Targets and functions of the Kaposi's Sarcoma associated herpesvirus microRNAs

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DESCRIPTION (provided by applicant): In the summer of 2010,1 am hoping to move to an independent faculty position to pursue the functional analysis of Kaposi's sarcoma associated herpesvirus (KSHV) microRNAs (miRNAs). MicroRNAs are a class of recently discovered ~22 nucleotide long non-coding RNAs that posttranscriptionally repress mRNAs bearing imperfect matches to the miRNA, primarily in their 3'UTR. KSHV expresses 12 viral miRNAs during latent infection. My immediate research goal is to gain a detailed knowledge of KSHV miRNA targets and to elucidate a possible protective role of these miRNAs against host cell innate immune responses including apoptosis and cell cycle arrest. An extensive set of candidate targets for KSVH miRNA-mediated regulation will be identified by combining gene expression analysis of B cell lines stably expressing physiological levels of one or multiple KSHV miRNAs with binding energy-based target prediction. Interference of the KSHV miRNAs with the induction of apoptosis and cell cycle arrest will be studied (a) based on highly promising candidate targets with known functions in these pathways, (b) through systematic functional interrogation of B cell lines or endothelial cells which ectopically express Individual or multiple KSHV miRNAs, (c) through systematic functional interrogation of latently KSHV Infected primary effusion lymphoma (PEL) cells in which the function of individual or multiple miRNAs has been blocked using antagomirs or sponges. During the mentored phase, I intend to acquire skills in bioinformatics, by taking classes offered at Duke. I will monitor my further development into an independent researcher through regular meetings with my mentor Bryan Cullen and a mentorship committee of experts in computational biology, herpes virology and apoptosis/cell cycle. Furthermore, I expect that the proposed research will both yield sufficient interesting data to apply for an R0l grant early in the independent phase and also further define my longer term research program. RELEVANCE: Relevance: The turnorigenic human gamma herpes viruses KSHV expresses 12 viral mIRNAs during latency. Elucidating functions of KSHV miRNAs is expected to strongly enhance our understanding of KSHV biology and may yield vital clues to the mechanisms of oncogenesis by KSHV and miR-155, an ortholog of the KSHV microRNA miR-K12-11.