Research Program
Schistosomes, or blood flukes, are flatworms that parasitize humans and cause schistosomiasis, a widespread tropical disease. Using molecular biological approaches, my laboratory is working to better understand the nervous system of schistosomes such as Schistosoma mansoni. The ultimate goal of this work is to provide possible molecular targets for new, potent, and specific antiparasitic agents.

Current Projects
Calcium channels reside in cell membranes, open in response to a voltage change across the cell’s membrane, and allow calcium to flow into the cell. This calcium current has two consequences: first, it contributes to the propagation of electrical signals in excitable cells; second, it changes the level of calcium within the cell. Calcium is an important messenger molecule in biological systems and regulates a variety of cellular events, including muscle contraction, neurosecretion and changes in gene expression. Calcium channel ß subunits are proteins that are associated with the calcium channel subunit ( 1) that actually forms the pore through which ions flow. The ß subunit modulates various properties of these 1 subunits.

Praziquantel is the drug of choice against schistosomiasis, yet the molecular mechanism by which it acts remains unclear. My lab has found that a particular component from schistosome calcium channels – namely, a certain type of ß subunit – confers praziquantel sensitivity to other calcium channels. This ß subunit is quite unique because it lacks specific sites at which a particular enzyme can add phosphate groups to the protein. We believe that those missing phosphorylation sites are critical determinants of its unusual functional properties and pharmacological sensitivities.

Low concentrations of praziquantel cause a rapid influx of calcium into the cells of the worm. Our results indicate that this is due to increased movement of calcium through calcium channels. This ability to confer praziquantel sensitivity is dependent upon the lack of the specific phosphorylation sites that are found in other ß subunits. If we artificially create those phosphorylation sites in the schistosome ß subunit, it no longer confers praziquantel sensitivity. If we remove those sites from other ß subunits that normally have them, those mutated ß subunits now confer praziquantel sensitivity. Based on these results, we are examining ß subunits in other praziquantel-sensitive organisms, as well as in strains of schistosomes that are resistant to the drug. We are also continuing to examine other properties of schistosome calcium channels, such as their levels of phosphorylation and the physical interaction between the 1 and ß subunits.

We have also begun a pilot project to screen venoms from cnidarians (jellyfish, anemones) for toxins that interact with voltage-gated calcium channels. Such toxins may prove to be valuable probes for ion channel structure and function, and may eventually lead to novel drugs for therapeutic use.

Finally, we continue our collaboration with Leonid Moroz at the Whitney Laboratory of the University of Florida to examine nitric oxide pathways in schistosomes. Nitric oxide is a gaseous intercellular signalling molecule that has been implicated in multiple physiological functions. These crucial roles for nitric oxide, as well as others we may yet discover, make the nitric oxide system a tempting potential target for new antiparasitic agents.