Paralysis of Nematode Parasites

 描述(由申请人提供)：线虫感染是人类发病率的主要原因，并显著导致残疾调整寿命年的损失。更重要的是，在许多情况下，例如丝虫感染，仍然无法获得有效的化疗。寄生线虫对家畜和植物的破坏性经济影响或许不太受重视，但对人类健康同样重要，而且在所有环境中都迫切需要新的驱虫剂和药物靶标。大多数用于治疗线虫感染的驱虫药作为关键受体的激动剂，通过干扰肌肉收缩和/或运动而导致瘫痪。这项应用的总体目标是促进以运动为靶点导致瘫痪的新驱虫剂的开发。我们利用线虫和猪蛔虫模型的实验优势，采用了一种创新的“双重系统”方法，表征了调节运动的关键单胺受体。线虫分子遗传学在分离关键受体基因方面发挥了重要作用，生物信息学方法随后确定了相应的寄生线虫cDNA，最终确定了四个关键的单胺受体作为有希望的驱虫靶标。在本研究中，我们将开发基于这些受体的创新的驱虫药筛选策略，通过在异源细胞中表征它们的激动剂敏感性，并在线虫中表达它们，以创建“嵌合”线虫来确认正统，并允许在生理条件下进行激动剂筛选。我们将确定这些受体的作用部位和生理作用。 用直接功能定位和电生理方法研究寄生线虫的运动回路。这些研究不仅将确定寄生线虫中调控运动的关键单胺受体，而且由于线虫之间的巨大多样性，它们也将突出这两个重要模式系统之间的潜在差异。运动对寄生线虫的生存至关重要，抑制运动的药物可以成功清除寄生线虫感染。这些研究将确定 为药物发现提供了大量潜在的新型分子靶点。

 DESCRIPTION (provided by applicant): Nematode infections are a major cause of human morbidity and contribute significantly to a loss of Disability Adjusted Life Years. More importantly, in many cases, such as filarial infection, effective chemotherapy is still not availabe. Perhaps less well appreciated, but equally important for human health, is the devastating economic impact of parasitic nematodes on livestock and plants, and new anthelmintic and drug targets are both desperately needed in all settings. Most anthelmintic in use against nematode infections act as agonists at key receptors and cause paralysis by interfering with muscle contraction and/or locomotion. The overall objective of this application is to promote the development of new anthelmintic that target locomotion to cause paralysis. We have characterized key monoamine receptors regulating locomotion using an innovative 'dual systems' approach that exploited the experimental advantages of the C. elegans and Ascaris suum models. Highlighting the utility of this approach, C. elegans molecular genetics was instrumental in isolating key receptor genes; bioinformatics approaches then identified corresponding parasitic nematode cDNAs, and ultimately, four key monoamine receptors were identified as promising possible anthelmintic targets. In the present study we will develop innovative anthelmintic drug screening strategies based on these receptors by characterizing their agonist sensitivities in heterologous cells, and expressing them in C. elegans, to create 'chimeric' nematodes to confirm orthodoxy and allow agonist screening under physiological conditions. We will establish the sites of action and physiological roles of these receptors in the locomotors circuitry of parasitic nematodes by direct functional localization and electrophysiological approaches. These studies will not only identify definitively key monoamine receptors regulating locomotion in parasitic nematodes, but because of the enormous diversity among nematodes, they will also highlight the potential differences between these two important model systems. Locomotion is critical to the survival of parasitic nematodes, and drugs that inhibit locomotion can successfully clear parasitic nematode infection. These studies will identify a wealth of potential novel molecular targets for drug discovery.