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"Project 3" Defining the in vivo function of ncRNAs during MHV68 latency and lymphomagenesis

“项目 3”定义 ncRNA 在 MHV68 潜伏期和淋巴瘤发生过程中的体内功能

基本信息

批准号：
10403017
负责人：
Scott A. Tibbetts
金额：
$ 30.02万
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/10403017
关键词：
Acquired Immunodeficiency Syndrome Animal Model B-Cell Lymphomas B-Lymphocytes Biological Biological Models Biology Cell physiology Chronic Code Collaborations Comparative Study Data Development Disease Epstein-Barr virus encoded RNA 1 Epstein-Barr virus encoded RNA 2 Event Foundations Genes Genetic Transcription Goals HIV Hematogenous Herpesviridae Human Human Herpesvirus 4 Human Herpesvirus 8 Hyperplasia Immunocompromised Host Immunologics Infection Lesion Link Lymphoma Lymphomagenesis Lymphoproliferative Disorders Malignant - descriptor Malignant Neoplasms Messenger RNA MicroRNAs Molecular Mus Nature Outcome Pathogenesis Pathway interactions Peripheral Phenotype Play Proteins RNA Regulation Reporting Repression Role Shapes Signal Pathway Site Small RNA Surface System Technology Testing Transcript Transfer RNA Translations Untranslated RNA Viral Viral Physiology Viral reservoir Virus Work base chronic infection defined contribution digital experimental study gammaherpesvirus in vivo infected B cell innovation latent infection mouse model mutant novel prevent programs rational design recombinant virus small hairpin RNA tumor tumor progression tumorigenesis

项目摘要

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 Cores 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.

项目总结