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The role of endothelial ceramides in coronary atherosclerosis

Award Number: R01HL181967
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 08/14/2026
PERIOD OF PERFORMANCE END DATE: 04/30/2030

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The role of endothelial ceramides in coronary atherosclerosis - Despite significant advancements in lowering-lipid therapies and surgeries, coronary artery disease (CAD) remains a leading cause of death worldwide. Emerging studies with large clinical cohorts showed that plasma sphingolipid ceramides are strong predictors of CAD, atherosclerotic plaque instability, and detrimental outcomes, independently of other classical risk factors, such as cholesterol. Ceramides also accumulate in atherosclerotic plaques. Yet, how these lipids change in the vascular wall and contribute to CAD remain virtually unknown. Very long chain ceramides (VLC) synthetized by ceramide synthase 2 (CerS2) are the most abundant in endothelial cells (EC), followed by C16:0-ceramide synthetized by CerS5 and defined long chain (LC) ceramide. Pilot data have shown that an increase in LC and decrease of VLC ceramides myocardial EC from hearts affected by coronary atherosclerosis, without change in total ceramides, suggesting that dysregulation of ceramide landscape rather that total ceramides is deleterious. Interestingly, CerS2 haploinsufficiency, shifting LC/VLC ratio in favor of LC, causes endothelial dysfunction, impairs flow-induced KLF2 transcription factor expression, and exacerbates coronary atherosclerosis in mice. Based on preliminary data, we hypothesize that that VLC ceramides protect from coronary atherosclerosis development and progression by preserving EC resilience to stressors via KLF2 expression. To test this hypothesis, we propose two aims. In Aim1 we will use mice specifically deleted of one Cers2 allele in EC to investigate the contribution of VLC ceramides to coronary atherosclerosis development and progression. In Aim2 we will determine the role of KLF2 in mediating the cell- autonomous effects of ceramides and preserve EC functions. Completing these aims will establish the key role of ceramides in preserving endothelial resilience to atherogenic stressors. Our studies will be the first to directly probe the causative or protective role of ceramides in atherosclerosis, a necessary stepstone for developing therapeutic strategies to cure this condition.


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 = $816,853 )
2026	2026	WEILL MEDICAL COLLEGE OF CORNELL UNIVERSITY	575 LEXINGTON AVE FL 9	NEW YORK	NY	10022	NEW YORK	USA	Cardiovascular Diseases Research	000	1	8/13/2026	NEW	$816,853
														Subtotal = $816,853

Grand Total All Awards = $816,853

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The role of endothelial ceramides in coronary atherosclerosis

Award Number: R01HL181967

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 08/14/2026

PERIOD OF PERFORMANCE END DATE: 04/30/2030

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