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Clock Regulation of Stress Pathways in HFpEF

Award Number: R01HL187848
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 08/17/2026
PERIOD OF PERFORMANCE END DATE: 04/30/2030

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Clock Regulation of Stress Pathways in HFpEF - Circadian disruption (CD) due to misalignment between external circadian cues and internal molecular clocks, as seen in 15-30% of the population due to shift work (SW) and social jet lag, increases the risk for hypertension, atherosclerosis, diabetes, and obesity. Preclinical models involving genetic loss of function of the ‘molecular clock’ have demonstrated clock disruption in cardiomyocytes (CMs) results in aging associated systolic heart failure (HF), due to metabolic impairment. However, role of circadian misalignment induced CD, as seen in SW, in cardiac remodeling is unclear. The cardiovascular disorders associated with SW are risk factors for Heart failure with preserved ejection fraction (HFpEF), which accounts for over half of all HF cases. There is significant paucity in our mechanistic understanding of the pathogenesis of HFpEF, a heterogeneous disorder with multiple phenogroups. While no animal models replicate most features of human HFpEF, there is increasing recognition of a ‘dual-hit or multi-hit’ model in the pathogenesis of HFpEF. Our preliminary data in a dual-hit preclinical mouse model reveal that chronic CD, simulating SW, in the presence of long-term high-fat diet (HFD)- mediated metabolic stress, results in ‘cardiometabolic’ HFpEF. The molecular circadian clock regulates ~10% of the cardiac transcriptome and proteome. HFpEF studies reveal mitochondrial TCA cycle intermediates to be low, suggesting impaired substrate utilization. Cardiac remodeling is frequently associated with ER-UPR and Mito-UPR with mitochondrial stress. It is not known if and how the circadian clock regulates the mitochondrial homeostatic mechanism. We hypothesize that circadian clock integrity is essential for cardiac resilience under metabolic stress, maintaining proteostatic, metabolic, and immune homeostasis to prevent HFpEF. In Aim 1, we will determine whether the circadian clock regulates the mitochondrial unfolded protein response (UPRMT) and whether impaired UPRMT contributes to HFpEF. In Aim 2, we will define how circadian disruption impairs metabolic substrate flexibility in cardiometabolic HFpEF. In Aim 3, we will dissect clock regulated fibroinflammatory mechanisms and cellular crosstalk underlying HFpEF pathophysiology. This project establishes a novel translationally relevant framework linking circadian misalignment to cardiometabolic HFpEF and identifies clock-regulated proteostatic, metabolic, and inflammatory pathways as therapeutic targets, and bridge the current knowledge gap of circadian regulation of stress pathways in the pathophysiology of HFpEF. Our long-term goal is to decipher temporal molecular and cellular mechanisms in the pathogenesis of HFpEF and identify novel therapeutic targets.


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: 2026 ( Subtotal = $774,398 )
2026	2026	UNIVERSITY OF PITTSBURGH - OF THE COMMONWEALTH SYSTEM OF HIGHER EDUCATION	4200 FIFTH AVENUE	PITTSBURGH	PA	15260	ALLEGHENY	USA	Cardiovascular Diseases Research	000	1	8/19/2026	NEW	$774,398
														Subtotal = $774,398

Grand Total All Awards = $774,398

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Clock Regulation of Stress Pathways in HFpEF

Award Number: R01HL187848

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 08/17/2026

PERIOD OF PERFORMANCE END DATE: 04/30/2030

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