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 EB病毒（EBV），一种普遍存在的DNA肿瘤病毒，与诸如伯基特氏、霍奇金氏、 和弥漫性大B细胞淋巴瘤。在感染过程中，EB病毒表达病毒微小RNA（miRNA），最近 研究已经证明EBV miRNAs以及细胞致癌miRNAs的重要作用 在B细胞转化过程中被EBV感染上调。此外，一些EBV miRNAs共享 与在癌症中失调的细胞miRNAs序列同源，并且潜在地，这些病毒miRNAs 可以连接并改变现有的miRNA调控网络。参与转化的miRNA靶点是 因此，系统地鉴定EBV感染细胞中由miRNA调控的基因， 这对于理解它们对病毒肿瘤发生的贡献及其在EBV生命周期中的作用至关重要。 这里概述的实验结合了来自miRNA多学科领域的最新技术，联合收割机 生物学，病毒学和生物信息学，全面询问miRNA靶组，并检查 转录景观的EBV感染的B细胞，以提取关键基因和途径的影响 病毒和细胞的miRNAs。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细胞肿瘤之外，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的培训，并相应地组建了一个科学咨询小组， 委员会将指导我建立和（或）进一步发展若干基本方法。的 K99/R 00奖励将为我在辅导阶段提供新培训的资源和时间，以便 学习基本的从头感染技术，并生成额外的数据和计算工具， 在我自己的实验室里使用的。通过整合miRNA靶组数据， 转录组数据和通过这些实验产生的表型数据，我希望阐明 miRNAs，特别是EBV miRNAs，导致持续性病毒感染的机制，以及 淋巴瘤的发展 最后，由于EBV不仅表达病毒miRNAs，而且进一步改变了致癌细胞的表达， miRNAs与许多与病毒感染无关的癌症有关，这些研究将有可能 提供了可以扩展到其他癌症模型的重要信息，并提供了对整体癌症模型的深入了解。 癌症中miRNA介导的基因调控机制。