Human Cytomegalovirus dysregulation of host hematopoietic progenitor cell signaling pathways to modulate latency, reactivation, and hematopoiesis during transplantation

人类巨细胞病毒对宿主造血祖细胞信号通路的失调，以调节移植过程中的潜伏期、重新激活和造血作用

• 批准号: 9753907
• 负责人: JAY A NELSON
• 金额: $ 182.08万
• 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/9753907
• 关键词: Address; Affect; Bioinformatics; Biometry; CD34 gene; Cell model; Cells; Clinical; Complex; Cytomegalovirus; Data; Databases; Epidermal Growth Factor Receptor; Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor; Equilibrium; Event; Gene Mutation; Genes; Genomics; Goals; Hematopoiesis; Hematopoietic Stem Cell Transplantation; Hematopoietic stem cells; Human; In Vitro; Individual; Infection; Liver; Maintenance; MicroRNAs; Modeling; Molecular; Morbidity - disease rate; Mus; Myelogenous; Myelosuppression; Organ; Organ Transplantation; Pathway interactions; Patients; Preparation; Process; Production; Proteins; Receptor Signaling; Regulation; Research Project Grants; Role; Sampling; Services; Signal Pathway; Signal Transduction; Solid; Source; Testing; Thymus Gland; Time; Transplant Recipients; Transplantation; Viral; Viral Genes; Virus; Virus Latency; Visceral; cytokine; data management; hematopoietic differentiation; human fetal bone marrow; humanized mouse; in vivo; mortality; mouse model; multiple omics; novel; programs; reactivation from latency; virus host interaction

OVERALL PROJECT SUMMARY/ABSTRACT The goal of our program is to elucidate the molecular mechanisms of HCMV regulation of host signaling in the establishment and maintenance of viral latency and reactivation, and determine how viral dysregulation of CD34+ Hematopoietic Progenitor Cells (HPCs) signaling may compromise hematopoiesis. HCMV remains a significant cause of morbidity and mortality after Solid Organ Transplantation (SOT) and Hematopoietic Stem Cell Transplantation (HSCT), and myelosuppression is a common clinical manifestation of HCMV infection in these patients. HPCs represent a critical reservoir of latent HCMV in the transplant recipient, thereby providing a source of virus for dissemination to visceral organs. Preliminary data from our group using an in vitro CD34+ HPC model and mice engrafted with human fetal bone marrow, liver and thymus (huBLT mice) have shown that HCMV regulation of Epidermal Growth Factor Receptor (EGFR) and downstream signaling in CD34+ HPCs is essential for viral latency and reactivation as well as hematopoiesis. Our group has shown that multiple HCMV genes expressed in latently infected CD34+ HPCs including the UL133-138 locus, US28, UL7 and HCMV miRNAs target multiple signaling pathways activated by EGFR to control viral latency/reactivation and hematopoiesis. We hypothesize that HCMV fine tunes the activity of EGFR and its downstream pathways to balance states of viral latency and reactivation. We also hypothesize that HCMV fine tunes signaling and cytokine secretion to impact hematopoiesis. Further, we propose that this regulation meets antagonistic needs to promote dissemination but limit broad hematopoietic differentiation to control reactivation. This program project will test each of these hypotheses using the in vitro CD34+ HPC model in combination with the huBLT mouse model and samples from SOT and HSCT patients. The complexity of signaling events and approaches to comprehensively address questions on viral latency and hematopoiesis can only be achieved through a collaborative effort under a PPG mechanism. Therefore we propose five highly integrated research projects (Project 1: UL133/8 regulation of host cell signaling in viral latency and hematopoiesis; Project 2: HCMV miRNA regulation of host cell signaling in viral latency and hematopoiesis; Project 3: HCMV US28 regulation of host cell signaling in viral latency and hematopoiesis; Project 4: HCMV UL7 regulation of host cell signaling in viral latency and hematopoiesis; Project 5: HCMV regulation of host cell signaling and cytokines in myelosuppression), two scientific cores (Humanized Mouse Core; Genomics, Biostatistics and Bioinformatics Core) to service these projects, and an Administrative Core to oversee and coordinate the entire program.

总体项目概要/摘要 我们项目的目标是阐明 HCMV 调节宿主信号传导的分子机制 病毒潜伏期和重新激活的建立和维持，并确定病毒的失调如何 CD34+ 造血祖细胞 (HPC) 信号传导可能会损害造血功能。 HCMV 仍然是 实体器官移植（SOT）和造血干细胞移植后发病率和死亡率的重要原因 细胞移植（HSCT）和骨髓抑制是 HCMV 感染的常见临床表现 这些病人。 HPC 是移植受者体内潜在 HCMV 的关键储存库，从而提供 传播至内脏器官的病毒来源。 我们小组使用体外 CD34+ HPC 模型和植入人胎骨的小鼠获得的初步数据 骨髓、肝脏和胸腺（huBLT 小鼠）显示 HCMV 对表皮生长因子的调节 CD34+ HPC 中的受体 (EGFR) 和下游信号传导对于病毒潜伏和重新激活至关重要，因为 还有造血功能。我们的小组已经表明，潜伏感染的 CD34+ 中表达了多个 HCMV 基因 包括 UL133-138 位点、US28、UL7 和 HCMV miRNA 的 HPC 靶向多个信号通路 由 EGFR 激活以控制病毒潜伏期/重新激活和造血。我们假设 HCMV 很好 调节 EGFR 及其下游通路的活性，以平衡病毒潜伏和重新激活的状态。我们 还假设 HCMV 微调信号传导和细胞因子分泌以影响造血。此外，我们 提出该规定满足了促进传播但限制广泛造血的对抗性需求 分化来控制再激活。 该计划项目将结合使用体外 CD34+ HPC 模型来测试这些假设 使用 huBLT 小鼠模型以及来自 SOT 和 HSCT 患者的样本。信号事件的复杂性 全面解决病毒潜伏期和造血问题的方法只能是 通过PPG机制下的协作努力来实现。因此我们提出了五种高度集成的 研究项目（项目1：病毒潜伏期和造血过程中宿主细胞信号传导的UL133/8调节； 项目2：HCMV miRNA对病毒潜伏期和造血过程中宿主细胞信号传导的调控；项目3：HCMV US28 对病毒潜伏期和造血过程中宿主细胞信号传导的调节；项目4：HCMV UL7调节 病毒潜伏期和造血过程中的宿主细胞信号转导；项目5：HCMV对宿主细胞信号传导的调节 骨髓抑制中的细胞因子），两个科学核心（人源化小鼠核心；基因组学、生物统计学和 生物信息学核心）为这些项目提供服务，以及管理核心来监督和协调整个项目 程序。