The Neglected Tropical Diseases (NTDs) include the soil-transmitted helminthiases (STHs) which are caused by diverse groups of intestinal nematodes. The parasites include Ascaris, Trichuris and hookworms. These infections are common. Ascariasis for example, affects 1.4 billion people worldwide and is most common in children between the ages of 3 and 8. Control of these nematode parasites relies on an effective supply of anthelmintics. Taking veterinary medicine as an example, we know that continued use of anthelmintic compounds for mass chemotherapy will lead to drug resistance. There is a need to identify novel target sites for anthelmintic development. Once such site is the nicotinic acetylcholine receptor on the nematode pharynx. We have discovered this receptor does not respond to currently used anrthelmintic drugs. Approach:
The specific aims of this application are: 1. Characterize nAChR responses in A. suum pharynx: using current-, voltage- &patch- clamp techniques. We will test the hypothesis that the A. suum pharynx nAChRs are pharmacologically distinct from the muscle nAChRs activated by cholinergic anthelmintics. 2. Identify &clone pharyngeal specific nicotinic acetylcholine receptor subunits. We will identify the nAChR subunit genes present in the pharynx required to produce functional receptors. 3. Characterize the pharyngeal cholinergic receptors in Xenopus laevis oocytes using voltage- &patch-clamp techniques. We will test the hypothesis that expression of pharyngeal nAChR subunits results in functioning receptors that are pharmacologically similar to those found in vivo. On completion of this project we will have characterized the pharmacology of an important new potential drug target in a parasitic nematode. We will have identified the genes that encode these receptors. Finally, we will have reconstituted the receptors in an accessible platform suitable for screening potential new anthelmintics. The longer term goal of this research is provide ion- channel drug targets from a range of important parasite species in a platform (Xenopus oocytes) suitable for drug discovery screening.

Public Health Relevance

The Neglected Tropical Diseases (NTDs) include soil transmitted nematode parasites like ascariasis, trichuriasis and hookworm. Ascariasis, for example, is one of the most common human parasitic infections. 1.5 billion people worldwide have ascariasis, and the disease is most common in children between the ages of 3 and 8. Treatment of helminthiasis includes use of nicotinic anthelmintics like pyrantel and oxantel which selectively paralyze nematodes by activating cholinergic ion-channels (nAChRs) on their muscle. However, resistance to anthelmintics drugs is a real concern. We have identified a novel potential target site for new anthelmintics, the nAChR on the nematode pharynx, which is not sensitive to currently used drugs. We propose to characterize the pharmacological properties of this receptor, clone the component subunit genes and express the functional receptor in Xenopus oocytes. On completion of the project we will have characterized a potential new drug target (the pharynx nAChR) and reconstituted it in a platform (Xenopus laevis oocytes) suitable for screening compound libraries to identify new anthelmintic compounds.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Exploratory/Developmental Grants (R21)
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Pathogenic Eukaryotes Study Section (PTHE)
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Rogers, Martin J
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Iowa State University
Veterinary Sciences
Schools of Veterinary Medicine
United States
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Abongwa, Melanie; Buxton, Samuel K; Robertson, Alan P et al. (2016) Curiouser and Curiouser: The Macrocyclic Lactone, Abamectin, Is also a Potent Inhibitor of Pyrantel/Tribendimidine Nicotinic Acetylcholine Receptors of Gastro-Intestinal Worms. PLoS One 11:e0146854
Abongwa, Melanie; Buxton, Samuel K; Courtot, Elise et al. (2016) Pharmacological profile of Ascaris suum ACR-16, a new homomeric nicotinic acetylcholine receptor widely distributed in Ascaris tissues. Br J Pharmacol 173:2463-77
Martin, R J; Puttachary, S; Buxton, S K et al. (2015) The Conqueror Worm: recent advances with cholinergic anthelmintics and techniques excite research for better therapeutic drugs. J Helminthol 89:387-97
Martin, Richard J; Verma, Saurabh; Choudhary, Shivani et al. (2015) Anthelmintics: The best way to predict the future is to create it. Vet Parasitol 212:18-24
Chehayeb, James F; Robertson, Alan P; Martin, Richard J et al. (2014) Proteomic analysis of adult Ascaris suum fluid compartments and secretory products. PLoS Negl Trop Dis 8:e2939
Buxton, Samuel K; Charvet, Claude L; Neveu, Cedric et al. (2014) Investigation of acetylcholine receptor diversity in a nematode parasite leads to characterization of tribendimidine- and derquantel-sensitive nAChRs. PLoS Pathog 10:e1003870
Robertson, A P; Buxton, S K; Martin, R J (2013) Whole-cell patch-clamp recording of nicotinic acetylcholine receptors in adult Brugia malayi muscle. Parasitol Int 62:616-8
Puttachary, Sreekanth; Trailovic, Sasa M; Robertson, Alan P et al. (2013) Derquantel and abamectin: effects and interactions on isolated tissues of Ascaris suum. Mol Biochem Parasitol 188:79-86
Martin, Richard J; Robertson, Alan P; Buxton, Samuel K et al. (2012) Levamisole receptors: a second awakening. Trends Parasitol 28:289-96
Charvet, Claude L; Robertson, Alan P; Cabaret, Jacques et al. (2012) Selective effect of the anthelmintic bephenium on Haemonchus contortus levamisole-sensitive acetylcholine receptors. Invert Neurosci 12:43-51