Anthelmintic drug targets in the nematode neuromusculature

肌肉协调是所有动物的一个定义特征，毒素的目标是诱导瘫痪和死亡。协调是通过神经递质信号传导来维持的，由调节膜电压梯度的细胞表面受体介导。这些五聚体离子通道受体在所有动物中高度保守，并且对动物生物学的研究至关重要。寄生蠕虫对人类健康和生产力的影响仅次于疟疾，是农业的一个重大财政和管理问题。药物是我们控制这些寄生虫的唯一有效手段，但抗药性的上升需要新的药物和技术来扩大我们现有药物的效用。大多数驱虫药激活五聚体离子通道，导致瘫痪，所以我研究的长期目标是了解寄生线虫肌肉的神经递质控制是如何维持的，特别是在面对驱虫药耐药性的情况下。自由生活的线虫C.线虫也许是最好的特征化的动物，并且作为近亲，已被证明是寄生虫的极其成功的模型。主要驱虫药物的靶标已经确定，并且这种知识转移到寄生线虫。在每种情况下，C。线虫离子通道受体与寄生虫中的受体相关但不同。这种差异对深入了解寄生虫神经肌肉组织的神经递质控制构成了最大的直接挑战。驱虫药抵抗的原因还不清楚，但可能涉及特定受体的丧失，令人惊讶的是，对正常肌肉协调几乎没有影响。冗余的神经递质受体可能存在，对现在推荐用于寄生虫控制的药物组合疗法具有深远的影响。对一种药物的耐药性可以防止对靶向补偿受体的药物的耐药性。如果亚基能够在抗性出现时相互替换，则在物种之间观察到的受体的可塑性也可能是重要的。我的短期目标是描述C.线虫和相关寄生虫，确定它们是否代表肌肉协调的冗余神经递质控制，检查受体亚基组装的机制，特别是这些如何导致物种之间的差异。我的新方法是识别和表征基因复制，非常适合于剖析控制受体组成变化的机制。这项工作的主要影响将是了解神经递质电路的基本机制以及受体如何在物种之间变化。我们将能够更有效地识别不同寄生虫物种中的新离子通道受体。它将建立重复基因分析作为标准技术，在驱虫药靶点研究领域产生范式转变。

Muscle coordination is a defining feature of all animals, targeted by toxins to induce paralysis and death. Coordination is maintained by neurotransmitter signalling, mediated by cell surface receptors that regulate the membrane voltage gradient. These pentameric ion-channel receptors are highly conserved in all animals and are fundamentally important to the study of animal biology. Parasitic helminths are second only to malaria for their impact on human health and productivity and are a major financial and management problem for agriculture. Drugs are the only effective means we have to control these parasites but the rise of resistance requires new drugs as well as techniques to extend the utility of drugs we have now. Most anthelmintics activate pentameric ion-channels, causing paralysis so the long term goal of my research is to understand how neurotransmitter control of parasitic nematode muscle is maintained, particularly in the face of developing anthelmintic resistance. The free living nematode, C. elegans, is perhaps the best characterized animal and as a close relative, has proved an extremely successful model for parasites. Targets of the major anthelmintic drugs have been identified and this knowledge transferred to parasitic nematodes. In every case, C. elegans ion-channel receptors are related but different from those in parasites. This difference poses the biggest immediate challenge for a deeper understanding of neurotransmitter control of parasite neuromusculature. The cause of anthelmintic resistance is not well understood but can involve loss of specific receptors, surprisingly, with little effect on normal muscle coordination. Redundant neurotransmitter receptors may be present with profound implications for drug combination therapies that are now recommended for parasite control. Resistance to one drug could prevent resistance to drugs that target a compensatory receptor. Plasticity of receptors observed between species may also be important if subunits are able to replace each other as resistance appears. My short term goals are to characterize new acetylcholine receptors in C. elegans and related parasites, determine if they represent redundant neurotransmitter control of muscle coordination, examine the mechanisms of receptor subunit assembly and specifically how these lead to differences between species. My novel approach is to identify and characterize gene duplications ideally suited to dissect the mechanism governing changing receptor composition. A major impact of this work will be understanding fundamental mechanisms of neurotransmitter circuitry and how receptors change between species. We will be able to identify new ion-channel receptors in different parasite species more effectively. It will establish the analysis of duplicate genes as a standard technique producing a paradigm-shift in the field of anthelmintic drug target research.**