ASCARIS SUUM, A NEW FUNCTIONAL GENOMICS PLATFORM FOR NEMATODE PARASITES

ASCARIS SUUM，一种新的线虫寄生虫功能基因组学平台

• 批准号: BB/M010392/1
• 负责人: ANGELA MOUSLEY
• 金额: $ 34.02万
• 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: 2015
• 资助国家: 英国
• 起止时间: 2015 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=BB%2FM010392%2F1
• 关键词: ASCARIS; SUUM; NEW; FUNCTIONAL; GENOMICS

Nematodes (roundworms) are members of the Phylum Nematoda. There are >25,000 species of nematodes and they are outnumbered only by the Arthropods. Their success is due to their ability to occupy a diverse range of habitats. They can either be free-living or parasites of humans, animals and plants. Nematode parasites are a common source of human disease where 1 in 4 people carry at least one nematode species. Human parasitic diseases are mainly restricted to the developing world where poverty, inadequate health care provision, and poor living conditions favour their survival. Some of the most prevalent human nematode parasites live in the gasterointestinal (GI) system feeding on human tissue, blood and gut contents. For example, Ascaris lumbricoides is one of the largest GI nematodes and can cause serious health problems associated with intestinal blockage and impaired growth, especially in children. In livestock, nematode parasites can be a significant problem as they impact not only on the health and well-being of the animal but also on the productivity and subsequent profitability of the farming industry. Haemonchus contortus and Teladorsagia circumcincta are the most pathogenic nematodes of sheep and goats. They are blood-feeders and heavy infections can lead to severe anaemia and animal death. Nematodes are also problematic to the crop industry. They can infect food crops such as tomatoes and potatoes or utility grasses including football pitches or golf courses. Meloidogyne spp are a particular problem because they infect a wide range of plant hosts. They impair plant health by setting up feeding sites in the plant root, removing nutrients needed for plant growth.Unfortunately the drugs that are available to treat parasitic nematode infections no longer work effectively or are environmentally toxic. We cannot continue to treat nematode infections with the current range of drugs and we must now actively seek new drug targets and develop novel drugs. This is particularly important to the UK as we have to ensure the sustainability of livestock farming for future food production.This project aims to uncover novel drug targets for the treatment of nematode parasites of livestock. In this project we will collaborate with an animal-health pharmaceutical company to accelerate the chance of identifying a novel drug target at which new drugs could be directed. This approach will make use of scientific research skills and the expertise of the pharmaceutical industry in drug discovery. In order to find new drug targets for nematode parasites, we must first identify proteins that are important to nematode biology and survival. Recently there has been an increase in the availability of gene sequences for a number of important parasitic nematodes, like those described above. We will search through these sequences and find those which code for protein targets which may be essential to parasite survival. We will select sequences that are found in multiple parasites so that we can identify a drug target which could be used to treat multiple nematode diseases. We will then use a technique called RNA interference (RNAi) which allows us to switch off genes in the parasitic nematode to find out their function. For example, if we switch off a gene and the nematode dies or stops moving/feeding/reproducing then we have identified a good drug target candidate as the nematode can no longer infect or remain in its host. We will perform RNAi in a model nematode parasite (Ascaris suum) that we can easily collect from pig intestines at local abattoirs and maintain in the lab. Once we have switched off the target genes, we will determine the impact to the parasite by examining how they survive, behave, move, reproduce, and respond to stimulants. We will then select the five 'best' targets, based on their impact to nematode biology, and deliver these to the pharmaceutical industry who will develop drugs against them.

