Grants and Contracts Details
The normal blood pressure (BP) circadian rhythm is essential to human health, as morning BP surge is associated with increased incidence of life-threatening cardiovascular events. Moreover, disruption of BP circadian rhythm, which occurs in up to 75% of diabetic patients, is emerging as an index for future target organ injury and poor cardiovascular outcomes. However, the mechanism by which BP circadian rhythm is disrupted in diabetes is largely unknown and an effective strategy to restore the disrupted BP circadian rhythm in diabetes, however, has not yet been identified. Our preliminary studies found that by limiting the time of food availability to active period (ATRF) provided striking protection of the diabetic db/db mice from the severe disruption of BP circadian rhythm. Such protection was associated with dramatic improvements in circadian rhythms in nuclear accumulation of the core clock gene, BMAL1, the energy expenditure, and urinary norepinephrine excretion. These intriguing findings suggest that ATRF can serve as a novel strategy to promote normal BP circadian rhythms, thus significantly improving the cardiovascular prognosis of diabetic patients. The current proposal will examine this exciting possibility by testing the specific hypothesis that active time-restricted feeding (ATRF) restores normal clock gene BMAL1 regulation and thus protects diabetic mice from disruption of the blood pressure circadian rhythm, and vascular and sympathetic dysfunction. The three specific aims are: 1). Determine the mechanism by which BMAL1 regulation is disrupted by diabetes and restored by ATRF. 2).Test the hypothesis that ATRF protects diabetic mouse from vascular contractile dysfunction and remodeling. 3). Define ATRF as a novel chrononutritional therapeutic strategy against disruption of BP circadian rhythm in diabetes. We will monitor the circadian rhythms of BP, vascular signaling and contractile function and cardiovascular sympathetic regulation under ad libitum and ATRF feeding regimens in various mouse models including diabetic db/db mice, db/db-per2Luc mice, high fat diet fed mice and smooth muscle BMAL1 knockout mice.
|Effective start/end date||1/15/19 → 10/31/23|
- National Heart Lung and Blood Institute: $2,507,690.00