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Targeting lipolytic sterol signaling to foster favorable foam cell modulation and atheroprotection.

Award Number: R01HL183900
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 06/15/2026
PERIOD OF PERFORMANCE END DATE: 02/28/2030

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Targeting lipolytic sterol signaling to foster favorable foam cell modulation and atheroprotection. - PROJECT SUMMARY A large proportion of lipids in atherosclerotic lesions are stored in cytoplasmic lipid droplets (LDs) of foamy macrophages. Although certain processes driving foam cell formation can trigger pro-inflammatory signals, recent analyses of lesional cells link foam cells to alternatively activated metabolic phenotypes. This suggests protective modulatory mechanisms that, if identified, could lead to novel atheroprotective strategies. The liver X receptor (LXR) pathway is a central regulator of foam cell biology that facilitates adaptation to cholesterol overload and represses inflammation. The natural LXR ligands are side-chain oxysterols and certain cholesterol synthesis intermediates. Like cholesterol, these sterols are abundantly stored as esters that are not readily available to access the receptors. Lipid droplet-associated hydrolase (LDAH) is a lipase/esterase with high affinity for LDs. In atheroma LDAH is associated with metabolic macrophage clusters poor in inflammatory markers, and gain- and loss-of-function studies identified LDAH as an atheroprotective player that also promotes stable lesion architectures. Various lipidomic analyses of macrophages and atheroma show that LDAH mobilizes sterol stores and has a robust impact on regulatory species, while transcriptomic profiles show that LDAH induces prototypical LXR targets and promotes a reparative phenotype. Our central hypothesis is that LDAH facilitates adaptive responses to lipid overload through lipolytic release of steroidal LXR ligands from LDs, while connecting lipid metabolism with favorable modulation of lesional cells. Importantly, LDAH’s induction of LXR targets is not paralleled by induction of lipogenic genes, suggesting that this mechanism of endogenous LXR activation is devoid of lipogenic side effects that hinder the use of synthetic agonists. Our overarching goal is to establish an LDAH-LXR axis as a driver of favorable modulation of vascular cells and atheroprotection and identify strategies to enhance this mechanism. Aim 1 will test the hypothesis that LDAH protects through LXR- dependent mechanisms and plays a main role in endogenous LXR activation. In Aim 2 newly generated reporter and LDAH-floxed models will be used to test the hypothesis that smooth muscle cells are indirectly modulated by LDAH-driven changes in myeloid cell activation and/or directly modulated by LDAH’s action on their own LDs, and significantly contribute to the development of fibroprotective architectures. Aim 3 will assess whether protective LXR activation can be enhanced through coordinated sterol mobilizing interventions and will leverage a stablished drug screening platform to identify compounds that activate this mechanism. The innovative aspect of this project lies in leveraging the metabolism of sterols that accumulate abundantly in arterial cells to enhance LXR activation. If successful, these studies may lead to novel translational opportunities.


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 = $586,474 )
2026	2026	ALBANY MEDICAL COLLEGE	47 NEW SCOTLAND AVE # A34	ALBANY	NY	12208	ALBANY	USA	Cardiovascular Diseases Research	000	1	6/18/2026	NEW	$586,474
														Subtotal = $586,474

Grand Total All Awards = $586,474

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Targeting lipolytic sterol signaling to foster favorable foam cell modulation and atheroprotection.

Award Number: R01HL183900

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 06/15/2026

PERIOD OF PERFORMANCE END DATE: 02/28/2030

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