Objective The macrocyclic lactones such as ivermectin are the cornerstone for the treatment of key nematode infections of livestock, crops and man. Resistance to many of these broad-spectrum anthelmintics is becoming commonplace, while new classes of active compounds are increasingly difficult to find, threatening food supplies and public heatlh worldwide. The exact molecular and biochemical mechanisms of resistance, particularly to the widely used macrocyclic lactone class, are still poorly understood, impeding the development of efficient strategies to control drug resistance. I hypothesize that the amphidial sensory organs of nematodes are the major route of macrocyclic lactone drug uptake and that mutations in this uptake mechanism represents the primary source of drug resistance. In the first phase of the project, I will develop laboratory methods for testing amphid function in two parasitic nematodes of veterinary significance, the trichostrongyles Haemonchus contortus and Teladorsagia circumcincta. These techniques will be applied on drug resistant and sensitive isolates to evaluate the role of amphids in ivermectin uptake. In the second phase, I will use the C. elegans model to generate mutants resistant to three major classes of anthelmintic drugs, ivermectin, the benzimidazole albendazole and the imidazothiazole levamisole. I will then apply genomic tools to identify alleles responsible of this multi-drug resistance phenotype. This project aims to understand the link between amphid defects, anthelmintic drug uptake, and development of resistance, and will generate a thorough knowledge of this unexplored and apparently widespread resistance mechanism in nematodes. These results will also pave the way to the implementation of a fast and reliable measurement of drug resistance in the field. On the whole, the project will bring a direct contribution to current veterinary and public health challenges by suggesting new strategies to limit the emergence of drug resistance. Fields of science medical and health scienceshealth sciencespublic healthnatural sciencesbiological sciencesgeneticsmutationagricultural sciencesagriculture, forestry, and fisheriesagricultureagricultural sciencesanimal and dairy sciencedomestic animalsanimal husbandrymedical and health sciencesbasic medicinepharmacology and pharmacydrug resistancemultidrug resistance Keywords anthelmintic resistance ivermectin nematodes drug uptake amphids macrocyclic lactones mulit-drug resistance trichostrongyle nematodes Programme(s) H2020-EU.1.3. - EXCELLENT SCIENCE - Marie Skłodowska-Curie Actions Main Programme H2020-EU.1.3.2. - Nurturing excellence by means of cross-border and cross-sector mobility Topic(s) MSCA-IF-2016 - Individual Fellowships Call for proposal H2020-MSCA-IF-2016 See other projects for this call Funding Scheme MSCA-IF - Marie Skłodowska-Curie Individual Fellowships (IF) Coordinator UNIVERSITY OF GLASGOW Net EU contribution € 195 454,80 Address University avenue G12 8QQ Glasgow United Kingdom See on map Region Scotland West Central Scotland Glasgow City Activity type Higher or Secondary Education Establishments Links Contact the organisation Opens in new window Website Opens in new window Participation in EU R&I programmes Opens in new window HORIZON collaboration network Opens in new window Other funding € 0,00
