Transcriptional mechanisms of natural killer cell responses during mouse cytomegalovirus infection
小鼠巨细胞病毒感染期间自然杀伤细胞反应的转录机制
基本信息
- 批准号:10382356
- 负责人:
- 金额:$ 45.35万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2019
- 资助国家:美国
- 起止时间:2019-05-06 至 2024-04-30
- 项目状态:已结题
- 来源:
- 关键词:ATG3 geneAcquired Immunodeficiency SyndromeActivated Natural Killer CellAdaptive Immune SystemAddressAntigensApoptosisAutophagocytosisBiological AssayBiological ProcessCell CountCell CycleCell DeathCell ProliferationCell SurvivalCellsChIP-seqClinicalClonal ExpansionCommunicable DiseasesCytomegalovirusCytomegalovirus InfectionsDNA sequencingDataDefectDominant-Negative MutationExcisionExhibitsFoundationsFrequenciesGene TargetingGenerationsGenesGenetic TranscriptionGenomicsGoalsHealthHumanImmune systemImmunizationIndividualInfectionInnate Immune SystemKnockout MiceLeadLifeLymphocyteLymphocyte FunctionMacacaMalignant NeoplasmsMeasuresMemoryMetabolismMitochondriaModelingMolecularMurid herpesvirus 1MusNatural Killer CellsNewborn InfantOrgan TransplantationPathway interactionsPatientsPatternPhaseProliferatingPropertyProtein IsoformsQuantitative Reverse Transcriptase PCRRegulatory ElementReporterReportingRepressionRiskRoleSignal TransductionSpecificityTP53 geneTestingTimeTransgenic MiceValidationViralVirusVirus DiseasesWorkcancer cellcdc Genesepidemiology studyexperimental studyimmunosuppressedin vivomitochondrial metabolismnext generationnovelnovel therapeuticsnovel vaccinesresponsetranscription factortranscriptometranscriptome sequencingvaccine strategy
项目摘要
Project Summary
Natural killer (NK) cells are lymphocytes of the immune system that can detect and kill virally infected cells.
Epidemiological studies have shown that immunosuppressed (e.g. cancer, organ transplant, AIDS) patients
and newborns display an enhanced risk for health complications associated with human cytomegalovirus
(HCMV) infection that can be life-threating. Previous work has shown that mouse cytomegalovirus (MCMV)
infection in mice can accurately model HCMV infection, and demonstrated that NK cells are critical for the
control of MCMV. Furthermore, NK cells have been shown to have properties of the adaptive immune system
such as recall responses, antigen-specificity, and clonal expansion in mice, macaques, and humans. Although
our work has made significant progress into elucidating how autophagy and mitophagy lead to the generation
of memory NK cells and the survival of proliferating lymphocytes, the upstream regulatory elements of these
fundamental biological processes remain poorly understood in lymphocytes in vivo. Our long-term goals seek
to identify the relevant transcriptional signals that induce autophagy, mitophagy, and survival of memory NK
cells following viral infection. In RNA-sequencing experiments, we have identified Trp73 (p73) as a
transcription factor selectively enriched in memory NK cells following murine cytomegalovirus (MCMV)
infection. Further experimental validation by qRT-PCR revealed that two dominant isoforms of Trp73 in mice
(TAp73 and ΔNp73) display distinct temporal expression patterns in NK cells during MCMV infection.
Importantly, the roles of p73 transcriptional isoforms in lymphocyte responses to viral infection in vivo are
unknown. Our exciting preliminary findings suggest that ΔNp73 is transiently induced in effector NK cells and is
required for clonal expansion and generation of memory NK cells. In contrast, TAp73 expression is sustained
in effector and memory NK cells and is dispensable for effector NK proliferation, but critical for the survival and
generation of memory NK cells. In Aim 1, we will determine whether TAp73 influences autophagic removal of
dysfunctional mitochondria in NK cells to promote the survival of effector NK cells as they transition to memory
cells using cutting-edge autophagy and metabolism assays. In Aim 2, we will determine whether ΔNp73 leads
to the proliferation of effector NK cells through repression of p53 to shield NK cells from apoptosis or relieve
cell cycle repression. In Aim 3, we will perform RNA and ChIP-sequencing experiments to determine the gene
targets of p73 in effector NK cells using genomic analyses. In summary, the proposed studies included in this
R01 proposal will contribute to our basic understanding of how primary cells induce mitophagy in vivo, while
also contributing to novel clinical strategies to enhance the use of adaptive NK cell responses for immunization
against infectious disease.
项目总结
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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Timothy E O'Sullivan其他文献
Timothy E O'Sullivan的其他文献
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{{ truncateString('Timothy E O'Sullivan', 18)}}的其他基金
Sex Differences in NK Cells Mediated by X-linked UTX
X连锁UTX介导的NK细胞性别差异
- 批准号:
10750843 - 财政年份:2023
- 资助金额:
$ 45.35万 - 项目类别:
Transcriptional mechanisms of natural killer cell responses during mouse cytomegalovirus infection
小鼠巨细胞病毒感染期间自然杀伤细胞反应的转录机制
- 批准号:
10596995 - 财政年份:2019
- 资助金额:
$ 45.35万 - 项目类别:
Transcriptional mechanisms of natural killer cell responses during mouse cytomegalovirus infection
小鼠巨细胞病毒感染期间自然杀伤细胞反应的转录机制
- 批准号:
9926225 - 财政年份:2019
- 资助金额:
$ 45.35万 - 项目类别:
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