Murine Model of Gammaherpesvirus Latency

伽马疱疹病毒潜伏期小鼠模型

• 批准号: 6514926
• 负责人: JEFFERY T SAMPLE
• 金额: $ 26.19万
• 依托单位: ST. JUDE CHILDREN'S RESEARCH HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-07-01 至 2006-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6514926
• 关键词: B lymphocyte; Burkitt's lymphoma; Epstein Barr virus; Kaposi's sarcoma; dendritic cells; disease /disorder model; gene induction /repression; host organism interaction; human herpesvirus 8; laboratory mouse; latent virus infection; macrophage; microorganism immunology; polymerase chain reaction; recombinant virus; southern blotting; virus genetics

DESCRIPTION (provided by applicant): The long-term objective of the proposed research is to define the mechanisms that enable the gamma herpesviruses to persist indefinitely within their immunocompetent hosts. These mechanisms underlie the pathogenesis and oncogenic potential associated with these viruses, particularly in individuals with acquired or inherited immunodeficiencies. Unfortunately, due to the extreme host restrictions of the human gamma-herpesviruses Epstein-Barr virus (EBV) and Kaposi's sarcoma-associated herpesvirus (KSHV), it has not been possible to directly address the mechanisms responsible for EBV and KSHV persistence in a relevant host setting. Infection of laboratory mice with the murine gamma-herpesvirus MHV-68 (closely related to KSHV) offers a highly tractable and potential model of human gamma-herpesvirus persistence, but viral latency in this system has not been sufficiently characterized at the molecular level to enable exploitation of this model for these purposes. Therefore, the immediate goals of the proposed research are to define the molecular characteristics of MHV-68 latency. To obtain our objective, we propose three specific aims. Under Aim 1 we will define the programs of MHV-68 latency gene expression during the establishment and maintenance phases of latency within the hematopoietic-cell reservoirs of latent virus (activated and resting B cells, macrophages, and dendritic cells). Specifically, we will screen these cells by RT-PCR and Southern blot hybridization for expression of the MHV-68 latency genes M2, M3, M1 1, 72, 73 and 74. Additionally, we propose to identify potentially novel MHV-68 latency genes expressed in these cells that are not apparent from analysis of the viral genornic DNA sequence. Under Aim 2 we will address the functions of three latency-associated genes: M2, 73 and 74, for which little or no information is available. Under Aim 3 we will define the impact of MHV-68 latency on cellular gene expression in vivo at the cellular level. Together, these specific aims will fill the significant gaps that currently remain in our knowledge of the latent life cycle of MHV-68, as well as provide better insight into the mechanisms that the gamma-herpesviruses as a group exploit to maintain latency, and thus contribute to their pathogenic potential.

描述（由申请人提供）：拟议的长期目标 研究的目的是确定伽马疱疹病毒的机制， 在免疫活性宿主体内无限期存在。这些机制 与此相关的发病机制和致癌潜力的基础 病毒，特别是在获得性或遗传性 免疫缺陷不幸的是，由于 人γ-疱疹病毒、EB病毒（EBV）和卡波西氏病毒 肉瘤相关疱疹病毒（KSHV），目前还不可能直接 解决机制负责EBV和KSHV持久性在相关的 主机设置。小鼠γ-疱疹病毒感染实验小鼠 MHV-68（与KSHV密切相关）提供了一个高度易处理和潜在的模型 人类γ-疱疹病毒的持久性，但在这个系统中的病毒潜伏期 在分子水平上没有得到充分的表征， 利用这种模式来实现这些目的。因此，近期目标 拟议的研究的一部分是确定MHV-68的分子特征 延迟。为了实现我们的目标，我们提出了三个具体目标。根据目标1 我们将确定MHV-68潜伏期基因表达的程序， 造血细胞内潜伏期的建立和维持阶段 潜伏病毒的储库（活化的和静息的B细胞、巨噬细胞和 树突细胞）。具体来说，我们将通过RT-PCR筛选这些细胞， Southern印迹杂交检测MHV-68潜伏基因M2，M3， M11、72、73和74。此外，我们建议确定潜在的新的 MHV-68潜伏基因在这些细胞中表达，这些基因在 病毒基因组DNA序列分析。在目标2下，我们将解决 三个潜伏期相关基因的功能：M2，73和74，很少或 没有资料。在目标3下，我们将定义MHV-68的影响 在细胞水平上对体内细胞基因表达的潜伏期。我们一起努力， 这些具体目标将填补我们目前存在的重大空白， 了解MHV-68的潜在生命周期，并提供更好的洞察力 γ-疱疹病毒作为一个群体用来维持 潜伏期，从而有助于其致病潜力。