The acetylcholine-gated chloride channel gene family in parasitic nematodes

感染寄生线虫在发展中国家和北美造成了相当大的疾病负担。目前，唯一的控制方法是使用杀线虫剂。然而，尽管人类和家畜都面临着巨大的疾病负担，抗药性的发生率也在上升，但可用的治疗方法相对较少。因此，发现和表征新的杀线虫目标，既能减少人类寄生虫造成的发病率，又能保持对牲畜寄生虫的控制，这将具有深远的全球影响。最近完成的几种寄生线虫基因组现在提供了一个机会，开始全面寻找潜在的新的和独特的杀线虫目标，同时增加我们对这些重要病原体生物学的了解。有一大类受体被称为Cys-loop受体，它们对寄生线虫的神经系统非常重要，因此有很好的潜力成为新的杀线虫靶标，而这个家族中的几个成员只在无脊椎动物中发现。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，最终目标是为未来的杀线虫找到新的有希望的靶标。只在无脊椎动物中发现的一组环状受体是乙酰胆碱门控氯通道(ACCs)。来自我的实验室的初步数据表明，这个受体家族在寄生线虫中发挥着重要的生物学作用。该项目将形成对经济上重要的线虫病原体螺旋血吸虫的这一受体家族的全面分析的开始阶段。具体地说，我们还将研究这些受体在体内的生物学功能以及乙酰胆碱结合部位的药理学和分子结构。该项目独特地将对进化上原始的受体家族的研究与对新的激动剂结合位点的全面分析结合在一起。这将为硕士和博士生提供关于环状受体功能的独特视角，以及与蛋白质结构/功能相关的研究、硅胶蛋白质建模和合理药物设计的相关培训。

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. **