Paralysis of Nematode Parasites

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 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.