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 至少有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），一种无处不在的DNA肿瘤病毒，与伯基特，霍奇金的癌症相关 和扩散的大B细胞淋巴瘤。在感染期间，EBV表达病毒microRNA（miRNA），最近 研究表明，EBV miRNA和细胞致癌miRNA具有重要作用 在B细胞转化过程中被EBV感染上调。此外，几个EBV miRNA共享 与细胞miRNA同源性的序列同源性，在癌症中及其潜在的这些病毒miRNA在癌症中失调 可以与现有的miRNA调节网络联系并改变现有的网络。转化涉及的miRNA目标是 尚未定义，因此从系统地识别受EBV感染细胞中miRNA调节的基因是 在EBV生命周期中了解其对病毒肿瘤发生及其作用的贡献至关重要。 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全面询问miRNA目标并检查 EBV感染的B细胞的转录景观，以提取受影响的关键基因和受影响的途径 病毒和细胞miRNA。这些研究将使用EBV驱动的体外B细胞转化进行 除了患者来源的EBV+ B细胞肿瘤外。为了成功地完成我的学业，我需要新的 在EBV生物学和生物信息学方面培训，并因此组装了科学咨询 委员会指导我建立和/或进一步开发几种基本方法。这 K99/R00奖将为我提供在指导阶段的新培训的资源和时间，以便为了 学习基本的从头感染技术，并生成其他数据和计算工具 在独立阶段，在我自己的实验室中使用。通过整合miRNA targetome数据， 转录组数据和通过这些实验生成的表型数据，我希望阐明 miRNA，尤其是EBV miRNA的机制有助于持续的病毒感染和 淋巴瘤的发展。 最后，由于EBV不仅表达病毒miRNA，还表达了进一步的改变致癌细胞的表达 与许多与病毒感染无关的癌症有关的miRNA，这些研究可能会潜在 提供可以扩展到其他癌症模型的重要信息，并提供有关整体的洞察力 控制miRNA介导的基因调节的机制。