The overall objective is to elucidate the mechanisms which regulate the expression of mitochondrial and nuclear genes during the life cycle of African trypanosomes and explore the mechanisms which coordinate these genetic regulatory processes. The immediate objectives are to characterize the expression of mitochondrial (maxicircle) and nuclear genes at the levels of transcription, transcript processing, and translation. The expression of mitochondrial and nuclear genes will be examined at these levels in different life cycle stages and stocks of Trypanosoma brucei to discern the mechanisms regulating these cell differentiations. Experiments are proposed to: 1. Characterize maxicircle transcripts that are diferentially expressed during the life cycle and those which differ among stocks. These experiments are designed to elucidate the mechanisms that regulate the differential expression of maxicircle genes that was discovered during the previous grant period and the mechanisms of maxicircle transcription and transcript processing. 2. Identify proteins encoded by the maxicircle and characterize their production in different life cycle stages. These experiments are designed to establish the relationship between the presence of specific maxicircle transcripts and mitochondrial proteins and hence mitochondrial function. 3. Identify and characterize nuclear genes that are differentially expressed during the life-cycle. Gene encoding proteins with varying physical and functional associations with proteins encoded by the maxicircle will be studied. 4. Characterize the expression of nuclear genes that are differentially expressed during the life cycle at the genomic level and at the levels of transcription, transcript processing and translation. These studies will be done in parallel with analogous studies of maxicircle genes in order to elucidate the genetic regulatory mechanisms that coordinate the control of these two genetic systems.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
2R01AI014102-11
Application #
3125635
Study Section
Bacteriology and Mycology Subcommittee 1 (BM)
Project Start
1978-09-01
Project End
1991-08-31
Budget Start
1986-09-01
Budget End
1987-08-31
Support Year
11
Fiscal Year
1986
Total Cost
Indirect Cost
Name
Seattle Biomedical Research Institute
Department
Type
DUNS #
City
Seattle
State
WA
Country
United States
Zip Code
98109
Cestari, Igor; Anupama, Atashi; Stuart, Kenneth (2018) Inositol polyphosphate multikinase regulation of Trypanosoma brucei life stage development. Mol Biol Cell 29:1137-1152
Cestari, Igor; Stuart, Ken (2018) Transcriptional Regulation of Telomeric Expression Sites and Antigenic Variation in Trypanosomes. Curr Genomics 19:119-132
Carnes, Jason; McDermott, Suzanne M; Stuart, Kenneth (2018) RNase III Domain of KREPB9 and KREPB10 Association with Editosomes in Trypanosoma brucei. mSphere 3:
Carnes, Jason; McDermott, Suzanne; Anupama, Atashi et al. (2017) In vivo cleavage specificity of Trypanosoma brucei editosome endonucleases. Nucleic Acids Res 45:4667-4686
McDermott, Suzanne M; Stuart, Kenneth (2017) The essential functions of KREPB4 are developmentally distinct and required for endonuclease association with editosomes. RNA 23:1672-1684
Cestari, Igor; Haas, Paige; Moretti, Nilmar Silvio et al. (2016) Chemogenetic Characterization of Inositol Phosphate Metabolic Pathway Reveals Druggable Enzymes for Targeting Kinetoplastid Parasites. Cell Chem Biol 23:608-617
McDermott, Suzanne M; Luo, Jie; Carnes, Jason et al. (2016) The Architecture of Trypanosoma brucei editosomes. Proc Natl Acad Sci U S A 113:E6476-E6485
McDermott, Suzanne M; Carnes, Jason; Stuart, Kenneth (2015) Identification by Random Mutagenesis of Functional Domains in KREPB5 That Differentially Affect RNA Editing between Life Cycle Stages of Trypanosoma brucei. Mol Cell Biol 35:3945-61
McDermott, Suzanne M; Guo, Xuemin; Carnes, Jason et al. (2015) Differential Editosome Protein Function between Life Cycle Stages of Trypanosoma brucei. J Biol Chem 290:24914-31
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

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