Acute and chronic lung diseases are leading causes of morbidity and mortality worldwide. Substantial scientific gaps exist in understanding mechanisms of lung disease pathogenesis, and in managing and treating pulmonary conditions, including asthma, COPD, IPF, pulmonary hypertension, acute lung injury, and sleep apnea. This workshop was designed to assess a new generation of circadian genomic findings, and identify opportunities to apply these discoveries to advance our understanding of lung disease pathophysiology and ability to diagnose and treat lung diseases.
The circadian clock is a highly conserved genomic system present in the brain and virtually every peripheral tissue, responsible for producing 24-hour rhythms in gene expression and coordinating the temporal organization of molecular pathways, cells, and tissues. Over the past decade, a new generation of discoveries has uncovered a mechanistic interface between the circadian clock and fundamental cellular processes including oxidative stress, cell metabolism, immune and inflammatory responses, epigenetic modification, hypoxia/hyperoxia response pathways, endoplasmic reticular stress, autophagy, and regulation of the stem cell environment. While each of these processes has been implicated in lung pathophysiology, the lung transcriptome exhibits robust circadian oscillations, and lung diseases such as asthma and COPD exhibit time-of-day specific exacerbations, the significance of circadian regulation in the pathogenesis and management of lung disease is not well-understood.
The charge to the working group was to discuss and identify research opportunities related to (1) elucidating mechanisms of lung disease, injury, and susceptibility closely-coupled to circadian clock regulation (2) evaluating current directions in lung disease research and strategies to determine whether impaired circadian rhythm exacerbates or ameliorates disease, (3) determining the relationship of circadian mechanisms to the repair and restoration of damaged lung tissues, (4) identifying opportunities to leverage advances in circadian biology to improve the diagnosis, management, and treatment of lung diseases.
The working group’s research recommendations have been organized into three overarching frameworks (1) circadian-coupled mechanisms of lung disease pathogenesis (2) circadian-based phenotypes of lung disease risk and stratification, and (3) circadian-based interventions for lung disease.
- Delineate circadian-coupled mechanisms involved in the pathogenesis and progression of lung disease.
Recent discoveries have uncovered a molecular interface between the circadian clock and fundamental cellular pathways and functions in peripheral tissues. The lung transcriptome is highly time-of-day (i.e. circadian) dependent, however, the significance of circadian regulation in the lung is not well understood. Research is needed to determine whether dysregulation of the circadian clock, and clock-controlled pathways contributes to lung disease pathophysiology, and whether modification of these pathways is an effective therapeutic strategy to ameliorate disease severity or progression.
- The group prioritized investigating circadian mechanisms involved in oxidative stress, cell senescence, and acute/chronic immune pathophysiology in the etiology, progression and management of lung diseases, including asthma, COPD, sleep apnea, pulmonary fibrosis, and pulmonary hypertension.
- The lung is a complex organ, and research is needed to delineate the role of specific lung cell types in circadian mediated lung function.
- Delineate circadian mechanisms underlying abnormalities in ventilatory control and breathing, including sleep apnea.
- Examine whether time-of-day (i.e. circadian phase) and clock-coupled pathways mediate the effects of environmental exposures (e.g. cigarette smoke, allergens, virus/bacteria, endotoxin, hypoxia/hyperoxia, sleep apnea) on lung pathophysiology and injury.
- Identify circadian-based phenotypes that stratify/predict pulmonary disease risk, severity, and subtype.
Circadian clock genes oscillate in the lung and form transcription factors that regulate 10-20% of gene expression in a time-of-day dependent manner. Research is needed to leverage this biology to identify circadian-based biomarkers and molecular phenotypes associated with lung disease.
- Identify circadian-based phenotypes that predict lung disease risk, disease severity and/or subtype, and inform underlying pathophysiology. Phenotypes/biomarkers may include clock gene polymorphisms and/or circadian-related gene expression profiles, taking into account the timing and frequency of sample collection, method of collection (exhaled breath condensate, sputum, nasal brushing, bronchoscopy), and tissue/cell type to be analyzed.
- Identify opportunities for circadian-based interventions to improve the management and treatment of lung disease.
Recent studies reveal that effectiveness of drug treatments for hypertension and cancer vary by when (i.e. time-of-day/circadian phase) medications are delivered. Furthermore, recent analyses show that 50% of the top 100 selling pharmaceutical agents target clock-controlled molecular pathways. These findings point to provocative questions regarding the opportunities to translate circadian genomics discovery to circadian-based strategies to improve the management and treatment of lung diseases.
- Identify circadian-based strategies, such as delivering medications at particular times of day (i.e. circadian phase), which improve the effectiveness of existing treatments for lung disease, and minimize adverse side-effects.
- Develop therapeutics (e.g. small molecules) or other strategies that target circadian genes and clock-controlled pathways to re-set rhythms in lung associated with pathophysiology and disease.
- Identify circadian biomarkers associated with lung pathophysiology/disease that can be used to personalize treatment of lung disease by predicting medication response, identifying which medications to use, or developing individualized drug delivery schedules.
Working Group Members
John Hogenesch, PhD - University of Pennsylvania
Avrum E. Spira, MD, MSc - Boston University
Working Group Speakers and Discussants
Joseph Bass, MD, PhD - Northwestern University
Alejandro Commelas, MD - University of Iowa
Phyllis A. Dennery, MD - The Children’s Hospital of Philadelphia
Tobias Eckle, MD, PhD - University of Colorado
Karyn A. Esser, PhD - University of Kentucky
Garret A. FitzGerald, MD - University of Pennsylvania
Jeffrey Haspel, MD, PhD - Harvard Medical School
Naftali Kaminski, MD - Yale School of Medicine
Atul Malhotra, MD - UCSD
Jerome S. Menet, PhD - Texas A&M University
Irfan Rahman, PhD - University of Rochester
R. Daniel Rudic, PhD - Georgia Regents University
Michael T. Sellix, PhD - University of Rochester
Stephen Shea, PhD - Oregon Health and Science University
Adam C. Silver, PhD - University of Hartford
Michael H. Smolensky, PhD - University of Texas
Rubin Tuder, MD - University of Colorado
Sally E. Wenzel, MD - University of Pittsburgh
Martin Young, PhD - University of Alabama
Marc Charette, PhD – NHLBI, Division of Cardiovascular Sciences
Zorina S. Galis, PhD – NHLBI, Division of Cardiovascular Sciences
James P. Kiley, PhD – NHLBI, Division of Lung Diseases
Aaron D. Laposky, PhD – NHLBI, Division of Lung Diseases
Michael Twery, PhD – NHLBI, Division of Lung Diseases