Grant: Discovery Grants Program - Individual

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.