Award

Mechanisms of circadian control by the cardiac molecular clock

Description: Critical biological processes are under control of the molecular circadian clock. Disruption of the clock (i.e. aging, shift-work) is casually linked to cardiovascular disease, the leading global cause of death. Current circadian paradigm proposes that the central clock in the suprachiasmatic nucleus (SCN) regulates clock activity in peripheral tissues to synchronize circadian function. However, our recently published and preliminary data demonstrate that the heart disrupts entrained central and peripheral (muscle) rhythms, suggesting that the cardiac clock can regulate circadian function in tissues outside of the heart. To capitalize on these novel and paradigm-shifting findings to translate circadian biology into cardiovascular medicine, there is a critical need to identify the mechanisms by which the heart is a novel regulator of circadian rhythms independent of central control. We will test the significant and novel overall hypothesis that the heart is a novel circadian regulator via SCN-independent mechanisms. We will test this hypothesis in three aims, using a transgenic mouse model that lacks cardiac-specific expression of the core clock protein Brain and Muscle ARNT-Like1 (Bmal1; Bmal1 cKO). In Aim 1, we will demonstrate that Bmal1 cKO mice have disrupted circadian rhythm, independent of central clock activity and the SCN. In Aim 2, we will determine if circadian dysfunction arises due to changes in cardiac circadian rhythmicity or due to impaired cardiac function. In Aim 3, we will identify the mechanisms by which a novel cardiokine disrupts peripheral circadian function in the muscle. These aims will be accomplished by a multidisciplinary team with expertise in cardiac and circadian biology. Together, this body of work will uncover a novel role for the heart in regulating circadian rhythm and lay the foundation for future efforts aimed at attenuating the maladaptive outcomes of circadian disruption.

Funder: American Heart Association

Amount: $300,000

Funding type: research

Funder scheme: Transformational Project Award

Start date: 2024-07-01

End date: 2027-06-30

Investigators: Danielle Bruns, Danielle Bruns

Institution: University of Wyoming

Topic: Circadian rhythm and melatonin

Subfield: Endocrine and Autonomic Systems

Field: Neuroscience

Domain: Life Sciences