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

超越连接组：解开寄生线虫中的神经肽信号传导，为药物发现管道提供信息

• 批准号: BB/T016396/1
• 负责人: ANGELA MOUSLEY
• 金额: $ 58.47万
• 依托单位: Queen's University Belfast
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2021
• 资助国家: 英国
• 起止时间: 2021 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=BB%2FT016396%2F1
• 关键词: Beyond; Connectome; Unravelling; Neuropeptide; Signalling

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.

线虫，或称蛔虫，是非常成功的无脊椎动物。有超过25，000种物种可以自由生活或寄生于人类，动物和植物，作为疾病的共同来源。人类寄生虫在经济欠发达国家特别普遍，在这些国家，贫困、医疗保健不足和生活条件差是司空见惯的，有利于线虫的持久性。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，在那里它们对宿主造成严重的健康问题。儿童感染会影响他们的身体和智力发育，而成年人的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）以及随后的英国农业食品行业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线虫感染的药物（驱虫剂）不再有效。事实上，线虫寄生虫的抗蠕虫药耐药性是一个主要的地方和全球性问题。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，绵羊和牛不能养殖。因此，在英国和全球都迫切需要开发治疗这种耐药线虫寄生虫的新药。新药对畜牧业的长期可持续性和未来的粮食生产至关重要。线虫的神经肌肉系统（神经肌肉系统）是一个被证明的药物靶点来源。事实上，大多数用于控制线虫感染的驱虫药都对这一系统产生了影响。线虫的神经肌肉系统协调行为，控制运动、进食和繁殖等重要过程。如果这些过程可以有效地中断，那么线虫寄生虫的存活和传播将显着减少。神经肌肉系统继续受到学术界和制药公司的关注，寻找新的药物靶点。事实上，线虫的神经肌肉系统目前作为药物靶点来源的开发不足，许多新的耐药性破坏靶点有待发现。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名为秀丽隐杆线虫的自由生活模式线虫。我们有C中每一个神经细胞（神经元）的详细地图。以及它们之间的联系。我们称之为连接体。然而，我们对连接体外部通过充满液体的体腔进行的通信一无所知。这是很重要的信号超越连接体（突触外信号通过体腔液）被认为是在线虫的通信系统的一个关键部分，但我们知道很少关于it.A更全面的了解线虫突触外信号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。 该项目使用各种先进的技术和工具，调查的程度和意义的突触外信号在线虫，利用大型胃肠道线虫寄生虫，猪蛔虫，作为一个模型系统。蛔虫的大小使我们能够轻松收集其体腔液并分析其包含的信号分子-这在以前没有做过，并且在其他线虫物种中非常困难。该项目产生的信息将帮助我们更好地了解线虫生物学，并为制药行业的药物发现提供有价值的数据。

项目成果

Clinical helminth infections alter host gut and saliva microbiota.

• DOI: 10.1371/journal.pntd.0010491
• 发表时间: 2022-06
• 期刊: PLoS neglected tropical diseases
• 影响因子: 3.8

Pan-phylum In Silico Analyses of Nematode Endocannabinoid Signalling Systems Highlight Novel Opportunities for Parasite Drug Target Discovery.

• DOI: 10.3389/fendo.2022.892758
• 发表时间: 2022
• 期刊: Frontiers in endocrinology
• 影响因子: 5.2

Exploring the antimicrobial peptidome of nematodes through phylum-spanning in silico analyses highlights novel opportunities for pathogen control.

• DOI: 10.1371/journal.pntd.0011618
• 发表时间: 2023-09
• 期刊: PLOS NEGLECTED TROPICAL DISEASES
• 影响因子: 3.8
• 作者: Irvine, Allister;Huws, Sharon A.;Atkinson, Louise E.;Mousley, Angela
• 通讯作者: Mousley, Angela

Transcriptome profiling of male and female Ascaris lumbricoides reproductive tissues.

• DOI: 10.1186/s13071-022-05602-2
• 发表时间: 2022-12-20
• 期刊: PARASITES & VECTORS
• 影响因子: 3.2
• 作者: Phuphisut, Orawan;Poodeepiyasawat, Akkarin;Yoonuan, Tippayarat;Watthanakulpanich, Dorn;Chotsiri, Palang;Reamtong, Onrapak;Mousley, Angela;Gobert, Geoffrey N. N.;Adisakwattana, Poom
• 通讯作者: Adisakwattana, Poom

Advancing Strongyloides omics data: bridging the gap with Caenorhabditis elegans.

• DOI: 10.1098/rstb.2022.0437
• 发表时间: 2024-01-15
• 期刊: PHILOSOPHICAL TRANSACTIONS OF THE ROYAL SOCIETY B-BIOLOGICAL SCIENCES
• 影响因子: 6.3
• 作者: Al-Jawabreh, Reem;Lastik, Dominika;Mckenzie, Darrin;Reynolds, Kieran;Suleiman, Mona;Mousley, Angela;Atkinson, Louise;Hunt, Vicky
• 通讯作者: Hunt, Vicky