Ascariasis and hookworm infection affect 1.6 billion people across the world. Anthelmintics, including levamisole and related drugs (pyrantel), are used to combat nematode parasites, and resistance is a threat. Our long-range objective is to improve human health by increasing the efficacy of anthelmintic drugs by identifying approaches to reverse resistance. The objective of this application is to test single-channel properties of levamisole receptors and a model that describes changes in the sensitivity of nematodes to levamisole and alters potency. Our central hypothesis is that the structure and pore of the L-subtype acetylcholine receptor ion-channel on nematode muscle makes it more sensitive to levamisole and more permeable to Ca;and the increased response of acetylcholine channels (modulation) produced by the neuropeptide, AF2,involves cAMP, Ca entry and kinase activity. The rationale for the research is that, as the mechanisms for modulating responses to levamisole activated receptor channels become known, pharmacological approaches can be formulated to overcome resistance. We will use muscle preparations of A. suum, C. elegans and null-mutants with current-clamp, voltage-clamp and patch-clamp technology to test the Ca permeability and subunit composition of L-subtype acetylcholine channels and to test a model for AF2 modulation. We will pursue 3 aims: 1) determine the Ca permeability of N-, L- and B- subtypes of A. suum muscle acetylcholine receptors and thereby identify a preferred target site;2) determine in patch-clamp experiments in C. elegans, the subunit requirements of the L-subtype acetylcholine channel;3) characterize, n A. suum muscle, the mechanism &pharmacology by which calcium and AF2 affect the opening of different AChR channel subtypes, in order to increase responses and potency of cholinergic anthelmintics. The research is innovative because we are combining new knowledge from C. elegans with advanced electrophysiology of nematode parasites including muscle-vesicle preparations for patch-clamp recordings. We expect the research to identify additional strategies that increase the potency of cholinergic anthelmintics. The research is significant because application of the results will to lead to new approaches to control and overcome resistance to anthelmintics of the levamisole class.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI047194-10
Application #
7750527
Study Section
Special Emphasis Panel (ZRG1-DDR-N (01))
Program Officer
Rogers, Martin J
Project Start
2000-12-15
Project End
2011-06-30
Budget Start
2010-01-01
Budget End
2011-06-30
Support Year
10
Fiscal Year
2010
Total Cost
$272,445
Indirect Cost
Name
Iowa State University
Department
Veterinary Sciences
Type
Schools of Veterinary Medicine
DUNS #
005309844
City
Ames
State
IA
Country
United States
Zip Code
50011
Zheng, Fudan; Du, Xiangwei; Chou, Tsung-Han et al. (2017) (S)-5-ethynyl-anabasine, a novel compound, is a more potent agonist than other nicotine alkaloids on the nematode Asu-ACR-16 receptor. Int J Parasitol Drugs Drug Resist 7:12-22
Zheng, Fudan; Robertson, Alan P; Abongwa, Melanie et al. (2016) The Ascaris suum nicotinic receptor, ACR-16, as a drug target: Four novel negative allosteric modulators from virtual screening. Int J Parasitol Drugs Drug Resist 6:60-73
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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
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Robertson, Alan P; Puttachary, Sreekanth; Buxton, Samuel K et al. (2015) Tribendimidine: mode of action and nAChR subtype selectivity in Ascaris and Oesophagostomum. PLoS Negl Trop Dis 9:e0003495
Trailovi?, Saša M; Marjanovi?, Djordje S; Nedeljkovi? Trailovi?, Jelena et al. (2015) Interaction of carvacrol with the Ascaris suum nicotinic acetylcholine receptors and gamma-aminobutyric acid receptors, potential mechanism of antinematodal action. Parasitol Res 114:3059-68
McCoy, Ciaran J; Warnock, Neil D; Atkinson, Louise E et al. (2015) RNA interference in adult Ascaris suum--an opportunity for the development of a functional genomics platform that supports organism-, tissue- and cell-based biology in a nematode parasite. Int J Parasitol 45:673-8
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

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