The overall objective of this research is to gain better understanding of serotonin-activated adenylate cyclase and enzymes that are regulated by cyclic AMP in trematodes. We plan to use Fasciola hepatica to study the cyclase system in depth. We will solubilize, purify, and characterize the serotonin receptors and the GTP-regulatory protein component of the cyclase. We plan to characterize and isolate the substrate(s) of cyclic AMP-dependent protein kinase from Fasciola. This includes phosphofructokinase (PFK) which has just been purified in our laboratory. We will study the control of fluke PFK through phosphorylation, and the relationship between PFK structure and its function to meet the metabolic needs of the parasite. We will continue with our investigation on the nature of serotonin activated adenylate cyclase from Schistosoma mansoni. Some characterization studies will be done on the serotonin receptors to see how related they are to the Fasciola enzyme. We plan to identify serotonin analogs that act as agonists or antagonists on these receptors in adult schistosomes and in schistosomules, and examine their effect on development of the parasites. We will test the possiblity that serotonin antagonists can adversely affect adult schistosomes or schistosomules in vitro as well as in the host. One essential theme that runs through our research is identification of the differences as well as the similarities of properties of these enzymes and receptors in parasite and host. Our ultimate goal is to identify sites in the parasite that are amenable to pharmacological manipulation without affecting the host.
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