Anthelmintic resistance in parasitic nematodes

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Ligand gated ion channels regulate nerve transmission throughout the animal kingdom and represent an ancient critical signaling system. Many drugs target these channels, including anesthetics, anti-depressants, anti-anxiety and anti-parasitic drugs. Nematodes have the largest family of ion-channel genes that combine to form pentameric cell surface receptors with highly diverse characteristics. Evolution of this gene family involves gene duplication and loss associated with changes in organism biology. The nematode nervous system is an important target for anti-parasitic drugs. Although these are highly effective, resistance is becoming a major concern for livestock production worldwide. My research program identifies genes that cause drug resistance, the molecular changes involved in this and the evolutionary processes that control its appearance and spread. The current proposal aims to identify the binding site for the newest anti-parasitic drug, monepantel. Doing so will facilitate future research, suggest possible new drug targets and help prevent the appearance and spread of monepantel resistance. Several genes targeted by the related drug, levamisole, have been duplicated in nematode parasites of livestock. This remodeling of the drug target coincides with the evolutionary adaptation to a parasitic lifestyle. This work will examine how these duplicated genes have changed in their regulation, function and sensitivity to levamisole. As a result we will be able to understand how the nervous system adapts to a new biological role as well as the forces that shape the ion-channels that control the nervous system. We will clarify how levamisole kills these parasites and how this is different from the model organisms used to investigate this in the past. The biggest challenge we face in this area is understanding how the many ion channel genes combine to produce their wide diversity. New bioinformatic techniques will be used to predict protein interactions and assist efforts to build an ion channel interaction map in the nematodes. The work outlined here will provide an ideal student training program and involve a wide range of techniques at the forefront of molecular research.