Noncoding RNAs in gamma-Herpesvirus Biology and AIDS Malignancies

γ-疱疹病毒生物学和艾滋病恶性肿瘤中的非编码 RNA

• 批准号: 9266979
• 负责人: ROLF F RENNE
• 金额: $ 135.64万
• 依托单位: UNIVERSITY OF FLORIDA
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-02-09 至 2022-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9266979
• 关键词: Acquired Immunodeficiency Syndrome; Address; Adherence; Animal Model; Award; Bioinformatics; Biology; Cell Differentiation process; Cell Proliferation; Cell Survival; Clinical; Collaborations; Comparative Study; Complement; Complex; Consultations; Coupled; Data; Development; EBV-associated malignancy; Environment; Florida; Funding; Gene Expression; Gene Expression Regulation; Generations; Genetic Transcription; Genomic approach; Goals; HIV; Herpesviridae; Human; Human Herpesvirus 4; Human Herpesvirus 8; Infection; Kaposi Sarcoma; Lymphoma; Lymphomagenesis; Malignant Neoplasms; MicroRNAs; Oncogenic; Pathogenesis; Pathway interactions; Patients; Pattern; Positioning Attribute; Process; Publishing; RNA; Regulatory Pathway; Reproducibility; Role; Services; Specimen; Techniques; Transcript; Tumor Suppressor Proteins; Tumor Tissue; United States National Institutes of Health; Universities; Untranslated RNA; Viral; Virus; base; experience; field study; gammaherpesvirus; genome-wide; genomic platform; in vivo; innovation; latent gene expression; mouse model; novel; programs; recombinant virus; repository; tissue culture; transcriptome sequencing; tumor; tumorigenesis; virus core

SUMMARY The unifying postulate of this P01 proposal is that comparative studies of KSHV, EBV, and MHV68 will accelerate the discovery of pathways regulated by long non-coding RNAs (lncRNAs) that contribute to gammaherpesvirus latency and tumorigenesis. Specifically, we hypothesize A) that herpesviruses utilize lncRNAs to regulate both virus and host gene expression, and B) that viral lncRNAs and/or virus-perturbed host lncRNAs directly contribute to the genesis of virus-associated AIDS malignancies. To address these hypotheses we propose three highly integrated projects with the goal of functionally analyzing lncRNAs and their mechanisms of action. Project 1, led by Dr. Renne (University of Florida, UF), will investigate KSHV- encoded lncRNAs and alteration of host lncRNA expression in the context of HIV-associated KSHV malignancies. Project 2, led by Dr. Flemington (Tulane University) will interrogate Epstein-Barr virus lncRNAs and alteration of host lncRNA expression in the context of HIV-associated EBV malignancies. Project 3 led by Dr. Tibbetts (UF) will investigate function of MHV68 lncRNAs and alteration of host lncRNAs in the context of latency and lymphomagenesis in a facile murine model. Importantly, all projects are supported by strong novel preliminary data, including the discovery of new gammaherpesvirus lncRNAs using a novel multi-platform genomics approach and implicating some of these lncRNAs in viral biology and pathogenesis. The well- organized Administrative core (Core A, Core Leader: Rolf Renne) will maintain oversight and organization of the program, including biostatisical consultation and adherence to reproducibility and transparency standards. Two additional service cores, which are already established and very productive, will support sequencing, bioinformatics and recombinant virus generation needs across the three projects: The Virus RNA-seq and Bioinformatics Core will be maintained at Tulane University (Core B, Core Leader: Erik Flemington). The Recombinant Virus Core, which was established with an NCI-funded RC2 award in 2009, will be maintained at UF (Core C, Core Leader: Rolf Renne). In addition, Dr. Parsons (LSUHSC, New Orleans), who leads the NIH- supported LSUHSC/LCRC HIV Clinical and Biospecimen Repository, will facilitate the acquisition of valuable Kaposi's sarcoma (KS) and lymphoma tumor specimens from HIV-infected patients. Our proposal is significant and highly innovative in terms of the field of study – “understanding virus and host lncRNA function in gammaherpesvirus tumorigenesis” – and in applying numerous state-of-the-art techniques across all three projects. Finally, studying pathogenesis-relevant tissue culture and animal models, complemented by the analysis of human tumor tissues from EBV- and KSHV-associated malignancies, will greatly increase our understanding of both viral and host lncRNAs in the context of AIDS malignancies.

概括 该P01提案的统一假设是KSHV，EBV和MHV68的比较研究将 加速有助于长的非编码RNA（LNCRNA）调节的途径，这些途径有助于 伽马广播病毒潜伏期和肿瘤发生。具体来说，我们假设a）疱疹病毒利用率 lncRNA调节病毒和宿主基因表达，b）病毒lncRNA和/或病毒扰动 宿主lncRNA直接有助于病毒相关的艾滋病的起源。解决这些 假设我们提出了三个高度集成的项目，目的是在功能上分析LNCRNA和 他们的作用机制。由Renne博士（UF佛罗里达大学）领导的项目1将调查KSHV- 在与HIV相关的KSHV的背景下，编码的LNCRNA和宿主LNCRNA表达的改变 恶性肿瘤。弗莱明顿博士（杜兰大学）领导的项目2将询问爱泼斯坦 - 巴尔病毒lncrnas 在与HIV相关的EBV恶性肿瘤的背景下，宿主lncRNA表达的改变。领导的项目3 Tibbetts博士（UF）将研究MHV68 LNCRNA的功能和宿主LNCRNA的改变。 柔和的鼠模型中的潜伏期和淋巴作用。重要的是，所有项目都得到了强大的小说的支持 初步数据，包括使用新型的多平台发现新的Gammaherpesvirus lncrnas 基因组学方法并隐含了这些LNCRNA在病毒生物学和发病机理中。福 有组织的行政核心（核心A，核心负责人：Rolf Renne）将保持监督和组织 该计划，包括生物统计咨询和遵守可重复性和透明度标准。 已经建立并且非常有生产力的另外两个服务核心将支持排序， 在这三个项目中，生物信息学和重组病毒的产生需求：病毒RNA-Seq和 生物信息学核心将在杜兰大学（Core B，核心负责人：Erik Flemington）维持。这 重组病毒核心于2009年获得了NCI资助的RC2奖，该核心将于2009年保持 UF（Core C，核心负责人：Rolf Renne）。此外，领导NIH-的Parsons博士（LSUHSC，新奥尔良） 支持的LSUHSC/LCRC HIV临床和生物传感存储库将有助于获得价值 来自HIV感染患者的Kaposi的肉瘤（KS）和淋巴瘤标本。我们的建议很重要 在研究领域方面高度创新的 - “了解病毒和宿主lncRNA功能 伽马梅氏病毒肿瘤的发生” - 在这三种方面应用大量最先进的技术 项目。最后，研究与发病机理相关的组织培养和动物模型，由 分析来自EBV和KSHV相关的恶性肿瘤的人类肿瘤组织将大大增加我们的 在AIDS MALIGNANCYS的背景下，了解病毒和宿主lncRNA。