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
基本信息
- 批准号:9753907
- 负责人:
- 金额:$ 182.08万
- 依托单位:
- 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 2022-07-31
- 项目状态:已结题
- 来源:
- 关键词:AddressAffectBioinformaticsBiometryCD34 geneCell modelCellsClinicalComplexCytomegalovirusDataDatabasesEpidermal Growth Factor ReceptorEpidermal Growth Factor Receptor Tyrosine Kinase InhibitorEquilibriumEventGene MutationGenesGenomicsGoalsHematopoiesisHematopoietic Stem Cell TransplantationHematopoietic stem cellsHumanIn VitroIndividualInfectionLiverMaintenanceMicroRNAsModelingMolecularMorbidity - disease rateMusMyelogenousMyelosuppressionOrganOrgan TransplantationPathway interactionsPatientsPreparationProcessProductionProteinsReceptor SignalingRegulationResearch Project GrantsRoleSamplingServicesSignal PathwaySignal TransductionSolidSourceTestingThymus GlandTimeTransplant RecipientsTransplantationViralViral GenesVirusVirus LatencyVisceralcytokinedata managementhematopoietic differentiationhuman fetal bone marrowhumanized mousein vivomortalitymouse modelmultiple omicsnovelprogramsreactivation from latencyvirus host interaction
项目摘要
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.
整体项目摘要/摘要
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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JAY A NELSON其他文献
JAY A NELSON的其他文献
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{{ truncateString('JAY A NELSON', 18)}}的其他基金
Human Cytomegalovirus dysregulation of host hematopoietic progenitor cell signaling pathways to modulate latency and reactivation
人类巨细胞病毒对宿主造血祖细胞信号通路的失调调节潜伏期和重新激活
- 批准号:
10327944 - 财政年份:2017
- 资助金额:
$ 182.08万 - 项目类别:
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 - 财政年份:2017
- 资助金额:
$ 182.08万 - 项目类别:
HCMV miRNA regulation of host cell signaling in viral latency and hematopoiesis
HCMV miRNA 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:
10216634 - 财政年份:2017
- 资助金额:
$ 182.08万 - 项目类别:
HCMV miRNA regulation of host cell signaling in viral latency and hematopoiesis
HCMV miRNA 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:
9980281 - 财政年份:2017
- 资助金额:
$ 182.08万 - 项目类别:
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:
9980274 - 财政年份:2017
- 资助金额:
$ 182.08万 - 项目类别:
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:
9208433 - 财政年份:2017
- 资助金额:
$ 182.08万 - 项目类别:
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