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Lipin-1 transcriptional coregulatory activity promotes macrophage pro-resolving response

Award Number: R01HL163106
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/01/2023
PERIOD OF PERFORMANCE END DATE: 07/31/2027

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Lipin-1 transcriptional coregulatory activity promotes macrophage pro-resolving response - Despite medical advances, atherosclerotic cardiovascular disease (ACVD) is a leading cause of death. ACVD is caused by chronic inflammatory due to both excessive inflammation and failed inflammation resolution. Unlike inhibition of inflammation that reduces ACVD but increases fatal infections, restoration of inflammation resolution may reduce ACVD without increased fatal infections. Macrophages resolve inflammation by secreting anti-in- flammatory mediators and phagocytosing dead cells in a process termed efferocytosis. Efferocytosis increases intracellular free fatty acids (FA) that must be processed either through β-oxidation, incorporation in glycerolipids or ceramides. The movement of FA into these different pathways is called lipid channeling. Increased β-oxidation is associated with macrophage resolution and is considered atheroprotective, while ceramide metabolism pro- motes inflammation and is considered atherogenic. However, there are several critical questions: 1) Is one path- way more critical to inflammation resolution than the other, 2) does the alteration of one lipid pathway alter the other, 3) how lipid channeling is regulated during resolution and plaque regression. Lipin-1 is a phosphatidic acid phosphatase with transcriptional coregulatory activity. My laboratory showed that macrophage-associated lipin- 1 is needed for inflammation resolution and atherosclerotic regression and likely does this through regulation of FA metabolism, independent of its enzymatic activity. Our central hypothesis is that lipin-1 is a dominant lipid channeling regulator in macrophages, promoting inflammation resolution and atherosclerosis regression by en- hancing β-oxidation and repressing ceramide synthesis. We will test our central hypothesis and accomplish the objective of this application by pursuing three specific aims. Aim 1 will explore the hypothesis that lipin-1 regu- lates the activity of metabolic transcription factors to fine-tune FA metabolic pathways to align with macrophage resolution activity. Aim 2 will examine which FA pathways (FA metabolism, β-oxidation, or ceramide metabolism) are critical to macrophage inflammation resolution response and find if the alteration in one pathway impacts the others. Aim 3 will explore the hypothesis that lipin-1 non-enzymatic activity promotes atherosclerotic regression and map the FA metabolic state of the regressing plaque. These proposed experiments will support the innova- tive idea that lipin-1 in macrophages is a dominant regulator of lipid channeling and promotes inflammation resolution by enhancing beta-oxidation while repressing ceramide synthesis. This application's beneficial impact will be the understanding that fatty acid metabolism is regulated to limit lipotoxicity and promote inflammation resolution to identify therapeutic targets to reduce the burden of atherosclerosis and its pathologic sequelae.


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 = $562,001 )
2025	2025	LOUISIANA STATE UNIVERSITY	1501 KINGS HWY	SHREVEPORT	LA	71103	CADDO	USA	Cardiovascular Diseases Research	000	3	8/2/2025	NON-COMPETING CONTINUATION	$562,001
														Subtotal = $562,001

Issue Date FY: 2024 ( Subtotal = $550,760 )
2024	2024	LOUISIANA STATE UNIVERSITY	1501 KINGS HWY	SHREVEPORT	LA	71103	CADDO	USA	Cardiovascular Diseases Research	000	2	6/26/2024	NON-COMPETING CONTINUATION	$550,760
														Subtotal = $550,760

Issue Date FY: 2023 ( Subtotal = $562,001 )
2023	2023	LOUISIANA STATE UNIVERSITY	1501 KINGS HWY	SHREVEPORT	LA	71103	CADDO	USA	Cardiovascular Diseases Research	000	1	8/8/2023	NEW	$562,001
														Subtotal = $562,001

Grand Total All Awards = $1,674,762

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Lipin-1 transcriptional coregulatory activity promotes macrophage pro-resolving response

Award Number: R01HL163106

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 09/01/2023

PERIOD OF PERFORMANCE END DATE: 07/31/2027

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