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Resolution of inflammation and atrial fibrillation

Award Number: R01HL165704
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 04/20/2023
PERIOD OF PERFORMANCE END DATE: 01/31/2028

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Resolution of inflammation and atrial fibrillation - Systemic inflammation and oxidative stress are common in patients with AF. In atrial cardiomyocytes (CMs), AF can be precipitated by NLRP3 inflammasome activation and IL-1β secretion. Since we have established cardiac NLRP3 activation and IL-1β can lead to AF, we will study upstream modulators of the cardiac NLRP3 inflammasome that can be manipulated to reduce AF risk in DM. We have found that enzymes producing pro-inflammatory molecules are elevated and inflammation resolving molecules are reduced in atria from humans and mice with DM. Specifically, we have found increased 12- lipoxygenase (12-LOX, encoded by ALOX12), an enzyme that processes arachidonic acid (AA) to pro- inflammatory metabolites in humans and mice. In humans and mice, we have found that cardiac pro-resolving lipid mediators (SPMs) are reduced, leucine-rich repeat containing G protein-coupled receptor 6 (LGR6, encoded by LGR6), a recently described receptor of SPMs, is downregulated, and 15-hydroxyprostaglandin dehydrogenase (15-PGDH; encoded by HPGD), an enzyme in the inactivation of SPMs, is increased in DM atria. Hypotheses to be tested: Since SPMs can reduce NLRP3 activation, this application explores whether DM- associated AF risk can be mitigated by enhancing SPM signaling by reducing inflammatory lipid mediator production (12-LOX inhibition), enhancing SPM signaling (upregulation of LGR6), or reducing SPM degradation (downregulating of 15-PGDH). Specific aims: Aim 1: Determine whether inhibition of cardiac 12-LOX upregulation can reduce atrial NLRP3 activation and AF burden in DM. Specific Aim 2: Determine whether upregulation of cardiac LGR6 can reduce atrial NLRP3 activation and AF burden in DM. Specific Aim 3: Determine whether downregulation of cardiac 15-PGDH can reduce atrial NLRP3 activation and AF burden in DM. Significance: This application explores new treatment paradigms of encouraging inflammation resolution to prevent DM-induced AF. Using parallel experiments in humans and mice will provide mechanistic insights and strengthen clinical relevance. A focus on prevention rather than treatment is novel and could prevent significant morbidity associated with AF onset.


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 = $706,861 )
2026	2026	REGENTS OF THE UNIVERSITY OF MINNESOTA	2221 UNIVERSITY AVE SE STE 100	MINNEAPOLIS	MN	55414	HENNEPIN	USA	Cardiovascular Diseases Research	000	4	4/13/2026	NON-COMPETING CONTINUATION	$622,998
2026	2026	REGENTS OF THE UNIVERSITY OF MINNESOTA	2221 UNIVERSITY AVE SE STE 100	MINNEAPOLIS	MN	55414	HENNEPIN	USA	Cardiovascular Diseases Research	001	4	4/24/2026	SUPPLEMENT FOR EXPANSION	$83,863
														Subtotal = $706,861

Issue Date FY: 2025 ( Subtotal = $719,575 )
2025	2025	REGENTS OF THE UNIVERSITY OF MINNESOTA	2221 UNIVERSITY AVE SE STE 100	MINNEAPOLIS	MN	55414	HENNEPIN	USA	Cardiovascular Diseases Research	001	3	9/19/2025	NON-COMPETING CONTINUATION	$71,956
2025	2025	REGENTS OF THE UNIVERSITY OF MINNESOTA	200 OAK ST SE	MINNEAPOLIS	MN	55455	HENNEPIN	USA	Cardiovascular Diseases Research	000	3	1/22/2025	NON-COMPETING CONTINUATION	$647,619
														Subtotal = $719,575

Issue Date FY: 2024 ( Subtotal = $705,184 )
2024	2024	REGENTS OF THE UNIVERSITY OF MINNESOTA	200 OAK ST SE	MINNEAPOLIS	MN	55455	HENNEPIN	USA	Cardiovascular Diseases Research	001	2	6/12/2024	NON-COMPETING CONTINUATION	$57,565
2024	2024	REGENTS OF THE UNIVERSITY OF MINNESOTA	200 OAK ST SE	MINNEAPOLIS	MN	55455	HENNEPIN	USA	Cardiovascular Diseases Research	000	2	2/1/2024	NON-COMPETING CONTINUATION	$647,619
														Subtotal = $705,184

Issue Date FY: 2023 ( Subtotal = $733,325 )
2023	2023	REGENTS OF THE UNIVERSITY OF MINNESOTA	200 OAK ST SE # 224	MINNEAPOLIS	MN	55455	HENNEPIN	USA	Cardiovascular Diseases Research	000	1	4/20/2023	NEW	$733,325
														Subtotal = $733,325

Grand Total All Awards = $2,864,945

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Resolution of inflammation and atrial fibrillation

Award Number: R01HL165704

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 04/20/2023

PERIOD OF PERFORMANCE END DATE: 01/31/2028

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