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Regulation of T cell immune response in Heart Failure with Preserved Ejection Fraction

Award Number: R01HL165725
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 04/01/2023
PERIOD OF PERFORMANCE END DATE: 07/31/2025

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Regulation of T cell immune response in Heart Failure with Preserved Ejection Fraction - The goal of this R01 application is to investigate the mechanisms by which T cells contribute to heart failure (HF) with preserved ejection fraction (HFpEF), affecting roughly 50% of the HF patients. Notably, the treatments that improve survival and outcomes in patients with HF with reduced ejection fraction (HFrEF) have not provided clinical benefit in HFpEF patients, who often present with multiple comorbidities that include obesity and hypertension. Correlative epidemiological studies in HFpEF patients, suggest a potential contribution of inflammation to HFpEF. However the underlying immune mechanisms remain largely unexplored. A unique myocardial hallmark of human HFpEF replicated in a pre-clinical model of cardiometabolic HFpEF is the downregulation of the unfolded protein response (UPR), which results in the cellular inability to cope with endoplasmic reticulum (ER) stress, the central function of the UPR, thus impairing cardiomyocyte relaxation. Our preliminary data using an experimental model of cardiometabolic HFpEF reveal the novel finding that cardiac T cell infiltration co-exists with diastolic dysfunction and cardiomyocyte hypertrophy, and that T cell deficient mice (Tcra-/-) do not develop diastolic dysfunction or cardiomyocyte hypertrophy under the same conditions. Our data also reveal that genes encoding specific ER stress response factors such as X-box protein 1 (XBP1s) and activating transcription factor 6 (ATF6), are remarkably downregulated in CD4+ T cells isolated from mice with cardiometabolic HFpEF, and not in T cells from mice with HFrEF. T cell downregulation of XBP1s has been implicated in enhanced T cell effector function and anti-tumor activity. This proposal will test the central hypothesis that dysregulation of T cell- intrinsic ER stress responses promotes detrimental inflammation in cardiometabolic HFpEF. In Aim1, we will use single cell antibody and RNA sequencing (CITE-Seq) to uncover the T cell transcriptional profiles throughout the development of cardiometabolic HFpEF in WT mice, investigate the antigen dependence of the T cell response, the dominant T cell subsets involved, and their ability to rescue the protective phenotype observed in Tcra-/- recipient mice. In Aim 2, we will determine the expression of the T cell UPR during the progression of cardiometabolic HFpEF and utilize gain-and loss-of- function approaches to define the mechanisms by which the T cell UPR is compromised in cardiometabolic HFpEF and impacts T cell pro- inflammatory effector function. In Aim 3, we will investigate the functional role of the T cell-intrinsic ER stress response in cardiomyocyte hypertrophy and function during the progression of HFpEF and the T cell derived factors altered by the compromised UPR that impact cardiomyocyte hypertrophy and function, using mice selectively lacking UPR effectors in T cells, and gain of function approaches,. Successful accomplishment of the Aims proposed is expected to identify novel T cell intrinsic mechanisms that foster detrimental immune responses in HFpEF, paving the way for the development of new immunomodulatory strategies to confront this deadly syndrome.


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 = $563,080 )
2026	2026	UNIVERSITY OF MIAMI	1320 S DIXIE HWY STE 1200	CORAL GABLES	FL	33146	MIAMI-DADE	USA	Cardiovascular Diseases Research	001	4	5/11/2026	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$563,080
2026	2025	TRUSTEES OF TUFTS COLLEGE	136 HARRISON AVE	BOSTON	MA	02111	SUFFOLK	USA	Cardiovascular Diseases Research	002	3	5/15/2026	NON-COMPETING CONTINUATION	$0
2026	2025	TRUSTEES OF TUFTS COLLEGE	136 HARRISON AVE	BOSTON	MA	02111	SUFFOLK	USA	Cardiovascular Diseases Research	000	3	4/29/2026	NON-COMPETING CONTINUATION	$0
														Subtotal = $563,080

Issue Date FY: 2025 ( Subtotal = $640,781 )
2025	2025	TRUSTEES OF TUFTS COLLEGE	136 HARRISON AVE	BOSTON	MA	02111	SUFFOLK	USA	Cardiovascular Diseases Research	000	3	3/1/2025	NON-COMPETING CONTINUATION	$576,704
2025	2025	TRUSTEES OF TUFTS COLLEGE	136 HARRISON AVE	BOSTON	MA	02111	SUFFOLK	USA	Cardiovascular Diseases Research	001	3	8/8/2025	NON-COMPETING CONTINUATION	$64,077
														Subtotal = $640,781

Issue Date FY: 2024 ( Subtotal = $640,498 )
2024	2024	TRUSTEES OF TUFTS COLLEGE	136 HARRISON AVE	BOSTON	MA	02111	SUFFOLK	USA	Cardiovascular Diseases Research	000	2	2/20/2024	NON-COMPETING CONTINUATION	$588,213
2024	2024	TRUSTEES OF TUFTS COLLEGE	136 HARRISON AVE	BOSTON	MA	02111	SUFFOLK	USA	Cardiovascular Diseases Research	001	2	6/20/2024	NON-COMPETING CONTINUATION	$52,285
														Subtotal = $640,498

Issue Date FY: 2023 ( Subtotal = $665,693 )
2023	2023	TRUSTEES OF TUFTS COLLEGE	136 HARRISON AVE	BOSTON	MA	02111	SUFFOLK	USA	Cardiovascular Diseases Research	000	1	3/29/2023	NEW	$665,693
														Subtotal = $665,693

Grand Total All Awards = $2,510,052

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Regulation of T cell immune response in Heart Failure with Preserved Ejection Fraction

Award Number: R01HL165725

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 04/01/2023

PERIOD OF PERFORMANCE END DATE: 07/31/2025

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