Transport mechanisms, anthelmintic resistance and novel receptors in parasitic nematodes

寄生线虫的转运机制、驱虫药耐药性和新型受体

• 批准号: 2777-2011
• 负责人: Prichard, Roger
• 金额: $ 3.5万
• 依托单位: McGill University
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2011
• 资助国家: 加拿大
• 起止时间: 2011-01-01 至 2012-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=473629
• 关键词: Transport; mechanisms; anthelmintic; resistance; novel

Parasitic nematodes are a major cause of losses in livestock production and cause disease and death. In cattle, sheep, goats they are controlled with anthelmintic drugs. Most anthelmintics act by disrupting transport mechanisms, involving ion channels and microtubules. Anthelmintic resistance is a major problem for animal production throughout the world. Transport mechanisms are often involved in the mechanisms of resistance. The transport systems in nematodes are different from those in mammals. For example, anthelmintics such as ivermectin, target chloride channels, such as glutamate-, dopamine-, serotonin-, and tyramine-gated Cl- channels, which do not occur in mammals. Other anthelmintics, act on classes of acetylcholine receptors not found in mammals. Benzimidazole anthelmintics bind to nematode tubulin, but not to mammalian tubulin, affecting the stability of nematode microtubules. Nematodes have a rich and diverse array of ABC transport genes, some of which are involved in anthelmintic resistance. For example, humans have two P-glycoproteins, whereas nematodes have up to 14 P-glycoproteins, 9 half transporters (haf genes, which are different from mammalian half-transporters, such as breast cancer resistant protein, and 8 multidrug resistant protein (MRP) genes, compared with 3 MRPs in mammals. The research objectives are to (a) characterize transport genes and their products in nematodes, to assess (b) their functions, (c) their involvement with anthelmintic action, or (d) with drug resistance mechanisms, (e) to advance knowledge of the biology of parasitic nematodes and assess the possibilities of targeting divergent transport systems for chemotherapy, (f) to identify drug resistance markers, and (g) to reduce the selection for resistance, or to overcome the resistance. The scientific approaches that will be used include the analysis of the parasite genomes to identify novel transport related genes, to clone, express and characterize novel transport genes and their products, to investigate the interaction of transport proteins with existing anthelmintics, to look for genetic changes causing resistance and, to develop molecular markers for the early detection and monitoring of resistance.

寄生线虫是畜牧业生产损失的主要原因，并导致疾病和死亡。在牛、绵羊、山羊中，它们用驱虫药控制。大多数驱虫药通过破坏转运机制发挥作用，包括离子通道和微管。抗蠕虫药物的抗性是全世界动物生产的主要问题。转运机制常常参与抗性机制。线虫的运输系统与哺乳动物不同。例如，驱虫剂如伊维菌素，靶向氯离子通道，如谷氨酸-、多巴胺-、5-羟色胺-和酪胺-门控的Cl-通道，其不存在于哺乳动物中。其他驱虫药作用于哺乳动物中未发现的乙酰胆碱受体。苯并咪唑类驱虫剂与线虫微管蛋白结合，但不与哺乳动物微管蛋白结合，影响线虫微管的稳定性。线虫具有丰富多样的ABC转运基因，其中一些与驱虫剂抗性有关。例如，人类具有两种P-糖蛋白，而线虫具有多达14种P-糖蛋白、9种半转运蛋白（haf基因，其不同于哺乳动物的半转运蛋白，如乳腺癌抗性蛋白）和8种多药耐药蛋白（MRP）基因，而哺乳动物中有3种MRP。研究目的是（a）描述线虫中转运基因及其产物的特征，评估（B）它们的功能，（c）它们与驱虫作用的关系，或（d）与耐药机制的关系，（e）提高寄生线虫生物学知识，评估靶向不同转运系统进行化疗的可能性，（f）鉴定耐药标记物，和（g）减少抗性选择或克服抗性。将采用的科学方法包括分析寄生虫基因组，以确定新的转运相关基因，克隆、表达和表征新的转运基因及其产物，研究转运蛋白与现有驱虫剂的相互作用，寻找导致抗药性的遗传变化，并开发早期发现和监测抗药性的分子标记。