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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI034536-08
Application #
6631930
Study Section
Tropical Medicine and Parasitology Study Section (TMP)
Program Officer
Rogers, Martin J
Project Start
1994-12-01
Project End
2005-02-28
Budget Start
2003-03-01
Budget End
2005-02-28
Support Year
8
Fiscal Year
2003
Total Cost
$262,587
Indirect Cost
Name
University of California Los Angeles
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
092530369
City
Los Angeles
State
CA
Country
United States
Zip Code
90095
Thomas, Sean; Green, Amanda; Sturm, Nancy R et al. (2009) Histone acetylations mark origins of polycistronic transcription in Leishmania major. BMC Genomics 10:152
Hitchcock, Robert A; Thomas, Sean; Campbell, David A et al. (2007) The promoter and transcribed regions of the Leishmania tarentolae spliced leader RNA gene array are devoid of nucleosomes. BMC Microbiol 7:44
Thomas, Sean; Yu, Michael C; Sturm, Nancy R et al. (2006) A non-universal transcription factor? The Leishmania tarentolae TATA box-binding protein LtTBP associates with a subset of promoters. Int J Parasitol 36:1217-26
Thomas, Sean; Westenberger, Scott J; Campbell, David A et al. (2005) Intragenomic spliced leader RNA array analysis of kinetoplastids reveals unexpected transcribed region diversity in Trypanosoma cruzi. Gene 352:100-8
Foldynova-Trantirkova, Silvie; Paris, Zdenek; Sturm, Nancy R et al. (2005) The Trypanosoma brucei La protein is a candidate poly(U) shield that impacts spliced leader RNA maturation and tRNA intron removal. Int J Parasitol 35:359-66
Zeiner, Gusti M; Foldynova, Silvie; Sturm, Nancy R et al. (2004) SmD1 is required for spliced leader RNA biogenesis. Eukaryot Cell 3:241-4
Zeiner, Gusti M; Sturm, Nancy R; Campbell, David A (2003) The Leishmania tarentolae spliced leader contains determinants for association with polysomes. J Biol Chem 278:38269-75
Campbell, David A; Thomas, Sean; Sturm, Nancy R (2003) Transcription in kinetoplastid protozoa: why be normal? Microbes Infect 5:1231-40
Orlando, Tereza C; Rubio, Mary Anne T; Sturm, Nancy R et al. (2002) Intergenic and external transcribed spacers of ribosomal RNA genes in lizard-infecting Leishmania: molecular structure and phylogenetic relationship to mammal-infecting Leishmania in the subgenus Leishmania (Leishmania). Mem Inst Oswaldo Cruz 97:695-701
Yu, Michael C; Orlando, T Cristina; Sturm, Nancy R et al. (2002) Two distinct functional spliced leader RNA gene arrays in Leishmania tarentolae are found in several lizard Leishmania species. Int J Parasitol 32:1411-22

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