Structure and Function of Schistosome Neuropeptide F

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DESCRIPTION (provided by the applicant): Schistosomes are flatworm parasites that cause schistosomiasis, which afflicts at least 200 million people worldwide. Since the disease is focused among underprivileged children in developing countries, it is very difficult to assess the total impact of the disease. The World Health Organization's Special Program for Research and Training in Tropical Diseases (TDR) considers schistosomiasis among its top five disease priorities, and identifies research into the basic biology of schistosome parasites as a primary need. Praziquantel is presently the only drug available for the treatment of schistosomiasis in most parts of the world, but there are growing reports of decreased sensitivity of parasites to this drug. Thus, there is an urgent need to identify potential targets for novel drugs, both for the benefit of those presently suffering from the disease, and to control the disease from re-emerging and becoming more widespread. Most of the available drugs that treat parasitic worms compromise their ability to coordinate muscle activity. It is known that muscle activity in schistosomes is modulated by peptides, designated neuropeptides because they are released by its nervous system. One family of these neuropeptides, designated the FMRFamide-like peptides or FLPs, plays a major role in the control of schistosome muscle activity through its direct actions on a receptor that occurs on schistosome muscle; the interaction of these peptides with schistosome muscle causes a rapid contraction. Since this peptide family is not well represented in humans and yet plays a fundamental role in parasite movement, we propose to unravel key facets of FLP activity in schistosomes and, in so doing, uncover new drug targets that could rapidly lead to novel drug discovery and subsequent improved control of these important parasites. To do this, we will characterize the schistosome FLP and the muscle-based receptor with which it interacts. Once we have identified these key molecules, we will proceed to investigate their distribution within the worm, the mechanisms they use to cause muscle contraction and their specific role within schistosome biology. During this process, we will prepare the FLP receptor for expression in a high throughput system that will facilitate downstream drug discovery efforts. In this way, this project intends to generate novel information on the basic biology of schistosomes and, at the same time, initiate efforts to exploit these discoveries by shortening the route to any potential chemotherapeutic outcomes.