Transport mechanisms and ion channels in nematodes

寄生线虫是畜牧业生产损失的主要原因，也是动物和人类健康不佳和死亡的来源。在牛、绵羊和山羊中，它们主要是通过驱虫药治疗来控制的。现有的大多数驱虫药都是通过破坏转运机制发挥作用的，包括配体门控离子通道。驱虫药耐药性正成为世界各地畜牧业生产的一个问题。涉及配体门控离子通道和ABC转运体的转运机制参与了耐药机制。线虫的运输系统与哺乳动物的不同；其中一些差异是驱虫剂对寄生虫的选择性毒性的原因。例如，大环内酯类驱虫剂，如伊维菌素，似乎以配体门控氯离子通道(LGIC)为靶点；其中一些，如谷氨酸、多巴胺、5-羟色胺和酪胺门控氯离子通道，在哺乳动物中不存在。其他驱虫药作用于不同类别的乙酰胆碱受体，其中一些在哺乳动物中没有发现。线虫似乎拥有丰富多样的ABC运输基因。一些膜转运蛋白似乎与驱虫药抗性有关。线虫和哺乳动物在这些运输机制上的差异可能是可能的。例如，人类有两个P-糖蛋白，而线虫可能有多达14个P-糖蛋白、9个半转运体(类似于在哺乳动物中发现的乳腺癌耐药蛋白)和8个多药耐药蛋白基因，而哺乳动物只有3个。我研究的目的是(A)鉴定线虫中一些与哺乳动物不同的运输基因及其产物，评估(B)它们在线虫中的功能，(C)增进对寄生线虫生物学的了解，并评估将分叉运输系统作为新的化疗靶点的可能性，(D)确定它们是否参与驱虫剂的作用，或(E)与驱虫药的抗药性机制有关。这些信息将对开发控制寄生线虫的新方法具有重要意义，对畜牧业、动物福利和人类健康都有好处。

Parasitic nematodes are a major cause of losses in livestock production, and are sources of ill health and death in animals and humans. In cattle, sheep, goats they are primarily controlled by treatment with anthelmintic drugs. Most of the existing anthelmintics act by disrupting transport mechanisms, involving ligand-gated ion channels. Anthelmintic resistance is becoming a problem for animal production throughout the world. Transport mechanisms involving ligand-gated ion channels and ABC transporters are involved in mechanisms of resistance. The transport systems in nematodes are different from those in mammals; some of these differences are responsible for the selective toxicity of anthelmintics against parasites. For example, the macrocyclic lactone anthelmintics, such as ivermectin, appear to target ligand-gated chloride channels (LGIC); some of which, e.g. glutamate-, dopamine-, serotonin-, and tyramine-gated Cl- channels do not occur in mammals. Other anthelmintics act on different classes of acetylcholine receptors, some of which are not found in mammals. Nematodes appear to have a rich and diverse array of ABC transport genes. Some membrane transporters appear to be involved in anthelmintic resistance. Differences between nematodes and mammals in these transport mechanisms may be propound. For example, humans have two P-glycoproteins, whereas nematodes may have up to 14 P-glycoproteins, 9 half transporters (similar to breast cancer resistant protein found in mammals), and 8 multidrug resistant protein genes, compared with 3 in mammals. The objectives of my research are to (a) characterize some of the transport genes and their products in nematodes which are divergent from those in mammals, to assess (b) their functions in nematodes, (c) to advance knowledge of the biology of parasitic nematodes and assess the possibilities of targeting divergent transport systems as novel targets for chemotherapy, (d) to determine their involvement with the action of anthelmintics, or (e) with mechanisms of resistance to anthelmintics. This information will be important for the development of novel means to control parasitic nematodes, with benefits to the animal industries, animal welfare and human health.