Control of Human Cytomegalovirus

人类巨细胞病毒的控制

• 批准号: 8243763
• 负责人: JEFFERY L MEIER
• 金额: --
• 依托单位: IOWA CITY VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-10-01 至 2015-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8243763
• 关键词: Acute; Antiviral Agents; Antiviral Therapy; Binding; Binding Proteins; Biological; Biology; Boxing; Cell model; Cells; Cessation of life; Code; Cues; Cytomegalovirus; Cytomegalovirus Infections; Data; Dendritic Cells; Development; Disease; Elements; Endothelial Cells; Enhancers; Environment; Epithelial Cells; Fibroblasts; Flow Cytometry; Gene Expression; Gene Expression Regulation; Genome; Goals; Health; Human; Immediate-Early Genes; In Vitro; Infection; Intervention; Investigation; Iowa; Knowledge; Laboratories; Lead; Link; Lytic; Methods; Microscopy; Modeling; Molecular; Myeloid Cells; Neurons; Pathway interactions; Phase; Population; Prevention; Primates; Proteins; Proteomics; Regulation; Regulatory Element; Regulatory Pathway; Research; Resources; Role; Signal Pathway; Signal Transduction; Stimulus; Structure; Supporting Cell; Technology; Testing; Universities; Veterans; Viral; Virus; Virus Latency; base; burden of illness; cell type; drug development; improved; innovation; innovative technologies; latent infection; meetings; nonhuman primate; novel; novel strategies; precursor cell; promoter; tool; transcription factor

DESCRIPTION (provided by applicant): Human cytomegalovirus (HCMV) persistently infects over half of the Veteran population and causes disease and death in a sizeable segment of this population despite advances in antiviral therapy. Novel strategies to mitigate the disease burden resulting from HCMV infection are needed. The HCMV MIE enhancer/promoter serves as the lytic switch for the virus. It is turned on to initiate the viral replicative cycle and turned off during viral latency. Knowledge about the ways in which the HCMV MIE lytic switch is controlled has the potential to inform the development of new therapies to pre-empt viral replication. Our laboratory is at the forefront of investigations into defining the control mechanisms. These early results have led us to hypothesize that the transcriptional regulatory hierarchies and cis-regulatory codes in control of HCMV MIE lytic switch activation differ between cell types in acutely productive and reactivation infections. Preliminary data in human pluripotent N-Tera2 cells (NT2) suggest that HCMV MIE reactivation is best achieved by a combination of different cues and multiple regulatory pathways. There is both a need to further elucidate the cues and regulatory pathways involved and a need to evaluate these findings in a HCMV latency model in dendritic- monocytic cell (D/M) precursors. These results will be the first to elucidate the molecular mechanisms controlling HCMV MIE lytic switch reactivation. Preliminary data in acutely infected permissive fibroblasts reveal a novel regulatory mechanism which functions atypically in the post-immediate-early phase of infection and acts together with another yet unidentified regulatory mechanism. Filling in the gaps in knowledge about action, mechanism, and purpose of this regulatory mechanism is anticipated to shift paradigm in explaining how the MIE enhancer governs HCMV replication. The specific aims of this project are to delineate the differential roles of specific transcription factor pathways and cis-regulatory codes in HCMV MIE lytic switch activation in: 1) acutely infected permissive fibroblast, endothelial, epithelial, and myeloid cells; and 2) quiescently infected NT2 and D/M precursors. The research plan will draw on both innovative approaches and tools. The use of advanced technology and state-of-the-art methods makes feasible the detailing of these pathways at unparalleled depth in diverse cellular settings of biological import. An outstanding research environment and an accomplished research team that interfaces well with the Central Microscopy Research, Proteomics, and Flow Cytometry facilities at the University of Iowa are ideally suited for carrying out this plan. The discovery of viral regulatory mechanisms that can be disrupted to stop HCMV gene expression and replication before it begins potentially provides a new direction in antiviral drug development, with the goal of improving Veterans' health.

描述（由申请人提供）： 人类巨细胞病毒（HCMV）持续感染了退伍军人人口的一半以上，并在该人群的大部分地区导致疾病和死亡，尽管抗病毒疗法进展。需要新的减轻HCMV感染导致疾病负担的策略。 HCMV MIE增强子/启动子用作病毒的裂解开关。它被打开以启动病毒复制周期并在病毒潜伏期期间关闭。有关HCMV MIE裂解开关的控制方式的知识有可能告知开发新疗法以抢占避免病毒复制的方法。我们的实验室处于定义控制机制的调查的最前沿。这些早期结果使我们假设在控制HCMV MIE裂解开关激活中，转录调控层次结构和顺式调节代码在细胞类型之间在急性生产和重新激活感染中有所不同。人多能N-TERA2细胞（NT2）中的初步数据表明，通过不同的提示和多个调节途径的组合，最好可以实现HCMV MIE重新激活。既需要进一步阐明涉及的提示和调节途径，又需要在树突单核细胞（D/M）前体中的HCMV潜伏期模型中评估这些发现。这些结果将是第一个阐明控制HCMV MIE裂解开关重新激活的分子机制的结果。急性感染的允许成纤维细胞中的初步数据揭示了一种新型的调节机制，该机制在后期的感染后期，并与另一种未识别但身份不明的调节机制一起起作用。预计该调节机制的作用，机制和目的的知识差距会改变范式，以解释MIE增强剂如何控制HCMV复制。该项目的具体目的是描述特定转录因子途径和顺式调节代码在HCMV MIE裂解开关激活中的差异作用：1）急性感染的允许成纤维细胞，内皮，上皮细胞和髓样细胞； 2）静止感染的NT2和D/M前体。该研究计划将借鉴创新方法和工具。先进技术和最先进的方法的使用使这些途径在生物进口的各种细胞环境中无与伦比的深度可行。一个杰出的研究环境和一个有成就的研究团队，与爱荷华大学的中央显微镜研究，蛋白质组学和流式细胞仪设施很好地相连，非常适合执行该计划。在开始潜在地发现了可能会破坏HCMV基因表达和复制的病毒调节机制，以阻止HCMV基因的表达和复制，这可能为抗病毒药物开发提供了新的方向，目的是改善退伍军人的健康。