Schistosome TRP ion channels as potential drug targets

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DESCRIPTION (provided by applicant): Blood flukes, parasitic flatworms of the genus Schistosoma, cause schistosomiasis, a tropical disease that affects hundreds of millions of people worldwide. The current drug of choice against schistosomiasis is praziquantel. Indeed, praziquantel is the only drug currently available in most parts of the world. Such a situation is perilous, particularly in light of reports of emerging parasite resistance to praziquantel. The nee for new therapeutics is therefore urgent. The majority of current anthelmintic drugs target ion channels, validating these proteins as outstanding therapeutic targets. This high-risk, high-payoff project will initiate studies on an entirely unexplored family of schistosome ion channels, the transient receptor potential (TRP) channels. Members of the TRP channel family are strikingly diverse in their activation mechanisms and ion selectivity, but share a common core structure. They are critical to transducing sensory signals, responding to a wide range of external stimuli, and are also involved in regulating levels of intracellular calcium. Mammalian TRP channels are currently under intense investigation as therapeutic targets for treatment of pain, cancer, and a variety of other conditions. We hypothesize that schistosome TRP channels are essential to fulfillment of the schistosome life cycle, which depends on external cues for host-finding and migration to predilection sites within the host, as well as regulation of intracellular calcium. However, the function of these channels in schistosomes and other parasites is entirely unexplored. This project will use parallel strategies to define the roles thee channels play in schistosome physiology, and has the potential to provide novel targets for new antischistosomal agents. The specific aims are to: 1. Determine the effects of genetic and pharmacological disruption of normal TRP channel function on schistosome survival and physiology, and 2. Functionally express and determine the properties and pharmacological sensitivities of a subset of S. mansoni TRP channels. PUBLIC HEALTH RELEVANCE: Schistosomiasis is a major tropical disease affecting hundreds of millions worldwide. It is caused by parasitic flatworms called schistosomes. There is currently only a single drug generally used to treat schistosomiasis, a very treacherous situation. Clearly, new antischistosomal agents are needed. Many of the drugs against parasitic worm infestations target ion channels, which are essential to normal functioning of the parasite's neuromusculature. Thus, ion channels are an excellent choice as potential targets for new anthelmintic drugs. This exploratory project will use a variety of approaches to study a family of schistosome ion channels that have not previously been investigated, with the goal of defining the roles they play in the parasite life cycle and ways to interfere with their function. These studies could eventually lead to new therapeutic strategies against schistosomiasis.