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: 10646224
• 负责人: ROLF F RENNE
• 金额: $ 150.57万
• 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 2027-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10646224
• 关键词: AIDS related cancer; Acceleration; Acquired Immunodeficiency Syndrome; Address; Adherence; Algorithmic Analysis; Algorithms; Bioinformatics; Biology; Biometry; Burkitt Lymphoma; Cell Line; Cells; Clinic; Clinical; Clustered Regularly Interspaced Short Palindromic Repeats; Code; Comparative Study; Consultations; DNA; Data; Development; Endothelium; Epstein-Barr Virus-Related Malignant Neoplasm; Epstein-Barr virus encoded RNA 1; Florida; Funding; Gene Expression; Generations; Goals; HIV; Human; Human Herpesvirus 4; Human Herpesvirus 8; Hybrids; Immune Evasion; In Vitro; Laboratories; Lesion; Link; Lymphoid Cell; Lymphomagenesis; Malignant Neoplasms; MicroRNAs; Microprocessor; Molecular; Mus; Oncogenic; Oral; Palate Kaposi' s Sarcoma; Pathogenesis; Pathology; Pathway interactions; Patients; Phenotype; Proliferating; Protocols documentation; Publications; Publishing; Quality Control; RNA; RNA Splicing; Reporting; Reproducibility; Research; Resolution; Role; Sampling; Seminal; Services; South Africa; System; Techniques; Therapeutic Intervention; Tissues; Transcript; Universities; Untranslated RNA; Viral; Viral Proteins; Virus; Virus Latency; Xenograft procedure; angiogenesis; biobank; cancer specimen resource; chronic infection; circular RNA; comparative; crosslink; data analysis pipeline; gammaherpesvirus; glucose metabolism; humanized mouse; in vitro Model; in vivo; innovation; malignant stomach neoplasm; maxillofacial; migration; mouse model; novel; novel therapeutic intervention; programs; recombinant virus; recruit; transcriptome; transcriptome sequencing; transcriptomics; tumor; tumorigenesis

SUMMARY The goal of this program is to use comparative analysis of KSHV, EBV and MHV68 short and long noncoding RNAs to reveal conserved functions of, and regulatory nodes targeted by, γ-herpesvirus noncoding RNAs during tumorigenesis. Our unifying hypothesis is that A) γ-herpesviruses utilize short and long noncoding RNAs to regulate both virus and host gene expression, and B) viral noncoding RNAs and/or virus-perturbed host lncRNAs directly contribute to the genesis of HIV-associated malignancies. In support of this hypothesis, our program has made a number of seminal findings during the first funding period, including: identification of high confidence miRNA targetomes across all three viruses; demonstration of host lncRNA de-regulation in γ-herpesvirus infected cells; discovery of circRNAs across all three viruses; global resolution of EBV and MHV68 transcriptomes and discovery of new noncoding transcripts; demonstration that noncoding RNAs are the predominant viral gene products detectable in some EBV+ malignancies; and demonstration of the first in vivo function for the long- studied EBV EBER1 noncoding RNA. To date, our results from the first cycle have been reported in 20 research publications and 5 review articles. To continue to address our unifying hypothesis we propose three highly integrated projects: Project 1, led by Dr. Renne (University of Florida, UF), will mechanistically study viral lncRNAs and how KSHV-encoded miRNAs induce alterations of host lncRNA expression in the context of HIV- associated KSHV malignancies. Project 2, led by Dr. Flemington (Tulane University) will interrogate the role of EBV (and KSHV) miRNA cluster inhibition of host miRNA maturation through “microprocessor overload” in the context of HIV-associated EBV malignancies. Project 3 led by Dr. Tibbetts (UF) will investigate the function of MHV68 miRNAs and short noncoding RNAs and EBV EBERs in a facile murine chronic infection and tumorigenesis system. The well-organized Administrative core (Core A, Leader: Rolf Renne) will continue to maintain oversight and organization of the program, including biostatistical consultation and adherence to rigor, reproducibility, and transparency standards. Three service cores support all three projects: The RNA-seq and Bioinformatics Core (Core B, Leader: Erik Flemington) at Tulane University will continue to have high impact by developing innovative algorithms and data analyses pipelines. The Recombinant Virus Core (Core C, Leader: Rolf Renne) at UF, which has supported the generation and quality control of more than 60 recombinant viruses, will continue to innovate by implementing CRISPR-Cas-based techniques. The Clinical Sample and Tumorigenesis Core (Core D, Leader: Scott Tibbetts) at UF will support the analysis of a significant numbers of EBV and KSHV-associated tumor samples and perform all proposed tumorigenesis studies. In summary, this program project, which has already had sustained impact on the field, will further increase our understanding of how viral noncoding RNAs and virus-perturbed host lncRNAs contribute to γ-herpesvirus tumorigenesis with the goal of defining new vulnerabilities for therapeutic intervention.

