Transport mechanisms and ion channels in nematodes

线虫的转运机制和离子通道

• 批准号: 2777-2012
• 负责人: Prichard, Roger
• 金额: $ 4.74万
• 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: 2012
• 资助国家: 加拿大
• 起止时间: 2012-01-01 至 2013-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=513103
• 关键词: Transport; mechanisms; ion; channels; nematodes

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.

寄生线虫是牲畜生产损失的一个主要原因，也是动物和人类健康不佳和死亡的根源。在牛、绵羊和山羊中，它们主要通过驱虫药治疗来控制。大多数现有的驱虫剂通过破坏运输机制起作用，涉及配体门控离子通道。驱虫抗药性正在成为全世界动物生产的一个问题。转运机制涉及配体门控离子通道和ABC转运体。线虫的运输系统不同于哺乳动物；其中一些差异导致了驱虫药对寄生虫的选择性毒性。例如，大环内酯驱虫剂，如伊维菌素，似乎针对配体门控氯通道（LGIC）；其中一些，如谷氨酸、多巴胺、血清素和酪胺门控的Cl-通道在哺乳动物中并不存在。其他驱虫药作用于不同种类的乙酰胆碱受体，其中一些在哺乳动物中没有发现。线虫似乎具有丰富多样的ABC转运基因。一些膜转运蛋白似乎与驱虫抗性有关。线虫和哺乳动物在这些运输机制上的差异可能是显而易见的。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个半转运蛋白（类似于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。我的研究目标是(a)表征线虫中与哺乳动物不同的一些运输基因及其产物，评估(b)它们在线虫中的功能，(c)推进对寄生线虫生物学的认识，并评估将不同运输系统作为化疗新靶点的可能性，(d)确定它们与驱虫药作用的关系，或(e)与对驱虫药的抗性机制。这一信息对于开发控制寄生线虫的新方法具有重要意义，有利于动物产业、动物福利和人类健康。