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

HCMV UL133/8 在病毒潜伏期和再激活过程中对宿主细胞信号传导的调节

基本信息

批准号：
10327948
负责人：
Felicia D Goodrum
金额：
$ 39.96万
依托单位：
OREGON HEALTH & SCIENCE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-08-15 至 2027-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10327948
关键词：
Address Amino Acids CD34 gene Cells Collaborations Complex Cytomegalovirus DNA Damage Data Defective Viruses Dependence Diagnostic Epidermal Growth Factor Receptor Event Genome Goals Growth Hematopoiesis Hematopoietic Hematopoietic Stem Cell Transplantation Hematopoietic stem cells Human In Vitro Individual Infection Integration Host Factors Interferons Ligands MEKs Maintenance Maps MicroRNAs Molecular Morbidity - disease rate Organ Outcome PI3K/AKT Pathway interactions Play Positioning Attribute Proteins Proto-Oncogene Proteins c-akt Reactive Inhibition Receptor Signaling Regulation Reporting Role STAT1 gene Signal Pathway Signal Transduction Solid Switching Complex Therapeutic Undifferentiated Viral Viral Proteins Virus Virus Latency Virus Replication attenuation collaborative approach humanized mouse in vitro Model in vivo Model insight knock-down mortality mouse model mutant novel novel virus programs reactivation from latency recombinant virus response scaffold trafficking transcription factor ubiquitin-specific protease virus host interaction

项目摘要

SUMMARY – PROJECT 1 The goal of our Program is to elucidate molecular mechanisms by which HCMV regulates host signaling in CD34+ hematopoietic progenitor cells (HPCs) for the establishment and maintenance of viral latency and reactivation from latency. HCMV remains a significant cause of morbidity and mortality 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 latency and reactivation by targeting host pathways. 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 human CD34+ HPCs and in vivo models in humanized mice, our Program will address the individual and combined roles of viral factors modulating host signaling. Our Project (Project 1) will address the roles of the latency determinant UL138 in modulating host signaling pathways regulated through its interactions with ubiquitin specific protease (USP) complexes that regulate STAT1 and AKT signaling. We have defined interactions between UL138 and WDR48 and WDR20, which serve as a scaffold to activate USP1, USP12, and USP46. We hypothesize that UL138-host interactions with WDR/USP complexes coordinate signaling to regulate the switch between latency and reactivation. In Aim 1, we will determine how UL138 impacts WDR48/USP complexes and function. We will map the amino acids in UL138 that are required for interaction with WDR48/USP complexes and generate recombinant viruses defective for these interactions. In Aim 2, we will determine how UL138-WDR48/USP interactions impact latency and reactivation and the role of UL138 in activating STAT1 and AKT using recombinant viruses and knockdown of host factors. Aim 3 will expand our understanding of the regulation of STAT1 and AKT signaling by analyzing a greater network of regulators, proteins and miRNAs, that regulate STAT1 and AKT signaling to drive outcomes of infection in collaboration with Project 2 and Project 3. 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. The network of viral and host factors we have identified uniquely position us to define novel host and viral targets for antiviral strategies to control HCMV latency or reactivation. Our collaborative approach will provide unparalleled insights into the complex multi-factorial mechanisms regulating HCMV latency and reactivation.

摘要 - 项目1 我们程序的目的是阐明HCMV调节CD34+中宿主信号的分子机制造血祖细胞（HPC），用于建立和维持病毒潜伏期和重新激活来自延迟。 HCMV仍然是固体器官和造血后发病率和死亡率的重要原因干细胞移植目的地诊断和治疗的进展。 HCMV潜伏期很复杂，并且建立和维持HCMV潜伏期的信号传导机制以及病毒的重新激活知之甚少。我们的计划已经确定了许多调节潜伏期的病毒蛋白和miRNA 和通过靶向主机途径重新激活。信号事件和方法的复杂性总体解决病毒潜伏期和造血的问题只能通过协作努力。在人CD34+ HPC中使用最先进的体外模型和体内模型人源化小鼠，我们的程序将解决调节宿主的病毒因素的个体和联合角色信号。我们的项目（项目1）将解决延迟确定器UL138在调节主机中的作用信号通路通过其与泛素特异性蛋白酶（USP）复合物的相互作用来调节调节STAT1和AKT信号。我们定义了UL138和WDR48和WDR20之间的相互作用，它是激活USP1，USP12和USP46的脚手架。我们假设UL138-HOST相互作用使用WDR/USP复合物协调信号传导，以调节潜伏期和重新激活之间的切换。目标 1，我们将确定UL138如何影响WDR48/USP复合物和功能。我们将在与WDR48/USP复合物相互作用并产生重组病毒所需的UL138 对于这些相互作用。在AIM 2中，我们将确定UL138-WDR48/USP相互作用如何影响潜伏期和重新激活和UL138在使用重组病毒和敲低的激活STAT1和AKT中的作用宿主因素。 AIM 3将通过分析A来扩展我们对STAT1和AKT信号调节的理解更大的调节器，蛋白质和miRNA网络，该网络调节STAT1和AKT信号以驱动结果与项目2和项目3合作感染。总的来说，我们的项目将提供第一个对主机信号的多方面调节的全面和机械洞察，以控制 HCMV延迟。我们已经确定的病毒和宿主因素网络唯一地定位了我们定义新型宿主以及控制HCMV潜伏期或重新激活的抗病毒策略的病毒靶标。我们的协作方法将对调节HCMV潜伏期的复杂多因素机制提供无与伦比的见解重新激活。