概括 该程序的目的是使用KSHV，EBV和MHV68简短和长期编码的比较分析 rNA揭示了由γ-鞘膜病毒非编码RNA靶向的配置功能和调节节点的配置函数 肿瘤发生。我们统一的假设是a）γ-HERPESVIRUS使用短而长的不编码RNA 调节病毒和宿主基因表达，b）病毒非编码RNA和/或病毒扰动的宿主lncRNA 直接有助于与HIV相关的恶性肿瘤的起源。为了支持这一假设，我们的计划有 在第一个资金期间进行了许多半协定，包括：识别高信心 所有三种病毒中的miRNA靶标；在感染的γ-HERPESVIRUS中宿主lncRNA脱离调节的演示 细胞；在所有三种病毒中发现circrnas； EBV和MHV68转录组的全球分辨率以及 发现新的非编码成绩单；证明非编码RNA是主要的病毒基因 在某些EBV+恶性肿瘤中可检测到的产品；并演示长期的第一个体内函数 研究了EBV EBER1非编码RNA。迄今为止，我们的第一个周期的结果已在20个研究中报道 出版物和5篇评论文章。为了继续解决我们的统一假设，我们提出了三个高度提议 综合项目：由Renne博士（佛罗里达大学，UF）领导的项目1将机械地研究病毒 lncRNA以及KSHV编码的miRNA如何影响HIV的背景下的宿主lncRNA表达的改变 相关的KSHV恶性肿瘤。由弗莱明顿（Flemington）（杜兰大学）领导的项目2将审问 EBV（和KSHV）miRNA簇抑制宿主miRNA的成熟，通过“微处理器过载” 与HIV相关的EBV恶性肿瘤的背景。 Tibbetts博士（UF）领导的项目3将调查 MHV68 miRNA和简单的鼠慢性感染中的简短编码RNA和EBV Ebers 肿瘤发生系统。组织良好的行政核心（核心A，负责人：Rolf Renne）将继续 维护该计划的监督和组织，包括生物统计学咨询和遵守严格 可重复性和透明度标准。三个服务核心支持所有三个项目：RNA-Seq和 杜兰大学的生物信息学核心（核心B，领导者：埃里克·弗莱明顿）将继续受到高影响 开发创新算法和数据分析管道。重组病毒核心（Core C，领导者： UF的Rolf Renne），它支持60多个重组病毒的产生和质量控制 将通过实施基于CRISPR-CAS的技术继续创新。临床样本和 UF的肿瘤发生核心（核心D，领导者：Scott Tibbetts）将支持大量的分析 EBV和KSHV相关的肿瘤样品，并进行所有提出的肿瘤发生研究。总而言之，这 已经对该领域产生了持续影响的计划项目将进一步提高我们对 病毒非编码的RNA和病毒扰动宿主LNCRNA如何有助于γ-疱疹病毒肿瘤发生 定义新的治疗干预漏洞的目标。