Determinants of age-related regulatory T cell function during influenza A virus-induced lung injury.
甲型流感病毒引起的肺损伤期间与年龄相关的调节性 T 细胞功能的决定因素。
基本信息
- 批准号:9911293
- 负责人:
- 金额:$ 7.77万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2020
- 资助国家:美国
- 起止时间:2020-03-01 至 2021-06-30
- 项目状态:已结题
- 来源:
- 关键词:AcuteAcute Lung InjuryAdoptive TransferAdult Respiratory Distress SyndromeAffectAgeAgingAlveolarAmphiregulinAntiviral AgentsArchitectureCD4 Positive T LymphocytesCause of DeathCell CountCell LineageCell ProliferationCell physiologyCellsCessation of lifeClinicalCuesDNA MethylationDataDecitabineDevelopmentElderlyEpigenetic ProcessEpithelialEpithelial CellsEpitheliumExperimental DesignsFailureFamily memberFellowshipFlow CytometryFluorescence-Activated Cell SortingFunctional disorderGene Expression ProfilingGenetic TranscriptionGoalsGrowth FactorHomeostasisHumanImmuneImpairmentIndividualInfectionInflammationInflammation MediatorsInflammatory ResponseInfluenza A virusLeadLearningLinkLiquid substanceLongevityLungLung diseasesMeasurementMentorsMethodsMethylationModificationMolecularMolecular TargetMorbidity - disease rateMusNational Research Service AwardsNatureOlder PopulationOutcomePatientsPhenotypePhysiciansPhysiologicalPlayPneumoniaPopulationPredispositionProcessProteinsRecoveryRecovery of FunctionRegulatory T-LymphocyteResearchResolutionRisk FactorsRoleScientistSeveritiesStructure of parenchyma of lungSystemT cell differentiationT cell responseT-LymphocyteTamoxifenTechniquesTestingTherapeuticTherapeutic InterventionTissuesTrainingUnited StatesVirus Diseasesadaptive immune responseage relatedagedalveolar epitheliumbasebisulfite sequencingcareercell agecell mediated immune responsedesignepigenetic therapyepigenomeexperimental studyhuman old age (65+)insightlung injurylung repairmethylation patternmortalitymouse modelmultiple chronic conditionsnovelprogramsregenerativerepairedresponserestorationskillssmall moleculetargeted treatmenttissue injurytissue repairtranscriptometranscriptome sequencing
项目摘要
PROJECT SUMMARY/ABSTRACT
The broad objectives of this NRSA Individual Postdoctoral Fellowship are two-fold: 1) to mentor the candidate to
become a successful physician-scientist through development of the necessary skills as described in her training
plan, and 2) to uncover the mechanisms that direct regulatory T cells to orchestrate resolution of severe lung
injury throughout the lifespan. The candidate and her mentors have designed a detailed training plan tailored to
the candidate’s specific needs and goals. The proposal focuses on the study of influenza A-induced lung injury,
its clinical counterpart the acute respiratory distress syndrome (ARDS) and how they both disproportionately
affect the elderly population. Despite decades of dedicated research, there are only a few antiviral drugs available
to target the IAV and no specific therapies for ARDS. Regulatory T (Treg) cells have been shown to decrease
inflammation and promote tissue repair through the expression of growth factors, such as amphiregulin, in mouse
models of lung injury. Treg cells also increase in the lungs of patients with ARDS, suggesting that they may play
a role in the human adaptive immune response to lung injury. DNA methylation regulates Treg cell lineage
identity and functional reprogramming throughout the lifespan in response to contextual cues. Whether the age-
related loss of Treg cell pro-recovery function and increased susceptibility to IAV-induced lung injury in aged
hosts is due to changes in their transcriptome or epigenome remains unknown. The focus of this proposal is to
understand how age-acquired DNA methylation patterns lead to changes in Treg cell-specific transcriptional and
functional programs to drive a dysregulated repair response following influenza A virus infection. The long-term
hope of the proposal is to identify novel small molecule- and cell-based therapeutics to control inflammation and
promote tissue repair in our increasingly older population.
