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.

项目总结