Parasitic flatworms of the genus Schistosoma cause schistosomiasis, a tropical disease affecting hundreds of millions of people worldwide. There is no vaccine, and only a single drug (praziquantel) available for treatment and control. Many anthelmintics, likely including praziquantel, act on ion channels, membrane protein complexes that are essential for normal functioning of the neuromusculature and other tissues. However, few helminth ion channel families have been assessed for their properties and for their roles in parasite physiology. One such overlooked group of helminth ion channels is the transient receptor potential (TRP) channel superfamily. Members of the TRP channel family are widely 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 other functions, such as regulating intracellular calcium and organellar ion homeostasis and trafficking. TRP channels also respond to endogenous agents, including those involved in inflammatory signaling. Our published and preliminary pharmacological and knockdown studies show that schistosome TRP channels can be targeted to impact normal neuromuscular and sensory function. More significantly, they appear to have novel pharmacological sensitivities. Specifically, our results are consistent with the schistosome TRPA channel (SmTRPA) having at least some of the pharmacological sensitivities of mammalian TRPV1 channels, particularly notable as there are no TRPV channels represented in schistosome genomes. Preliminary functional expression studies support this contention. We hypothesize that in schistosomes, SmTRPA fulfills some of the roles of missing TRPV channels. We also hypothesize that SmTRPA and perhaps other schistosome TRP channels regulate critical parasite-host interactions required for successful infection. This project will use parallel strategies to define the roles SmTRPA and other TRP channels play in schistosome biology, including parasite-host interactions, and assess SmTRPA channel function directly. Finally, we hypothesize that the schistosome TRP channel, SmTRPML, plays key roles in schistosome endolysosomal physiology that can impact autophagy and nutrient acquisition. Our studies will elucidate the biological roles and physiological properties of an almost entirely unexplored family of parasite ion channels, information which could in the future be used to provide novel candidate targets for new or repurposed antischistosomal agents. The specific aims of this project are to: 1) Determine the role that SmTRPA and other TRP channels play in the schistosome life cycle, including in parasite-host interactions; 2) Use functional expression to test whether schistosome sensitivity to TRPV1 modulators is mediated specifically by SmTRPA; and 3) Elucidate the role of the schistosome TRPML channel in endolysosomal functions, includi...