In Specific Aim 1, the candidate will determine whether the failure of aged Treg cells to resolve IAV-induced lung
injury results from cell-autonomous or microenvironmentally-driven changes in their transcriptome, epigenome
and function. In Specific Aim 2, the candidate will determine whether aging causes loss of Treg cell pro-repair
function by decreased expression of amphiregulin. We will use standard techniques to assess severity of lung
injury, heterochronic (age mis-matched) adoptive Treg cell transfer, a tamoxifen-based inducible system in mice,
flow cytometry, fluorescence-activated cell sorting, transcriptional profiling with RNA-sequencing and DNA
methylation profiling with modified reduced representation bisulfite sequencing as the primary methods to
support the experimental design of this proposal.
项目总结/摘要
这个NRSA个人博士后奖学金的广泛目标是双重的:1)指导候选人,
通过发展培训中所述的必要技能,成为一名成功的医学科学家
计划,2)揭示指导调节性T细胞协调重度肺结核缓解的机制。
整个生命周期的伤害。候选人和她的导师设计了一个详细的培训计划,
候选人的具体需求和目标。该提案的重点是研究甲型流感引起的肺损伤,
其临床对应的急性呼吸窘迫综合征(ARDS),以及它们如何不成比例地
影响老年人口。尽管进行了数十年的专门研究,但只有少数抗病毒药物可用
以IAV为目标,没有针对ARDS的特殊疗法。调节性T(Treg)细胞已被证明减少
通过表达生长因子如双调蛋白,在小鼠中调节炎症并促进组织修复
肺损伤模型。Treg细胞在ARDS患者的肺中也会增加,这表明它们可能在ARDS患者的肺中起作用。
在人类对肺损伤的适应性免疫反应中的作用。DNA甲基化调控Treg细胞谱系
在整个生命周期中,身份和功能的重新编程,以响应上下文线索。年龄是否-
老年人Treg细胞促恢复功能的相关丧失和对IAV诱导的肺损伤的易感性增加
宿主是由于其转录组或表观基因组的变化仍然未知。本提案的重点是
了解年龄获得性DNA甲基化模式如何导致Treg细胞特异性转录和
功能性程序,以驱动甲型流感病毒感染后失调的修复反应。长期
该提案的希望是确定新的基于小分子和细胞的治疗方法来控制炎症,
促进我们日益老龄化的人口的组织修复。
在具体目标1中,候选人将确定老化Treg细胞是否未能解决IAV诱导的肺
损伤由细胞自主或微环境驱动的转录组、表观基因组
和功能在具体目标2中,候选人将确定衰老是否会导致Treg细胞前修复功能丧失
通过减少双调蛋白的表达发挥作用。我们将使用标准技术来评估肺部
损伤,异时(年龄不匹配)过继性Treg细胞转移,小鼠中基于他莫昔芬的诱导系统,
流式细胞术、荧光激活细胞分选、RNA测序和DNA转录谱分析
以改良的还原亚硫酸氢盐测序作为主要方法的甲基化谱分析,
支持本提案的实验设计。
项目成果
期刊论文数量(0)
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科研奖励数量(0)
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Luisa Morales-Nebreda其他文献
Luisa Morales-Nebreda的其他文献
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{{ truncateString('Luisa Morales-Nebreda', 18)}}的其他基金
Mechanisms of regulatory T-cell mediated endothelial repair following viral pneumonia in aged hosts
老年宿主病毒性肺炎后调节性 T 细胞介导的内皮修复机制
- 批准号:
10687164 - 财政年份:2021
- 资助金额:
$ 7.77万 - 项目类别:
Mechanisms of regulatory T-cell mediated endothelial repair following viral pneumonia in aged hosts
老年宿主病毒性肺炎后调节性 T 细胞介导的内皮修复机制
- 批准号:
10283771 - 财政年份:2021
- 资助金额:
$ 7.77万 - 项目类别:
Mechanisms of regulatory T-cell mediated endothelial repair following viral pneumonia in aged hosts
老年宿主病毒性肺炎后调节性 T 细胞介导的内皮修复机制
- 批准号:
10491354 - 财政年份:2021
- 资助金额:
$ 7.77万 - 项目类别:
Determinants of age-related regulatory T cell function during influenza A virus-induced lung injury.
甲型流感病毒引起的肺损伤期间与年龄相关的调节性 T 细胞功能的决定因素。
- 批准号:
10376720 - 财政年份:2020
- 资助金额:
$ 7.77万 - 项目类别:
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