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Investigating how lifestyles selectively modify clonal hematopoiesis in atherosclerosis through immuno-metabolic reprogramming

Award Number: R01HL182870
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 08/01/2026
PERIOD OF PERFORMANCE END DATE: 05/31/2030

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Investigating how lifestyles selectively modify clonal hematopoiesis in atherosclerosis through immuno-metabolic reprogramming - ABSTRACT Clonal hematopoiesis (CH) arises when hematopoietic stem cells (HSCs) acquire somatic mutations that provide proliferative advantages and increases risk for cardiovascular diseases (CVDs). It remains unknown whether CH is entirely deterministic or if extrinsic and environmental factors can modify clone evolution and CH-driven atherosclerosis. By studying how sleep and exercise – evolutionarily conserved behaviors that ensure cardiovascular and immune health – modify CH and its associated atherosclerosis, we will identify new evolutionarily tested and potent therapeutic targets. Our preliminary data, in humans and mice, demonstrate that CH mutant cells are selectively and uniquely responsive to lifestyles and that sleep and exercise reprogram the immunometabolic status of CH mutant cells − but not neighboring WT cells − in the bone marrow and aorta to influence CH clonal evolution and associated atherosclerosis. We hypothesize that sleep and exercise selectively restrict the detrimental immuno-metabolic programming of CH mutant cells, thereby diminishing clone expansion and locally modifying CH mutant aortic macrophages to slow atherosclerosis. In Aim 1, we will model three mutations and CH-accelerated atherosclerosis in high fat diet fed Ldlr-/- mice and exposed them to 12 weeks of sleep fragmentation (SF), voluntary exercise, or a sedentary lifestyle. We will track the expansion of mutant (CD45.2) cells over time. The abundance, proliferation, inflammasome and metabolic status of mutant and WT HSCs in the BM and spleen will be measured. CH cell-specific genetic deletion of Il1r1 or Pfkfb3, or pharmacological blockade of IL-1β or glycolysis, will causally test how lifestyle influences these key pathways to alter CH mutant, but not neighboring WT HSCs. In Aim 2, we will test how sleep and exercise alter the progression of CH-accelerated atherosclerosis by selectively reprogramming mutant aortic macrophages through CLEC4e-inflammasome signaling and Pfkfb3-mediated glycolysis, respectively. In atherosclerotic mice with and without CH and exposed to lifestyles, we will perform confocal and PET imaging; proteomics; CD45.1/2 oligotagged scRNA-seq and CellChat analysis; extracellular flux and isotope tracer assays to uncover new mechanisms by which sleep and exercise selectively alter the crosstalk, immune, and metabolic reprogramming of mutant, but not WT, aortic macrophages. CH cell specific deletion of Clec4e or Pfkfb3 will uncover how these specific and new mechanisms causally link lifestyle to CH mutant macrophage function in atherosclerosis. Whether sufficient sleep or exercise selectively limit the detrimental effects of CH by locally reprogramming CH mutant cells, without impacting neighboring WT cells, is a novel and clinically important question. Our studies will redefine the relationship between CH and atherosclerosis and uncover evolutionarily conserved, mechanistically defined, and therapeutically actionable pathways that selectively reprogram CH mutant cells while preserving the function of healthy WT cells, enabling personalized anti-CH and anti-atherosclerotic therapies.


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 = $839,536 )
2026	2026	ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI	1 GUSTAVE L LEVY PL	NEW YORK	NY	10029	NEW YORK	USA	Cardiovascular Diseases Research	000	1	8/4/2026	NEW	$839,536
														Subtotal = $839,536

Grand Total All Awards = $839,536

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Investigating how lifestyles selectively modify clonal hematopoiesis in atherosclerosis through immuno-metabolic reprogramming

Award Number: R01HL182870

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 08/01/2026

PERIOD OF PERFORMANCE END DATE: 05/31/2030

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