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Macrophage-specific IEX-1 ? A Novel Mechanism in the Pathogenesis of Atherosclerosis

Award Number: SC3GM135023
ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 03/01/2020
PERIOD OF PERFORMANCE END DATE: 10/31/2022

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Macrophage-specific IEX-1 ? A Novel Mechanism in the Pathogenesis of Atherosclerosis - Macrophage-specific IEX-1 – A Novel Mechanism in the Pathogenesis of Atherosclerosis Atherosclerosis is a chronic inflammatory disease characterized by the accumulation of lipids in the artery wall. It is the leading cause of morbidity and mortality in the US. Several immune cells are involved in genesis of atherosclerosis; however, macrophages play a central role in all stages of the disease. Emerging evidence suggests that both the quantity and phenotype of macrophages influence the inception and progression of atherosclerotic lesions. Several macrophages subsets have been identified in atherosclerotic plaques, including classically-activated (CAMs), alternatively-activated (AAMs), and Mox based on their distinct gene expression. Macrophages with CAMs-like characteristics play a crucial role in initiation of atherosclerosis by infiltrating in sub-endothelial space and promoting inflammation. They engulf lipids and become foam cell to form plaque. In contrast, AAMs-like macrophages are enriched in regressing plaques. They inhibit inflammation and exhibit reduced foam cell formation. However, the identity of bona fide factors that critically regulate macrophage phenotype remain poorly understood. As a result, there is a dearth of the effective strategies to inhibit pro-atherogenic phenotype of macrophages to reduce atherosclerosis. IEX-1 is a stress- inducible gene that is highly expressed in macrophages. Our preliminary investigation revealed that IEX-1 is essential for atherosclerosis development and that its deficiency protected mice against atherosclerosis without impacting cholesterol metabolism. Interestingly, IEX-1 deficiency reversed the phenotype of macrophages infiltrated in aorta from CAMs to a AAMs-like state, with only little effect on macrophage infiltration. AAMs- biased polarization preceded the development of atherosclerotic plaque. In the current proposal we will address the hypothesis that IEX-1 activity in macrophages is required for atherogenesis. To address this, we propose to use a novel mouse model in which IEX-1 will be selectively deleted from macrophages on ApoE- deficiency background. We will study its impact on atherosclerotic plaque formation, aortic macrophage phenotype, and inflammatory status. Furthermore, to gain a mechanistic insight into how IEX-1 contributes to atherosclerosis, we plan to investigate a role of apoptosis and glycolysis in macrophage polarization and foam cell formation, the central step in plaque formation. We will employ several pharmacological approaches to alter IEX-1 expression or glycolysis and evaluate its impact on macrophage phenotype and foam cell production. Together, these studies will advance our understanding of how macrophage phenotype regulates atherosclerosis. The results may help develop promising therapeutic or diagnostic approaches for lipid-driven inflammatory conditions such as atherosclerosis, diabetes, and obesity.


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: 2023 ( Subtotal = -$250,815 )
2023	2022	CHICAGO STATE UNIVERSITY	9501 S KING DR	CHICAGO	IL	60628	COOK	USA	Biomedical Research and Research Training	003	3	3/9/2023	NON-COMPETING CONTINUATION	-$111,000
2023	2022	CHICAGO STATE UNIVERSITY	9501 S KING DR	CHICAGO	IL	60628	COOK	USA	Biomedical Research and Research Training	000	3	11/1/2022	NON-COMPETING CONTINUATION	$0
2023	2021	CHICAGO STATE UNIVERSITY	9501 S KING DR	CHICAGO	IL	60628	COOK	USA	Biomedical Research and Research Training	002	2	3/9/2023	NON-COMPETING CONTINUATION	-$111,000
2023	2020	CHICAGO STATE UNIVERSITY	9501 S KING DR	CHICAGO	IL	60628	COOK	USA	Biomedical Research and Research Training	001	1	3/9/2023	NEW	-$28,815
														Subtotal = -$250,815

Issue Date FY: 2022 ( Subtotal = $111,000 )
2022	2022	CHICAGO STATE UNIVERSITY	9501 S KING DR	CHICAGO	IL	60628	COOK	USA	Biomedical Research and Research Training	001	3	6/20/2022	NON-COMPETING CONTINUATION	$11,100
2022	2022	CHICAGO STATE UNIVERSITY	9501 S KING DR	CHICAGO	IL	60628	COOK	USA	Biomedical Research and Research Training	000	3	3/1/2022	NON-COMPETING CONTINUATION	$99,900
														Subtotal = $111,000

Issue Date FY: 2021 ( Subtotal = $111,000 )
2021	2021	CHICAGO STATE UNIVERSITY	9501 S KING DR	CHICAGO	IL	60628	COOK	USA	Biomedical Research and Research Training	000	2	2/25/2021	NON-COMPETING CONTINUATION	$111,000
														Subtotal = $111,000

Issue Date FY: 2020 ( Subtotal = $111,000 )
2020	2020	CHICAGO STATE UNIVERSITY	9501 S KING DR	CHICAGO	IL	60628	COOK	USA	Biomedical Research and Research Training	000	1	2/20/2020	NEW	$111,000
														Subtotal = $111,000

Grand Total All Awards = $82,185

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Macrophage-specific IEX-1 ? A Novel Mechanism in the Pathogenesis of Atherosclerosis

Award Number: SC3GM135023

ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 03/01/2020

PERIOD OF PERFORMANCE END DATE: 10/31/2022

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