Monday, June 30, 2025 6/30/2025

Clonal expansion, resistance to efferocytosis and innate immunity in atherosclerosis

Award Number: R35HL144475
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 01/15/2019
PERIOD OF PERFORMANCE END DATE: 12/31/2024

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Clonal expansion, resistance to efferocytosis and innate immunity in atherosclerosis - PROJECT SUMMARY/ABSTRACT Recent studies have shown that the vascular smooth muscle cell (SMC) can ‘de-differentiate’ and undergo substantial ‘phenotypic modulation’ during atherogenesis. Novel lineage-tracing data revealed that a subset of these cells assume a ‘stem-like’ phenotype and undergo significant clonal expansion, likely potentiating plaque progression. Unfortunately, we do not yet know the mechanism by which these clonal populations arise, how they promote disease, or whether they can be targeted for translational purposes. The broad, long-term goal of this proposal is to precisely define how clonal expansion occurs and how to suppress it. In doing so, we will learn how to target the ‘atherosclerosis stem cell’ and develop novel therapies for heart disease. Using new preliminary data generated via single-cell RNA-seq analysis of multicolor lineage-tracer models, our team will test the hypothesis that ‘stem-like’ SMCs evade phagocytic removal (allowing them to undergo clonal expansion) and activate the complement cascade (causing them to exacerbate vascular inflammation). The project combines unique transgenic animals, highly specialized human biorepository specimens and new interdisciplinary collaborations. The program is focused on three broad efforts which will: 1. Determine if pro-phagocytic therapies can specifically prevent clonal expansion; 2. Determine whether the ‘stem-like’ SMC requires the classical complement cascade to promote disease; and 3. Determine if clonal SMC expansion also has translational relevance to human atherosclerosis. This proposal will provide important insights into the root causes of SMC plasticity and determine how programmed cell removal, or ‘efferocytosis’ (from Greek, meaning to carry the dead to the grave) contributes to atherosclerosis. Ultimately, discoveries made in this highly flexible R35 project will support the stated mission of the National Institutes of Health, provide tools for other HLBS investigators, train the next generation of investigators, and lead to the development of new translational therapies for patients with cardiovascular disease.


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: 2025 ( Subtotal = -$14,413 )
2025	2024	THE LELAND STANFORD JUNIOR UNIVERSITY	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Cardiovascular Diseases Research	001	6	4/29/2025	NON-COMPETING CONTINUATION	-$14,413
2025	2024	THE LELAND STANFORD JUNIOR UNIVERSITY	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Cardiovascular Diseases Research	000	6	4/16/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = -$14,413

Issue Date FY: 2024 ( Subtotal = $837,017 )
2024	2024	THE LELAND STANFORD JUNIOR UNIVERSITY	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Cardiovascular Diseases Research	000	6	12/26/2023	NON-COMPETING CONTINUATION	$768,687
2024	2024	THE LELAND STANFORD JUNIOR UNIVERSITY	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Cardiovascular Diseases Research	001	6	6/14/2024	NON-COMPETING CONTINUATION	$68,330
														Subtotal = $837,017

Issue Date FY: 2023 ( Subtotal = $853,998 )
2023	2023	THE LELAND STANFORD JUNIOR UNIVERSITY	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Cardiovascular Diseases Research	001	5	3/3/2023	NON-COMPETING CONTINUATION	$85,399
2023	2023	THE LELAND STANFORD JUNIOR UNIVERSITY	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Cardiovascular Diseases Research	002	5	4/5/2023	NON-COMPETING CONTINUATION	$0
2023	2023	LELAND STANFORD JUNIOR UNIVERSITY, THE	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Cardiovascular Diseases Research	000	5	1/11/2023	NON-COMPETING CONTINUATION	$768,599
														Subtotal = $853,998

Issue Date FY: 2022 ( Subtotal = $853,792 )
2022	2022	LELAND STANFORD JUNIOR UNIVERSITY, THE	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Cardiovascular Diseases Research	001	4	6/9/2022	NON-COMPETING CONTINUATION	$85,381
2022	2022	LELAND STANFORD JUNIOR UNIVERSITY, THE	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Cardiovascular Diseases Research	000	4	12/23/2021	NON-COMPETING CONTINUATION	$768,411
														Subtotal = $853,792

Issue Date FY: 2021 ( Subtotal = $853,512 )
2021	2021	LELAND STANFORD JUNIOR UNIVERSITY, THE	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Cardiovascular Diseases Research	000	3	1/9/2021	NON-COMPETING CONTINUATION	$768,162
2021	2021	LELAND STANFORD JUNIOR UNIVERSITY, THE	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Cardiovascular Diseases Research	001	3	5/24/2021	NON-COMPETING CONTINUATION	$85,350
														Subtotal = $853,512

Issue Date FY: 2020 ( Subtotal = $853,390 )
2020	2020	LELAND STANFORD JUNIOR UNIVERSITY, THE	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Cardiovascular Diseases Research	002	2	4/22/2020	NON-COMPETING CONTINUATION	$0
2020	2020	LELAND STANFORD JUNIOR UNIVERSITY, THE	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Cardiovascular Diseases Research	001	2	3/13/2020	NON-COMPETING CONTINUATION	$42,671
2020	2020	LELAND STANFORD JUNIOR UNIVERSITY, THE	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Cardiovascular Diseases Research	000	2	12/20/2019	NON-COMPETING CONTINUATION	$810,719
														Subtotal = $853,390

Issue Date FY: 2019 ( Subtotal = $853,060 )
2019	2019	LELAND STANFORD JUNIOR UNIVERSITY, THE	450 SERRA MALL	STANFORD	CA	94305	SANTA CLARA	USA	Cardiovascular Diseases Research	000	1	1/11/2019	NEW	$853,060
														Subtotal = $853,060

Grand Total All Awards = $5,090,356

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Clonal expansion, resistance to efferocytosis and innate immunity in atherosclerosis

Award Number: R35HL144475

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 01/15/2019

PERIOD OF PERFORMANCE END DATE: 12/31/2024

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