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: 9911293
• 负责人: Luisa Morales-Nebreda
• 金额: $ 7.77万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 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: https://reporter.nih.gov/project-details/9911293
• 关键词: Acute; Acute Lung Injury; Adoptive Transfer; Adult Respiratory Distress Syndrome; Affect; Age; Aging; Alveolar; Amphiregulin; Antiviral Agents; Architecture; CD4 Positive T Lymphocytes; Cause of Death; Cell Count; Cell Lineage; Cell Proliferation; Cell physiology; Cells; Cessation of life; Clinical; Cues; DNA Methylation; Data; Decitabine; Development; Elderly; Epigenetic Process; Epithelial; Epithelial Cells; Epithelium; Experimental Designs; Failure; Family member; Fellowship; Flow Cytometry; Fluorescence-Activated Cell Sorting; Functional disorder; Gene Expression Profiling; Genetic Transcription; Goals; Growth Factor; Homeostasis; Human; Immune; Impairment; Individual; Infection; Inflammation; Inflammation Mediators; Inflammatory Response; Influenza A virus; Lead; Learning; Link; Liquid substance; Longevity; Lung; Lung diseases; Measurement; Mentors; Methods; Methylation; Modification; Molecular; Molecular Target; Morbidity - disease rate; Mus; National Research Service Awards; Nature; Older Population; Outcome; Patients; Phenotype; Physicians; Physiological; Play; Pneumonia; Population; Predisposition; Process; Proteins; Recovery; Recovery of Function; Regulatory T-Lymphocyte; Research; Resolution; Risk Factors; Role; Scientist; Severities; Structure of parenchyma of lung; System; T cell differentiation; T cell response; T-Lymphocyte; Tamoxifen; Techniques; Testing; Therapeutic; Therapeutic Intervention; Tissues; Training; United States; Virus Diseases; adaptive immune response; age related; aged; alveolar epithelium; base; bisulfite sequencing; career; cell age; cell mediated immune response; design; epigenetic therapy; epigenome; experimental study; human old age (65+); insight; lung injury; lung repair; methylation pattern; mortality; mouse model; multiple chronic conditions; novel; programs; regenerative; repaired; response; restoration; skills; small molecule; targeted treatment; tissue injury; tissue repair; transcriptome; transcriptome sequencing

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。