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

卡波西肉瘤相关疱疹病毒 microRNA 的靶标和功能

• 批准号: 7739205
• 负责人: Eva Henriette Gottwein
• 金额: $ 9.88万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-01 至 2011-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7739205
• 关键词: 3' Untranslated Regions; Apoptosis; Apoptotic; B-Lymphocytes; Binding; Bioinformatics; Biological Assay; Biology; Cell Cycle; Cell Cycle Arrest; Cell Cycle Progression; Cell Cycle Progression Pathway; Cell Line; Cells; Classification; Collaborations; Computational Biology; Computers; Data; Development; Ectopic Expression; Endothelial Cells; Faculty; Functional RNA; Gene Expression; Goals; Grant; Herpesviridae; Human; Human Herpesvirus 8; Immune response; Individual; Induction of Apoptosis; Knowledge; Laboratories; Lymphoma; Mediating; Mentors; Mentorship; Messenger RNA; MicroRNAs; Microarray Analysis; Monitor; Nucleotides; Orthologous Gene; Outcome; Pathogenesis; Pathway interactions; Phase; Physiological; Porifera; Positioning Attribute; Regulation; Research; Research Personnel; Role; Universities; Viral; base; effusion; interest; knock-down; latent infection; meetings; programs; research study; skills; tumorigenesis; virology

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.

描述（由申请人提供）：在2010年夏天，AM希望搬到独立的教师职位，以进行Kaposi肉瘤相关的疱疹病毒（KSHV）microRNA（miRNA）的功能分析。 microRNA是一类最近发现的〜22个核苷酸长的非编码RNA，这些核苷酸长的RNA在转录后抑制miRNA与miRNA不完善的mRNA，主要是在其3'UTR中。 KSHV在潜在感染期间表达12个病毒miRNA。我的直接研究目标是获得有关KSHV miRNA靶标的详细知识，并阐明这些miRNA对宿主细胞先天免疫反应的保护作用，包括细胞凋亡和细胞周期停滞。通过结合B细胞系的基因表达分析，稳定表达一个或多个KSHV miRNA的生理水平与基于结合能量的目标预测，将确定一组广泛的KSVH miRNA介导调节的候选靶标。将研究KSHV miRNA与诱导凋亡和细胞周期停滞的干扰（a）基于高度有希望的候选靶标的在这些途径中具有已知功能的高度有前途的候选靶标，（（b）通过B细胞线或内皮细胞的系统功能询问，这些概念会通过临时表达个体或多个KSHV miRNAS，（C）的脑电图（c）脑部的脑电图（c），这些细胞均通过系统地表达了rym ksshv rym ksshv rym ksshv consss contection（b）。个体或多个miRNA的功能已使用Antagomirs或海绵阻断。在指导阶段，我打算通过在杜克大学上课来获得生物信息学的技能。我将通过与我的导师布莱恩·卡伦（Bryan Cullen）和计算生物学，疱疹病毒学和凋亡/细胞周期的专家指导委员会的定期会议来监视我的进一步发展。此外，我希望拟议的研究将产生足够的有趣数据，以便在独立阶段早期申请R0L赠款，并且还进一步定义了我的长期研究计划。 相关性：相关性：转角人类γ疱疹病毒KSHV在潜伏期期间表达12个病毒miRNA。阐明KSHV miRNA的功能有望强烈增强我们对KSHV生物学的理解，并可能为KSHV和MiR-155的肿瘤发生机制带来重要线索，KSHV和Mir-155是KSHV MicroRNA miR-K12-11的直系同源物。