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Processing of Apoptotic Cell-Derived Cargo by Macrophages Continues Efferocytosis and Drives Atherosclerosis Regression

Award Number: R00HL145131
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 03/01/2021
PERIOD OF PERFORMANCE END DATE: 02/28/2025

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Processing of Apoptotic Cell-Derived Cargo by Macrophages Continues Efferocytosis and Drives Atherosclerosis Regression - Atherosclerotic cardiovascular disease (CVD) is the leading cause of death in the industrialized world. Most atherosclerotic plaques are clinically silent; however, a subset can lead to myocardial infarction, stroke, or sudden death. Atheromas that are linked to clinical events are characterized by large necrotic cores, which result from the defective clearance of apoptotic cells (ACs). When functioning normally, clearance of ACs, termed “efferocytosis”, resolves inflammation. Therefore, enhancing efferocytosis in advanced lesions may stabilize rupture-prone plaques and reduce clinical events. While the mechanisms that lead to phagocytosis of one AC have been well-defined, individual macrophages (MΦs) must engulf many ACs, termed “continued efferocytosis”, in vivo. Accordingly, two critical, unanswered questions are (a) how do MΦs process the cargo derived from degrading an AC, and (b) what mechanisms are in place that cue MΦs that have previously ingested an AC to internalize a subsequent AC. Therefore, the overall objective of this proposal is to understand the signaling and metabolic pathways that enable the continued clearance of ACs and to harness these pathways towards a novel treatment strategy. This proposal tests two new pathways critical for continued efferocytosis. In the first pathway, MΦs metabolize AC-derived arginine into putrescine, through the sequential action of arginase 1 (Arg1) and ornithine decarboxylase (ODC), to remodel the actin cytoskeleton. In the second pathway, MΦs respond to the overabundance of AC-derived nutrients by stimulating the nutrient sensor mTORC1 to recycle vesicles to the cell surface and supply the developing phagosome with plasma membrane. Aim 1 will explore the hypothesis that AC-derived arginine is metabolized into putrescine and examine the mechanisms by which putrescine regulates cytoskeletal remodeling. Aim 2 will test the hypothesis and investigate the mechanisms therein, that the putrescine-synthesizing enzymes Arg1 and ODC drive atherosclerosis regression and inflammation resolution. Aim 3 will explore the hypothesis that SLC38A9 senses AC-derived arginine and cholesterol to activate mTORC1 and identify the mechanisms that drive the internalization of a second AC. Successful completion of these aims will provide new mechanistic insight in how MΦs sense and metabolize the cargo from ingested ACs, which will provide new therapeutic opportunities to curb 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 = -$4,536 )
2025	2023	LOUISIANA STATE UNIVERSITY	1501 KINGS HWY	SHREVEPORT	LA	71103	CADDO	USA	Cardiovascular Diseases Research	000	5	8/7/2025	NON-COMPETING CONTINUATION	-$4,536
														Subtotal = -$4,536

Issue Date FY: 2023 ( Subtotal = $249,000 )
2023	2023	LOUISIANA STATE UNIVERSITY	1501 KINGS HWY	SHREVEPORT	LA	71103	CADDO	USA	Cardiovascular Diseases Research	000	5	3/1/2023	NON-COMPETING CONTINUATION	$249,000
														Subtotal = $249,000

Issue Date FY: 2022 ( Subtotal = $249,000 )
2022	2022	LOUISIANA STATE UNIVERSITY	1501 KINGS HWY	SHREVEPORT	LA	71103	CADDO	USA	Cardiovascular Diseases Research	000	4	3/1/2022	NON-COMPETING CONTINUATION	$249,000
														Subtotal = $249,000

Issue Date FY: 2021 ( Subtotal = $253,536 )
2021	2021	LOUISIANA STATE UNIVERSITY	1501 KINGS HWY	SHREVEPORT	LA	71103	CADDO	USA	Cardiovascular Diseases Research	001	3	7/1/2021	EXTENSION WITH OR WITHOUT FUNDS	$4,536
2021	2021	LOUISIANA STATE UNIVERSITY	1501 KINGS HWY	SHREVEPORT	LA	71103	CADDO	USA	Cardiovascular Diseases Research	000	3	2/8/2021	EXTENSION WITH OR WITHOUT FUNDS	$249,000
														Subtotal = $253,536

Grand Total All Awards = $747,000

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Processing of Apoptotic Cell-Derived Cargo by Macrophages Continues Efferocytosis and Drives Atherosclerosis Regression

Award Number: R00HL145131

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 03/01/2021

PERIOD OF PERFORMANCE END DATE: 02/28/2025

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