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Cross-tissue multi-omic approaches to characterize the role of clonal hematopoiesis of indeterminate potential in atherosclerotic cardiovascular disease

Award Number: F30HL188445
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS
PERIOD OF PERFORMANCE START DATE: 03/18/2027
PERIOD OF PERFORMANCE END DATE: 03/17/2028

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Cross-tissue multi-omic approaches to characterize the role of clonal hematopoiesis of indeterminate potential in atherosclerotic cardiovascular disease - PROJECT SUMMARY Atherosclerotic cardiovascular disease (ASCVD) remains a leading cause of death and disability globally, affecting over 20 million Americans and leading to nearly 400,000 deaths per year in the United States. Although current risk-assessment strategies are effective, significant challenges remain in accurately identifying chronic ASCVD patients at the highest risk for major adverse cardiovascular events. Recent epidemiological studies have identified clonal hematopoiesis of indeterminate potential (CHIP) as a significant risk factor for cardiovascular events in patients with ASCVD. CHIP is defined as the clonal expansion of mutated hematopoietic stem cells in the absence of hematological malignancy and is associated with increased cardiovascular mortality. Recent breakthrough studies have demonstrated stronger efficacy of antiinflammatory therapies for cardiovascular risk reduction in CHIP carriers, with gene-specific effects, establishing CHIP as a promising target for precision anti-inflammatory therapy. However, the gene-specific inflammatory mechanisms underlying CHIP-mediated cardiovascular risk in humans remain incompletely characterized. Our preliminary data supports gene-specific patterns of transcriptomic and epigenomic pathway dysregulation in CHIP carriers, with TET2 showing substantially greater epigenomic and transcriptomic perturbations than DNMT3A or ASXL1, consistent with epidemiological data demonstrating TET2's stronger association with cardiovascular risk. Previous work from others along with our preliminary data demonstrate that CHIP mutant cells infiltrate atherosclerotic plaques in a non-preferential manner. However, differential gene expression analysis between plaques from CHIP carriers versus non-carriers reveals increased inflammatory signaling and T cell activity, suggesting that despite being a small population, CHIP mutant cells drive amplified inflammatory responses in the plaque microenvironment. The central hypothesis of this proposal is that different CHIP mutations activate distinct inflammasome-mediated pathways in blood and atherosclerotic plaques. In Aim 1, comprehensive multi-omic profiling will be performed on peripheral whole blood samples from ASCVD patients to identify CHIP gene-specific regulatory mechanisms and integrated signatures and test their associations with cardiovascular risk. In Aim 2, single-cell transcriptomics with somatic variant detection will be applied to paired blood and plaque samples to define how CHIP mutant cells activate inflammasomes and drive inflammatory amplification networks in atherosclerotic tissue. Completion of this work will address critical gaps in our understanding of CHIP-mediated cardiovascular disease risk and provide molecular insights for precision medicine approaches in this high-risk population.


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 = $55,114 )
2026	2026	NEW YORK UNIVERSITY	550 1ST AVE	NEW YORK	NY	10016	NEW YORK	USA	Cardiovascular Diseases Research	000	1	9/17/2026	NEW	$55,114
														Subtotal = $55,114

Grand Total All Awards = $55,114

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Cross-tissue multi-omic approaches to characterize the role of clonal hematopoiesis of indeterminate potential in atherosclerotic cardiovascular disease

Award Number: F30HL188445

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS

PERIOD OF PERFORMANCE START DATE: 03/18/2027

PERIOD OF PERFORMANCE END DATE: 03/17/2028

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