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Targeting timing of food intake as a novel strategy against disruption of blood pressure circadian rhythm in diabetes

Award Number: R01HL141103
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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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 has not yet been identified. Our preliminary studies found that by limiting the time of food available to the active period (ATRF) provided striking protection of the diabetic db/db mice from the severe disruption of BP circadian rhythm. Moreover, BMAL1, an obligatory clock gene, is required for and glucagon-like peptide-1 (GLP-1) receptor activation mimics the protection of BP circadian rhythm by ATRF. 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 new exciting possibility by testing the specific hypothesis that active time- restricted feeding (ATRF) or GLP-1 activation restores normal smooth muscle and renal BMAL1 and sympathetic oscillations thus protects diabetic mice from disruptions of blood pressure circadian rhythm. The three specific aims are 1). Determine the mechanism by which BMAL1 is dysregulated in diabetes and restored by ATRF. 2). Test the hypothesis that ATRF protects BP circadian rhythm via smooth muscle and renal BMAL1 in diabetes. 3). Define ATRF as a novel chrononutritional therapy and targeting GLP-1 as a new pharmacological therapy to protect BP circadian rhythm in diabetes. We will monitor the circadian rhythms of BP, food intake, BMAL1 regulation, vascular smooth muscle function and signaling, renal function, and sympathetic regulation under ad libitum and ATRF feeding regimens. The various mouse models will be used are diabetic db/db mice, db/db-per2Luc mice, high-fat diet fed mice, smooth muscle and renal BMAL1 knockout mice.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2022 ( Subtotal = $541,009 )
2022	2022	UNIVERSITY OF KENTUCKY	500 S LIMESTONE 109 KINKEAD HALL	LEXINGTON	KY	40526	FAYETTE	USA	Cardiovascular Diseases Research	000	4	11/5/2021	NON-COMPETING CONTINUATION	$541,009


Issue Date FY: 2021 ( Subtotal = $601,123 )
2021	2021	UNIVERSITY OF KENTUCKY	500 S LIMESTONE 109 KINKEAD HALL	LEXINGTON	KY	40526	FAYETTE	USA	Cardiovascular Diseases Research	000	3	11/30/2020	NON-COMPETING CONTINUATION	$541,009
2021	2021	UNIVERSITY OF KENTUCKY	500 S LIMESTONE 109 KINKEAD HALL	LEXINGTON	KY	40526	FAYETTE	USA	Cardiovascular Diseases Research	001	3	5/24/2021	NON-COMPETING CONTINUATION	$60,114


Issue Date FY: 2020 ( Subtotal = $601,123 )
2020	2020	UNIVERSITY OF KENTUCKY	500 S LIMESTONE 109 KINKEAD HALL	LEXINGTON	KY	40526	FAYETTE	USA	Cardiovascular Diseases Research	000	2	11/27/2019	NON-COMPETING CONTINUATION	$571,067
2020	2020	UNIVERSITY OF KENTUCKY	500 S LIMESTONE 109 KINKEAD HALL	LEXINGTON	KY	40526	FAYETTE	USA	Cardiovascular Diseases Research	001	2	1/23/2020	NON-COMPETING CONTINUATION	$30,056


Issue Date FY: 2019 ( Subtotal = $704,321 )
2019	2019	UNIVERSITY OF KENTUCKY	500 S LIMESTONE 109 KINKEAD HALL	LEXINGTON	KY	40526	FAYETTE	USA	Cardiovascular Diseases Research	000	1	1/10/2019	NEW	$704,321


Grand Total All Awards = $2,447,576

Sum of Action Amount is $2,447,576;

Grand Total = $2,447,576

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Targeting timing of food intake as a novel strategy against disruption of blood pressure circadian rhythm in diabetes

Award Number: R01HL141103

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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