权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

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.

项目摘要/摘要流感和新冠肺炎对老年患者的影响不成比例。甲型流感病毒与SARS-CoV-2 导致严重的病毒性肺炎，损伤肺部导致急性呼吸窘迫综合征(ARDS)，哪些抗病毒疗法的疗效有限，ICU干预仍然是支持性的。感染病毒的老年患者- 诱导性ARDS恢复缓慢，导致ICU停留时间延长，往往预示着并发症的发生严重呼吸道感染老年存活者的多发病和功能受限观察。我们老年重症病毒性肺炎患者年轻人的分解和修复途径被激活的原因将加强康复，以延长老年ICU幸存者的健康跨度。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内。 ARDS患者的间隙，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细胞在促进流感后的康复功能，但未能上调上皮生长因子两性调节素。从机制上讲，DNA甲基化特征的表观遗传学改变代表了一种标志性的衰老过程调节Treg细胞的功能，以及衰老小鼠和基因组不稳定诱导的早产小鼠的Treg细胞与年轻小鼠的Treg细胞相比，衰老显示出显著的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的情况下诱导Treg细胞的DNA超甲基化- 诱导衰老损害老年宿主病毒性肺炎后Treg细胞的预恢复功能未知。我们假设DNMT活性和uhrf1在Treg细胞中诱导DNA高甲基化衰老损害老年宿主严重病毒性肺炎后Treg细胞的修复功能。我们建议三个特定的目标，使用尖端的小鼠系统，一项翻译的人类病例对照研究，以及验证我们假设的计算平台。目标1将揭示DNMT活动或uhrf1是否是必需的在衰老过程中诱导Treg细胞DNA高甲基化。在目标2中，我们将确定是否存在瞬时损失流感康复期间Treg细胞中的DNMT活性或uhrf1恢复转录程序和双调节蛋白依赖功能存在于年轻人中，但随着年龄的增长而丧失。目标3将阐明两者之间的联系年龄、肺泡树突状细胞DNA甲基化特征与重症患者30天死亡率之间的关系甲型流感或新冠肺炎病毒性肺炎。我们的提案将建立因果证据，将药物靶向详细的生理读数的机制。阐明这些因果联系将有助于发展亲缘关系。老年患者中重症流感、新冠肺炎和其他原因引起的ARDS的康复治疗方法。