Transport mechanisms, anthelmintic resistance and novel receptors in parasitic nematodes

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Parasitic nematodes are a major cause of losses in livestock production and cause disease and death. In cattle, sheep, goats they are controlled with anthelmintic drugs. Most anthelmintics act by disrupting transport mechanisms, involving ion channels and microtubules. Anthelmintic resistance is a major problem for animal production throughout the world. Transport mechanisms are often involved in the mechanisms of resistance. The transport systems in nematodes are different from those in mammals. For example, anthelmintics such as ivermectin, target chloride channels, such as glutamate-, dopamine-, serotonin-, and tyramine-gated Cl- channels, which do not occur in mammals. Other anthelmintics, act on classes of acetylcholine receptors not found in mammals. Benzimidazole anthelmintics bind to nematode tubulin, but not to mammalian tubulin, affecting the stability of nematode microtubules. Nematodes have a rich and diverse array of ABC transport genes, some of which are involved in anthelmintic resistance. For example, humans have two P-glycoproteins, whereas nematodes have up to 14 P-glycoproteins, 9 half transporters (haf genes, which are different from mammalian half-transporters, such as breast cancer resistant protein, and 8 multidrug resistant protein (MRP) genes, compared with 3 MRPs in mammals. The research objectives are to (a) characterize transport genes and their products in nematodes, to assess (b) their functions, (c) their involvement with anthelmintic action, or (d) with drug resistance mechanisms, (e) to advance knowledge of the biology of parasitic nematodes and assess the possibilities of targeting divergent transport systems for chemotherapy, (f) to identify drug resistance markers, and (g) to reduce the selection for resistance, or to overcome the resistance. The scientific approaches that will be used include the analysis of the parasite genomes to identify novel transport related genes, to clone, express and characterize novel transport genes and their products, to investigate the interaction of transport proteins with existing anthelmintics, to look for genetic changes causing resistance and, to develop molecular markers for the early detection and monitoring of resistance.