Mechanisms of MCMV reactivation in immunodeficient transplant recipients
Mechanisms of MCMV reactivation in immunodeficient transplant recipients
批准号:
9295934
负责人:
Michael M Abecassis
金额:
$44.3万
依托单位国家:
美国
项目类别:
财政年份:
2014
资助国家:
美国
项目状态:
已结题
起止时间:
2014-07-01 至 2019-06-30
关键词:
AcuteAllogenicAlpha CellAntiviral AgentsB-LymphocytesBindingBiological ModelsBone MarrowBone Marrow CellsCell Differentiation processCell modelCellsChromatinCollaborationsCytomegalovirusDataDendritic CellsDevelopmentDiseaseEarly PromotersEpigenetic ProcessGene ExpressionGenetic TranscriptionGenomeGoalsHematopoieticHematopoietic stem cellsHerpesviridaeHistonesHumanImmediate-Early GenesImmunocompromised HostIn VitroInfectionInflammation MediatorsInflammatoryInflammatory ResponseInterleukin-18Interleukin-6KidneyKidney TransplantationLIF geneLatent VirusLeadLysineLyticMediatingMediator of activation proteinMethylationModelingMolecularMorbidity - disease rateMurid herpesvirus 1MusNatural Killer CellsOrgan TransplantationOrganismPhenotypePlasmaRegulationRoleSignal PathwaySignal TransductionSignal Transduction PathwaySimplexvirusSiteSpecies SpecificityStudy modelsSystemT-LymphocyteTNFSF5 geneTestingTherapeutic InterventionTranscriptional ActivationTransplant RecipientsTransplantationUnited States National Institutes of HealthViralViral GenesViral GenomeVirusVirus Latencydemethylationextracellularhistone demethylasehistone methylationhistone methyltransferasein vitro Modelin vivoinhibitor/antagonistlatent infectionlytic replicationmonocytemortalityneutralizing antibodynovelnovel strategiesnovel therapeuticspathogenpreventprogramspublic health relevancereactivation from latencyresponsetherapeutic targettranscription factorviral DNA
中文摘要
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英文摘要
DESCRIPTION (provided by applicant): Reactivation of latent human cytomegalovirus (HCMV) remains a significant cause of morbidity and mortality in transplant recipients, despite the use of antiviral drugs. Therefore, new approaches are required to reduce the complications from this pathogen. Due to the species specificity of HCMV, we have developed a novel transplant model using the highly related murine CMV (MCMV) as a model to study CMV latency and reactivation in the context of organ transplantation. In this model, MCMV latently infected kidneys are transplanted into immunocompromised NOD.Cg-PrkdcscidIL2rgtm1Wjl/Szj (NSG) mice, which are deficient in T, B, and NK cells. Transplantation of latently infected kidneys into NSG recipients results in reactivation of latent virus in the donor kidney, which disseminates systemically. Reactivation of HCMV is associated with various inflammatory insults. Our preliminary data shows that IL-6, soluble CD40L, IL-18, and LIF are elevated in the plasma of recipient mice with timing consistent with a causal role in reactivation. IL-6 induces reactivation of HCMV in hematopoietic cell models. The central hypothesis of this proposal is that the inflammatory response elicited by the transplanted kidney results in the release of mediators in the recipient mice. The resulting signaling cascade stimulates epigenetic reprogramming of latent viral genomes, transcriptional reactivation of viral immediate early (IE) gene expression, and in immunocompromised recipients, re-entry of latent virus into the lytic replication program. To test this hypothesis, in Aim 1 we will investigate the requirement for candidate factors identified in our preliminary studies, and their downstream signaling intermediates, in inducing reactivation in the NSG model. Our previous studies and those of others show that lytic viral gene expression is repressed in CMV latency due to heterochromatinization of viral genomes. In addition, we have shown that transplant-induced reactivation of MCMV immediate early gene expression is associated with epigenetic reprogramming. Previous studies by our collaborator, Dr. Thomas Kristie, have identified epigenetic inhibitors that suppress reactivation of latent herpes simplex virus. In Aim 2 we will investigate these promising therapeutic interventions for their ability to prevent reactivation of latent MCMV in the NSG model. Finally, in Aim 3 we will investigate new in vitro models for MCMV latency and differentiation-induced reactivation in murine hematopoietic progenitor cells. This complementary in vitro model would be exceptionally useful for defining molecular mechanisms in the absence of the complexity of the organism. Upon completion, our studies will have identified signaling pathways that lead to epigenetic reprogramming of viral chromatin to reactivate latent MCMV in response to transplantation and potential therapeutic targets.
