Locomotion in Parasitic Nematodes

描述（由申请方提供）：线虫感染是人类发病的主要原因，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，如丝虫感染，仍然没有有效的化疗。寄生线虫对牲畜和植物的破坏性经济影响可能不太受重视，但对人类健康同样重要，因此在所有情况下都迫切需要新的驱虫药和药物靶点。大多数用于对抗线虫感染的驱虫剂作为关键受体的激动剂，并通过干扰肌肉收缩和/或运动引起麻痹。我们先前资助的补助金“寄生线虫运动”（AI 072644）的更新申请的总体目标是促进新的驱虫药的开发，这些驱虫药的目标是导致瘫痪的运动。在上一个资助期，我们使用创新的“双系统”方法，利用C。elegans和猪蛔虫模型。强调这种方法的实用性，C。elegans分子遗传学有助于分离关键受体基因;然后，生物信息学方法鉴定了相应的寄生线虫cDNA，最终，四种关键单胺受体被鉴定为有希望的可能的驱虫靶标。在本研究中，我们将开发基于这些受体的创新驱虫药物筛选策略，通过表征它们在异源细胞中的激动剂敏感性，并在C. elegans，以创建“嵌合”线虫，以确认直系同源性，并允许在生理条件下进行激动剂筛选。我们将通过直接的功能定位和电生理学方法建立这些受体在寄生线虫运动回路中的作用位点和生理作用。我们还将继续采用双系统方法，使用开发良好的C。elegans '工具包'来研究这些受体下游的信号通路，并定义它们在做出运动决定的'中央'回路中的确切作用。这些研究不仅将明确确定调节寄生线虫运动的关键单胺受体，而且由于线虫之间的巨大多样性，它们还将突出这两个重要模型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地 明确寄生线虫感染。这些研究将为药物发现确定大量潜在的新分子靶点。

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 anthelmintics and drug targets are both desperately needed in all settings. Most anthelmintics 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 renewal application of our previously funded grant 'Locomotion in Parasitic Nematodes' (AI072644) is to promote the development of new anthelmintics that target locomotion to cause paralysis. In the previous funding period we 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 orthology and allow agonist screening under physiological conditions. We will establish the sites of action and physiological roles of these receptors in the locomotory circuitry of parasitic nematodes by direct functional localization and electrophysiological approaches. We will also continue the dual-systems approach, using the well-developed C. elegans 'toolkit' to investigate signaling pathways downstream of these receptors, and define their precise roles in 'central' circuits that make locomotory decisions. 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.