Humans exhibit marked circadian rhythms in multiple cardiovascular (CV) parameters, including heart rate, cardiac output, and blood pressure. To date, circadian rhythms in physiological CV parameters have been attributed to the same neurohumoral stimuli (e.g. sympathetic activity) believed to be responsible for fatal CV events (e.g. myocardial infarctions, arrhythmias, and sudden cardiac death). Our studies expose a novel molecular mechanism within cardiomyocytes that directly regulates myocardial gene expression, metabolism, and function over the course of the day. This mechanism is the intramyocellular circadian clock. Circadian clocks are transcriptionally-based mechanisms that confer the selective advantage of anticipation, enabling the cardiomyocyte/heart to respond rapidly and appropriately to environmental stimuli upon their onset. The broad objective of this proposal is to test the hypothesis that the circadian clock within the cardiomyocyte synchronizes responsiveness of the heart to the environment, and that impairment of this mechanism results in an inability of the heart to respond appropriately to its environment (i.e. maladaptation). Altered myocardial metabolism plays a central role in the pathogenesis of contractile dysfunction associated with hypertrophic, diabetic, and ischemic heart disease, conditions in which the circadian clock within the cardiomyocyte is impaired. We therefore intend to address the following specific aims: 1) identify the mechanisms by which the circadian clock within the cardiomyocyte modulates myocardial metabolism;and 2) determine the pathophysiological consequences of impairment of the circadian clock within the cardiomyocyte. For these studies, we will utilize our unique mouse model in which the circadian clock is specifically impaired within cardiomyocytes.
For Specific Aim 1, we will utilize isolated working mouse hearts to identify the mechanisms by which the circadian clock within the cardiomyocyte channels fatty acids and glucose into oxidative versus non-oxidative pathways.
For Specific Aim 2, we will investigate whether impairment of the circadian clock within the cardiomyocyte augments ischemia/reperfusion-, diabetes mellitus-, pressure overload-, aging-, and/or simulated shift work- mediated contractile dysfunction. Our long-term objectives are to establish causal links between impairment of the circadian clock within the cardiomyocyte with development of CV disease in humans.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL074259-10
Application #
8215799
Study Section
Myocardial Ischemia and Metabolism Study Section (MIM)
Program Officer
Evans, Frank
Project Start
2003-07-01
Project End
2014-01-31
Budget Start
2012-02-01
Budget End
2014-01-31
Support Year
10
Fiscal Year
2012
Total Cost
$366,250
Indirect Cost
$116,250
Name
University of Alabama Birmingham
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
063690705
City
Birmingham
State
AL
Country
United States
Zip Code
35294
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Gamble, Karen L; Berry, Ryan; Frank, Stuart J et al. (2014) Circadian clock control of endocrine factors. Nat Rev Endocrinol 10:466-75
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Gamble, Karen L; Young, Martin E (2013) Metabolism as an integral cog in the mammalian circadian clockwork. Crit Rev Biochem Mol Biol 48:317-31
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Ko, Michael L; Shi, Liheng; Tsai, Ju-Yun et al. (2011) Cardiac-specific mutation of Clock alters the quantitative measurements of physical activities without changing behavioral circadian rhythms. J Biol Rhythms 26:412-22

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