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Targeting the Active Resolution of Inflammation for Cardiovascular Disease Prevention

Award Number: R01HL160799
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 12/01/2021
PERIOD OF PERFORMANCE END DATE: 11/30/2026

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Targeting the Active Resolution of Inflammation for Cardiovascular Disease Prevention - PROJECT SUMMARY Inflammation is crucial for the host defense response, but unregulated inflammation is a key element of atherothrombosis and links plaque initiation to subsequent growth and acute rupture, leading to clinical cardiovascular (CVD) events. Clinical trials of inflammation inhibition have significantly reduced CVD events, confirmed the inflammation-CVD hypothesis, and stimulated interest in targeting inflammation specifically for CVD prevention. Such therapies could have widespread impact, since residual inflammatory risk in clinical practice is common and undertreated. Importantly, recent evidence demonstrates that the resolution of inflammation is not a passive process but occurs in an active coordinated process involving chemical mediators called specialized pro-resolving mediators (SPMs) that include resolvins, maresins, lipoxins, protectins (neuroprotectins), and aspirin-triggered pro-resolving mediators, each with characteristic biological actions. Yet a major gap in knowledge is which specific SPMs or sets of SPMs may be cardioprotective in human populations. Motivated by our exciting preliminary findings that plasma levels of certain SPMs are related to CVD risk and inflammatory traits, and in response to NHLBI NOT-ES-20-018: Promoting Fundamental and Applied Research in Inflammation Resolution to identify the role of SPMs in CVD, we propose to test the hypothesis that specific SPMs are early indicators of CVD protection from inflammation and are associated with its resolution over time. This cost-efficient proposal leverages resources from three well-phenotyped and genotyped prospective studies. We will examine an extensive panel of circulating plasma SPMs and proinflammatory mediators using a high-throughput mass spectrometry assay in relation to incident CVD (total 2339 cases) including repeated measures over time in a subset. Our primary aims are to: 1) Evaluate associations of SPMs with future CVD events in primary and secondary prevention populations enriched with chronic inflammation, and assess effect modification by randomized aspirin therapy vs placebo since aspirin has important pro-resolving effects on SPM biosynthesis; 2) Examine associations of circulating SPMs with CVD risk factors and downstream biomarkers and cytokines of systemic inflammation; and perform genome-wide association study of circulating SPMs, to better understand biological pathways for mechanistic insights into SPM functions; and 3) Assess temporal changes in SPMs over time in relation to concomitant changes in levels of downstream proinflammatory biomarkers and cytokines, and examine modulation of SPMs with randomized low-dose methotrexate vs placebo. We will examine functional actions of the relevant CVD-associated SPMs using ex vivo leukocyte assays for inflammatory gene expression and macrophage pro-resolving function. Results from this proposal will identify and validate resolution mediators and pathways that may play a pivotal role in cardioprotection and could have important public health significance since residual inflammatory risk is common and remains undertreated with current therapeutics.


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 = $0 )
2026	2025	BRIGHAM & WOMENS HOSPITAL INC	75 FRANCIS ST	BOSTON	MA	02115	SUFFOLK	USA	Cardiovascular Diseases Research	000	4	10/7/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2025 ( Subtotal = $755,921 )
2025	2025	BRIGHAM & WOMENS HOSPITAL INC	75 FRANCIS ST	BOSTON	MA	02115	SUFFOLK	USA	Cardiovascular Diseases Research	001	4	8/18/2025	NON-COMPETING CONTINUATION	$75,591
2025	2025	BRIGHAM & WOMENS HOSPITAL INC	75 FRANCIS ST	BOSTON	MA	02115	SUFFOLK	USA	Cardiovascular Diseases Research	000	4	1/3/2025	NON-COMPETING CONTINUATION	$680,330
														Subtotal = $755,921

Issue Date FY: 2024 ( Subtotal = $742,480 )
2024	2024	BRIGHAM & WOMENS HOSPITAL INC	75 FRANCIS ST	BOSTON	MA	02115	SUFFOLK	USA	Cardiovascular Diseases Research	001	3	6/12/2024	NON-COMPETING CONTINUATION	$60,609
2024	2024	BRIGHAM & WOMENS HOSPITAL INC	75 FRANCIS ST	BOSTON	MA	02115	SUFFOLK	USA	Cardiovascular Diseases Research	000	3	11/17/2023	NON-COMPETING CONTINUATION	$681,871
														Subtotal = $742,480

Issue Date FY: 2023 ( Subtotal = $759,294 )
2023	2023	BRIGHAM & WOMENS HOSPITAL INC	75 FRANCIS ST	BOSTON	MA	02115	SUFFOLK	USA	Cardiovascular Diseases Research	001	2	2/11/2023	NON-COMPETING CONTINUATION	$75,928
2023	2023	BRIGHAM & WOMENS HOSPITAL INC	75 FRANCIS ST	BOSTON	MA	02115	SUFFOLK	USA	Cardiovascular Diseases Research	000	2	12/19/2022	NON-COMPETING CONTINUATION	$683,366
														Subtotal = $759,294

Issue Date FY: 2022 ( Subtotal = $781,070 )
2022	2022	BRIGHAM AND WOMEN'S HOSPITAL, INC., THE	75 FRANCIS ST	BOSTON	MA	02115	SUFFOLK	USA	Cardiovascular Diseases Research	000	1	11/24/2021	NEW	$781,070
														Subtotal = $781,070

Grand Total All Awards = $3,038,765

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Targeting the Active Resolution of Inflammation for Cardiovascular Disease Prevention

Award Number: R01HL160799

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 12/01/2021

PERIOD OF PERFORMANCE END DATE: 11/30/2026

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