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.
项目摘要/摘要
NRSA个人博士后奖学金的主要目标有两个:1)指导候选人
通过培养培训中所描述的必要技能,成为一名成功的内科科学家
计划,以及2)揭示指导调节性T细胞协调重症肺的解决的机制
在整个生命周期中都受到伤害。应聘者和她的导师设计了一份详细的培训计划,以
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)以及两者如何不成比例地
影响老年人口。尽管进行了几十年的专门研究,但可用的抗病毒药物寥寥无几
以IAV为靶点,ARDS没有特定的治疗方法。调节性T(Treg)细胞已显示出减少
通过表达生长因子,如两性调节素,促进小鼠的炎症和组织修复
肺损伤模型。ARDS患者肺部的Treg细胞也增加,这表明它们可能在
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,身份和功能重新编程以响应上下文线索。无论年龄-
老年人Treg细胞促恢复功能丧失与IAV致肺损伤易感性增加
寄主是由于它们的转录组或表观基因组的变化而未知。这项提议的重点是
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
在甲型流感病毒感染后驱动失调修复反应的功能程序。长期的
该提案的希望是找到新的基于小分子和细胞的疗法来控制炎症和
在我们日益老龄化的人口中促进组织修复。
在特定的目标1中,候选人将确定老化的Treg细胞是否无法分解IAV诱导的肺
损伤是由细胞自主或微环境驱动的转录组、表观基因组的变化造成的
和功能。在特定的目标2中,候选人将确定衰老是否导致Treg细胞修复前期的丢失
通过减少双调节蛋白的表达而发挥作用。我们将使用标准技术来评估肺部的严重程度
损伤,异慢性(年龄不匹配)过继Treg细胞转移,基于他莫昔芬的小鼠诱导系统,
流式细胞术、荧光激活细胞分选、RNA测序转录图谱和DNA
以改良还原代表性亚硫酸氢盐测序为主要方法的甲基化图谱分析
支持这一提议的实验设计。
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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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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