The protozoan parasite Trypanosoma brucei is the causative agent of African sleeping sickness. T. brucei has served as a model system for the study of the related pathogens Trypanosoma cruzi and Leishmania spp. Due to the breakdown of vector control, African sleeping sickness is dramatically increasing in incidence. There is no vaccine for this disease, which is invariably fatal if untreated. The emergence of drug resistant strains increases the need for new therapeutic options. The project focuses on phosphoproteins of trypanosomes, and their role in critical cellular functions such as proliferation and development. Such functions could serve as important targets for drug discovery. Precedents in other organisms demonstrate the necessity of identifying a batter of signaling molecules and their targets as a prelude to efficiently defining the regulatory circuits controlling cell function. Our initial studies examined a phosphoprotein, Nopp44/46, and a protein kinase, NrkA. NrkA is developmentally regulated and that it contains a PH domain. Nopp44/46 is a nucleolar phosphoprotein that is developmentally regulated at the level of protein abundance and tyrosine phosphorylation. The identification of candidate molecules with which these proteins interact, including a novel G protein and casein kinase 2, provides impetus for expansion of these studies. The focus of the next grant period will be to further examine the function of each of these molecules using genetic approaches. Within the context of our specific aims, will be development new approaches to examine protein interactions in vivo, to regulate gene expression, and to explore parasite functions using yeast as a cellular test tube. Interwoven are studies of nucleolar function and proliferation. This will form a scaffold to which new findings can be linked, and allow phosphorylation pathways in T. brucei to be elucidated.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI031077-12
Application #
6642832
Study Section
Tropical Medicine and Parasitology Study Section (TMP)
Program Officer
Rogers, Martin J
Project Start
1992-02-01
Project End
2005-04-14
Budget Start
2003-07-01
Budget End
2005-04-14
Support Year
12
Fiscal Year
2003
Total Cost
$370,822
Indirect Cost
Name
Seattle Biomedical Research Institute
Department
Type
DUNS #
070967955
City
Seattle
State
WA
Country
United States
Zip Code
98109
Jensen, Bryan C; Kifer, Charles T; Parsons, Marilyn (2011) Trypanosoma brucei: Two mitogen activated protein kinase kinases are dispensable for growth and virulence of the bloodstream form. Exp Parasitol 128:250-5
Chou, Seemay; Jensen, Bryan C; Parsons, Marilyn et al. (2010) The Trypanosoma brucei life cycle switch TbPTP1 is structurally conserved and dephosphorylates the nucleolar protein NOPP44/46. J Biol Chem 285:22075-81
Worthen, Christal; Jensen, Bryan C; Parsons, Marilyn (2010) Diverse effects on mitochondrial and nuclear functions elicited by drugs and genetic knockdowns in bloodstream stage Trypanosoma brucei. PLoS Negl Trop Dis 4:e678
Flaspohler, John A; Jensen, Bryan C; Saveria, Tracy et al. (2010) A novel protein kinase localized to lipid droplets is required for droplet biogenesis in trypanosomes. Eukaryot Cell 9:1702-10
Jensen, Bryan C; Sivam, Dhileep; Kifer, Charles T et al. (2009) Widespread variation in transcript abundance within and across developmental stages of Trypanosoma brucei. BMC Genomics 10:482
Jensen, Bryan C; Kifer, Charles T; Brekken, Deirdre L et al. (2007) Characterization of protein kinase CK2 from Trypanosoma brucei. Mol Biochem Parasitol 151:28-40
Parsons, Marilyn; Worthey, Elizabeth A; Ward, Pauline N et al. (2005) Comparative analysis of the kinomes of three pathogenic trypanosomatids: Leishmania major, Trypanosoma brucei and Trypanosoma cruzi. BMC Genomics 6:127
Jensen, Bryan C; Brekken, Deirdre L; Randall, Amber C et al. (2005) Species specificity in ribosome biogenesis: a nonconserved phosphoprotein is required for formation of the large ribosomal subunit in Trypanosoma brucei. Eukaryot Cell 4:30-5
Naula, Christina; Parsons, Marilyn; Mottram, Jeremy C (2005) Protein kinases as drug targets in trypanosomes and Leishmania. Biochim Biophys Acta 1754:151-9
El-Sayed, Najib M; Myler, Peter J; Bartholomeu, Daniella C et al. (2005) The genome sequence of Trypanosoma cruzi, etiologic agent of Chagas disease. Science 309:409-15

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