Transport mechanisms in parasitic nematodes

寄生线虫造成家畜疾病、生产损失和死亡，需要使用昂贵的驱虫药物控制措施。几乎所有的驱虫剂都以线虫的运输机制为目标，这表明这些运输机制在线虫中代表了独特的目标。例如，伊维菌素等驱虫药会在线虫体内打开独特的氯离子通道，导致肌肉麻痹。然而，膜蛋白，如p -糖蛋白（Pgps），可以调节驱虫药在其作用部位的浓度。了解这些运输系统的功能将促进我们对线虫细胞生理学和药物作用和耐药性机制的认识。提出的研究目标将是进一步阐明寄生线虫运输机制的生物学细节。我们将利用家畜致病性寄生虫——弯曲血蜱和模式线虫秀丽隐杆线虫。我们的研究将着眼于各种转运蛋白的表达调控、表达位点和底物特异性。这将通过分析Pgp基因的启动子序列，线虫Pgp的表达和确定其底物特异性来进行。我们将研究独特的线虫离子通道的电生理学，它们对一系列底物和驱虫药的反应，以及它们在线虫中的表达位点。线虫微管蛋白的等位基因改变，影响线虫细胞的运输和结构功能，以及抗寄生虫药物的易感性，将被研究。这项新研究将极大地促进我们对线虫体内转运机制的认识，更好地阐明抗寄生虫药物的作用机制和线虫的耐药机制。这一知识对于改善动物寄生虫控制、动物福利和生产具有重要意义。

Parasitic nematodes cause disease, loss of production and death in farm animals requiring the use of expensive control measures using anthelmintic drugs. Virtually all anthelmintics target transport mechanisms in nematodes, indicating that these transport mechanisms represent unique targets in nematodes. For example, anthelmintics such as ivermectin, opens unique chloride channels in nematodes, causing muscle paralysis. However, membrane proteins, such as P-glycoproteins (Pgps), may regulate the concentration of anthelmintics at their sites of action. Understanding the functioning of these transport systems will advance our knowledge of nematode cellular physiology and the mechanisms of drug action and resistance. The objectives of the proposed research will be to further elucidate details of the biology of transport mechanisms in parasitic nematodes. We will utilize the pathogenic parasite of livestock, Haemonchus contortus as well as the model nematode Caenorhabditis elegans. Our research will look at regulation of expression, sites of expression and substrate specificity of various transporters. This will be undertaken by analyzing the promoter sequences of Pgp genes, expression of nematode Pgps and determination of their substrate specificity. The electrophysiology of unique nematode ion channels will be investigated, their responses to a range of substrates and anthelmintic drugs, and their expression sites in the nematodes will be determined. Allelic alterations in nematode tubulin proteins, which affect transport and structural functions in nematode cells, and susceptibility to antiparasitic drugs, will be investigated. This novel research will significantly advance in our understanding of transport mechanisms in nematodes and better elucidate the mechanisms of the action of antiparasitic drugs and the mechanisms of drug resistance in nematodes. This knowledge is important to improve parasite control in animals, animal welfare and production.