# Cardiac fibroblast MHCII contribution to cardiac pathophysiology in Doxorubicin cardiomyopathy

> **NIH NIH F31** · TUFTS UNIVERSITY BOSTON · 2024 · $45,162

## Abstract

PROJECT SUMMARY
Cancer patients receiving Doxorubicin (Dox) chemotherapy often develop cardiac complications which can result
in heart failure (HF). Some of the prominent hallmarks of Dox HF patients are cardiac fibrosis, cardiac atrophy,
systolic dysfunction as well as heightened systemic inflammation. Cardiac fibrosis and cardiac inflammation often
coincide in nearly all forms of HF, and while the concept that cardiac fibroblasts, a heterogeneous and plastic
cell type in response to stressors, and immune cells communicating with each other to exert cardiac pro-fibrotic
and pro-inflammatory responses is emerging, it remains incompletely understood, and the immune and fibrotic
mechanisms involved in Dox HF are understudied. My lab previously reported that one way of communicating is
that cardiac fibroblasts can function as antigen presenting cells through the major histocompatibility complex
class II (MHC-II), which is induced by IFN-γ, and my preliminary data using a mouse model of Dox
cardiomyopathy demonstrate increased expression of MHC-II on a subset of cardiac fibroblast, coinciding with
increased infiltration of IFNγ+ T cell subsets and cardiac fibrosis. My data also demonstrate that MHC-II induction
on cardiac fibroblasts is T cell dependent and that specific deletion of cardiac fibroblast MHC-II in mice results
in preserved systolic function and decreased fibrosis. In two aims I will test the central hypothesis that Dox
induces a pro-inflammatory cardiac fibroblast state characterized by MHC-II expression through T cell IFN-γ
signals that contribute to cardiac fibrosis and pathophysiology. In SA1, I will investigate the mechanisms by which
MHC-II on cardiac fibroblasts contribute to T cell immune responses and cardiac fibrosis during the progression
of Dox cardiomyopathy. In SA2, I will interrogate whether cardiac fibroblast MHC-II expression dictates fibroblast
function and crosstalk with T cells in Dox cardiomyopathy. I will combine in vitro and in vivo gain and loss of
function approaches. Overall, my project will identify novel mechanisms in the fibroblast-T cell interface that may
be targeted to ameliorate Dox cardiomyopathy, while supporting my PhD training.

## Key facts

- **NIH application ID:** 10994472
- **Project number:** 1F31HL175911-01
- **Recipient organization:** TUFTS UNIVERSITY BOSTON
- **Principal Investigator:** Maria Antonia Zambrano
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $45,162
- **Award type:** 1
- **Project period:** 2024-12-01 → 2027-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10994472

## Citation

> US National Institutes of Health, RePORTER application 10994472, Cardiac fibroblast MHCII contribution to cardiac pathophysiology in Doxorubicin cardiomyopathy (1F31HL175911-01). Retrieved via MORVS 2026-10-24 from https://api.morvs.ai/grant/nih/10994472. Licensed CC0.

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