Circadian rhythms are an integral component of life, structuring temporal patterns of biochemistry, physiology and behavior. These cycles are driven by an internal biological clock with an endogenous <24 hr period. The master circadian pacemaker is located in the mammalian hypothalamic suprachiasmatic nucleus (SCN). Disorders of the circadian timing system have been linked to a mental illness and metabolic disorders and understanding the neurobiology and physiology of circadian rhythms should lead to the development of new medical treatments. We propose to study the role of Inhibitor of DNA-binding (Id) genes as potential modulators of the mammalian circadian system. Our preliminary studies reveal that Id genes are rhythmically expressed within the SCN and peripheral tissues;that Id2 null mice show circadian disorder phenotypes, including an enhanced speed of reentrainment of the clock following a large time-zone transition;the ability for ID proteins to inhibit the activity of known clock components;and that a subset of normal circadian outputs in the liver are disrupted in Id2 null mice. Our proposed research will focus on 1) characterizing the protein-protein interaction between ID2 and canonical clock proteins CLOCK, BMAL1 and other relevant bHLH transcription factors;2) define the molecular basis for the described phenotypes, utilizing both traditional methods of gene and protein expression visualization, and real-time analysis of gene/protein expression using the mPER2-LUCIFERASE mouse system;and 3) examine the role of ID2 in regulating transcriptional pathways of clock output, focusing upon mouse hepatic and metabolic systems. It is expected that these collective studies will provide a greater understanding of the role of Id genes in the molecular clockwork of the mammalian central and peripheral circadian clocks.

Public Health Relevance

Disorders of the circadian timing system have been linked to mental illness, such as depression and sleep disorders, and metabolic disorders, and understanding the neurobiology, physiology and molecular basis of circadian rhythms should lead to the development of new treatments. We propose to study the role of Inhibitor of DNA-binding (Id) genes as components of the mammalian circadian system. It is expected that these collective studies will provide greater understanding of the role of ID transcriptional regulators in the molecular clockwork of the mammalian central and peripheral circadian clocks. Disorders of the circadian timing system have been linked to mental illness, such as depression and sleep disorders, and metabolic disorders, and understanding the neurobiology, physiology and molecular basis of circadian rhythms should lead to the development of new treatments. We propose to study the role of Inhibitor of DNA-binding (Id) genes as components of the mammalian circadian system. It is expected that these collective studies will provide greater understanding of the role of ID transcriptional regulators in the molecular clockwork of the mammalian central and peripheral circadian clocks.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM087508-05
Application #
8710249
Study Section
Biological Rhythms and Sleep Study Section (BRS)
Program Officer
Sesma, Michael A
Project Start
2010-08-01
Project End
2015-07-31
Budget Start
2014-08-01
Budget End
2015-07-31
Support Year
5
Fiscal Year
2014
Total Cost
$289,575
Indirect Cost
$96,525
Name
University of Notre Dame
Department
Biology
Type
Schools of Arts and Sciences
DUNS #
824910376
City
Notre Dame
State
IN
Country
United States
Zip Code
46556
Suckow, Mark A; Wolter, William R; Duffield, Giles E (2017) The Impact of Environmental Light Intensity on Experimental Tumor Growth. Anticancer Res 37:4967-4971
Sheppard, Aaron D; Rund, Samuel S C; George, Gary F et al. (2017) Light manipulation of mosquito behaviour: acute and sustained photic suppression of biting activity in the Anopheles gambiae malaria mosquito. Parasit Vectors 10:255
Hughes, Michael E; Abruzzi, Katherine C; Allada, Ravi et al. (2017) Guidelines for Genome-Scale Analysis of Biological Rhythms. J Biol Rhythms 32:380-393
Rund, Samuel S C; Yoo, Boyoung; Alam, Camille et al. (2016) Genome-wide profiling of 24 hr diel rhythmicity in the water flea, Daphnia pulex: network analysis reveals rhythmic gene expression and enhances functional gene annotation. BMC Genomics 17:653
Zhou, Peng; Robles-Murguia, Maricela; Mathew, Deepa et al. (2016) Impaired Thermogenesis and a Molecular Signature for Brown Adipose Tissue in Id2 Null Mice. J Diabetes Res 2016:6785948
Zhou, Peng; Werner, John H; Lee, Donghoon et al. (2015) Dissociation between diurnal cycles in locomotor activity, feeding behavior and hepatic PERIOD2 expression in chronic alcohol-fed mice. Alcohol 49:399-408
Zhou, Peng; Hummel, Alyssa D; Pywell, Cameron M et al. (2014) High fat diet rescues disturbances to metabolic homeostasis and survival in the Id2 null mouse in a sex-specific manner. Biochem Biophys Res Commun 451:374-81
Leming, Matthew T; Rund, Samuel S C; Behura, Susanta K et al. (2014) A database of circadian and diel rhythmic gene expression in the yellow fever mosquito Aedes aegypti. BMC Genomics 15:1128
Metzinger, Matthew N; Miramontes, Bernadette; Zhou, Peng et al. (2014) Correlation of X-ray computed tomography with quantitative nuclear magnetic resonance methods for pre-clinical measurement of adipose and lean tissues in living mice. Sensors (Basel) 14:18526-42
Zhou, Peng; Ross, Ruth A; Pywell, Cameron M et al. (2014) Disturbances in the murine hepatic circadian clock in alcohol-induced hepatic steatosis. Sci Rep 4:3725

Showing the most recent 10 out of 21 publications