding and reproduction. If these processes can be effectively interrupted then nematode parasite survival and transmission will be significantly reduced. The neuromuscular system continues to receive attention from academics and pharmaceutical companies searching for new drug targets. Indeed the neuromuscular system in nematodes is currently underexploited as a drug target source, with many novel resistance-breaking targets awaiting discovery. In order to develop new drugs that target the neuromuscular system of parasites we need a better understanding of the nematode nervous system structure and function. The nematode nervous system is complex and our current knowledge on its structure is based on a free-living model nematode called Caenorhabditis elegans. We have a detailed map of every single nerve cell (neuron) in C. elegans and all of the connections between them. We call this the connectome. However, we do not know anything about the communication that can occur outside of the connectome, via the fluid-filled body cavity. This is important as signalling beyond the connectome (extrasynaptic signalling via the body cavity fluid) is believed to be a key part of the communication system in nematodes, and yet we know very little about it. A more comprehensive understanding of nematode extrasynaptic signalling will enable us to better exploit the neuromuscular system as a drug target resource. This project uses a variety of sophisticated technologies and tools to investigate the extent and significance of extrasynaptic signalling in nematodes, by exploiting the large gastrointestinal nematode parasite, Ascaris suum, as a model system. The size of Ascaris allows us to easily collect its body cavity fluid and analyse the signalling molecules it contains - this has not been done before and would be very difficult in other nematode species. The information generated from this project will help us to better understand nematode biology and will provide valuable data for drug discovery by the pharmaceutical industry.