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: 10216629
• 负责人: JAY A NELSON
• 金额: $ 180.81万
• 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/10216629
• 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 dissemination; 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.

总体项目摘要/摘要 我们程序的目的是阐明宿主信号调节宿主信号的分子机制 建立和维持病毒潜伏期和重新激活，并确定病毒失调的方式 CD34+造血祖细胞（HPC）信号传导可能会损害造血。 HCMV仍然是一个 固体器官移植（SOT）和造血茎后发病和死亡率的重大原因 细胞移植（HSCT）和骨髓抑制是HCMV感染的常见临床表现 这些患者。 HPCS代表移植接收者中潜在HCMV的关键储层，从而提供 传播内脏器官的病毒来源。 我们组的初步数据使用体外CD34+ HPC模型和植入人胎骨的小鼠 骨髓，肝脏和胸腺（Hublt小鼠）表明，表皮生长因子的HCMV调节 CD34+ HPC中的受体（EGFR）和下游信号传导对于病毒潜伏期和重新激活至关重要 以及造血。我们的小组表明，在潜在感染的CD34+中表达了多个HCMV基因 HPC包括UL133-138基因座，US28，UL7和HCMV miRNA目标多个信号通路 由EGFR激活以控制病毒潜伏/重新激活和造血。我们假设HCMV很好 调整EGFR及其下游途径的活性，以平衡病毒潜伏期和重新激活状态。我们 还假设HCMV微调信号传导和撞击造血的细胞因子分泌。此外，我们 建议该法规满足促进传播但限制广泛造血的拮抗需要 分化以控制重新激活。 该程序项目将使用体外CD34+ HPC模型组合测试这些假设 使用Hublt小鼠模型和来自SOT和HSCT患者的样品。信号事件的复杂性 以及全面解决有关病毒潜伏期和造血的问题的方法，只能是 通过PPG机制的协作努力实现。因此，我们提出了五个高度整合的 研究项目（项目1：UL133/8病毒潜伏期和造血中宿主细胞信号的调节； 项目2：病毒潜伏期和造血中宿主细胞信号传导的HCMV miRNA调节；项目3：HCMV US28病毒潜伏期和造血中宿主细胞信号的调节；项目4：HCMV UL7的规定 病毒潜伏期和造血的宿主细胞信号传导；项目5：HCMV调节宿主细胞信号传导和 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，以及一个管理核心，以监督和协调整个项目 程序。