ASCARIS SUUM, A NEW FUNCTIONAL GENOMICS PLATFORM FOR NEMATODE PARASITES

线虫(蛔虫)是线虫门的成员。有25,000种线虫，它们的数量仅次于节肢动物。它们的成功是因为它们有能力占据不同的栖息地。它们既可以是自由生活的，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，每四个人中就有一个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，那里的贫困、卫生保健提供不足和恶劣的生活条件有利于它们的生存。一些最流行的人类线虫寄生在胃肠道(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，可导致严重的健康问题，与肠道阻塞和发育障碍有关，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，而且还影响养殖业的生产力和随后的盈利能力。缠绕血圆线虫和环状线虫是绵羊和山羊最致病的两种线虫。它们是血液喂食者，严重感染可能导致严重贫血和动物死亡。线虫也是农作物行业的问题。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杂草。根结线虫是一个特殊的问题，因为它们侵染了广泛的植物寄主。它们在植物根部建立取食点，移除植物生长所需的养分，从而损害植物的健康。不幸的是，现有的治疗寄生性线虫感染的药物不再有效，或者对环境有害。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，开发新的药物。这对英国尤其重要，因为我们必须确保家畜养殖的可持续性，以用于未来的食品生产。该项目旨在发现治疗家畜线虫寄生虫的新药物靶标。在这个项目中，我们将与一家动物保健制药公司合作，以加快确定新药靶标的机会，以针对新药。这种方法将利用科研技能和制药业在药物发现方面的专业知识。为了找到针对线虫寄生虫的新药物靶点，我们必须首先识别对线虫生物学和生存至关重要的蛋白质。最近，一些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，找到那些编码可能对寄生虫生存至关重要的蛋白质靶标的序列。我们将选择在多种寄生虫中发现的序列，以便我们能够确定可以用于治疗多种线虫疾病的药物靶点。然后，我们将使用一种名为RNA干扰(RNAi)的技术，这种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/取食/繁殖，那么我们就确定了一个很好的候选药物，因为线虫不能再感染或停留在它的宿主中。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道中收集这种寄生虫，并在实验室中进行维护。一旦我们关闭了目标基因，我们将通过检查它们如何生存、行为、移动、繁殖和对刺激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“最好的”目标，并将这些目标提供给制药行业，后者将开发针对它们的药物。

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.