Anthelmintic resistance in parasitic nematodes

驱虫药是全世界畜牧业生产的重要组成部分，尽管抗药性上升对其使用构成严重威胁。详细描述导致抗药性的特定分子变化可以用来寻找有效的替代品。许多驱虫药以线虫神经肌肉中的配体门控离子通道(LGIC)为靶标，可用于探索线虫神经系统的基本生物学，从而提供对神经冲动传递的总体洞察。为了与这一领域相关，我们还需要了解耐药性演变和传播的机制，从而设计出更有效的药物应用和动物管理计划。11种线虫寄生虫的基因组计划将在10年内完成，开启新的分析技术。为了有效地利用这些，我们必须了解寄生虫的遗传学。我的研究计划是在分子水平上确定具体的抗药性机制，并描述寄生虫的遗传学特征，以了解抗药性的进化。我之前在大环内酯抗性扭转血吸虫中发现了两个LGIC改变，这是一种广泛存在的绵羊和山羊的模式寄生虫。它们的表达模式和药理学解释了药物的生理效应，耐药形式的变化改变了寄生虫对体内药物暴露的反应。我已经在扭曲血吸虫的部分基因组序列中鉴定了大约85个LGIC基因，其中30个基因的完整或部分cDNA是已知的。在我的研究计划的第一部分，我建议进一步表征大环内酯抗性LGICs的功能变化，并将剩余的LGICs从螺旋体中分离出来。与左旋咪唑耐药性和新报道的氨基乙腈驱虫药相关的特异性LGICs的功能将被检测。对于第二个，我建议确定基因是如何结合在一起影响抗性的，并描述基因之间的遗传联系。这将提供有关LGIC功能的一般信息和引起大环内酯耐药的特定变化；扩大我们对家畜重要病原体的认识，并可能识别新的药物靶点；为LGIC研究和后基因组时代对螺旋体抗药性的分析奠定基础。

Anthelmintic drugs are an essential component of livestock production throughout the world although rising resistance poses a serious threat to their use. Detailing specific molecular changes that cause resistance can be used to find effective alternatives. Many anthelmintics target ligand-gated ion-channels (LGIC) in nematode neuromusculature and can be used to probe basic biology of the nematode nervous system, providing insight into nerve impulse transmission in general. To be relevant in the field we also need to understand mechanisms by which resistance evolves and spreads and so devise more effective drug application and animal management programs. Genome projects for 11 nematode parasites will be completed within 10 years, opening new analysis techniques. To make effective use of these we must understand parasite genetics. My research program is to determine specific mechanisms of resistance at the molecular level and characterize parasite genetics to understand the evolution of resistance. I previously identified two LGICs altered in macrocyclic lactone resistant Haemonchus contortus, a widespread model parasite of sheep and goats. Their expression pattern and pharmacology explain the physiological effects of the drug and changes in the resistant forms alter the parasite response to drug exposure in vivo. I have identified about 85 LGIC genes in the partial genome sequence of H. contortus and full or partial cDNAs are known for 30 of these. For the first part of my research program I propose to further characterize functional changes in macrocyclic lactone resistant LGICs and isolate the remaining LGICs from H. contortus. The function of specific LGICs linked with resistance to levamisole and the newly reported amido acetonitrile anthelmintics will be examined. For the second I propose to determine how genes act in combination to effect resistance and to characterize genetic linkage between genes. This will provide information on the function of LGICs in general and specific changes that cause macrocyclic lactone resistance; extend our knowledge of an important pathogen of livestock and possibly identify new drug targets; lay a foundation for LGIC research and the post-genomic era analysis of resistance in H. contortus.