This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Schistosomiasis is an intravascular infection that affects approximately 207 million people. Praziquantel is the only drug in widespread use for treatment of the disease but the drug does not kill juvenile schistosomes. As a result, a single dose of praziquantel is unlikely to break the cycle of infection. In addition, some field strains of schistosomes may be developing resistance to the drug.
The aim of our study is to identify Schistosoma proteins that can be used as targets against which a new, more effective drug can be designed. It was originally planned to identify such targets among gene products that were differentially regulated as a result of stress. One of our original stressors was praziquantel and as a result of microarray data obtained recently we have focused on the trying to elucidate the mechanism of action of this drug. To fulfill this aim we have been using activity based protein profiling techniques and microarray analysis of praziquantel treated mature schistosomes. These approaches have suggested several pathways by which praziquantel may kill adult worms and which are currently being explored. In addition, the PI visited Kisumu, Kenya and has infected snails and mice with field isolates derived from discarded patient feces. These isolates will be used to determine whether potential therapeutic targets are expressed in field strains and to assess drug resistance. Identifying the molecular pathway(s) on which praziquantel acts should provide valuable insights into how variable schistosome praziquantel sensitivities evolve and how a new generation of therapeutics might be developed.
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