NHLBI Workshop

Circadian-Coupled Cellular Function and Disease in Heart, Lung, and Blood

Executive Summary

Purpose

The National Heart, Lung, and Blood Institute in partnership with the National Institute on Aging, and the National Cancer Institute convened a Working Group to discuss circadian-coupled function in peripheral cardiovascular, metabolic, lung, and hematopoient tissues on September 20, 2007, in Baltimore, Maryland. The panel included investigators with expertise ranging from epidemiology to genetics, genomics, physiology, and cell biology. The working group assessed the role of circadian-coupled dysregulation in peripheral tissue pathophysiology, and the importance of clock-related proteins as “sensors” that translates chemical signals from the cellular environment into specific genomic responses within peripheral organs such as heart, lung, blood, vasculature, liver, pancreas, fat, and muscle.

At an organismal level, circadian-related proteins are critical to most forms of life. The circadian genes are highly conserved evolutionarily and their expression ubiquitous. Several lines of emerging evidence link circadian-coupled proteins to both the temporal organization of cellular function, and to inducible transcriptional networks responsive to stimuli such as hypoxia, light, temperature, nutrients, catecholamines, anabolic hormones, and toxic molecules. Recent studies in which circadian transcription networks were disrupted at the genomic, proteomic, cellular or physiological levels implicate abnormalities in circadian-coupled cellular function with myocardial infarction, arrhythmogenicity, hypoxic injury, congestive heart failure, skeletal muscle weakness, coagulopathy, metabolic syndrome, glucose and lipid dysregulation. These findings suggest that recent advances in understanding circadian-coupled function in peripheral tissues have significant implications for our understanding of cardiovascular and metabolic homeostasis, and whether environmental or genetic disruption of these cell autonomous molecular mechanisms contribute to the development of cardiometabolic syndrome and disorders of the lung and blood.

Major Recommendations

1. Incorporate the concept of circadian genes serving as environmental sensors and transcriptional regulators into existing and future genomic resources, especially those involved in genomic applications, in genome wide association phenotype planning, in plans for proteome and transcriptome network analyses, and developing tissue bank resources. Resources based on cross-sectional snapshots of gene expression and function under-utilize existing knowledge and capabilities to understand pathogenic mechanisms.
   
2. Incorporate circadian variation in cell and tissue function into experimental designs analyzing cardiovascular and metabolic phenotypes, especially parameters such as glucose/insulin, triglyceride, fatty acid, inflammatory cytokine production, coagulation, blood pressure, myocardial injury-response and fluid dynamics.
   
3. Elucidate circadian pathways through which the role of clock protein mediates cellular metabolism using targeted mutants with tissue specific or conditional deletions including heart, blood vessel, liver, brown and white adipose, skeletal and smooth muscle, hematopoietic tissues, pancreas, and neuroendocrine cells.
   
4. Investigate the mechanistic relationship of processes regulated by circadian clocks within cell types relevant to cardiovascular physiology and pathophysiology, and metabolic homeostasis (e.g. cardiomyocytes, endothelial cells, vascular smooth muscle cells, fibroblasts, skeletal myocytes, hepatocytes, adipocytes, pancreatic cells).
   
5. Investigate the relationship of abnormalities in peripheral circadian clocks to cardiopulmonary and hematopoietic disease states and the progression of disease.
   
6. Elucidate the role of circadian mechanisms in post-transcriptional regulatory events using proteomics and assays of cellular function.
   
7. Investigate the role of circadian mechanisms as a sensor of the cellular environment and mediator of the genomic response. As a transcriptional regulator, clock influences cellular pathways known to accelerate the development of cardiometabolic syndrome development (e.g. altered caloric intake, physical activity, sleep duration). As such, the circadian clock is a potential target for gene-environment interaction studies addressing cardiometabolic syndrome development in humans.

Workshop Members

Co-Chairs

• Joseph Bass, M.D., Ph.D., Northwestern University Feinberg School of Medicine, Evanston, IL
• Martin E. Young, D.Phil., Baylor College of Medicine, Houston, TX
  

Members

• Marina Antoch, Ph.D., Roswell Park Cancer Institute, Buffalo, NY
• Eric L. Bittman, Ph.D., University of Massachusetts, Amherst, MA
• Molly S. Bray, Ph.D., Baylor College of Medicine, Houston, TX
• Jian M. Ding, Ph.D., East Carolina University, Greenville, NC
• Karyn A. Esser, Ph.D., University of Kentucky, Lexington, KY
• Martha U. Gillette, Ph.D., University of Illinois at Urbana-Champaign, Urbana, IL
• Jeffrey Gimble, M.D., Ph.D., Pennington Biomedical Research Center, Baton Rouge, LA
• Carla Green, Ph.D., University of Virginia, Charlottesville, VA
• Paul E. Hardin, Ph.D., Texas A&M University, College Station, TX
• John Hogenesch, Ph.D., University of Pennsylvania, Philadelphia, PA
• R. Daniel Rudic, Ph.D., Medical College of Georgia, Augusta, GA
• Jared P. Rutter, Ph.D., University of Utah, Salt Lake City, UT
• Joseph S. Takahashi, Ph.D., Northwestern University, Evanston, IL
• Fred Turek, Ph.D., Northwestern University, Evanston, IL
• Martin Zatz, Ph.D., M.D., Editor, Journal of Biological Rhythms, Bethesda, MD

NIH Staff

• Al Golden, M.P.H., Division of Lung Diseases, NHLBI, Bethesda, MD
• Jennie Larkin, Ph.D., Division of Lung Diseases, NHLBI, Bethesda, MD
• Michael Twery, Ph.D., Division of Lung Diseases, NHLBI, Bethesda, MD
• David C. Klein, Ph.D., Section on Neuroendocrinology, NICHD, Bethesda, MD
• Andy A. Monjan, Ph.D., M.P.H., Neuroscience & Neuropsychology of Aging Program, NIA, Bethesda, MD
  

March 2008