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: 10818838
• 负责人: ROLF F RENNE
• 金额: $ 4.68万
• 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/10818838
• 关键词: Acquired Immunodeficiency Syndrome; Animal Model; B-Cell Lymphomas; B-Lymphocytes; Biology; Code; Collaborations; Development; Disease; Epstein-Barr virus encoded RNA 1; Genes; Hematogenous; Human; Human Herpesvirus 4; Human Herpesvirus 8; Hyperplasia; Infection; Lesion; Lymphoma; Lymphomagenesis; Lymphoproliferative Disorders; Malignant - descriptor; Malignant Neoplasms; Messenger RNA; MicroRNAs; Molecular; Mus; Nature; Pathogenesis; Peripheral; Play; Proteins; Repression; Role; Shapes; Signal Pathway; Site; Small RNA; Untranslated RNA; Viral; Viral reservoir; Virus; Work; chronic infection; defined contribution; gammaherpesvirus; in vivo; infected B cell; latent infection; mouse model; mutant; prevent; programs; rational design; recombinant virus; tumorigenesis

Project Summary The transforming human gammaherpesviruses EBV and KSHV establish stable latent infections in B cells, providing a lifelong reservoir of virus that can contribute to the development of malignant disease. Thus, defining the mechanisms that govern long-term latency and tumorigenesis is critical for designing rational strategies to prevent disease. In vivo studies of gammaherpesviruses in humans have been severely limited by the difficulties of working in the natural host. Murine gammaherpesvirus 68 (MHV68) is related to EBV and KSHV and causes lymphomas and lymphoproliferative disease in mice, providing a readily manipulatable small animal model for mechanistic studies of the virus/host relationship in vivo. Like EBV and KSHV, MHV68 expresses multiple forms of ncRNAs whose functions during infection and pathogenesis are largely unknown. In contrast to most gammaherpesvirus protein-coding genes, gammaherpesvirus ncRNAs are abundantly expressed in vivo during chronic infection and in hyperplastic lesions during lymphoproliferative disease, suggesting that these ncRNAs may play key conserved roles in latency and tumorigenesis. In support of this, we have demonstrated that MHV68 TMER4 and EBV EBER1 share a conserved function in hematogenous dissemination, and that in vivo suppression of a conserved miRNA target promotes B cell latency. Further, our new preliminary findings implicate both small ncRNAs and miRNAs in the genesis and progression of virus-induced B cell lymphoma. Thus, we hypothesize that gammaherpesviruses utilize a broad array of ncRNAs to shape critical B cell signaling pathways and thereby promote virus dissemination, latency and tumorigenesis. In Aim 1 (in collaboration with Project 2 and with support from Core C and D), we will define the mechanisms by which gammaherpesvirus small RNAs promote the egress and dissemination of infected B cells, facilitate B cell latency at peripheral sites, and drive key stages of lymphomagenesis. In Aim 2 (in collaboration with Projects 2 and 3, and with support from Cores B, C and D) we will define the contribution of gammaherpesvirus miRNA repression of host mRNAs and lncRNAs to B cell latency and lymphomagenesis. The highly collaborative nature of this program, along with the systematic in vivo analyses of ncRNA mutants and recombinant viruses carrying EBV or KSHV genes, provides an extremely powerful means to determine the specific molecular mechanisms by which ncRNAs contribute to gammaherpesvirus latency and tumorigenesis.

项目摘要 转化的人γ掌病毒EBV和KSHV在B细胞中建立稳定的潜在感染， 提供终生的病毒储层，可以有助于恶性疾病的发展。因此，定义 控制长期潜伏和肿瘤发生的机制对于设计理性策略至关重要 预防疾病。人类γ掌病毒的体内研究受到了困难的严重限制 在天然主机中工作。鼠伽马犬68（MHV68）与EBV和KSHV有关 小鼠的淋巴瘤和淋巴增生性疾病，为可操纵的小动物模型提供 体内病毒/宿主关系的机械研究。像EBV和KSHV一样，MHV68表示多种形式 在感染和发病机理中功能的NCRNA在很大程度上未知。与大多数 伽马疱疹病毒蛋白编码基因，γ鞘病毒NCRNA在体内大量表达在体内 慢性感染和淋巴增生性疾病期间的增生性病变，表明这些NCRNA 可能在潜伏和肿瘤发生中起关键的保守作用。为此，我们证明了 MHV68 TMER4和EBV EBER1在血源传播中具有保守的功能，并且体内具有 抑制保守的miRNA靶标会促进B细胞潜伏期。此外，我们的新初步发现暗示 病毒诱导的B细胞淋巴瘤的发生和进展中的小NCRNA和miRNA。因此，我们 假设γ掌病毒利用大量的NCRNA来塑造关键B细胞信号通路 从而促进病毒传播，潜伏期和肿瘤发生。在AIM 1中（与项目2合作 在Core C和d）的支持下，我们将定义gammaherpesvirus small rnas的机制 促进受感染的B细胞的出口和传播，促进B细胞潜伏在外围部位，并驱动 淋巴作用的关键阶段。在AIM 2中（与项目2和3合作，并在核心的支持下 b，c和d）我们将定义宿主mRNA和lncRNA的γ鞘病毒miRNA抑制的贡献 B细胞潜伏期和淋巴作用。该计划的高度协作性质以及系统的 携带EBV或KSHV基因的NCRNA突变体和重组病毒的体内分析提供了一种 确定NCRNA有助于的特定分子机制的极其强大的手段 伽马广播病毒潜伏期和肿瘤发生。