Mechanistic evaluation of the role of circadian rhythms in acute lung injury and subsequent recovery

昼夜节律在急性肺损伤及随后恢复中作用的机制评估

• 批准号: 10299011
• 负责人: Shaon Sengupta
• 金额: $ 53.06万
• 依托单位: CHILDREN'S HOSP OF PHILADELPHIA
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-20 至 2026-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10299011
• 关键词: ARNTL gene; Acute; Acute Lung Injury; Address; Adult; Affect; Alveolar; Antiviral Agents; Bioinformatics; Biological Assay; Cell Cycle Regulation; Cell Death; Cells; Circadian Dysregulation; Circadian Rhythms; Clinical; Custom; Data; Ensure; Epithelial; Evaluation; Exposure to; Genes; Genetic; Goals; Health; Histologic; Hospitalization; Immune; Impairment; Infection; Inflammatory; Influenza; Influenza A virus; Injury; Jet Lag Syndrome; Knock-out; Ligands; Lung; Modeling; Mus; Myelogenous; Natural regeneration; Organoids; Other Genetics; Outcome; Pathway interactions; Pattern; Phase; Phenotype; Physiologic pulse; Publishing; Recovery; Regenerative capacity; Reporter; Risk Factors; Role; Sampling; Sentinel; Signal Transduction; Testing; Therapeutic; Time; Tissues; Vaccines; Viral; Viral Load result; Virus Diseases; Virus Replication; Work; biobank; circadian; circadian pacemaker; circadian regulation; experimental study; immunopathology; in vivo; influenza infection; inhibitor/antagonist; injury and repair; lung injury; lung regeneration; lung repair; mortality; novel; novel therapeutic intervention; regenerative biology; repaired; tool; transcriptomics; virology

Project Summary Our overall aim is to define the mechanisms underlying the circadian regulation of acute lung injury and subsequent recovery. Our published work shows that circadian rhythms confer a time of day specific protection from Influenza A Virus (IAV) infection. Mice infected at dawn had 3-fold better survival than those infected at dusk. While, we cannot clinically control the time of exposure to IAV, these data suggest that altering the circadian health of the host could affect outcomes. In fact, disrupting circadian rhythms genetically in mice, by deleting the core clock gene, Bmal1, worsened mortality from IAV. Further proof of the translational relevance of our mechanistic work came from our analyses of the UK biobank which revealed that disrupted circadian rhythms was an independent risk factor for Influenza related hospitalization. Severe influenza infection is characterized by extensive immunopathology and dysplastic lung repair and regeneration, often independent of viral burden. Both vaccines and anti-viral agents have limited efficacy. The current proposal addresses this need in the field by exploring a novel target—circadian rhythms as determinant of outcomes in IAV. Since the last submission, we have generated exciting preliminary data that shows that disruption of the AT2 clock is associated with (a) worse acute mortality, immunopathology and necroptosis and (b) delayed recovery in vivo and poor regeneration on organoid assays. Our overall goals are to: (1) Test the hypothesis that the disruption of the AT2 clock leads to a pro-inflammatory state at baseline that is further exacerbated by IAV infection, thereby worsening necroptosis. (2) To test the hypothesis that the circadian clock contributes to lung regeneration through Wnt- responsive regulation of the cell cycle via the Axin2+ epithelial niche. Our approach employs tissue specific circadian knock-out models induced in adulthood, circadian sampling throughout 24hrs, other genetic/environmental models of circadian disruption and tools form lung regenerative biology, customized to the circadian context. I have also gathered an outstanding team of collaborators and consultants with expertise in cell death, circadian bioinformatics, lung regeneration and virology. Elucidating these mechanisms is the critical next step towards modulating the host circadian rhythms for therapeutic purposes. While, we use influenza as our model, the principles uncovered thus, should be generalizable to other viral conditions of the lung.

项目摘要 我们的总体目的是定义昼夜节律急性肺损伤调节的机制 和随后的恢复。我们发表的工作表明，昼夜节律会议是一天中的时间 免受流感病毒（IAV）感染的保护。黎明时感染的小鼠比那些的小鼠生存更好3倍 在黄昏中感染。虽然我们无法从临床上控制暴露于IAV的时间，但这些数据表明 改变宿主的昼夜节律可能会影响结果。实际上，在遗传上破坏昼夜节律的节奏 在小鼠中，通过删除核心时钟基因BMAL1，IAV的死亡率恶化了。翻译的进一步证明 我们的机械工作的相关性来自我们对英国生物库的分析，该库揭示了这一中断 昼夜节律是与流感相关住院的独立危险因素。严重影响 感染的特征是广泛的免疫病理学和发育不良的肺修复和再生，通常 独立于病毒负担。疫苗和抗病毒药物的效率有限。当前的建议 通过探索一个新颖的目标来满足现场的需求 - 确定结果的circadian节奏 IAV。自上次提交以来，我们已经生成了令人兴奋的初步数据 AT2时钟与（a）急性死亡率，免疫病理学和坏死性较差以及（b）有关 体内恢复的延迟，器官分析的再生不良。我们的总体目标是： （1）检验以下假设：AT2时钟的破坏导致促炎状态 IAV感染进一步加剧了基线，从而后悔坏死。 （2）检验昼夜节律时钟通过Wnt-有助于肺部再生的假设 通过AXIN2+上皮小众对细胞周期的反应调节。 我们的方法员工组织特定的昼夜节律敲除模型 在整个24小时内，昼夜节律破坏和工具的其他遗传/环境模型形成肺部再生 生物学，根据昼夜节律定制。我还聚集了一个杰出的合作者团队， 具有细胞死亡专业知识的顾问，昼夜节律生物信息学，肺部再生和病毒学。阐明 这些机制是调节宿主昼夜节律治疗的关键下一步 目的。虽然我们将影响力作为模型，但发现的原则应推广到 肺的其他病毒状况。