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 加速发现长非编码 RNA (lncRNA) 调控的通路，这些通路有助于 具体来说，我们遵循 A) 疱疹病毒所利用的。 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直接导致病毒相关艾滋病恶性肿瘤的发生。 假设我们提出了三个高度集成的项目，其目标是对 lncRNA 进行功能分析， 他们的行动机制由 Renne 博士（佛罗里达大学，佛罗里达大学）领导，将研究 KSHV- HIV 相关 KSHV 中编码的 lncRNA 和宿主 lncRNA 表达的改变 由 Flemington 博士（杜兰大学）领导的项目 2 将研究 Epstein-Barr 病毒 lncRNA 项目 3 领导的 HIV 相关 EBV 恶性肿瘤背景下宿主 lncRNA 表达的改变。 Tibbetts 博士（佛罗里达大学）将研究 MHV68 lncRNA 的功能以及宿主 lncRNA 在以下情况下的改变 简单的小鼠模型中的潜伏期和淋巴瘤发生重要的是，所有项目都得到了强大的新颖性的支持。 初步数据，包括使用新型多平台发现新的伽玛疱疹病毒lncRNA 基因组学方法并暗示其中一些 lncRNA 在病毒生物学和发病机制中的作用。 有组织的行政核心（核心 A，核心领导者：Rolf Renne）将维持监督和组织 该计划，包括生物统计咨询以及遵守可重复性和透明度标准。 两个额外的服务核心已经建立并且非常高效，将支持排序， 三个项目的生物信息学和重组病毒生成需求：病毒 RNA-seq 和 生物信息学核心将由杜兰大学维护（核心 B，核心领导者：Erik Flemington）。 重组病毒核心于 2009 年由 NCI 资助的 RC2 奖项建立，将维持在 UF（核心 C，核心领导者：Rolf Renne）此外，Parsons 博士（LSUHSC，新奥尔良）领导 NIH-。 支持的 LSUHSC/LCRC HIV 临床和生物样本存储库，将有助于获取有价值的 来自 HIV 感染者的卡波西肉瘤 (KS) 和淋巴瘤肿瘤标本具有重要意义。 在研究领域具有高度创新性——“了解病毒和宿主lncRNA的功能” 伽马疱疹病毒肿瘤发生”——并在这三个方面应用了众多最先进的技术 最后，研究发病机制相关的组织培养和动物模型，并辅以 对 EBV 和 KSHV 相关恶性肿瘤的人类肿瘤组织进行分析，将大大提高我们的研究能力 了解艾滋病恶性肿瘤背景下的病毒和宿主 lncRNA。