: In the last few years the study of the biology of Trypanosoma brucei, the agent of sleeping sickness in humans and nagana in cattle, has witnessed an incredible growth due to two major advances: the completion of the T. brucei genome sequence and the discovery by our laboratory of RNA interference (RNAi). By interfacing genome information with down-regulating gene function by RNAi, it is now realistic to investigate complex cellular mechanisms using global approaches. As transcription regulation plays a minor role in T. brucei, the emphasis on regulation of gene expression is primarily on post-transcriptional regulatory mechanisms. Thus, we anticipate that the enzymes governing mRNA metabolism are essential for these parasites. This proposal focuses on aspects of RNA metabolism that are either unique to trypanosomes (cap 4 biosynthesis and function) or are novel concepts in eukaryotic biology (coupling of trans-splicing and polyadenylation and the RNAi pathway). The long-term goal of this proposal remains the characterization of molecular mechanisms involved in RNA metabolism and their relevance to trypanosome biology. In the next funding period we plan to: 1. Characterize the specific RNA methyltransferases involved in cap 4 biosynthesis and investigate whether there is a mechanistic link between cap 4 formation and polyadenylation. 2. Further our understanding of the coupling of trans-splicing and polyadenylation by using a variety of approaches, including monitoring the association of processing factors along transcribed genes in living cells. 3. Further characterize the RNAi pathway in terms of its components and how the interaction of TbAGO1 with translating ribosomes is brought about.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
2R01AI028798-16
Application #
6870867
Study Section
Tropical Medicine and Parasitology Study Section (TMP)
Program Officer
Rogers, Martin J
Project Start
1989-12-01
Project End
2009-12-31
Budget Start
2005-01-01
Budget End
2005-12-31
Support Year
16
Fiscal Year
2005
Total Cost
$645,693
Indirect Cost
Name
Yale University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
043207562
City
New Haven
State
CT
Country
United States
Zip Code
06520
Shi, Huafang; Butler, Kiantra; Tschudi, Christian (2018) A single-point mutation in the RNA-binding protein 6 generates Trypanosoma brucei metacyclics that are able to progress to bloodstream forms in vitro. Mol Biochem Parasitol 224:50-56
Kolev, Nikolay G; Ramsdell, Trisha K; Tschudi, Christian (2018) Temperature shift activates bloodstream VSG expression site promoters in Trypanosoma brucei. Mol Biochem Parasitol 226:20-23
Shi, Huafang; Butler, Kiantra; Tschudi, Christian (2018) Differential expression analysis of transcriptome data of Trypanosoma brucei RBP6 induction in procyclics leading to infectious metacyclics and bloodstream forms in vitro. Data Brief 20:978-980
Srivastava, Ankita; Badjatia, Nitika; Lee, Ju Huck et al. (2018) An RNA polymerase II-associated TFIIF-like complex is indispensable for SL RNA gene transcription in Trypanosoma brucei. Nucleic Acids Res 46:1695-1709
Damasceno, Jeziel D; Silva, Gabriel LA; Tschudi, Christian et al. (2017) Evidence for regulated expression of Telomeric Repeat-containing RNAs (TERRA) in parasitic trypanosomatids. Mem Inst Oswaldo Cruz 112:572-576
Kolev, Nikolay G; Günzl, Arthur; Tschudi, Christian (2017) Metacyclic VSG expression site promoters are recognized by the same general transcription factor that is required for RNA polymerase I transcription of bloodstream expression sites. Mol Biochem Parasitol 216:52-55
Christiano, Romain; Kolev, Nikolay G; Shi, Huafang et al. (2017) The proteome and transcriptome of the infectious metacyclic form of Trypanosoma brucei define quiescent cells primed for mammalian invasion. Mol Microbiol 106:74-92
Alves e Silva, Thiago Luiz; Savage, Amy F; Aksoy, Serap (2016) Transcript Abundance of Putative Lipid Phosphate Phosphatases During Development of Trypanosoma brucei in the Tsetse Fly. Am J Trop Med Hyg 94:890-3
Savage, Amy F; Kolev, Nikolay G; Franklin, Joseph B et al. (2016) Transcriptome Profiling of Trypanosoma brucei Development in the Tsetse Fly Vector Glossina morsitans. PLoS One 11:e0168877
Ramey-Butler, Kiantra; Ullu, Elisabetta; Kolev, Nikolay G et al. (2015) Synchronous expression of individual metacyclic variant surface glycoprotein genes in Trypanosoma brucei. Mol Biochem Parasitol 200:1-4

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