Summary: Schistosomes are intravascular parasitic worms that cause the debilitating disease schistosomiasis which affects > 200 million people in > 70 countries. In this proposal, we focus on polyamine metabolism in schistosomes. Polyamines are ubiquitous organic compounds that play multiple vital roles in cellular physiology. An exhaustive search of genome databases reveals that schistosomes lack all the de novo polyamine biosynthetic enzymes. This makes schistosomes the only known metazoans that are auxotrophic for polyamines. How these worms acquire these essential metabolites is not known. The P5-type ATPase, CATP5, identified in the nematode C. elegans has been shown to function as a polyamine transporter. Here we describe our newly identified CATP5 homolog in S. mansoni - SmCATP5 - that is found in the schistosome tegument (skin) where, we hypothesize, it functions to import polyamines from host blood. Knockdown of SmCATP5 expression using RNAi debilitates the worms in culture, while polyamine supplementation enhances worm viability. In this proposal, we aim to characterize the functionality, specificity and kinetics of polyamine transport in schistosomes. We will examine SmCATP5 function using a heterologous expression system in a polyamine-uptake-deficient cell line (CHO-MG) as well as directly in schistosome parasites. This work is designed to reveal the physiological function of SmCATP5 and should yield significant new information on the molecular mechanisms used by schistosomes to obtain vital nutrients (polyamines). Since schistosomes are completely dependent on their hosts as a source of polyamines, blocking SmCATP5 function should debilitate the worms and could form the basis of a new anti-schistosome therapy – the long-term aim of this work.