The acetylcholine-gated chloride channel gene family in parasitic nematodes

寄生线虫中乙酰胆碱门控氯离子通道基因家族

• 批准号: RGPIN-2015-05284
• 负责人: Forrester, Sean
• 金额: $ 1.75万
• 依托单位: University of Ontario Institute of Technology
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2019
• 资助国家: 加拿大
• 起止时间: 2019-01-01 至 2020-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=680020
• 关键词: acetylcholine; gated; chloride; channel; gene

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. **

寄生线虫感染在发展中国家和北美造成了相当大的疾病负担。 目前，唯一的控制方法是通过使用杀线虫剂。 然而，尽管人类和家畜的疾病负担很重，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，发现和表征新的杀线虫靶标以降低由人类寄生虫引起的发病率以及保持对家畜寄生虫的控制将具有深远的全球影响。 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的目标，同时增加我们对这些重要的病原体的生物学的理解。有一个大家族的受体称为cys环受体，具有良好的潜力作为新的杀线虫剂的目标，因为它们对寄生线虫的神经系统很重要，并且该家族的几个成员仅在无脊椎动物中发现。loop受体家族的研究，最终目标是发现未来杀线虫剂的新的有希望的靶标。 仅在无脊椎动物中发现的一组cys环受体是乙酰胆碱门控氯离子通道（ACCs）。 从我的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的分析，在经济上重要的线虫病原体捻转血矛线虫的受体家族的开始阶段。 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一个进化上原始的受体家族的研究和对一个新的激动剂结合位点的全面分析。这将为硕士和博士生提供关于cys环受体功能的独特视角，以及与蛋白质结构/功能，计算机蛋白质建模和合理药物设计相关的研究相关培训。