期刊论文(3)
专著(0)
科研奖励(0)
会议论文
DOI:
10.18103/imr.v3i3.385
发表时间:
2017-03
期刊:
Internal medicine review (Washington, D.C. : Online)
影响因子:
--
作者:
[Liu XF, Hummel M, Abecassis M]
通讯作者:
Abecassis M
DOI:
10.26717/bjstr.2019.14.002617
发表时间:
2019-02
期刊:
Biomedical journal of scientific & technical research
影响因子:
--
作者:
[Longhui Qiu;Z. Zhang]
通讯作者:
Longhui Qiu;Z. Zhang
Integrating Mechanistic Insights from Diverse Models to Prevent CMV Reactivation following Transplantation
-
批准号:8934950
-
项目类别:
-
资助金额:$230.59万
-
财政年份:2015
-
负责人:Michael M Abecassis
-
依托单位:
Integrating Mechanistic Insights from Diverse Models to Prevent CMV Reactivation following Transplantation
-
批准号:9303245
-
项目类别:
-
资助金额:$231.72万
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财政年份:2015
-
负责人:Michael M Abecassis
-
依托单位:
Integrating Mechanistic Insights from Diverse Models to Prevent CMV Reactivation following Transplantation
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批准号:9099718
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项目类别:
-
资助金额:$230.82万
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财政年份:2015
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负责人:Michael M Abecassis
-
依托单位:
Role of innate immunity and injury in transplant-induced reactivation of MCMV
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批准号:8227285
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项目类别:
-
资助金额:$19.31万
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财政年份:2012
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负责人:Michael M Abecassis
-
依托单位:
Role of innate immunity and injury in transplant-induced reactivation of MCMV
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批准号:8435351
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项目类别:
-
资助金额:$23.18万
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财政年份:2012
-
负责人:Michael M Abecassis
-
依托单位:
Biomarker Profiles for Prediction and Diagnosis of Post-Transplant Renal Injury
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批准号:7804107
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项目类别:
-
资助金额:$10.0万
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财政年份:2010
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负责人:Michael M Abecassis
-
依托单位:
Role of Toll-like Receptors in Transplant-Induced Reactivation of Cytomegalovirus
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批准号:8086118
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项目类别:
-
资助金额:$3.58万
-
财政年份:2010
-
负责人:Michael M Abecassis
-
依托单位:
Living Donor Liver Transplant - Predictive Models for Long-Term Health Outcomes
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批准号:8014622
-
项目类别:
-
资助金额:$30.9万
-
财政年份:2010
-
负责人:Michael M Abecassis
-
依托单位:
Role of Toll-like Receptors in Transplant-Induced Reactivation of Cytomegalovirus
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批准号:7739139
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项目类别:
-
资助金额:$22.88万
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财政年份:2009
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负责人:Michael M Abecassis
-
依托单位:
Role of Toll-like Receptors in Transplant-Induced Reactivation of Cytomegalovirus
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批准号:7906627
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项目类别:
-
资助金额:$18.87万
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财政年份:2009
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负责人:Michael M Abecassis
-
依托单位:
Proteogenomics for Organ Transplantation: Prediction, Diagnosis, Intervention
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批准号:8131698
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项目类别:
-
资助金额:$210.81万
-
财政年份:2009
-
负责人:Michael M Abecassis
-
依托单位:
Proteogenomics for Organ Transplantation: Prediction, Diagnosis, Intervention
-
批准号:7934564
-
项目类别:
-
资助金额:$216.52万
-
财政年份:2009
-
负责人:Michael M Abecassis
-
依托单位:
Proteogenomics for Organ Transplantation: Prediction, Diagnosis, Intervention
-
批准号:8527681
-
项目类别:
-
资助金额:$199.09万
-
财政年份:2009
-
负责人:Michael M Abecassis
-
依托单位:
Proteogenomics for Organ Transplantation: Prediction, Diagnosis, Intervention
-
批准号:7737645
-
项目类别:
-
资助金额:$221.46万
-
财政年份:2009
-
负责人:Michael M Abecassis
-
依托单位:
Proteogenomics for Organ Transplantation: Prediction, Diagnosis, Intervention
-
批准号:8319542
-
项目类别:
-
资助金额:$201.15万
-
财政年份:2009
-
负责人:Michael M Abecassis
-
依托单位:
Transplant Surgery Scientist Training Program
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批准号:8692420
-
项目类别:
-
资助金额:$12.73万
-
财政年份:2007
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负责人:Michael M Abecassis
-
依托单位:
Transplant Surgery Scientist Training Program
-
批准号:8707650
-
项目类别:
-
资助金额:$5.65万
-
财政年份:2007
-
负责人:Michael M Abecassis
-
依托单位:
Transplant Surgery Scientist Training Program
-
批准号:9272490
-
项目类别:
-
资助金额:$8.87万
-
财政年份:2007
-
负责人:Michael M Abecassis
-
依托单位:
Transplant Surgery Scientist Training Program
-
批准号:7455061
-
项目类别:
-
资助金额:$11.29万
-
财政年份:2007
-
负责人:Michael M Abecassis
-
依托单位:
Transplant Surgery Scientist Training Program
-
批准号:8890560
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项目类别:
-
资助金额:$6.12万
-
财政年份:2007
-
负责人:Michael M Abecassis
-
依托单位:
海外基金