线虫（线虫）是线虫动物门的成员。有超过25，000种线虫，它们的数量仅超过节肢动物。它们的成功是由于它们能够占据各种各样的栖息地。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。线虫寄生虫是人类疾病的常见来源，其中四分之一的人携带至少一种线虫物种。人类寄生虫病主要局限于发展中国家，在那里，贫穷、保健服务不足和恶劣的生活条件有利于它们的生存。一些最普遍的人类线虫寄生虫生活在胃肠道（GI）系统中，以人体组织、血液和肠道内容物为食。例如，蛔虫是最大的胃肠道线虫之一，可引起与肠道堵塞和生长受损相关的严重健康问题，特别是在儿童中。在牲畜中，线虫寄生虫可能是一个重大问题，因为它们不仅影响动物的健康和福祉，而且影响农业的生产力和随后的盈利能力。捻转血矛线虫和环状Teladorsagia circumcincta是绵羊和山羊的主要病原线虫。它们是吸血动物，严重感染可导致严重贫血和动物死亡。线虫对农作物产业也是个问题。它们可以感染西红柿和土豆等粮食作物或包括足球场或高尔夫球场在内的实用草。根结线虫是一个特殊的问题，因为它们感染广泛的植物宿主。它们通过在植物根部建立取食场所，带走植物生长所需的营养物质，从而损害植物健康。不幸的是，可用于治疗寄生线虫感染的药物不再有效或对环境有毒。我们不能继续用现有的药物治疗线虫感染，我们现在必须积极寻找新的药物靶点并开发新药。这对英国尤为重要，因为我们必须确保畜牧业的可持续性，以促进未来的粮食生产。该项目旨在发现治疗牲畜线虫寄生虫的新药物靶点。在这个项目中，我们将与一家动物保健制药公司合作，以加快确定新药靶点的机会。这种方法将利用科学研究技能和制药业在药物发现方面的专门知识。为了找到新的药物靶标线虫寄生虫，我们必须首先确定蛋白质是重要的线虫生物学和生存。最近，许多重要的寄生线虫的基因序列的可用性有所增加，如上文所述的那些。我们将搜索这些序列，并找到那些可能对寄生虫生存至关重要的蛋白质靶点的编码。我们将选择在多种寄生虫中发现的序列，以便我们可以确定可用于治疗多种线虫疾病的药物靶标。然后，我们将使用一种称为RNA干扰（RNAi）的技术，该技术允许我们关闭寄生线虫中的基因，以找出它们的功能。例如，如果我们关闭一个基因，线虫死亡或停止移动/进食/繁殖，那么我们已经确定了一个很好的药物靶点候选者，因为线虫不再感染或留在其宿主中。我们将在一种模型线虫寄生虫（猪蛔虫）中进行RNAi，我们可以很容易地从当地屠宰场的猪肠中收集并在实验室中保存。一旦我们关闭了靶基因，我们将通过检查寄生虫如何生存，行为，移动，繁殖和对刺激物的反应来确定对寄生虫的影响。然后，我们将根据它们对线虫生物学的影响选择五个“最佳”靶标，并将其提供给制药行业，他们将开发针对它们的药物。

项目成果

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

RNA interference in adult Ascaris suum--an opportunity for the development of a functional genomics platform that supports organism-, tissue- and cell-based biology in a nematode parasite.

• DOI: 10.1016/j.ijpara.2015.05.003
• 发表时间: 2015-09
• 期刊: International journal for parasitology
• 影响因子: 4
• 作者: McCoy CJ;Warnock ND;Atkinson LE;Atcheson E;Martin RJ;Robertson AP;Maule AG;Marks NJ;Mousley A
• 通讯作者: Mousley A

Clinical helminthiases in Thailand border regions show elevated prevalence levels using qPCR diagnostics combined with traditional microscopic methods

• DOI: 10.1186/s13071-020-04290-0
• 发表时间: 2020-08-12
• 期刊: PARASITES & VECTORS
• 影响因子: 3.2
• 作者: Adisakwattana, Poom;Yoonuan, Tippayarat;Gobert, Geoffrey N.
• 通讯作者: Gobert, Geoffrey N.

Unraveling flp-11/flp-32 dichotomy in nematodes.

• DOI: 10.1016/j.ijpara.2016.05.010
• 发表时间: 2016-10
• 期刊: INTERNATIONAL JOURNAL FOR PARASITOLOGY
• 影响因子: 4
• 作者: Atkinson, Louise E.;Miskelly, Iain R.;Moffett, Christy L.;McCoy, Ciaran J.;Maule, Aaron G.;Marks, Nikki J.;Mousley, Angela
• 通讯作者: Mousley, Angela

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