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：
Luisa Morales-Nebreda
金额：
$ 7.77万
依托单位：
NORTHWESTERN UNIVERSITY AT CHICAGO
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：
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

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.

项目概要/摘要该 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描述的必要技能，成为一名成功的医师科学家计划，2) 揭示指导调节性 T 细胞协调解决严重肺部疾病的机制候选人和她的导师设计了一份针对整个生命周期的伤害的详细培训计划。候选人的具体需求和目标该提案侧重于甲型流感引起的肺损伤的研究，其临床对应物急性呼吸窘迫综合征 (ARDS) 以及它们如何不成比例地尽管进行了数十年的专门研究，但可用的抗病毒药物仍然很少。以 IAV 为靶点，但没有针对 ARDS 的特定疗法显示可减少调节性 T (Treg) 细胞。通过在小鼠体内表达生长因子（例如双调蛋白）促进炎症和组织修复肺损伤模型中，ARDS 患者肺部中的 Treg 细胞也有所增加，表明它们可能发挥作用。 DNA 甲基化在人类对肺损伤的适应性免疫反应中发挥作用，调节 Treg 细胞谱系。整个生命周期中根据背景线索进行身份和功能重新编程。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的转录组或表观基因组的变化仍然未知，该提案的重点是。年龄了解获得性 DNA 甲基化模式如何导致 Treg 细胞特异性转录和长期的甲型流感病毒感染后驱动失调的修复反应的功能程序。该提案的希望是确定新的基于小分子和细胞的疗法来控制炎症和促进日益老龄化的人口的组织修复。在具体目标 1 中，考生将确定老化的 Treg 细胞是否无法解决 IAV 诱导的肺部问题损伤是由细胞自主或微环境驱动的转录组、表观基因组变化引起的在具体目标 2 中，考生将确定衰老是否会导致 Treg 细胞修复功能的丧失。通过双调蛋白表达减少来评估功能我们将使用标准技术来评估肺部的严重程度。损伤、异时性（年龄不匹配）过继性 Treg 细胞移植、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 转录分析以改良简化代表性亚硫酸氢盐测序为主要方法的甲基化分析支持本提案的实验设计。