NIAMS Extramural Scientific Planning Retreat 2013 April 4, 2013 Session 2: The Circadian Cycle in NIAMS-Relevant Tissues

The Circadian Cycle in NIAMS- Relevant Tissues Goal: – Inform NIAMS staff about this emerging area of investigation and explore research opportunities relevant to diseases and tissues within the mission of NIAMS Guest Speakers: – Dr. Fred Turek, Northwestern University – Dr. Karyn Esser, University of Kentucky

The Circadian Cycle in NIAMS-Relevant Tissues—Discussion Questions What role do clock mechanisms play in regulating complex biological processes? How does this basic process influence and/or cause disease? What are the high priority basic research questions? 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?

The Circadian Cycle—History of Circadian Publications

Diabetes Cancer Cardiovascular Disease (CVD) Provided for comparison Number of Publications Identified in Web of Science Search, Keyword = Circadian

The Circadian Cycle—Examples of NIAMS Grants for this Discussion Grant NumberProgram AreaPrincipal InvestigatorGrant TitleRelevance to Retreat Session R01 AR046122Arthritis and Rheumatic Diseases Lin ChangNeuroendocrine Alterations in Fibromyalgia and IBS Medium R01 AR056666Extracellular Matrix Biology Andrzej T. SlominskiRole of Exogenous Melatonin in Skin BiologyLow R01 AR055246Muscle Biology and Diseases Karyn Ann EsserCircadian Rhythms and Skeletal MuscleHigh R03 AR05641Muscle Biology and Diseases John Joseph McCarthyCircadian Regulation of MyoD1 TranscriptionHigh R01 AR056439Skin Biology and DiseasesBogi AndersenControl of Hair Follicle CyclingMedium R01 AR042177Skin Biology and DiseasesCheng-Ming ChuongDevelopment and Regeneration of Skin Appendages Medium F32 AR059471Skin Biology and DiseasesYang Sui BrooksRole of RORa in Epidermal Differentiation Control Low T32 AR007465Skin Biology and DiseasesSarah E. MillarDermatology Research Training GrantLow R01 AR045433Bone Biology and DiseasesClifford J. RosenGenetics of IGF1 and Bone Density: the role of Nocturnin High R21 AR055633Bone Biology and DiseasesClifford J. RosenSeasonal Bone Loss in MiceHigh K01 AR062132Skin Biology and DiseasesJun DaiGrowth/Differentiation Control of Keratinocytes by ROR Alpha Low For more information about these and other grants, see

The Circadian Cycle— All Cells Have Clocks Central Clock – Suprachiasmatic nucleus (SCN) – Entrained by light Peripheral Clocks – Time setting (entrainment) done through neurohumoral factors – Time of feeding and time of activity can set peripheral clocks, independent of light Molecular clocks can be reset by exposure to external stimuli: split time of light vs. time of feeding or vs. time of activity can disrupt clock synchrony in system, leading to “social jetlag”

The Circadian Cycle—Molecular Clock’s Non-Timekeeping Function Clock controlled genes (CCGs) – Very few (e.g., Dbp) are common across tissues – Most are unique to each tissue and include genes that contribute to cell physiology

The Circadian Cycle—Rheumatoid Arthritis Diurnal Pattern of Rheumatoid Arthritis Symptoms Corresponds to Rhythms of Circulating Cytokines, Particularly IL-6 Sierakowski and Cutolo. Scand J Rheumatol Suppl 125:1.

The Circadian Cycle—Rheumatoid Arthritis Integration of Molecular, Endocrine, and Immunological Circadian Patterns may Enable Optimization of Timing for Rheumatoid Arthritis Treatment Cutolo. Curr Opin Rheumatol (3): 312.

The Circadian Cycle in NIAMS-Relevant Tissues—Opportunities Explore availability of NIH Common Fund support Utilize existing resources to look at circadian rhythms in conjunction with disease research – Some databases include tissues from adrenal glands, suprachiasmatic nucleus (SCN), muscle, heart, and liver Include sleep/wake cycles in clinical trials – However, including sleep data does not necessarily encompass everything relevant to circadian rhythms Generate datasets to query for circadian gene expression Study injury repair at different times of day Raise NIAMS researcher communities’ awareness of the effects of circadian rhythms on relevant tissues – Consider novel strategies to support teams of investigators with experience in NIAMS-relevant tissues and circadian rhythm research