The circadian clock regulates many aspects of physiology including metabolism and cardiovascular function. The past decade of research has seen the development of a scaffold model of oscillator function in which the suprachiasmatic nucleus of the hypothalamus harbors a "master clock" and orchestrates peripheral oscillators present in most major organ systems. These central and peripheral oscillator systems generate a cascade of circadian transcriptional rhythms that ultimately culminate in observed physiological and behavioral oscillations. Genetic disruption of this organization in animal models results in pathophysiological consequences such as glucose intolerance and insulin resistance, components of the metabolic syndrome seen in people at high risk for cardiovascular disease. We present compelling evidence that communication between clocks is more sophisticated and can involve peripheral-to-peripheral and peripheral-to-central clock communication. Here we test the central hypothesis that communication between peripheral and central oscillators is bidirectional and that peripheral oscillators may directly influence each others'function. Using cell type specific conditional mouse models in which Bmal1, a required component of the oscillator, is deleted, we will use physiological and systems approaches to test the hypothesis that oscillator function in endothelial cells regulates vascular smooth muscle function (and vice versa) and influences diurnal variation in blood pressure, thrombogenesis, and locomotor activity (Specific Aim 1). We will also test the hypothesis that oscillator function in adipocytes regulates macrophage function (and vice versa) and influences glucose homeostasis, response to inflammatory stimuli, and feeding rhythms (Specific Aim 2). Furthermore, we propose testing a mechanistic hypothesis that cell type specific disruption of oscillator function results in oscillator abnormalities in nearby cells, and that this disruption propagates to the liver, adrenal, kidneys, and the brain (Specific Aim 3). Finally, using systems approaches we will examine network level changes provoked by genetic disruption of oscillator function in specific cell types and begin to probe network to network conveyance of circadian information as well as identify candidate signaling molecules (Specific Aim 4).

Public Health Relevance

Many physiological and behavioral processes are regulated by the circadian clock, which keeps body time on the 24 hour scale. Timing of feeding, metabolism, and cardiovascular function are critical aspects of maintaining homeostasis, which when disrupted through genetic mutation or behavioral alterations such as shift work, results in diseases such as diabetes and heart disease. This proposal focuses on the idea that communication between metabolic and cardiovascular systems, as well as between these and the brain, is critical in maintaining health.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL097800-04
Application #
8301637
Study Section
Special Emphasis Panel (ZHL1-CSR-N (S1))
Program Officer
Laposky, Aaron D
Project Start
2009-09-15
Project End
2013-07-31
Budget Start
2012-08-01
Budget End
2013-07-31
Support Year
4
Fiscal Year
2012
Total Cost
$490,386
Indirect Cost
$183,895
Name
University of Pennsylvania
Department
Pharmacology
Type
Schools of Medicine
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
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