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Exploiting stem cell biology for liver fluke control

利用干细胞生物学控制肝吸虫

基本信息

批准号：
BB/T002727/1
负责人：
Aaron Gordon Maule
金额：
$ 58.43万
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：
2020
资助国家：
英国
起止时间：
2020 至无数据
项目状态：
已结题

来源：
https://gtr.ukri.org/projects?ref=BB%2FT002727%2F1
关键词：
Exploiting stem cell biology liver

项目摘要

Liver fluke (Fasciola species) are flatworm parasites that infect diverse mammals including humans and ruminant livestock such as cattle, goats and sheep. In humans, the parasite causes the disease fascioliasis which is a neglected tropical disease with an estimated 17 million people believed to be infected. The worm impacts global food security as it undermines the health and productivity of livestock in which it causes fasciolosis, estimated to cause losses of ~$US3 billion/year worldwide. Major concerns are that: the Animal and Plant Health Agency list liver fluke as the most commonly diagnosed helminth parasite of sheep and cattle in UK; recent estimates of changing prevalence in the UK have forecast unprecedented levels of fasciolosis risk by 2050; farmers rely on the administration of drugs which are becoming less effective due to drug resistance. Adult worms live in the bile ducts and juveniles occur encysted on vegetation; after being swallowed the juveniles excyst and migrate from the intestine through the liver to the bile ducts. The juvenile worm is the key pathogen, causing profound damage to the liver as it moves from the intestine to the bile duct. It is this stage that can kill lambs and sheep and the stage against which there is only one effective drug, triclabendazole (TCBZ). Critically, TCBZ-resistance threatens the sustainability of livestock farming in many regions of the world such that new flukicides and/or a vaccine are needed. Key impediments to research studies on liver fluke have included the lack of good genomic resources, the absence of a model system for functional studies and the reliance on host animal-based in vivo experiments to inform fluke biology. The new bioinformatic resources as well as the ability to culture the juvenile fluke in the laboratory outside of a host, mean that experiments on fluke developmental biology are now possible, stimulating this project. Our ability to culture growing juveniles, for sustained timeframes, and to selectively disrupt gene targets provides an opportunity to transform approaches to liver fluke biology and the discovery of new drug targets. We have found that liver fluke stem cells are critical to their growth and development and as such, are an appealing resource for new drug targets. Whilst the critical role played by stem cells in chemotherapy and drug resistance is established in the cancer field, their role in parasite-drug interactions and potential exploitation in parasite control have not been investigated. Our preliminary data expose a critical role for these stem cells in liver fluke growth and indicate that they play a role in parasite-drug interaction, encouraging their exploitation for the discovery of new drug targets. In this project, supported by an industrial partner, we propose to discover key genes involved in liver fluke stem cell biology and to evaluate their potential as novel drug targets for new flukicides. To do this we propose to generate new bioinformatics resources on the genes expressed in juvenile liver fluke stem cells. We will also evaluate the importance of stem cells to parasite-drug interactions to help inform their role in how liver fluke parasites tolerate/recover from drug exposure. We will study the relationships between parasite drug sensitivities and stem cell biology and the consequences of disrupting liver fluke stem cells on parasite responses to drug treatments. Finally, we will evaluate a sub-set of liver fluke stem cell genes for their potential as new drug targets using the functional genomics tools we have established. Prioritized and validated targets will be entered into new drug screens by our industrial collaborator to initiate the discovery of new drugs to control liver fluke. The approaches taken here have direct relevance to liver fluke and indirect relevance to other parasitic worms that cause a diverse range of important diseases of animals and humans.

肝吸虫（片形吸虫属）是感染多种哺乳动物（包括人类和反刍家畜，如牛、山羊和绵羊）的扁形虫寄生虫。在人类中，这种寄生虫导致片形吸虫病，这是一种被忽视的热带疾病，据信有1700万人感染。该蠕虫影响全球粮食安全，因为它破坏牲畜的健康和生产力，导致片形吸虫病，估计每年在全球造成约30亿美元的损失。主要担忧是：动物和植物卫生署将肝吸虫列为英国最常诊断的绵羊和牛的蠕虫寄生虫;最近对英国流行率变化的估计预测到2050年肝片吸虫病风险达到前所未有的水平;农民依赖于药物的管理，由于耐药性，药物变得不那么有效。蠕虫生活在胆管中，幼虫在植物上被包囊;被吞食后，幼虫从肠道通过肝脏迁移到胆管。幼年蠕虫是关键的病原体，当它从肠道移动到胆管时，会对肝脏造成严重损害。正是这个阶段可以杀死羔羊和绵羊，并且只有一种有效的药物，三氯苯达唑（TCBZ）。至关重要的是，TCBZ耐药性威胁到世界许多地区畜牧业的可持续性，因此需要新的杀吸虫剂和/或疫苗。肝吸虫研究的主要障碍包括缺乏良好的基因组资源，缺乏功能研究的模型系统，以及依赖宿主动物体内实验为吸虫生物学提供信息。新的生物信息学资源以及在实验室中在宿主外培养幼年吸虫的能力意味着现在可以进行吸虫发育生物学实验，从而刺激了该项目。我们培养成长中的青少年，持续的时间框架，并选择性地破坏基因靶点的能力提供了一个机会，以改变方法肝吸虫生物学和发现新的药物靶点。我们发现肝吸虫干细胞对其生长和发育至关重要，因此是新药物靶点的吸引力资源。虽然干细胞在化疗和耐药性中发挥的关键作用在癌症领域已经确立，但它们在寄生虫-药物相互作用中的作用以及在寄生虫控制中的潜在利用尚未研究。我们的初步数据揭示了这些干细胞在肝吸虫生长中的关键作用，并表明它们在寄生虫-药物相互作用中发挥作用，鼓励它们用于发现新的药物靶点。在这个项目中，由一个工业合作伙伴的支持，我们建议发现参与肝吸虫干细胞生物学的关键基因，并评估其作为新型杀吸虫剂的新型药物靶点的潜力。要做到这一点，我们建议产生新的生物信息学资源的基因表达的幼年肝吸虫干细胞。我们还将评估干细胞对寄生虫-药物相互作用的重要性，以帮助了解它们在肝吸虫寄生虫如何耐受/从药物暴露中恢复中的作用。我们将研究寄生虫药物敏感性和干细胞生物学之间的关系，以及破坏肝吸虫干细胞对寄生虫对药物治疗反应的影响。最后，我们将使用我们已经建立的功能基因组学工具评估肝吸虫干细胞基因的子集作为新药物靶点的潜力。我们的工业合作者将优先考虑和验证的靶点进入新药筛选，以开始发现控制肝吸虫的新药。这里采取的方法与肝吸虫直接相关，与其他寄生蠕虫间接相关，这些寄生虫引起动物和人类的各种重要疾病。