Scientific Retreats 2013

September 4, 2013

Session Topic: The Circadian Cycle in NIAMS-Relevant Tissues

Introduction

It has long been known that animals are subject to an approximate 24 hour circadian cycle. Over the years, scientists have discovered that there is a discrete portion of the brain (the suprachiasmatic nucleus, or SCN) that is considered the central circadian clock. The SCN appears to play a significant role in growth control and cancer, and the core clock genes that regulate a body’s sleep-wake and feeding cycles have been implicated in obesity, type 2 diabetes, aging, and Alzheimer’s disease. It functions by the systematic production and degradation of core clock proteins, a process that begins anew approximately every 24 hours. Core clock proteins have since been discovered in peripheral tissues, including muscle, liver, and kidneys, and non-clock, tissue-specific proteins have demonstrated cycling behavior.

There are some notable publications showing the importance of circadian regulation in NIAMS’ mission areas. In rheumatic and autoimmune diseases, the functions of macrophages and T cells are known to be influenced by sleep and circadian rhythm regulators. In the skin, recent work demonstrated that circadian clock genes are expressed in keratinocytes and their activities influence keratinocyte proliferation and stem cell behavior and distribution. In the case of skeletal muscle, mice lacking core clock genes run significantly less and display abnormal expression of genes important in muscle structure and function. Drugs that treat type 2 diabetes interfere with a nuclear receptor (PPARγ) with a circadian expression pattern, possibly causing disruptions in osteogenesis. However, these fields are still in their infancy, as indicated by the record of publications. Several seminal papers were published in the early 1990s that lead to a tripling of the number of annual publications in the field, and shortly thereafter NIAMS-related publications began to appear. Still, the numbers are notably low. Only 73 of the 1756 publications in 2012 are in NIAMS-specific fields. This is particularly surprising given that one of the key peripheral clock tissues is muscle.

Circadian dysfunction can lead to human disease. In addition, disease, poor lifestyle habits (including sleep and exercise), and drugs (notably corticosteroids) can lead to alterations in the circadian cycle. Understanding the role of the circadian cycle may have broad translational implications. The observation that cells cycle over a 24-hour period suggests that timing of eating, sleeping, exercise, and medicine delivery is significant and should be taken into consideration by physicians and scientists involved in health care and research studies.

Goals of the Session

The purpose of the session is to inform NIAMS staff about this emerging area of investigation and to discover research opportunities relevant to diseases and tissues within the mission of NIAMS.

Key Questions

  • What are the high priority basic research questions that are likely to lead to significant advances?
  • What role do clock mechanisms play in regulating complex biological processes in the tissues of relevance to NIAMS?
  • How does this basic process influence and/or cause disease?
  • What are the current opportunities for translating knowledge of basic mechanisms into new therapies and/or more effective treatment regimens?
  • What is the best formula for building multidisciplinary teams to promote integration of knowledge and to explore new experimental modalities?

References

    Cutolo M. Chronobiology and the treatment of rheumatoid arthritis. Curr Opin Rheumatol.2012 May;24(3):312-8. doi: 10.1097/BOR.0b013e3283521c78. PMID: 22410544

    Geyfman M, Andersen B. Clock genes, hair growth and aging. Aging. 2010 Mar 31;2(3):122-8. PMID: 20375466

    Kawai M, Rosen CJ. PPARγ: a circadian transcription factor in adipogenesis and osteogenesis. Nat Rev Endocrinol. 2010 Nov;6(11):629-36. doi: 10.1038/nrendo.2010.155. Epub 2010 Sep 7. PMID: 20820194

    Lange T, Dimitrov S, Born J. Effects of sleep and circadian rhythm on the human immune system. Ann N Y Acad Sci. 2010 Apr;1193:48-59. doi: 10.1111/j.1749-6632.2009.05300.x. PMID: 20398008