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Molecular Analysis of HSV-1 Reactivation from Latency

HSV-1 潜伏期重新激活的分子分析

基本信息

批准号：
7173328
负责人：
Nancy M. Sawtell
金额：
$ 27.61万
依托单位：
CINCINNATI CHILDRENS HOSP MED CTR
依托单位国家：
美国
项目类别：
财政年份：
1992
资助国家：
美国
起止时间：
1992-01-01 至 2010-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7173328
关键词：
Molecular Analysis HSV Reactivation Latency

项目摘要

DESCRIPTION (provided by applicant): Herpes simplex virus (HSV) infection continues at epidemic levels in the global human population with serious health consequences. Intervention of the reactivation of HSV from the latent state is a critical component of efforts to control this epidemic. The long-term goal of the proposed research is to acquire knowledge of the molecular mechanisms controlling the transition from latent to lytic phase transcription for use in the rational design of intervention strategies. It is widely accepted that the viral/host cell interactions initiating the viral lytic cascade during primary infection are distinct from those initiating the lytic cascade from the latent viral genome. This notion is rooted in the fact that the alpha gene transinducing factor (VP16) is brought in with the virion as a protein and not made until late in the lytic cycle when it is incorporated as protein into the virion. Thus this important viral transactivator is thought to be absent during latency as well as during activation of transcription from the latent viral genome. This presents the necessity to identify a viral/host transcriptional activation interface other than the well-defined VP16/Octl/HCF/taatgarat complex. Although the IE gene ICP0 has been viewed as the likely candidate to "replace" VP16 in initiating the lytic cycle, and studies of ICP0 function have revealed much about the role of this protein in modifying the host cell environment, there remains no evidence that ICP0 initiates entry into the lytic cycle. We have generated compelling data, both phenotypic and biochemical that marks VP16 as a critical player in the initiation of reactivation. This key observation calls for a focused examination of the mechanism of upregulation of viral IE gene transcription from latency. The following specific aims will guide us through a systematic dissection of (1) the role of VP16 during the initiation of reactivation; (2) the VP16 promoter elements required for its stress driven upregulation; and (3) the role of viral genome structure in the regulation of transcriptional silencing and initiation of reactivation. The development and refinement of methodologies to facilitate routine examination and quantification of the events occurring in individual neurons in the ganglia have been fundamental to our progress. These analytical tools together with precision engineering of the viral genome and advances in the analysis of chromatin structure will be utilized for these studies.

描述（由申请方提供）：单纯疱疹病毒（HSV）感染在全球人群中持续流行，并造成严重的健康后果。干预HSV从潜伏状态的再激活是控制这种流行病的努力的关键组成部分。拟议研究的长期目标是获得控制从潜伏期到裂解期转录的分子机制的知识，用于合理设计干预策略。广泛接受的是，在初次感染期间启动病毒裂解级联的病毒/宿主细胞相互作用不同于从潜伏病毒基因组启动裂解级联的病毒/宿主细胞相互作用。这一概念植根于以下事实：α基因反式诱导因子（VP 16）作为蛋白质与病毒体一起引入，并且直到裂解周期的后期才产生，此时它作为蛋白质掺入病毒体中。因此，这种重要的病毒反式激活因子被认为在潜伏期期间以及在从潜伏病毒基因组转录的激活期间不存在。这提出了鉴定除了明确定义的VP 16/Octl/HCF/taatgarat复合物之外的病毒/宿主转录激活界面的必要性。尽管IE基因ICP 0被认为是启动裂解周期中“替代”VP 16的可能候选者，并且对ICP 0功能的研究已经揭示了该蛋白在修饰宿主细胞环境中的作用，但仍然没有证据表明ICP 0启动进入裂解周期。我们已经产生了令人信服的数据，无论是表型和生化标志着VP 16作为一个关键的球员在启动重新激活。这一关键观察结果要求重点检查病毒IE基因转录从潜伏期上调的机制。以下具体目标将引导我们系统地剖析（1）VP 16在再活化起始期间的作用;（2）其应激驱动上调所需的VP 16启动子元件;和（3）病毒基因组结构在转录沉默和再活化起始的调节中的作用。发展和完善的方法，以促进常规检查和量化的事件发生在个别神经元的神经节中一直是我们的进步的基础。这些分析工具连同病毒基因组的精密工程和染色质结构分析的进展将用于这些研究。