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

基本信息

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
项目类别：
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

项目摘要

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.

项目摘要/摘要 - ESI-LED项目4 流感和Covid-19对老年患者产生了不成比例的影响。流感病毒和SARS-COV-2 引起严重的病毒性肺炎，伤害肺部以诱导急性呼吸窘迫综合征（ARDS），因为哪些抗病毒疗法的效率有限，ICU干预措施仍然支持。老年病毒患者诱导的ARDS经历缓慢的恢复，导致旷日持久的ICU持续存在，通常预示着复合在严重呼吸道感染的较旧生存中观察到的多物种和功能限制。我们重度严重病毒性肺炎患者的青年分辨率和修复途径激活的原因将有潜在的恢复以扩展较旧的ICU存活的健康状况。 CD4+ FOXP3+调节t（Treg）细胞实验性急性肺损伤后协调分辨率和修复。这些细胞出现在肺泡中 ARDS患者的空间和显示鼠预测的表观遗传和转录特征实验。与年轻小鼠的小鼠相反，来自老年小鼠的Treg细胞在攻击功能遵循影响力和未能更新上皮生长因子两极分裂蛋白。从机械上讲，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来自老年小鼠和小鼠的Treg细胞功能，具有基因组不稳定性诱导的过早的Treg细胞与年轻小鼠的Treg细胞相比，衰老显示出打击DNA高甲基化特征。脱氧核糖核酸甲基转移酶（DNMT）活性和DNMT适配器UHRF1介导Treg中的DNA甲基化特征细胞，但是这些因素是否在正常和基因组不稳定性期间诱导Treg细胞中的DNA高甲基化 - 诱导的衰老会损害病毒性肺炎后，损害treg细胞恢复功能未知。我们假设DNMT活性和UHRF1在Treg细胞中影响DNA高甲基化老年宿主严重病毒性肺炎后，老化会损害Treg细胞的修复功能。我们建议三个使用尖端鼠系统的特定目的，一项翻译的人案例对照和新颖计算平台来检验我们的假设。 AIM 1将揭示DNMT活动还是UHRF1是必要的在衰老过程中诱导Treg细胞中的DNA高甲基化。在AIM 2中，我们将确定是否暂时丢失从影响力恢复期间，Treg细胞中的DNMT活性或UHRF1恢复了转录程序和青年时期具有依赖性蛋白的功能，但由于衰老而迷失。 AIM 3将阐明协会在年龄之间，肺泡Treg细胞DNA甲基化特征和重度患者的30天死亡率 rangationza a或covid-19病毒肺炎。我们的建议将建立可因果关系的因果证据详细的生理读数机制。阐明这些因果关系将使促进严重影响力，COVID-19的恢复疗法方法和其他老年患者ARDS的其他原因。