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dc.contributorNot Applicableen_US
dc.contributor.authorFISK, JOHN C. Principal Investigatoren_US
dc.date31-Aug-11en_US
dc.date2010en_US
dc.date.accessioned2011-04-18T21:06:03Zen_US
dc.date.accessioned2011-04-19T18:31:09Z
dc.date.available1-Sep-09en_US
dc.date.available2011-04-18T21:06:03Zen_US
dc.date.available2011-04-19T18:31:09Z
dc.date.issued2011-04-18T21:06:03Zen_US
dc.identifier7940852en_US
dc.identifier5F32AI077185-02en_US
dc.identifier77185en_US
dc.identifier.urihttp://hdl.handle.net/10477/1058
dc.descriptionAffect;African Trypanosomiasis;Arginine;Binding (Molecular Function);Blood Circulation;Complex;Down-Regulation;Drug Delivery Systems;Drug resistance;Gene Expression;Gene Expression Regulation;gene interaction;Genes;Genetic;genetic regulatory protein;Goals;Guide RNA;Human;Immunoprecipitation;In Vitro;in vivo;Insect Vectors;insertion/deletion mutation;Left;Leishmania (genus);Life Cycle Stages;Livestock;Mediating;Messenger RNA;Methylation;Mitochondria;mitochondrial messenger RNA;Mitochondrial Proteins;Mitochondrial RNA;Modification;nagana;novel;Parasites;pathogen;Pharmaceutical Preparations;Play;Process;protein complex;protein protein interaction;Protein-Arginine N-Methyltransferase;Proteins;Protozoa;public health relevance;Reaction;Regulation;Regulator Genes;RNA Editing;RNA Interference;RNA-Binding Proteins;RNA-Protein Interaction;Role;Sedimentation process;Staging;Transcript;Trypanosoma brucei brucei;Trypanosoma cruzi;Uridine;en_US
dc.descriptionAmount: $ 53810en_US
dc.description.abstractDESCRIPTION (provided by applicant): The parasitic protozoan, Trypanosoma brucei, is the causative agent of sleeping sickness in humans and nagana in domestic livestock. Sleeping sickness is invariably fatal if left untreated. Current drugs are ineffective and toxic, and drug resistance is on the rise, highlighting the importance of identifying novel drug targets. In T. brucei mitochondria, post-transcriptional RNA editing is required for the creation of translatable mRNAs. Editing is an essential process in both the procyclic insect vector stage (PF) and the bloodstream mammalian host stage (BF) life cycle stages. Thus, proteins involved in RNA editing are promising targets for chemotherapeutic attack. The RNA binding protein, RBP16, is an essential multi-functional gene regulatory protein that acts as an RNA editing accessory factor for CYb mRNA, as well as stabilizing several never-edited mitochondrial RNAs, in PF T. brucei. RBP16 is modified by methylation on several arginine residues, and this modification is important for its macromolecular interactions and gene regulatory functions in PF. In T. brucei, mitochondrial gene expression is dramatically regulated between PF and BF life cycle stages. RBP16 is relatively abundant in BF stage that infects humans; however, nothing is known about its role in mitochondrial gene regulation in this stage of the parasite. In this application, we will examine the role of RBP16 in BF T. brucei mitochondrial gene regulation using RNAi-mediated down-regulation. We will determine the effect of RBP16 depletion on both RNA editing and stabilization in BF. We will analyze RBP16 protein-protein and protein-RNA interactions in BF using immunoprecipitation and gradient sedimentation analyses. Finally, we will determine the roles of two major protein arginine methyltransferases in RBP16 methylation and macromolecular interactions in BF T. brucei. Our hypothesis is that RBP16 regulates the editing and/or abundance of specific mitochondrial mRNA in BFs, distinct from those it affects in PFs. Furthermore, we propose that RBP16 does so in conjunction with additional mitochondrial proteins and that these protein-protein interactions may be impacted by protein arginine methylation. PUBLIC HEALTH RELEVANCE: Together, the proposed studies will greatly expand the understanding of both mitochondrial gene regulation and the functions of arginine methylation in the human infectious form of T. brucei.en_US
dc.titleROLE OF THE GUIDE RNA BINDING PROTEIN RBP16 IN THE BLOODSTREAM FORM OF T. BRUCEIen_US
dc.typeNIH Grant Awarden_US


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