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Characterizing a novel mechanism that contributes to the development of atherosclerosis

Award Number: K99HL181309
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP
PERIOD OF PERFORMANCE START DATE: 06/01/2026
PERIOD OF PERFORMANCE END DATE: 05/31/2028

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Characterizing a novel mechanism that contributes to the development of atherosclerosis - Project Summary/Abstract: The development of atherosclerosis is characterized by excessive lipid accumulation in macrophages. For many density lipoprotein (LDL) species contribute years, the field has focused primarily on how interactions with to lipid accumulation. macrophage modified monomeric low- However, in atherosclerotic lesions, the most abundant source of LDL encountered by macrophages is aggregated LDL (agLDL) that is tightly linked to the extracellular matrix so that it cannot be endocytosed or phagocytosed. Our lab has described the formation of an extracellular, acidic, hydrolytic compartment by which macrophages hydrolyze agLDL in a novel process we termed digestive exophagy. This process is marked by actin polymerization around agLDL to form a tightly sealed compartment and exocytosis of lysosomes into the extracellular space. We have evidence that slowing digestive exophagy may the slow development of atherosclerosis. The hypothesis of this proposal is that digestive exophagy has important consequences in the pathophysiology of atherosclerosis and a more complete understanding of this process may lead to improved therapies for atherosclerosis. I recently identified release of Ca2+ from the ER as critical for digestive exophagy. One important role for ER Ca2+ release is refilling lysosomal Ca2+ stores. I have new data that both inhibition and activation of the lysosomal Ca2+ channel, TRPML1, blocks digestive exophagy. The first aim of this proposal will characterize the upstream activation of TRPML1, and the downstream pathways controlled by TRPML1 during digestive exophagy. Upstream, I will focus on reactive oxygen species, which are reported modulators of TRPML1. Downstream, I will focus on Synaptotagmin VII, a Ca2+-dependent protein important for lysosome exocytosis in osteoclasts. I will also test whether modulating TRPML1 function can improve atherosclerosis in mice. Aim 2 focuses on understanding the interplay between macrophages and oxidation of agLDL. Though little is that, macrophage polymerization state known about how oxidation affects this interaction is likely critical given in human atherosclerotic lesions unstable plaques tend to have highly oxidized LDL and increased infiltration . I have preliminary data that macrophages do more lysosome exocytosis, but less actin when exposed to oxidized agLDL compared to agLDL. In this aim, I will test how the oxidation of agLDL affects digestive exophagy and whether digestive exophagy leads to oxidation of agLDL. macrophage interactions with agLDL, , Aim 3 centers around identifying and characterizing novel regulators of digestive exophagy. I developed a flow cytometry-based screen of a library of CRISPR knockout macrophages to identify knockouts defective in digestive exophagy. In my preliminary results, I identified Daglb, an enzyme with a key role in the endocannabinoid system, as a high-confidence hit that connects with known digestive exophagy pathways. All together, this research project, support from my mentoring committee, and attending workshops and conferences will help me to achieve my goal of establishing my own independent research group.


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 = $129,600 )
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	6/23/2026	NEW	$129,600
														Subtotal = $129,600

Grand Total All Awards = $129,600

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Characterizing a novel mechanism that contributes to the development of atherosclerosis

Award Number: K99HL181309

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP

PERIOD OF PERFORMANCE START DATE: 06/01/2026

PERIOD OF PERFORMANCE END DATE: 05/31/2028

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