# Circadian origins of vascular disease in obesity

> **NIH NIH R01** · AUGUSTA UNIVERSITY · 2021 · $685,300

## Abstract

PROJECT SUMMARY
 It is well known that obesity drives cardiovascular disease, but the mechanisms involved are incompletely
understood and interventions that break the links between weight gain and vascular disease remain a critical
barrier to treatment. Upregulation of NOX1-derived oxidants is a key mechanism of endothelial dysfunction in
obesity but the factors precipitating this impairment are unknown.
 A fundamental concept in cardiovascular physiology is that blood flow is regulated to service metabolism
and when metabolism is deranged in obesity, this relationship breaks down and cardiovascular function falters.
A major link between cardiovascular function and metabolic demand is the circadian clock, a transcriptional
network that regulates daily metabolic rhythms and programs cardiovascular gene expression to anticipate these
changes. Genetic disruption of the clock in mice results in endothelial dysfunction and disruptive circadian
lifestyles in humans leads to a higher incidence of cardiovascular disease. How the vascular clock becomes
disrupted and the subsequent ontology of disease are unknown and resolving these critical deficits in our
understanding is the focus of this application.
 New data from our laboratories have identified extensive circadian disruption in the db/db mouse, which
exhibits profound obesity and NOX1-mediated endothelial dysfunction. Breeding these mice to a per luc reporter
mouse revealed near abrogation of circadian rhythms in the aorta along with an 80% reduction in cyclic gene
expression and diminished expression of clock regulated genes. Subsequent studies identified exaggerated
hyperglycemia as a potential circadian disruptor and Galectin-3 and Cezanne as novel mechanisms that may
influence NOX1 – eNOS balance to promote vascular dysfunction.
 Based on these observations, the core hypothesis of this proposal is that obesity causes vascular
disease secondary to loss of function of the vascular circadian clock. We will test hypothesis in vivo in
novel animal models of obesity with manipulated components of circadian control and in vitro to identify new
cellular mechanisms that may be targets for the treatment of vascular disease in obesity.

## Key facts

- **NIH application ID:** 10137303
- **Project number:** 5R01HL147159-03
- **Recipient organization:** AUGUSTA UNIVERSITY
- **Principal Investigator:** David J Fulton
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $685,300
- **Award type:** 5
- **Project period:** 2019-04-15 → 2023-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10137303

## Citation

> US National Institutes of Health, RePORTER application 10137303, Circadian origins of vascular disease in obesity (5R01HL147159-03). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10137303. Licensed CC0.

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