Human Cytomegalovirus Episome Maintenance and Propagation of Genetic Damage

人类巨细胞病毒附加体的维持和遗传损伤的传播

基本信息

  • 批准号:
    7939889
  • 负责人:
  • 金额:
    $ 1.9万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2008
  • 资助国家:
    美国
  • 起止时间:
    2008-09-30 至 2011-02-07
  • 项目状态:
    已结题

项目摘要

DESCRIPTION (provided by applicant): Human cytomegalovirus (HCMV) infects over 70 percent of the population worldwide and like other herpesviruses, it establishes a lifelong latent infection that upon reactivation can have devastating consequences in the very young, very old, or immunosuppressed. Recent research has demonstrated possible causal roles for HCMV in atherosclerosis, autoimmunity and tumorigenesis. In vitro studies have shown that certain HCMV proteins are mutagenic and that specific breaks in chromosome 1 are induced when fibroblasts are infected during S-phase. S-phase infected fibroblasts undergo mitosis and divide, and therefore it has been hypothesized that viral episome segregation during mitosis could result in one of the daughter cells lacking the HCMV-induced block to cell cycle progression and permitting the genetic damage to propagate. Further, in contrast to its interaction with fibroblasts, HCMV replicates in some endothelial cells without blocking cell cycle progression, providing another opportunity for propagation of virus-induced damage to the cellular genome. The overall objective of this application is to test the hypothesis that HCMV-induced damage to the genome of a host cell can be propagated to progeny cells, potentially dysregulating cell growth. Aim 1: To characterize specific HCMV-induced genetic damage in human cell types in which cell cycle progression is not inhibited by HCMV, specifically, aortic endothelial cells. Aim 2: To investigate and document the propagation of HCMV-induced genetic damage by (1) developing a "tagging" method to identify cells infected with HCMV or daughter cells thereof, irrespective of viral genome or gene product maintenance or concentration and (2) isolating cells identified to have lost viral genomes for further analysis of replication ability, growth kinetics and genetic damage. Cells will be cloned to encode a mCherry sequence that is preceded by a loxP-flanked STOP sequence such that infection with cre-encoded HCMV will induce cleavage of the STOP sequence and mCherry will be expressed. PUBLIC HEALTH RELEVANCE: This application seeks to document HCMV's ability to induce and propagate genetic damage in human cells, which may lead to cancer development and other diseases.
描述(申请人提供):人类巨细胞病毒(HCMV)感染全球70%以上的人口,与其他疱疹病毒一样,它建立了一种终身潜伏感染,一旦重新激活,可能会对非常年轻、非常年长或免疫抑制的人造成毁灭性的后果。最近的研究表明,人巨细胞病毒在动脉粥样硬化、自身免疫和肿瘤发生中可能起到致病作用。体外研究表明,某些巨细胞病毒蛋白具有致突变性,在S期感染成纤维细胞可引起1号染色体的特异性断裂。S期感染的成纤维细胞经历了有丝分裂和分裂,因此推测病毒在有丝分裂过程中的Episome分离可能导致其中一个子细胞缺乏巨细胞病毒诱导的细胞周期进程的阻断,从而允许遗传损伤的传播。此外,与其与成纤维细胞的相互作用相反,HCMV在一些内皮细胞中复制而不阻止细胞周期进程,为病毒引起的细胞基因组损伤的传播提供了另一种机会。这项应用的总体目标是检验这样一个假设,即巨细胞病毒对宿主细胞基因组的破坏可以传播到后代细胞,潜在地扰乱细胞生长。目的1:研究人巨细胞病毒对细胞周期进程无抑制作用的细胞类型,特别是主动脉内皮细胞,研究巨细胞病毒所致的特异性遗传损伤。目的:通过(1)建立一种“标记”方法来识别感染了HCMV的细胞或其子代细胞,而与病毒基因组或基因产物的维持或浓度无关;(2)分离已丢失病毒基因组的细胞,以进一步分析复制能力、生长动力学和遗传损伤,以研究和记录HCMV引起的遗传损伤的传播。细胞将被克隆以编码mCherry序列,该mCherry序列之前是loxP侧翼的停止序列,因此感染cre编码的HCMV将诱导停止序列的切割并表达mCherry。公共卫生相关性:这项申请旨在证明巨细胞病毒在人类细胞中诱导和传播遗传损伤的能力,这可能导致癌症和其他疾病的发展。

项目成果

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Teresa D. Beeson其他文献

Teresa D. Beeson的其他文献

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{{ truncateString('Teresa D. Beeson', 18)}}的其他基金

Human Cytomegalovirus Episome Maintenance and Propagation of Genetic Damage
人类巨细胞病毒附加体的维持和遗传损伤的传播
  • 批准号:
    7611337
  • 财政年份:
    2008
  • 资助金额:
    $ 1.9万
  • 项目类别:
Human Cytomegalovirus Episome Maintenance and Propagation of Genetic Damage
人类巨细胞病毒附加体的维持和遗传损伤的传播
  • 批准号:
    7915225
  • 财政年份:
    2008
  • 资助金额:
    $ 1.9万
  • 项目类别:

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