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.
Parasitic nematodes cause significant medical, veterinary and agricultural problems worldwide. Anti-nematode drugs paralyze nematodes by activating receptors and downstream signaling cascades that regulate locomotion. These studies characterize four monoamine receptors in parasitic nematodes that regulate locomotion and therefore may be important drug targets, focusing on pharmacology, physiological function, and innovative drug screening strategies.
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