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Investigating the Novel Roles of FFAR4 in Foam Cell Formation and Atherosclerosis

Award Number: F31HL165927
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS
PERIOD OF PERFORMANCE START DATE: 04/07/2023
PERIOD OF PERFORMANCE END DATE: 02/27/2025

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Investigating the Novel Roles of FFAR4 in Foam Cell Formation and Atherosclerosis - PROJECT SUMMARY/ABSTRACT Cardiovascular disease (CVD) is the leading cause of death in the United States. Atherosclerosis, a major cause of CVD, is an inflammatory disease resulting from the build-up of cholesterol in plaque along the artery walls. These plaques are formed by accumulation of macrophage foam cells as an inflammatory response to oxidized low-density lipoprotein (oxLDL) in damaged endothelial cells. Free fatty acid receptor 4 (FFAR4), also known as G-protein coupled receptor 120 (GPR120), is a long-chain unsaturated fatty acid receptor expressed in adipocytes, endothelial cells, and macrophages. Activation of FFAR4 helps maintain metabolic homeostasis by regulating adipogenesis, insulin sensitivity, and inflammation. While FFAR4 is best known for its protective role in preventing obesity and diabetes, recent studies have demonstrated that FFAR4 may also play an important role in the prevention of atherosclerosis and CVD. Given FFAR4’s importance in anti-inflammatory signaling and high expression levels in macrophages, we designed experiments to test the hypothesis that FFAR4 plays a cardioprotective role by preventing pathways that lead to atherosclerosis. These experiments will require macrophages harvested from wild-type and FFAR4-knockout mice, and in some cases, macrophages treated with FFAR4 agonists. In Aim 1, we will investigate the effects of FFAR4 deficiency on macrophage foam cell formation. Specifically, we will determine whether FFAR4 deficiency increases oxLDL uptake (Aim 1.1), decreases cholesterol efflux (Aim 1.2), and decreases macrophage migration (Aim 1.3). In Aim 2, we will investigate the signaling mechanisms utilized by FFAR4 to protects against foam cell formation and test the hypothesis that canonical Gaq/11 FFAR4 signaling reduces cholesterol uptake and promotes cholesterol efflux by inhibiting the transcription factor PPARg. In Aim 3, we will investigate the physiological role of FFAR4 in atherosclerosis. Aim 3.1 will examine how FFAR4 deficiency in vivo impacts lipid levels and circulating inflammatory cytokines. Aim 3.2 will assess atherosclerotic lesion size differences and immune cell activation status in the aorta of LDLR-/- mice following transplantation of bone marrow from FFAR4+/+ or FFAR4-/- mice. The outcomes of these proposed studies will uncover the biological functions of FFAR4 and mechanisms that underlie how FFAR4 protects against macrophage foam cell formation, a hallmark of atherosclerosis. Ultimately, our combined current and future studies may identify FFAR4 as a novel therapeutic target for atherosclerosis.


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 = -$9 )
2026	2024	THE MEDICAL COLLEGE OF WISCONSIN, INC.	8701 WATERTOWN PLANK RD	MILWAUKEE	WI	53226	MILWAUKEE	USA	Cardiovascular Diseases Research	000	2	3/24/2026	NON-COMPETING CONTINUATION	-$9
														Subtotal = -$9

Issue Date FY: 2025 ( Subtotal = -$3,236 )
2025	2024	THE MEDICAL COLLEGE OF WISCONSIN, INC.	8701 WATERTOWN PLANK RD	MILWAUKEE	WI	53226	MILWAUKEE	USA	Cardiovascular Diseases Research	000	2	6/17/2025	NON-COMPETING CONTINUATION	-$3,236
														Subtotal = -$3,236

Issue Date FY: 2024 ( Subtotal = $48,974 )
2024	2024	THE MEDICAL COLLEGE OF WISCONSIN, INC.	8701 WATERTOWN PLANK RD	MILWAUKEE	WI	53226	MILWAUKEE	USA	Cardiovascular Diseases Research	001	2	9/6/2024	NON-COMPETING CONTINUATION	$1,280
2024	2024	THE MEDICAL COLLEGE OF WISCONSIN, INC.	8701 WATERTOWN PLANK RD	MILWAUKEE	WI	53226	MILWAUKEE	USA	Cardiovascular Diseases Research	000	2	3/28/2024	NON-COMPETING CONTINUATION	$47,694
														Subtotal = $48,974

Issue Date FY: 2023 ( Subtotal = $47,694 )
2023	2023	MEDICAL COLLEGE OF WISCONSIN, INC., THE	8701 WATERTOWN PLANK RD	MILWAUKEE	WI	53226	MILWAUKEE	USA	Cardiovascular Diseases Research	000	1	4/7/2023	NEW	$47,694
2023	2023	MEDICAL COLLEGE OF WISCONSIN, INC., THE	8701 WATERTOWN PLANK RD	MILWAUKEE	WI	53226	MILWAUKEE	USA	Cardiovascular Diseases Research	001	1	4/7/2023	NEW	$0
														Subtotal = $47,694

Grand Total All Awards = $93,423

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Investigating the Novel Roles of FFAR4 in Foam Cell Formation and Atherosclerosis

Award Number: F31HL165927

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS

PERIOD OF PERFORMANCE START DATE: 04/07/2023

PERIOD OF PERFORMANCE END DATE: 02/27/2025

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