Control of Human Cytomegalovirus

人类巨细胞病毒的控制

• 批准号: 8598021
• 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/8598021
• 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）： 人巨细胞病毒（HCMV）持续感染超过一半的退伍军人人口，并导致疾病和死亡，在相当大的一部分人口，尽管在抗病毒治疗的进展。需要新的策略来减轻由HCMV感染引起的疾病负担。HCMV MIE增强子/启动子充当病毒的裂解开关。它被打开以启动病毒复制周期，并在病毒潜伏期期间关闭。关于HCMV MIE裂解开关控制方式的知识有可能为开发新的治疗方法以预防病毒复制提供信息。我们的实验室是在确定控制机制的调查的最前沿。这些早期的结果使我们假设，在急性生产性感染和再激活感染中，控制HCMV MIE裂解开关激活的转录调控层次和顺式调控代码在细胞类型之间存在差异。人多能N-Tera 2细胞（NT 2）的初步数据表明，通过不同线索和多种调节途径的组合最能实现HCMV MIE再激活。需要进一步阐明所涉及的线索和调控途径，并且需要在树突状单核细胞（D/M）前体中的HCMV潜伏期模型中评估这些发现。这些结果将首次阐明控制HCMV MIE裂解开关再激活的分子机制。在急性感染的允许成纤维细胞的初步数据揭示了一种新的监管机制，其功能在感染后立即早期阶段，并与另一种尚未确定的监管机制一起发挥作用。填补知识的空白，这种调控机制的作用，机制和目的，预计将改变范式，解释如何MIE增强子管理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裂解开关激活中的不同作用：1）急性感染的容许成纤维细胞、内皮细胞、上皮细胞和骨髓细胞; 2）静止感染的NT 2和D/M前体细胞。研究计划将利用创新的方法和工具。使用先进的技术和最先进的方法使得在生物进口的不同细胞环境中以无与伦比的深度详细描述这些途径成为可能。一个优秀的研究环境和一个有成就的研究团队，与中央显微镜研究，蛋白质组学和流式细胞仪设施在爱荷华州大学的接口很好，是执行这一计划的理想选择。发现病毒调控机制，可以中断，以停止HCMV基因表达和复制之前，它可能提供了一个新的方向，在抗病毒药物的开发，以改善退伍军人的健康。