# Investigating the Time-Dependent Reversibility of DCM-Induced Epigenetic, Matrix, and Functional Remodeling

> **NIH NIH F31** · UNIVERSITY OF WASHINGTON · 2022 · $41,619

## Abstract

Project Summary
Dilated cardiomyopathy (DCM) is a highly prevalent inherited cardiac disease, characterized by systolic
dysfunction, eccentric hypertrophy, and left ventricle dilation. While pharmacologic and mechanical treatments
have been shown to partially improve cardiac function, these results are often short lived and highly variable
from patient to patient. Moreover, recent studies have demonstrated that epigenetic and matrix dysregulation
can persist, even in patients with improved systolic function after treatment. Given that aberrant chromatin
remodeling and extracellular matrix (ECM) deposition have been identified as drivers of dilated remodeling—and
that chromatin and ECM remodeling can become irreversible over time—it is crucial to understand the time-
dependent effects of DCM mutations on reversing maladaptive remodeling at the genome, myocyte, and matrix
levels. The central hypothesis of this proposal is that the reversibility of the DCM phenotype is time-dependent
due to the accumulation of permanent ECM and chromatin remodeling as the disease progresses. To complete
this proposal, I will utilize a DCM mouse model created by the Davis lab which contains a mutation (I61Q) in
cardiac troponin C (cTnC) that directly decreases the myofilament’s Ca2+ sensitivity, leading to eccentric
hypertrophy, systolic dysfunction, and left ventricle dilation. Importantly, expression of this mutant can be
temporally controlled with doxycycline to specifically test our central hypothesis. In this proposal I will 1)
Determine the time-dependent effects of I61Q cTnC expression on myocyte, matrix, and chromatin accessibility,
2) Examine the reversibility of DCM remodeling in myocyte, matrix, and chromatin accessibility at different stages
of the disease, and 3) Determine if myocytes retain epigenetic memories of the mechanical disequilibrium caused
by DCM. Improving our understanding of the time-dependent reversibility of DCM remodeling will better inform
therapeutic targets and treatment windows for patients with DCM. Moreover, completion of this project will
enhance Bella’s training as an independent scientist and prepare her to one day become a professor in
cardiovascular engineering. Receiving the NIH F31 predoctoral fellowship will facilitate important experiments
and training that will aid in her pursuit of this career goal. In this project, Bella will gain expertise in multi-omic
approaches—such as proteomics, RNAseq, and ATACseq—which are growing in popularity due to their
unbiased screening capabilities. The UW Genomics Core will assist Bella in learning how to effectively use these
tools, which will not only benefit this project but will also be an incredibly useful skillset for Bella’s future career.
Given the clinical relevance of this project, we have engaged Farid Moussavi-Harami, MD, an acting physician-
scientist who practices cardiology within the UW Department of Medicine. Dr. Moussavi-Harami’s input as a
clinician will be crucial for...

## Key facts

- **NIH application ID:** 10535260
- **Project number:** 1F31HL165834-01
- **Recipient organization:** UNIVERSITY OF WASHINGTON
- **Principal Investigator:** Isabella Reichardt
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $41,619
- **Award type:** 1
- **Project period:** 2022-09-16 → 2025-09-15

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10535260

## Citation

> US National Institutes of Health, RePORTER application 10535260, Investigating the Time-Dependent Reversibility of DCM-Induced Epigenetic, Matrix, and Functional Remodeling (1F31HL165834-01). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10535260. Licensed CC0.

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