NIAMS Extramural Scientific Planning Retreat 2013April 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

The Circadian Cycle—History of Circadian Publications

DiabetesCancer

CardiovascularDisease (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 Number Program Area Principal Investigator Grant Title Relevance to Retreat Session

R01 AR046122 Arthritis and Rheumatic Diseases

Lin Chang Neuroendocrine Alterations in Fibromyalgia and IBS

Medium

R01 AR056666 Extracellular Matrix Biology

Andrzej T. Slominski Role of Exogenous Melatonin in Skin Biology Low

R01 AR055246 Muscle Biology and Diseases

Karyn Ann Esser Circadian Rhythms and Skeletal Muscle High

R03 AR05641 Muscle Biology and Diseases

John Joseph McCarthy Circadian Regulation of MyoD1 Transcription High

R01 AR056439 Skin Biology and Diseases Bogi Andersen Control of Hair Follicle Cycling Medium

R01 AR042177 Skin Biology and Diseases Cheng-Ming Chuong Development and Regeneration of Skin Appendages

Medium

F32 AR059471 Skin Biology and Diseases Yang Sui Brooks Role of RORa in Epidermal Differentiation Control

Low

T32 AR007465 Skin Biology and Diseases Sarah E. Millar Dermatology Research Training Grant Low

R01 AR045433 Bone Biology and Diseases Clifford J. Rosen Genetics of IGF1 and Bone Density: the role of Nocturnin

High

R21 AR055633 Bone Biology and Diseases Clifford J. Rosen Seasonal Bone Loss in Mice High

K01 AR062132 Skin Biology and Diseases Jun Dai Growth/Differentiation Control of Keratinocytes by ROR Alpha

Low

For more information about these and other grants, see http://projectreporter.nih.gov

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 ArthritisDiurnal Pattern of Rheumatoid Arthritis Symptoms Corresponds to Rhythms of Circulating Cytokines,

Particularly IL-6

Sierakowski and Cutolo. Scand J Rheumatol. 2011. 40 Suppl 125:1.

The Circadian Cycle—Rheumatoid ArthritisIntegration of Molecular, Endocrine, and Immunological

Circadian Patterns may Enable Optimization of Timing for Rheumatoid Arthritis Treatment

Cutolo. Curr Opin Rheumatol. 2012. 24(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