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Myocardial-associated B lymphocytes and inflammatory injury

Award Number: R01HL160716
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 01/01/2022
PERIOD OF PERFORMANCE END DATE: 12/31/2025

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Myocardial-associated B lymphocytes and inflammatory injury - Project Summary/Abstract: Heart failure is a debilitating disease. A growing body of evidence indicates that inflammation plays an important role in the development and progression of this disease. However, the development of immunomodulatory based treatments for heart failure has, so far, been mostly unsuccessful. The PI recently described a population of circulating B cells that adheres to the myocardial endothelium and found that B cell deficient animals have alterations in cardiac structure and function. Moreover, he found that, in rodents, small molecule-mediated modulation of myocardial B cells improves cardiac function after heart attacks. These findings, together with emerging evidence from other research groups, suggest that B cells might be a powerful target for the development of immunomodulatory therapies to prevent and treat cardiac dysfunction. However, our current understanding of myocardial B cell biology is critically lacking. Heart damage triggers a local and systemic inflammatory response characterized by recruitment of inflammatory cells to the injured heart and rapid changes in the spleen. Currently, it is unclear if and how B cells are recruited into the injured myocardium. Moreover, even though B cells account for about half of all the cells in the spleen, and splenic inflammatory changes induced by heart damage have been shown to play a critical role in the progression of heart failure, it is unclear if B cells play a role in the splenic immune response triggered by heart damage. In addition, it remains unknown whether B cell mediated antigen presentation (that together with antibody production and cytokine secretion is one of the 3 prototypical functions of B cells) plays any role within the inflammatory response triggered by cardiac injury. Finally, at an even more basic level, it is unknown how B cells adhere to the endothelium of the uninjured heart. Here, the PI proposes to fill these gaps in knowledge by testing the hypothesis that circulating B cells bind to the myocardial endothelium through specific adhesion molecules and, in response to myocardial injury, enter the myocardium through a CXCL13-CCR5 dependent process, are activated and proliferate in an antigen independent manner, and recirculate between the heart and the spleen to amplify the inflammatory reaction elicited by cardiac damage via MHC-II mediated antigen presentation. The long-term goal of the PI is to use the knowledge gained to facilitate the development of B cell-targeted therapies for heart failure. The PI has been a pioneer in the study of the interaction between B cells and the heart. He is a junior investigator, but he has mastered all the techniques needed to test this hypothesis, he is supported by several seasoned scientists that are co-investigators or collaborators in this proposal, and works within a highly collaborative research environment focused on excellence and innovation. He, therefore, is aptly qualified to effectively test this innovative hypothesis and address, within the timeline of this proposal, the critical knowledge gaps described.


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	THE JOHNS HOPKINS UNIVERSITY	3400 N CHARLES ST	BALTIMORE	MD	21218	BALTIMORE CITY	USA	Cardiovascular Diseases Research	000	4	6/10/2026	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2025 ( Subtotal = $524,689 )
2025	2025	THE JOHNS HOPKINS UNIVERSITY	3400 N CHARLES ST	BALTIMORE	MD	21218	BALTIMORE CITY	USA	Cardiovascular Diseases Research	001	4	8/14/2025	NON-COMPETING CONTINUATION	$52,468
2025	2025	THE JOHNS HOPKINS UNIVERSITY	3400 N CHARLES ST	BALTIMORE	MD	21218	BALTIMORE CITY	USA	Cardiovascular Diseases Research	000	4	12/13/2024	NON-COMPETING CONTINUATION	$472,221
														Subtotal = $524,689

Issue Date FY: 2024 ( Subtotal = $461,927 )
2024	2024	THE JOHNS HOPKINS UNIVERSITY	3400 N CHARLES ST	BALTIMORE	MD	21218	BALTIMORE CITY	USA	Cardiovascular Diseases Research	000	3	1/15/2024	NON-COMPETING CONTINUATION	$424,218
2024	2024	THE JOHNS HOPKINS UNIVERSITY	3400 N CHARLES ST	BALTIMORE	MD	21218	BALTIMORE CITY	USA	Cardiovascular Diseases Research	001	3	6/19/2024	NON-COMPETING CONTINUATION	$37,709
														Subtotal = $461,927

Issue Date FY: 2023 ( Subtotal = $471,353 )
2023	2023	JOHNS HOPKINS UNIVERSITY, THE	3400 N CHARLES ST	BALTIMORE	MD	21218	BALTIMORE CITY	USA	Cardiovascular Diseases Research	000	2	1/23/2023	NON-COMPETING CONTINUATION	$471,353
														Subtotal = $471,353

Issue Date FY: 2022 ( Subtotal = $479,563 )
2022	2022	JOHNS HOPKINS UNIVERSITY, THE	3400 N CHARLES ST	BALTIMORE	MD	21218	BALTIMORE CITY	USA	Cardiovascular Diseases Research	000	1	12/23/2021	NEW	$479,563
														Subtotal = $479,563

Grand Total All Awards = $1,937,532

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Myocardial-associated B lymphocytes and inflammatory injury

Award Number: R01HL160716

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 01/01/2022

PERIOD OF PERFORMANCE END DATE: 12/31/2025

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