Leishmaniasis, African Sleeping Sickness and Chagas Disease are fatal or debilitating diseases that afflict over 20 million people annually in tropical countries and are caused by infections with related trypanosomatid protozoa. We are studying features of trypanosomatid gene expression that are shared among the pathogens, but which are absent in the human host. The expression of the parasite's Spliced Leader RNA gene and the role of its primary transcript, the SL RNA, in the maturation of nuclear messenger RNAs (mRNA) via trans-splicing is the focus of our research. We are taking molecular genetic and biochemical approaches to defining the promoter that directs initiation of SL RNA gene transcription, and characterizing protein(s) that bind to the SL RNA gene promoter. In the next funding period we propose to: 1) define the protein-DNA interactions in transcription initiation from the SL RNA gene promoter, and to identify the RNA polymerase that transcribes the SL RNA gene through a genetic approach, 2) define additional regions of the SL RNA gene that are necessary for transcription termination and efficient transcription initiation, and 3) analyze the effect of mutations in the Spliced Leader that may affect translation. These experiments will identify new molecules and elucidate essential protein-DNA and RNA-RNA interactions that distinguish the parasite's metabolism from that of the human host. These unique features represent potential targets for selective therapeutic intervention.
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