Anthelmintic resistance in parasitic nematodes

配基门控离子通道调节整个动物界的神经传递，代表着一个古老的关键信号系统。许多药物针对这些渠道，包括麻醉药、抗抑郁药、抗焦虑和抗寄生虫药物。线虫拥有最大的离子通道基因家族，这些基因结合在一起形成具有高度多样性特征的五聚体细胞表面受体。这个基因家族的进化涉及与生物体生物学变化相关的基因复制和丢失。线虫神经系统是抗寄生虫药物的重要靶点。尽管这些措施非常有效，但耐药性正在成为世界各地畜牧业生产的主要关切。我的研究项目确定了导致耐药性的基因，参与其中的分子变化，以及控制其外观和传播的进化过程。目前的提案旨在确定最新抗寄生虫药物Monepantel的结合部位。这样做将有助于未来的研究，提出可能的新药靶点，并有助于防止莫帕酮耐药性的出现和传播。相关药物左旋咪唑针对的几个基因已经在家畜线虫寄生虫中复制。这种药物靶标的重塑与寄生生活方式的进化适应相吻合。这项工作将研究这些复制的基因如何在其调节、功能和对左旋咪唑的敏感性方面发生变化。因此，我们将能够理解神经系统如何适应新的生物角色，以及塑造控制神经系统的离子通道的力量。我们将阐明左旋咪唑是如何杀死这些寄生虫的，以及这与过去用于研究这一点的模型生物有何不同。我们在这一领域面临的最大挑战是了解许多离子通道基因是如何结合在一起产生其广泛的多样性的。新的生物信息学技术将被用来预测蛋白质的相互作用，并协助建立线虫中的离子通道相互作用图。这里概述的工作将提供一个理想的学生培训计划，并涉及分子研究前沿的广泛技术。

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.