Transport mechanisms, anthelmintic resistance and novel receptors in parasitic nematodes

寄生线虫是畜牧业生产损失的主要原因，也是疾病和死亡的主要原因。在牛、绵羊和山羊中，它们是用驱虫药控制的。大多数驱虫药的作用方式是破坏离子通道和微管的转运机制。驱虫药耐药性是世界各地畜牧业生产面临的主要问题。在抗性机制中，常常涉及转运机制。线虫的运输系统与哺乳动物的不同。例如，驱虫剂，如伊维菌素，靶向氯通道，如谷氨酸、多巴胺、5-羟色胺和酪胺门控氯通道，这些在哺乳动物中不存在。其他驱虫药作用于哺乳动物中没有的乙酰胆碱受体。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，其中一些与驱虫药抗性有关。例如，人类有两个P-糖蛋白，而线虫有多达14个P-糖蛋白，9个半转运蛋白(HIF基因，不同于哺乳动物的半转运蛋白，如乳腺癌耐药蛋白)和8个多药耐药蛋白(MRP)基因，而哺乳动物有3个MRP。研究的目标是(A)鉴定线虫的转运基因及其产物，评估(B)它们的功能，(C)它们参与驱虫作用，或(D)与耐药机制有关，(E)增进对寄生线虫生物学的了解，并评估针对不同的运输系统进行化疗的可能性，(F)识别耐药标记，以及(G)减少对耐药性的选择，或克服耐药性。将使用的科学方法包括分析寄生虫基因组以确定新的运输相关基因，克隆、表达和鉴定新的运输基因及其产物，调查运输蛋白与现有驱虫剂的相互作用，寻找引起耐药性的遗传变化，以及开发用于早期检测和监测耐药性的分子标记。

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.