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

基本信息

批准号：
9334358
负责人：
Rebecca L Skalsky
金额：
$ 24.9万
依托单位：
OREGON HEALTH & SCIENCE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-09-01 至 2019-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9334358
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 DNA Tumor Viruses Data Development Epithelial Epithelial Cells Epstein-Barr Virus Infections Event Gene Expression Gene Expression Regulation Gene Targeting Genes Goals Growth Health Hodgkin Disease Homologous Gene Human Human Herpesvirus 4 Immunoprecipitation In Vitro 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 Primary Infection 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 cell transformation cellular targeting computerized tools crosslink deep sequencing differential expression in vivo infected B cell inhibitor/antagonist insight large cell Diffuse non-Hodgkin&apos s lymphoma latent infection latent persistent infection lymphoblastoid cell line member multidisciplinary new therapeutic target phenotypic data programs research study transcriptome transcriptome sequencing tumorigenesis uncontrolled B lymphocyte proliferation viral RNA virology

项目摘要

DESCRIPTION (provided by applicant): 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.

描述（由申请人提供）：至少六分之一的人类癌症与病毒感染有关。其中一部分可归因于 Epstein-Barr 病毒 (EBV)，这是一种普遍存在的 DNA 肿瘤病毒，与伯基特病、霍奇金病和弥漫性大 B 细胞淋巴瘤等癌症相关。在感染过程中，EBV 表达病毒 microRNA (miRNA)，最近的研究表明 EBV miRNA 以及 EBV 感染上调的细胞致癌 miRNA 在 B 细胞转化过程中发挥着重要作用。此外，一些 EBV miRNA 与癌症中失调的细胞 miRNA 具有序列同源性，这些病毒 miRNA 可能会结合并改变现有的 miRNA 调控网络。参与转化的 miRNA 靶点尚未确定，因此，系统地识别 EBV 感染细胞中 miRNA 调控的基因对于了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 miRNA 生物学、病毒学和生物信息学多学科领域的最先进技术，全面探究 miRNA 靶标组并检查 EBV 感染的 B 细胞的转录景观，以提取受影响的关键基因和途径通过病毒和细胞 miRNA。除了患者来源的 EBV+ B 细胞肿瘤之外，这些研究还将使用 EBV 驱动的体外 B 细胞转化模型进行。为了成功地开展我的研究，我需要 EBV 生物学和生物信息学方面的新培训，并相应地组建了一个科学咨询委员会来指导我建立和/或进一步开发几种基本方法。 K99/R00 奖项将为我在指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，以便在独立阶段在我自己的实验室中使用。通过整合这些实验产生的 miRNA 靶标组数据、转录组数据和表型数据，我希望阐明 miRNA，特别是 EBV miRNA，导致持续性病毒感染和淋巴瘤发展的机制。最后，由于 EBV 不仅表达病毒 miRNA，还进一步改变致癌细胞 miRNA 的表达，而这些 miRNA 与许多与病毒感染无关的癌症有关，因此这些研究将有可能提供重要的信息，这些信息可以扩展到其他癌症模型，并深入了解控制癌症中 miRNA 介导的基因调控的总体机制。