The acetylcholine-gated chloride channel gene family in parasitic nematodes

寄生虫感染在发展中国家和北美造成相当大的疾病负担。目前，唯一的控制方法是使用杀线虫剂。然而，尽管对人类和家畜造成了重大的疾病负担，而且耐药性的发生率也在上升，但可用的治疗方法相对较少。因此，发现和鉴定新的杀线虫靶点，既能降低人类寄生虫的发病率，又能保持对牲畜寄生虫的控制，将具有深远的全球意义。最近完成的几个寄生线虫基因组现在提供了一个机会，开始全面搜索潜在的新的和独特的杀线虫靶点，同时增加了我们对这些重要病原体生物学的理解。有一个被称为cys-loop受体的大家族，由于它们对寄生线虫的神经系统很重要，并且该家族的一些成员仅在无脊椎动物中发现，因此具有作为新型杀线虫剂的良好潜力。我研究的长期目标是了解cys-loop受体家族在寄生线虫中的功能，最终目标是发现未来杀线虫剂的新靶点。一组仅在无脊椎动物中发现的cys-loop受体是乙酰胆碱门控氯通道（ACCs）。我实验室的初步数据表明，这个受体家族在寄生线虫中起着重要的生物学作用。这个项目将形成一个全面分析这个家族的受体在经济上重要的线虫病原体弯曲血蜱的开始阶段。具体来说，我们将研究这些受体在体内的生物学功能以及乙酰胆碱结合位点的药理学和分子结构。该项目独特地融合了对进化原始受体家族的研究，并对一种新型激动剂结合位点进行了全面分析。这将为硕士生和博士生提供一个独特的视角来研究cys-loop受体的功能，并在蛋白质结构/功能、硅蛋白建模和合理药物设计方面进行相关的研究培训。**

Infection with parasitic nematodes causes considerable disease burden in developing countries as well as North America.  Currently, the only method of control is through the use of nematocides.  However, despite the significant disease burden for both humans and domestic animals and rising incidences of drug resistance there are relatively few treatments available.  Therefore, the discovery and characterization of new nematocidal targets to both reduce the morbidity caused by human parasites as well as maintain the control of parasites of livestock will have far reaching global implications.  The recent completion of several parasitic nematode genomes has now provided an opportunity to begin a comprehensive search for potential new and unique nematocidal targets while at the same time increasing our understanding of the biology of these important pathogens. There is a large family of receptors called cys-loop receptors that have good potential as targets for new nematocides since they are important for the nervous system of parasitic nematodes and several members of this family are found only in invertebrates. The long term goal of my research is to understand the function of the cys-loop receptor family in parasitic nematodes with the ultimate goal to discover new promising targets for future nematocides.   One group of cys-loop receptors that are found only in invertebrates are the acetylcholine-gated chloride channels (ACCs).  Preliminary data from my laboratory suggest that this receptor family plays an important biological role in parasitic nematodes.  This project will form the beginning stages of a comprehensive analysis of this family of receptors in the economically important nematode pathogen Haemonchus contortus.  Specifically, we will examine both the biological function of these receptors in vivo as well as the pharmacology and molecular structure of the acetylcholine binding site. This project uniquely blends the study of an evolutionarily primitive family of receptors with a comprehensive analysis of a novel agonist binding site. This will provide masters and doctoral students with a unique perspective on the function of cys-loop receptors and relevant training in research related to protein structure/function, in silico protein modelling and rational drug design. **