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Chylomicrons and endothelial biology

Award Number: R01HL160891
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 01/01/2023
PERIOD OF PERFORMANCE END DATE: 12/31/2026

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Chylomicrons and endothelial biology - ABSTRACT The first steps in atherosclerosis are the transendothelial movement and subendothelial accumulation of lipoprotein lipid. Endothelial cell (EC) transcytosis of LDL involves two receptors, scavenger receptor-BI (SR-BI) and activin-like kinase 1 (ALK1). We showed that ECs also internalize undigested chylomicrons via SR-BI and process them in lysosomes, leading to storage of some lipid as lipid droplets and the release of small extracellular vesicles (sEVs) that cause lipid accumulation in macrophages. While many have considered chylomicrons as non-atherogenic and too large to cross the EC barrier, this concept is now outdated with the understanding that lipoprotein entry into the artery is a receptor-mediated process. The overall goal of this project is to determine how EC chylomicron uptake affects EC biology, delivers lipids to the artery, and accelerates atherosclerosis. In Aim 1, we propose to determine how triglyceride-rich lipoproteins affect lipid transfer across the vascular endothelium. We provide preliminary data suggesting that N-terminal apoB18 has separate ligand binding regions for ALK1 and SR-BI. We will determine whether lipoprotein size or apoB length determines exposure of these two different regions. We also will determine how sEVs from chylomicron-conditioned ECs cause lipid accumulation in macrophages and determine the differences between sEVs released from control and chylomicron-treated ECs. In Aim 2, we propose in vivo studies to determine the role of the EC-chylomicron uptake pathway in tissue lipid delivery and atherosclerosis. We provide preliminary data suggesting that chylomicrons that accumulate in lipoprotein lipase (LpL) deficient mice increase atherosclerosis. We will use genetically modified mice and knockdown strategies to assess the uptake of LDL and chylomicron lipids into arteries and will assess whether more extensive atherosclerosis in mice with combined deficiency of LpL and the LDL receptor is due to hyperchylomicronemia. Finally, we will determine whether AAV-mediated overexpression of apoB18 reduces EC uptake of apoB lipoproteins in vivo and alters atherosclerosis. Completion of the proposed studies promises to alter our view of the relationship of chylomicrons to vascular disease, define a novel pathway for arterial accumulation of atherogenic lipids, and illustrate a possible approach to prevent these lipids from entering the artery.


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 = $786,489 )
2026	2026	NEW YORK UNIVERSITY	550 1ST AVE	NEW YORK	NY	10016	NEW YORK	USA	Cardiovascular Diseases Research	000	4	1/31/2026	NON-COMPETING CONTINUATION	$786,489
														Subtotal = $786,489

Issue Date FY: 2025 ( Subtotal = $827,884 )
2025	2025	NEW YORK UNIVERSITY	550 1ST AVE	NEW YORK	NY	10016	NEW YORK	USA	Cardiovascular Diseases Research	000	3	12/18/2024	NON-COMPETING CONTINUATION	$745,095
2025	2025	NEW YORK UNIVERSITY	550 1ST AVE	NEW YORK	NY	10016	NEW YORK	USA	Cardiovascular Diseases Research	001	3	8/15/2025	NON-COMPETING CONTINUATION	$82,789
														Subtotal = $827,884

Issue Date FY: 2024 ( Subtotal = $811,326 )
2024	2024	NEW YORK UNIVERSITY	550 1ST AVE	NEW YORK	NY	10016	NEW YORK	USA	Cardiovascular Diseases Research	001	2	6/12/2024	NON-COMPETING CONTINUATION	$66,231
2024	2024	NEW YORK UNIVERSITY	550 1ST AVE	NEW YORK	NY	10016	NEW YORK	USA	Cardiovascular Diseases Research	000	2	12/14/2023	NON-COMPETING CONTINUATION	$745,095
														Subtotal = $811,326

Issue Date FY: 2023 ( Subtotal = $827,884 )
2023	2023	NEW YORK UNIVERSITY	550 1ST AVE	NEW YORK	NY	10016	NEW YORK	USA	Cardiovascular Diseases Research	000	1	12/26/2022	NEW	$827,884
														Subtotal = $827,884

Grand Total All Awards = $3,253,583

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Chylomicrons and endothelial biology

Award Number: R01HL160891

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 01/01/2023

PERIOD OF PERFORMANCE END DATE: 12/31/2026

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