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Circadian regulation of vascular aging

Award Number: R01HL146103
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 01/18/2019
PERIOD OF PERFORMANCE END DATE: 12/31/2025

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Circadian regulation of vascular aging - Vascular aging, the age-related molecular, structural and functional changes in the blood vessels, not only impairs normal vascular contraction and compliance but also increases the incidence of cardiovascular disease, including hypertension, coronary artery disease, heart failure, stroke and peripheral artery disease, as well as vascular complications in metabolic disease, such as diabetes. Therefore, better understanding of the molecular regulation of vascular aging may offer greater opportunities to identify promising targets for potential novel clinical interventions to prevent or retard vascular aging and age-related cardiovascular disease. The current application aims to fill the unmet scientific gaps to elucidate the molecular determinants in vascular aging. Vascular smooth muscle cell (VSMC) proliferation, migration, mineralization, extracellular matrix (ECM) deposition, and senescence contribute to age-related vascular structural and functional changes. As a result, increased medial and neointimal thickness, arterial stiffness, ECM degradation and calcification are manifestations of vascular aging, which promotes cardiovascular disease including atherosclerosis, hypertension, vascular calcification and stroke. We found that a key transcription factor Runx2 is elevated in an age-dependent manner, and SMC-specific deletion of Runx2 inhibited vascular complications that are more pronounced in aging, including atherosclerosis, neointimal formation and vascular calcification. Furthermore, Runx2 deficiency in VSMC inhibited the expression of VSMC matrix proteins and senescence, two hallmarks of VSMC aging, supporting a novel function of Runx2 in regulating vascular aging that is beyond its known function in regulating VSMC calcification. Mechanistically, we identified a previously unrecognized Runx2 oscillation in VSMC in culture as well as in mouse arteries in vivo. Runx2 oscillation in VSMC was associated with the oscillation of the key clock regulator, BMAL1, and the clock-regulated FOXO1. Coincidently, increased expression of BMAL1 and FOXO1 was demonstrated in aging arterials, similar to that of Runx2. With the use of loss-of-function approaches, our preliminary studies further demonstrated a causative function of circadian clock (BMAL1) and O-GlcNAcylation in regulating Runx2 expression. These results support the hypothesis that interplay of clock rhythm and protein O-GlcNAcylation promotes vascular aging through the FOXO/Runx2 signaling axis. Using novel inducible SMC-specific BMAL1, OGT and Runx2 deficient animal models, the proposal will characterize circadian clock-regulated vascular aging in mice (Aim 1); and delineate mechanisms underlying circadian regulation of vascular aging (Aim 2). Results from the proposed studies will develop a novel paradigm underlying vascular clock and O-GlcNAcylation regulation of the FOXO/Runx2 signaling axis in vascular aging, which will advance our understanding of basic mechanisms governing vascular aging. As vascular aging promotes many diseases, the novel mechanisms uncovered in this application should also have broad scientific and translational impact on increasing human lifespan and improving public health.


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: 2025 ( Subtotal = -$1,828,421 )
2025	2022	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH STREET	BIRMINGHAM	AL	35294	JEFFERSON	USA	Cardiovascular Diseases Research	003	4	7/10/2025	NON-COMPETING CONTINUATION	$0
2025	2022	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH STREET	BIRMINGHAM	AL	35294	JEFFERSON	USA	Cardiovascular Diseases Research	002	4	6/25/2025	NON-COMPETING CONTINUATION	-$628,446
2025	2022	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH STREET	BIRMINGHAM	AL	35294	JEFFERSON	USA	Cardiovascular Diseases Research	000	3	6/25/2025	NON-COMPETING CONTINUATION	-$324,951
2025	2022	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH STREET	BIRMINGHAM	AL	35294	JEFFERSON	USA	Cardiovascular Diseases Research	001	3	6/25/2025	SUPPLEMENT FOR EXPANSION	$0
2025	2021	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH STREET	BIRMINGHAM	AL	35294	JEFFERSON	USA	Cardiovascular Diseases Research	000	3	6/25/2025	NON-COMPETING CONTINUATION	-$550,072
2025	2021	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH STREET	BIRMINGHAM	AL	35294	JEFFERSON	USA	Cardiovascular Diseases Research	001	3	6/25/2025	SUPPLEMENT FOR EXPANSION	-$324,951
														Subtotal = -$1,828,421

Issue Date FY: 2024 ( Subtotal = $0 )
2024	2022	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH STREET	BIRMINGHAM	AL	35294	JEFFERSON	USA	Cardiovascular Diseases Research	000	4	12/14/2023	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2022 ( Subtotal = $628,446 )
2022	2022	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH ST	BIRMINGHAM	AL	35294	JEFFERSON	USA	Cardiovascular Diseases Research	000	4	12/22/2021	NON-COMPETING CONTINUATION	$565,601
2022	2022	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH ST	BIRMINGHAM	AL	35294	JEFFERSON	USA	Cardiovascular Diseases Research	001	4	5/31/2022	NON-COMPETING CONTINUATION	$62,845
														Subtotal = $628,446

Issue Date FY: 2021 ( Subtotal = $999,696 )
2021	2021	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH ST	BIRMINGHAM	AL	35294	JEFFERSON	USA	Cardiovascular Diseases Research	000	3	1/1/2021	NON-COMPETING CONTINUATION	$565,601
2021	2021	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH ST	BIRMINGHAM	AL	35294	JEFFERSON	USA	Cardiovascular Diseases Research	002	3	5/24/2021	NON-COMPETING CONTINUATION	$62,845
2021	2021	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH ST	BIRMINGHAM	AL	35294	JEFFERSON	USA	Cardiovascular Diseases Research	001	3	4/13/2021	SUPPLEMENT FOR EXPANSION	$371,250
														Subtotal = $999,696

Issue Date FY: 2020 ( Subtotal = $628,446 )
2020	2020	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH ST	BIRMINGHAM	AL	35294	JEFFERSON	USA	Cardiovascular Diseases Research	000	2	2/3/2020	NON-COMPETING CONTINUATION	$628,446
														Subtotal = $628,446

Issue Date FY: 2019 ( Subtotal = $628,446 )
2019	2019	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH ST	BIRMINGHAM	AL	35294	JEFFERSON	USA	Cardiovascular Diseases Research	000	1	1/16/2019	NEW	$628,446
														Subtotal = $628,446

Grand Total All Awards = $1,056,613

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Circadian regulation of vascular aging

Award Number: R01HL146103

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 01/18/2019

PERIOD OF PERFORMANCE END DATE: 12/31/2025

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