The overall project goal is to elucidate the processes that control the switch between glycolysis and oxidation-phosphorylation modes of ATP generation during the life cycle of Trypanosoma brucei. The studies are focused on the processes that regulate the expression of mitochondrial (mt) genes and that control RNA editing during the life cycle. Experiments are proposed to: (1) Identify and characterize the remaining protein coding sequences, sequences directing editing and regulatory sequences. The nucleotide sequences of (A) uncharacterized maxicircle transcripts that appear to be extensively edited and the remaining 1.9 kb variable region DNA will be determined and analyzed to identify their functions and (B) gRNAs and gRNA genes will be isolated and characterized to assess minicircle coding capacity and provide materials essential to subsequent studies. Alterations in the genetic potential and editing of mutants will be examined, as will RNA processing. (2)Identify and characterize translation products of maxicircle transcripts to assess the physiological consequences of editing. The in vivo translation of edited transcripts in different life cycle stages and the possibility that different proteins may be produced from the same gene depending on editing will be determined. This will assess the physiological consequences of editing. (3)Identify and characterize genes encoding some components of the editosome to determine the precise characteristics of editosome components, their production during the life cycle, the taxonomic distribution of editing and the existence of related but uncharacterized RNA processing mechanisms. (4)Characterize the developmental regulation of editing at the level of gRNA, mRNA, editosomes or other factors in order to identify and characterize the regulatory system that controls editing. These studies are intended increase our understanding of basic molecular genetic processes, especially those which are important to the survival of parasites.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Method to Extend Research in Time (MERIT) Award (R37)
Project #
5R37AI014102-23
Application #
2886356
Study Section
Special Emphasis Panel (NSS)
Program Officer
Fairfield, Alexandra
Project Start
1978-09-01
Project End
2002-03-31
Budget Start
1999-04-01
Budget End
2000-03-31
Support Year
23
Fiscal Year
1999
Total Cost
Indirect Cost
Name
Seattle Biomedical Research Institute
Department
Type
DUNS #
City
Seattle
State
WA
Country
United States
Zip Code
98109
Carnes, Jason; Anupama, Atashi; Balmer, Oliver et al. (2015) Genome and phylogenetic analyses of Trypanosoma evansi reveal extensive similarity to T. brucei and multiple independent origins for dyskinetoplasty. PLoS Negl Trop Dis 9:e3404
Carnes, Jason; Lerch, Melissa; Kurtz, Irina et al. (2015) Bloodstream form Trypanosoma brucei do not require mRPN1 for gRNA processing. RNA 21:28-35
Demir, Ozlem; Labaied, Mehdi; Merritt, Chris et al. (2014) Computer-aided discovery of Trypanosoma brucei RNA-editing terminal uridylyl transferase 2 inhibitors. Chem Biol Drug Des 84:131-9
Beck, Kirsten; Acestor, Nathalie; Schulfer, Anjelique et al. (2013) Trypanosoma brucei Tb927.2.6100 is an essential protein associated with kinetoplast DNA. Eukaryot Cell 12:970-8
Guo, Xuemin; Carnes, Jason; Ernst, Nancy Lewis et al. (2012) KREPB6, KREPB7, and KREPB8 are important for editing endonuclease function in Trypanosoma brucei. RNA 18:308-20
Carnes, Jason; Lewis Ernst, Nancy; Wickham, Carey et al. (2012) KREX2 is not essential for either procyclic or bloodstream form Trypanosoma brucei. PLoS One 7:e33405
Lerch, Melissa; Carnes, Jason; Acestor, Nathalie et al. (2012) Editosome accessory factors KREPB9 and KREPB10 in Trypanosoma brucei. Eukaryot Cell 11:832-43
Carnes, Jason; Soares, Carmen Zelaya; Wickham, Carey et al. (2011) Endonuclease associations with three distinct editosomes in Trypanosoma brucei. J Biol Chem 286:19320-30
Ernst, Nancy Lewis; Panicucci, Brian; Carnes, Jason et al. (2009) Differential functions of two editosome exoUases in Trypanosoma brucei. RNA 15:947-57
Tarun Jr, Salvador Zipagan; Schnaufer, Achim; Ernst, Nancy Lewis et al. (2008) KREPA6 is an RNA-binding protein essential for editosome integrity and survival of Trypanosoma brucei. RNA 14:347-58

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