The role of viral and cellular miRNAs in B-cell lymphomagenesis

病毒和细胞 miRNA 在 B 细胞淋巴瘤发生中的作用

• 批准号: 8634961
• 负责人: Rebecca L Skalsky
• 金额: $ 10万
• 依托单位: OREGON HEALTH & SCIENCE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-01 至 2016-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8634961
• 关键词: AIDS-Related Diffuse Large B-cell Lymphoma; Acquired Immunodeficiency Syndrome; Acute; Address; Adult; Advisory Committees; Apoptosis; Apoptotic; Automobile Driving; Award; B Cell Proliferation; B lymphoid malignancy; B-Cell Activation; B-Cell Lymphomas; B-Cell Neoplasm; B-Lymphocytes; Binding; Bioinformatics; Biological; Biological Assay; Biological Models; Biology; Cancer Model; Cell Survival; Cells; Clinical; Critiques; DNA Tumor Viruses; Data; Development; Epithelial; Epithelial Cells; Epstein-Barr Virus Infections; Event; Gene Expression; Gene Expression Profile; Gene Expression Regulation; Gene Targeting; Genes; Goals; Growth; Hodgkin Disease; Homologous Gene; Human; Human Herpesvirus 4; Immunoprecipitation; In Vitro; Individual; Infection; Infectious Mononucleosis; LMP1; Laboratories; Lead; Learning; Libraries; Life; Life Cycle Stages; Link; Luciferases; Lymphoma; Lymphomagenesis; Lymphoproliferative Disorders; Malignant Neoplasms; Malignant lymphoid neoplasm; Mediating; Mentors; Messenger RNA; Methodology; MicroRNAs; Modeling; Molecular; Oncogenic; Outcome; Pathogenesis; Pathway interactions; Patients; Phase; Play; Population; Porifera; Process; Regulation; Reporter; Resources; Ribonucleosides; Role; Sequence Homology; Signal Pathway; Signal Transduction; Staging; TNFRSF5 gene; Techniques; Time; Training; Viral; Viral Pathogenesis; Viral Proteins; Virus; Virus Diseases; Western Blotting; Writing; cell transformation; cellular targeting; computerized tools; crosslink; deep sequencing; in vivo; infected B cell; inhibitor/antagonist; insight; large cell Diffuse non-Hodgkin' s lymphoma; latent infection; latent persistent infection; lymphoblastoid cell line; meetings; member; multidisciplinary; new therapeutic target; programs; public health relevance; research study; tumorigenesis; uncontrolled B lymphocyte proliferation; viral RNA; virology

Project Summary At least one in six human cancers is linked to viral infection. A portion of these can be attributed to Epstein-Barr virus (EBV), a ubiquitous DNA tumor virus associated with cancers such as Burkitt's, Hodgkin's, and diffuse large B cell lymphomas. During infection, EBV expresses viral microRNAs (miRNAs), and recent studies have demonstrated an important role for the EBV miRNAs as well as the cellular oncogenic miRNAs upregulated by EBV infection in the B cell transformation process. Furthermore, several EBV miRNAs share sequence homology with cellular miRNAs that are dysregulated in cancers and potentially, these viral miRNAs can tie into and alter existing miRNA-regulated networks. The miRNA targets involved in transformation are not yet defined, and thus, systemically identifying the genes regulated by miRNAs in EBV-infected cells is essential to understanding their contributions to viral oncogenesis and their roles during the EBV life cycle. Experiments outlined here combine state-of-the-art techniques from the multidisciplinary fields of miRNA biology, virology, and bioinformatics to comprehensively interrogate the miRNA targetome and examine the transcriptional landscape of EBV-infected B cells in order to extract critical genes and pathways influenced by viral and cellular miRNAs. These studies will be carried out using an EBV-driven in vitro B cell transformation model in addition to patient-derived EBV+ B cell tumors. To successfully carry out my studies, I require new training in both EBV biology and bioinformatics, and have accordingly assembled a scientific advisory committee to guide me in establishing and/or further developing several of the essential methodologies. The K99/R00 award will provide me both resources and time for new training during the mentored phase in order to learn fundamental de novo infection techniques and generate additional data and computational tools to be used in my own laboratory during the independent phase. By integrating the miRNA targetome data, transcriptome data, and phenotypic data generated through these experiments, I hope to elucidate the mechanisms by which miRNAs, particularly EBV miRNAs, contribute to persistent viral infection and the development of lymphoma. Finally, since EBV expresses not only viral miRNAs but further alters expression of oncogenic cellular miRNAs that have been linked to many cancers not associated with viral infection, these studies will potentially provide important information that can be extended to other cancer models and provide insight into the overall mechanisms governing miRNA-mediated gene regulation in cancers.

项目摘要 至少六分之一的人类癌症与病毒感染有关。其中一部分可以归因于 爱泼斯坦-巴尔病毒(EBV)是一种普遍存在的DNA肿瘤病毒，与Burkitt‘s，Hodgkin’s， 弥漫性大B细胞淋巴瘤。在感染期间，EBV表达病毒microRNAs(MiRNAs)，最近 研究表明EBV miRNAs以及细胞致癌miRNAs具有重要作用 在B细胞转化过程中受EBV感染上调。此外，几个EBV miRNA共享 与细胞miRNAs的序列同源性，这些miRNAs在癌症和潜在的病毒miRNAs中调节失调 可以绑定和改变现有的miRNA调控的网络。参与转化的miRNA靶标有 尚未定义，因此，系统地识别EBV感染细胞中受miRNAs调控的基因是 对于了解它们在病毒致癌中的作用以及它们在EBV生命周期中的作用至关重要。 这里概述的实验结合了miRNA多学科领域的最新技术 生物学、病毒学和生物信息学，以全面询问miRNA目标组并检查 EB病毒感染B细胞的转录图谱以提取关键基因和受其影响的途径 病毒和细胞miRNAs。这些研究将使用EBV驱动的体外B细胞转化来进行 除了患者来源的EBV+B细胞肿瘤外，还有一种模型。为了成功地进行我的学习，我需要新的 在EBV生物学和生物信息学方面的培训，并相应地汇编了一份科学咨询 委员会指导我建立和/或进一步发展几种基本的方法。这个 K99/R00奖将在指导阶段为我提供资源和时间进行新的培训，以便 学习新感染的基本技术，并生成更多数据和计算工具 在我自己的实验室中使用，在独立阶段。通过整合miRNA靶标数据， 转录组数据，以及通过这些实验产生的表型数据，我希望能阐明 MiRNAs，特别是EBV miRNAs促进持续病毒感染的机制和 淋巴瘤的发展。 最后，由于EBV不仅表达病毒miRNAs，而且进一步改变致癌细胞的表达 已经与许多与病毒感染无关的癌症相关的miRNAs，这些研究可能 提供可推广到其他癌症模型的重要信息，并提供对整体 肿瘤中miRNA介导的基因调控机制。