# Characterizing mechanisms of T cell-mediated cardiac pathology in Heart Failure with Preserved Ejection Fraction

> **NIH NIH F31** · TUFTS UNIVERSITY BOSTON · 2022 · $42,348

## Abstract

Project Summary
The goal of this F31 proposal is to investigate the mechanisms by which T cells contribute to diastolic dysfunction
in heart failure with preserved ejection fraction (HFpEF), a leading cause of mortality in the USA, with rising
incidence, few direct treatment options, and no cure. I will perform the proposed studies while completing a
tailored training plan that will assist in my development as an independent cardio-immunologist, while I complete
the requirements of my PhD degree. HFpEF is characterized by impaired relaxation of the left ventricle and
diastolic dysfunction, without significant impairment of cardiac contractility. None of the therapeutics available
reduce mortality in patients with HFpEF, which comprise about half of all HF patients. A key characteristic of
HFpEF is systemic chronic low-grade inflammation, which is also independently associated with HFpEF
comorbidities such as obesity and hypertension. While obesity and hypertension each induce specific T cell
immune responses, they do not independently induce HFpEF, and whether their combination induces specific T
cell immune responses that contribute to HFpEF remains unknown. Obesity and hypertension combined,
generate endoplasmic reticulum stress that is unresolved by a dysfunctional unfolded protein response (UPR).
Remarkably, a downregulation of the UPR protein spliced X-box binding protein 1 (XBP1s) is observed in the
myocardium of HFpEF patients, but not in HFrEF patients, suggesting this pathway may be specific for
contributing to diastolic dysfunction. However, the role of T cell immunity in diastolic dysfunction and HFpEF,
and how this may be modulated by the UPR, remain elusive. Using a recently established mouse model of
HFpEF induced by obesity and hypertension in combination, my preliminary data demonstrate that cardiac T cell
infiltration concomitant with diastolic dysfunction and cardiomyocyte hypertrophy occur. Furthermore, my data
show that T cell-deficient mice (Tcra-/-) do not develop diastolic dysfunction or cardiomyocyte hypertrophy under
the same conditions, supporting a role for T cells in HFpEF. I also found that T cells from HFpEF mice have
downregulated XBP1s expression compared to T cells from control mice. In two specific aims, I will test the
central hypothesis that combined risk factors of HFpEF induce UPR alterations in T cells that result in enhanced
T cell effector function and survival, and contribute to diastolic dysfunction and cardiometabolic HFpEF. In SA1,
I will characterize the spatiotemporal activation of T cells in HFpEF, identify dominant T cell subsets, and define
the expression of T cell XBP1s and UPR molecules over time, before and during the onset of diastolic
dysfunction. In SA2, I will decipher the mechanisms by which XBP1s modulates T cell effector function, survival,
and inflammatory potential in cardiometabolic HFpEF. Altogether, this project thoroughly interrogates the roles
of T cells and the T cell UPR in dias...

## Key facts

- **NIH application ID:** 10462140
- **Project number:** 1F31HL159907-01A1
- **Recipient organization:** TUFTS UNIVERSITY BOSTON
- **Principal Investigator:** Sandra Smolgovsky
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $42,348
- **Award type:** 1
- **Project period:** 2022-06-01 → 2025-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10462140

## Citation

> US National Institutes of Health, RePORTER application 10462140, Characterizing mechanisms of T cell-mediated cardiac pathology in Heart Failure with Preserved Ejection Fraction (1F31HL159907-01A1). Retrieved via AI Analytics 2026-06-01 from https://api.ai-analytics.org/grant/nih/10462140. Licensed CC0.

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