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

基本信息

批准号：
10403014
负责人：
ROLF F RENNE
金额：
$ 156.95万
依托单位：
UNIVERSITY OF FLORIDA
依托单位国家：
美国
项目类别：
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/10403014
关键词：
AIDS related cancer 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 Foundations Funding GTP-Binding Protein alpha Subunits, Gs 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&apos s Sarcoma Pathogenesis Pathology Pathway interactions Patients Phenotype Protocols documentation Publications Publishing Quality Control RNA RNA Splicing RNA Viruses Regulation 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 base 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 virus core

项目摘要

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.

概括该程序的目标是使用 KSHV、EBV 和 MHV68 短非编码和长非编码的比较分析 RNA揭示了γ-疱疹病毒非编码RNA的保守功能和其靶向的调控节点我们的统一假设是 A) γ-疱疹病毒利用短和长非编码 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 直接导致艾滋病毒相关恶性肿瘤的发生为了支持这一假设，我们的项目已经在第一个资助期间取得了一些开创性的发现，包括：确定高可信度所有三种病毒的 miRNA 靶标组；证明 γ-疱疹病毒感染后宿主 lncRNA 失调细胞；发现所有三种病毒的 circRNA；EBV 和 MHV68 转录组的全局解析；发现新的非编码转录本；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；并首次展示了长期体内功能研究了 EBV EBER1 非编码 RNA 迄今为止，我们第一个周期的结果已在 20 项研究中得到报道。为了继续解决我们的统一假设，我们提出了三个高度一致的假设。综合项目：项目 1，由 Renne 博士（佛罗里达大学，佛罗里达大学）领导，将机械地研究病毒 lncRNA 以及 KSHV 编码的 miRNA 如何在 HIV 背景下诱导宿主 lncRNA 表达的改变由 Flemington 博士（杜兰大学）领导的项目 2 将探讨 KSHV 相关恶性肿瘤的作用。 EBV（和 KSHV）miRNA 簇通过“微处理器过载”抑制宿主 miRNA 成熟由 Tibbetts 博士（佛罗里达大学）领导的项目 3 将研究与 HIV 相关的 EBV 恶性肿瘤的功能。 MHV68 miRNA 和短非编码 RNA 以及 EBV EBER 在小鼠慢性感染和组织良好的行政核心（核心A，领导者：Rolf Renne）将继续维护和监督该计划的组织，包括生物统计咨询和遵守严格性，三个服务核心支持所有三个项目：RNA-seq 和杜兰大学生物信息学核心（核心 B，领导者：Erik Flemington）将继续产生巨大影响开发创新算法和数据分析管道（核心 C，领导者： UF 的 Rolf Renne）支持了 60 多种重组病毒的生成和质量控制，将通过实施基于 CRISPR-Cas 的技术继续创新。佛罗里达大学的肿瘤发生核心（核心 D，领导者：Scott Tibbetts）将支持对大量肿瘤发生的分析 EBV 和 KSHV 相关肿瘤样本并进行所有提议的肿瘤发生研究。总之，这。计划项目已经对该领域产生了持续影响，将进一步加深我们对病毒非编码RNA和病毒扰动的宿主lncRNA如何促进γ-疱疹病毒肿瘤发生确定治疗干预的新脆弱性的目标。