Project 4: Epigenetic modifiers of regulatory T cell function following viral pneumonia

项目 4：病毒性肺炎后调节性 T 细胞功能的表观遗传修饰

• 批准号: 10269677
• 负责人: Benjamin David Singer
• 金额: $ 50.5万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-15 至 2026-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10269677
• 关键词: 2019-nCoV; AREG gene; Acute; Acute Lung Injury; Adoptive Transfer; Adult Respiratory Distress Syndrome; Age; Aging; Alveolar; Amphiregulin; Antiviral Therapy; COVID-19; COVID-19 pandemic; Case-Control Studies; Cell physiology; Cells; DNA; DNA Methylation; DNA Modification Methylases; DNA methyltransferase inhibition; Data; Development; Drug Targeting; Elderly; Epigenetic Process; Epithelial; Exhibits; FOXP3 gene; Functional disorder; Funding Opportunities; Gene Expression Profile; Generations; Genetic Transcription; Genomic Instability; Global Change; Growth Factor; Human; Hypermethylation; Impairment; Inflammation; Influenza; Influenza A virus; Injury; Instruction; Intervention; Link; Longevity; Lung; Mediating; Mus; Paper; Pathway interactions; Patients; Phase; Phenotype; Physiological; Premature aging syndrome; Process; Publishing; Recovery; Recovery of Function; Regulatory T-Lymphocyte; Research; Resolution; Respiratory Tract Infections; Risk; Role; Survivors; System; Testing; Therapeutic; Time; Viral; Viral Pneumonia; Virus; Wild Type Mouse; Youth; age related; aged; cell age; computational platform; computerized tools; experience; experimental study; healthspan; influenza epidemic; lung injury; lung repair; methylation pattern; mortality; mouse model; multiple chronic conditions; normal aging; novel; older patient; predictive signature; premature; programs; repair function; repaired

PROJECT SUMMARY/ABSTRACT – ESI-LED PROJECT 4 Influenza and COVID-19 exert a disproportionate impact on older patients. Influenza A virus and SARS-CoV-2 cause severe viral pneumonia, injuring the lung to induce the acute respiratory distress syndrome (ARDS), for which anti-viral therapies have limited efficacy and ICU interventions remain supportive. Older patients with virus- induced ARDS experience slow recovery, leading to protracted ICU stays that often herald the compounding multi-morbidity and functional limitation observed among elderly survivors of severe respiratory infection. We reason that activation of youthful resolution and repair pathways in older patients with severe viral pneumonia will potentiate recovery to extend the health-span of older ICU survivors. CD4+Foxp3+ regulatory T (Treg) cells coordinate resolution and repair following experimental acute lung injury. These cells appear in the alveolar spaces of patients with ARDS and display epigenetic and transcriptional signatures predicted by murine experiments. In contrast with young mice, Treg cells from aged mice exhibit a cell-autonomous impairment in pro-recovery function following influenza and fail to upregulate the epithelial growth factor amphiregulin. Mechanistically, epigenetic alterations in DNA methylation signatures represent a hallmark aging process that modulates Treg cell function, and Treg cells from aged mice and mice with genomic instability-induced premature aging display a striking DNA hypermethylation signature compared with Treg cells from young mice. DNA methyltransferase (DNMT) activity and the DNMT adapter Uhrf1 mediate DNA methylation signatures in Treg cells, but whether these factors induce DNA hypermethylation in Treg cells during normal and genomic instability- induced aging to impair Treg cell pro-recovery function following viral pneumonia in aged hosts remains unknown. We hypothesize that DNMT activity and Uhrf1 induce DNA hypermethylation in Treg cells during aging to impair Treg cell reparative function following severe viral pneumonia in older hosts. We propose three Specific Aims, which use cutting-edge murine systems, a translational human case-control study, and novel computational platforms to test our hypothesis. Aim 1 will reveal whether DNMT activity or Uhrf1 is necessary to induce DNA hypermethylation in Treg cells during aging. In Aim 2 we will determine whether transient loss of DNMT activity or Uhrf1 in Treg cells during recovery from influenza restores the transcriptional programs and amphiregulin-dependent function present in youth but lost with aging. Aim 3 will elucidate the association between age, alveolar Treg cell DNA methylation signature, and 30-day mortality in selected patients with severe influenza A or COVID-19 viral pneumonia. Our proposal will establish causal evidence linking drug-targetable mechanisms to detailed physiologic readouts. Elucidating these causal links will enable the development of pro- recovery therapeutic approaches for severe influenza, COVID-19, and other causes of ARDS in older patients.

项目概要/摘要- ESI-LED项目4 流感和COVID-19对老年患者的影响不成比例。甲型流感病毒与SARS冠状病毒 引起严重的病毒性肺炎，损伤肺部诱发急性呼吸窘迫综合征（ARDS）， 抗病毒治疗的疗效有限，ICU干预仍是支持性的。感染病毒的老年患者- 诱导的ARDS经历缓慢的恢复，导致长期的ICU停留，通常预示着复合 在严重呼吸道感染的老年幸存者中观察到多种发病率和功能限制。我们 老年重症病毒性肺炎患者中年轻消退和修复途径激活的原因 将加强恢复，以延长老年ICU幸存者的健康寿命。CD 4 + Foxp 3+调节性T（Treg）细胞 实验性急性肺损伤后的协调解决和修复。这些细胞出现在肺泡 空间的ARDS患者，并显示表观遗传和转录签名预测的小鼠 实验与年轻小鼠相比，来自老年小鼠的Treg细胞在生长过程中表现出细胞自主性损伤。 流感后的促恢复功能，并且不能上调上皮生长因子双调蛋白。 从机制上讲，DNA甲基化特征的表观遗传改变代表了一个标志性的衰老过程， 调节Treg细胞功能，以及来自老年小鼠和具有基因组不稳定性诱导的早产小鼠的Treg细胞 与年轻小鼠的Treg细胞相比，衰老小鼠的Treg细胞显示出惊人的DNA超甲基化特征。DNA 甲基转移酶（DNMT）活性和DNMT衔接子Uhrf 1介导Treg中的DNA甲基化特征 细胞，但这些因素是否在正常和基因组不稳定期间诱导Treg细胞中的DNA超甲基化- 在老年宿主病毒性肺炎后，诱导衰老损害Treg细胞促恢复功能仍然存在 未知我们假设DNMT活性和Uhrf 1在Treg细胞中诱导DNA超甲基化， 老年宿主中严重病毒性肺炎后衰老损害Treg细胞修复功能。我们提出 三个特定目标，使用尖端的鼠系统、转化的人类病例对照研究和新颖的 来测试我们的假设目的1将揭示DNMT活性或Uhrf 1是否是必需的 在衰老过程中诱导Treg细胞的DNA超甲基化。在目标2中，我们将确定 从流感恢复期间Treg细胞中的DNMT活性或Uhrf 1恢复转录程序， 双调蛋白依赖性功能存在于年轻时，但随着年龄的增长而丧失。目标3将阐明 年龄、肺泡Treg细胞DNA甲基化特征和30天死亡率之间的关系。 甲型流感或COVID-19病毒性肺炎。我们的建议将建立因果证据， 详细的生理读数。阐明这些因果关系将有助于发展亲， 老年患者中严重流感、COVID-19和其他原因导致的ARDS的恢复治疗方法。