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

基本信息

批准号：
10491281
负责人：
Shaon Sengupta
金额：
$ 61.91万
依托单位：
CHILDREN'S HOSP OF PHILADELPHIA
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：
2021-09-20 至 2026-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10491281
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 injury and repair lung injury lung regeneration lung repair mortality novel novel therapeutic intervention regenerative biology repaired tool transcriptomics virology

项目摘要

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.

项目概要我们的总体目标是确定急性肺损伤昼夜节律调节的机制我们发表的研究表明，昼夜节律赋予一天中的特定时间。黎明时感染甲型流感病毒 (IAV) 的小鼠的存活率是正常小鼠的 3 倍。虽然我们无法在临床上控制接触 IAV 的时间，但这些数据表明事实上，改变宿主的昼夜节律健康可能会影响结果。在小鼠中，通过删除核心时钟基因 Bmal1，加剧了 IAV 的死亡率。我们机械工作的相关性来自于我们对英国生物样本库的分析，该分析揭示了昼夜节律是流感相关住院的独立危险因素。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，通常疫苗和抗病毒药物的功效均有限。这通过探索一个新的目标——昼夜节律作为结果的决定因素来满足该领域的需求。自上次提交以来，我们生成了令人兴奋的初步数据，显示了 IAV 的中断。 AT2 时钟与 (a) 更严重的急性死亡率、免疫病理学和坏死性凋亡有关，以及 (b) 体内恢复延迟和类器官检测再生不良我们的总体目标是： (1) 检验 AT2 时钟的破坏导致促炎症状态的假设 IAV 感染进一步加剧基线，从而使坏死性凋亡恶化。 (2) 检验生物钟通过 Wnt- 促进肺再生的假设通过 Axin2+ 上皮微环境对细胞周期进行响应性调节。我们的方法采用在成年期诱导的组织特异性昼夜节律敲除模型，昼夜节律采样在整个 24 小时内，昼夜节律紊乱的其他遗传/环境模型和工具形成肺再生我还聚集了一支优秀的合作者团队和根据昼夜节律定制的生物学。拥有细胞死亡、昼夜节律生物信息学、肺再生和病毒学专业知识的顾问。这些机制是调节宿主昼夜节律以进行治疗的关键下一步虽然我们使用流感作为我们的模型，但由此揭示的原理应该可以推广到肺部的其他病毒性疾病。