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Epigenetic modifiers of regulatory T cell function following viral pneumonia

病毒性肺炎后调节性 T 细胞功能的表观遗传修饰

基本信息

批准号：
10209664
负责人：
Benjamin David Singer
金额：
$ 6.29万
依托单位：
NORTHWESTERN UNIVERSITY AT CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-04-15 至 2021-09-14
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10209664
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 Gene Expression Profile Generations Genetic Transcription Genomic Instability Global Change Growth Factor Human Hypermethylation Impairment Inflammation Influenza Influenza A virus Injury Intervention Link Longevity Lung Lung Inflammation Mediating Morbidity - disease rate Mus Pathway interactions Patients Phase Phenotype Physiological Premature aging syndrome Process Publishing Recovery Recovery of Function Regulatory T-Lymphocyte Resolution Respiratory Tract Infections Risk Role Survivors System T-Lymphocyte Subsets 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 novel therapeutics older patient patient population predictive signature premature programs repair function repaired

项目摘要

PROJECT SUMMARY/ABSTRACT 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/摘要流感和 COVID-19 对老年患者产生了不成比例的影响。甲型流感病毒和 SARS-CoV-2 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），抗病毒疗法的疗效有限，ICU 干预措施仍然是支持性的。老年病毒感染者—— 诱发的 ARDS 恢复缓慢，导致 ICU 住院时间延长，这往往预示着病情的加重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年轻消退和修复途径激活的原因将促进康复，延长 ICU 老年幸存者的健康寿命。 CD4+Foxp3+ 调节性 T (Treg) 细胞协调实验性急性肺损伤后的解决和修复。这些细胞出现在肺泡中 ARDS 患者的空间并显示小鼠预测的表观遗传和转录特征实验。与年轻小鼠相比，老年小鼠的 Treg 细胞在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，以及来自衰老小鼠和基因组不稳定导致的早产小鼠的 Treg 细胞与年轻小鼠的 Treg 细胞相比，衰老显示出显着的 DNA 高甲基化特征。脱氧核糖核酸甲基转移酶 (DNMT) 活性和 DNMT 接头 Uhrf1 介导 Treg 中的 DNA 甲基化特征细胞，但这些因素是否会在正常和基因组不稳定期间诱导 Treg 细胞 DNA 高甲基化？诱导衰老会损害老年宿主病毒性肺炎后 Treg 细胞的促恢复功能未知。我们假设 DNMT 活性和 Uhrf1 在 Treg 细胞中诱导 DNA 高甲基化老年宿主严重病毒性肺炎后，衰老会损害 Treg 细胞的修复功能。我们建议三个具体目标，使用尖端的小鼠系统、转化人类病例对照研究和新颖的测试我们假设的计算平台。目标 1 将揭示 DNMT 活动或 Uhrf1 是否必要诱导衰老过程中 Treg 细胞 DNA 高甲基化。在目标 2 中，我们将确定是否存在瞬时丢失流感恢复期间 Treg 细胞中的 DNMT 活性或 Uhrf1 可恢复转录程序并双调蛋白依赖性功能在年轻时存在，但随着衰老而消失。目标 3 将阐明关联特定重症患者的年龄、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。我们的提案将建立与药物靶向相关的因果证据详细生理读数的机制。阐明这些因果关系将有助于开发亲针对严重流感、COVID-19 和老年患者 ARDS 的其他原因的恢复治疗方法。