HCMV UL133/8 regulation of host cell signaling in viral latency and hematopoiesis

HCMV UL133/8 对病毒潜伏期和造血过程中宿主细胞信号传导的调节

• 批准号: 10216633
• 负责人: Felicia D Goodrum
• 金额: $ 21.99万
• 依托单位: OREGON HEALTH & SCIENCE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-08-15 至 2022-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10216633
• 关键词: Address; Affect; Antiviral Agents; Bone Marrow; CD34 gene; Cell Surface Receptors; Code; Collaborations; Complex; Complication; Cytomegalovirus; Data; Data Set; Diagnostic; Disease; Epidermal Growth Factor Receptor; Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor; Equilibrium; Event; Family; Genes; Genome; Goals; Hematopoiesis; Hematopoietic Stem Cell Transplantation; Hematopoietic stem cells; Human; In Vitro; Individual; Infection; Integration Host Factors; Life; Link; Liver; Maintenance; Mediating; MicroRNAs; Modeling; Molecular; Morbidity - disease rate; Mus; Myelosuppression; Organ; Organ Transplantation; Pathway interactions; Positioning Attribute; Protein Isoforms; Proteins; Receptor Signaling; Regulation; Risk; Role; Signal Pathway; Signal Transduction; Solid; Surface; System; Therapeutic; Thymus Gland; Transplantation; Viral; Viral Proteins; Virus; Virus Diseases; Virus Latency; Virus Replication; Work; base; blood formation; cytokine; humanized mouse; in vitro Model; in vivo; in vivo Model; insight; knock-down; mortality; novel; preservation; programs; reactivation from latency; recombinant virus; reconstitution; stem cells; trafficking; transcriptome; virus host interaction

PROJECT SUMMARY The goal of our Program is to elucidate the molecular mechanisms by which HCMV regulates host signaling in CD34+ hematopoietic progenitor cells (HPCs) for the establishment and maintenance of viral latency and reactivation, and to determine how viral dysregulation of signaling contributes to HCMV myelosuppression. HCMV remains a significant cause of morbidity and mortality via myelosuppression after solid organ and hematopoietic stem cell transplantation despite advances in diagnostics and therapeutics. HCMV latency is complex and the signaling mechanisms for establishment and maintenance of HCMV latency, as well as for reactivation of virus are poorly understood. Our program has identified a number of viral proteins and miRNAs that regulate both latency and hematopoiesis by targeting epidermal growth factor receptor (EGFR) and signaling pathways downstream of EGFR. The complexity of signaling events and approaches to comprehensively address questions on viral latency and hematopoiesis can only be achieved through a collaborative effort. Using state-of-the art in vitro models in primary, human CD34+ HPCs and in vivo models in mice humanized with bone marrow, liver and thymus, our Program will address the individual and combined roles of viral factors modulating host signaling. Our Project (Project 1) will address the roles of proteins encoded within the UL133/8 “latency locus” in modulating host signaling. We have defined roles for the four genes encoded by the UL133/8 locus in either positively or negatively regulating the maintenance of viral latency. Intriguingly, these genes opposingly regulate the trafficking and activation of EGFR. We have shown that EGFR and downstream PI3K signaling is important for the maintenance of latency and inhibitors of EGFR or PI3K stimulate reactivation and replication. We hypothesize that EGFR is a critical signaling axis targeted by UL133/8 proteins to modulate viral latency, reactivation and hematopoiesis. In Aim 1, we will use a systems approach to define the global pathways regulated by UL133/8 proteins in the context of infection in CD34+ HPCs. We will then define the significance of UL133/8-modulation of host signaling to viral latency and reactivation in Aim 2 and to hematopoiesis in Aim 3. Throughout our studies we will integrate our data sets with those of the other Projects to determine how UL133/8 interfaces with other viral proteins (US28 in Project 3; UL7 in Project 4) and viral miRNAs (Project 2) and contributes to the broader regulation of host signaling in regulating latency, reactivation and hematopoiesis. Project 5, focused on defining the hematopoieitic signaling pathways targeted by HCMV, will inform our understanding of pathways targeted by UL133/8 proteins to regulate hematopoiesis. Collectively, our projects will provide the first comprehensive and mechanistic insights into the multi-faceted regulation of host signaling for the control of HCMV latency and myelosuppression. The network of viral factors we have identified uniquely position us to define novel host and viral targets for antiviral strategies to control HCMV latency, reactivation and myelosuppression.

项目摘要 本项目的目标是阐明HCMV在细胞内调节宿主信号传导的分子机制， CD 34+造血祖细胞（HPC）用于建立和维持病毒潜伏期， 重新激活，并确定病毒信号失调如何导致HCMV骨髓抑制。 HCMV仍然是实体器官移植后通过骨髓抑制导致发病和死亡的重要原因， 造血干细胞移植，尽管诊断和治疗的进步。HCMV潜伏期是 复杂和信号机制的建立和维持HCMV潜伏期，以及 对病毒的再活化知之甚少。我们的项目已经鉴定了许多病毒蛋白和miRNAs 通过靶向表皮生长因子受体（EGFR）调节潜伏期和造血， EGFR下游的信号通路。信号事件和方法的复杂性， 全面解决病毒潜伏期和造血问题只能通过 合作的努力。在原代人CD 34 + HPC中使用最先进的体外模型，在 小鼠人源化与骨髓，肝脏和胸腺，我们的计划将解决个人和组合 病毒因子调节宿主信号传导的作用。我们的项目（项目1）将解决蛋白质的作用 编码在调制宿主信号的UL 133/8“潜伏期位点”内。我们为四个人定义了角色 由UL 133/8基因座编码的基因正向或负向调节病毒的维持， 延迟。有趣的是，这些基因相反地调节EGFR的运输和激活。我们已经表明 EGFR和下游PI 3 K信号传导对于维持EGFR的潜伏期和抑制剂是重要的， 或PI 3 K刺激再激活和复制。我们假设EGFR是一个关键的信号传导轴， UL 133/8蛋白调节病毒潜伏期、再活化和造血。在目标1中，我们将使用 一种确定在CD 34+细胞感染背景下由UL 133/8蛋白调控的全局途径的方法 HPC。然后，我们将定义UL 133/8调节宿主信号对病毒潜伏期的意义， 目的2中的再活化和目的3中的造血。在整个研究过程中，我们将把我们的数据集与 其他项目的那些，以确定UL 133/8如何与其他病毒蛋白质相互作用（项目3中的US 28; UL 7在项目4中）和病毒miRNA（项目2），并有助于更广泛地调节宿主信号传导， 调节潜伏期、再激活和造血。项目5，专注于定义造血信号传导 HCMV靶向的途径，将告知我们对UL 133/8蛋白靶向的途径的理解， 调节造血。总的来说，我们的项目将提供第一个全面和机械的见解， 进入宿主信号传导的多方面调节，用于控制HCMV潜伏期和骨髓抑制。的 我们已经确定的病毒因子网络使我们能够确定新的宿主和病毒靶点， 控制HCMV潜伏期、再激活和骨髓抑制的策略。