# Differentially methylated gene regions (DMRs) induced by doxorubicin in heart: significance and clinical application

> **NIH NIH R21** · JOHNS HOPKINS UNIVERSITY · 2022 · $204,688

## Abstract

Project Summary
Chemotherapy that includes doxorubicin is used to treat 50% of all pediatric cancer patients, and while highly
effective against tumors, 11% of patients treated as children with doxorubicin develop heart dysfunction/ failure
as adults. Mechanisms of delayed doxorubicin cardiotoxicity are not clearly understood and no cardioprotective
agent is currently FDA-approved for use in children. Our unique rat model of doxorubicin cardiotoxicity results
in cardiac dysfunction after a seven-month latency, allowing the study of cardioprotective treatments in pediatric
cancer (osteosarcoma) in immunocompetent rats. In this model, we have identified a set of differentially
methylated regions of DNA (DMRs) in hearts of doxorubicin-treated rats, using a Methyl-Seq Target Enrichment
System platform. We hypothesize that doxorubicin treatments alter patterns of DNA methylation in
cardiomyocytes of susceptible individuals, including animals and human patients. This aberrant DNA methylation
could serve as a DNA biomarker for post- doxorubicin damage. We further hypothesize that DNA methylation
changes in critical gene-regulatory regions can be minimized by effective cardioprotective agent therapy,
diminishing heart function deficits, myocardial degeneration, interstitial fibrosis and oxidative stress DNA
damage. In Aim 1, we will determine the temporal features of differentially methylated regions (DMRs) in DNA
induced by doxorubicin in heart and how cardioprotective agents modulate the DNA methylation pattern. Using
a robust panel of 6 DMRs that we identified in preliminary studies, we will define the temporal development of
doxorubicin-induced DNA methylation in male and female rats. We will also test effects of cardioprotective agents
on DNA methylation, to verify relationships between DNA methylation and cardiotoxicity, and will determine
potential effectiveness of these agents for preventing heart disease, monitored by echocardiography, troponin I
measurements, and histology scores. We will also determine whether DNA methylation in shore regions
represent early changes that can spread methylation into the CpG islands and affect RNA expression. To provide
a bridge to translational human studies, we will examine doxorubicin-induced DNA methylation changes in hearts
of immunocompetent rats bearing osteosarcoma. In Aim 2, we will determine whether human heart DNA from
doxorubicin treated patients have differentially methylated regions compared to age matched control patients.
Banked frozen myocardium from doxorubicin treated patients will be compared to age matched controls using
the Illumina Infinium human methylation 450 beadchip array to determine DMR patterns. To determine if these
patterns are doxorubicin specific, recently published DNA methylation data from ischemic heart disease patients
(publically available) will be compared to DNA methylation from the doxorubicin-exposed patients. Our long-term
goal (PA-19-111) is to identify novel heart s...

## Key facts

- **NIH application ID:** 10463850
- **Project number:** 5R21HL156224-02
- **Recipient organization:** JOHNS HOPKINS UNIVERSITY
- **Principal Investigator:** KATHLEEN Louise GABRIELSON
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $204,688
- **Award type:** 5
- **Project period:** 2021-08-15 → 2025-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10463850

## Citation

> US National Institutes of Health, RePORTER application 10463850, Differentially methylated gene regions (DMRs) induced by doxorubicin in heart: significance and clinical application (5R21HL156224-02). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10463850. Licensed CC0.

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