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.
John Hogenesch, PhD - University of Pennsylvania
Avrum E. Spira, MD, MSc - Boston University
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