# The role of N-6-adenosine and its writer, METTL3, in the cardiac hypertrophic response

> **NIH NIH F30** · OHIO STATE UNIVERSITY · 2021 · $51,036

## Abstract

Project Summary / Abstract
Cardiac hypertrophy is a major risk factor for the development of heart failure (HF). Hypertrophy occurs due to
structural and functional changes in cardiomyocytes resulting from altered gene and protein expression. Much
of the previous work on HF pathogenesis has focused on transcriptional regulation of genes, but post-
transcriptional regulation during HF is only beginning to be explored. The most common post-transcriptional
mRNA modification, methylation of adenosines (called N6-methyladenosine or m6A), is catalyzed by the enzyme
Methyltransferase-like 3 (METTL3) and has recently been identified as a regulator of protein expression. Our
goal is to identify how m6A and METTL3 influence cardiac hypertrophy and the mechanism by which they do so.
Our lab's previous work has demonstrated that either gain- or loss-of function of METTL3 in isolated
cardiomyocytes have opposing effects on hypertrophy, enhancing and repressing hypertrophy, respectively.
Based on these observations, our main hypothesis is that METTL3 modulates cardiomyocyte hypertrophy by
promoting the stability of a subset of mRNAs during cardiac stress and heart failure. To test this hypothesis, in
Aim 1 we will subject cardiomyocyte-specific METTL3 overexpressing mice to cardiac stress in the form of aging
and pressure-overload surgery. This strategy will allow us to determine if METTL3 can drive hypertrophy in vivo.
In contrast, in Aim 2 we will subject cardiomyocyte-specific METTL3 knockout mice to the same forms of cardiac
stress to determine if METTL3 is necessary for cardiac hypertrophy to develop. To better understand the impact
of METTL3 on hypertrophy and HF, in Aim 3 we will determine the specific mechanism by which m6A
modifications influence pro-hypertrophic mRNAs in isolated cardiomyocytes stimulated to hypertrophy. This work
will be carried out in the laboratory of Dr. Federica Accornero, an expert in post-transcriptional regulation of
cardiac hypertrophy, and under the co-supervision of Dr. Paul Janssen, a leader in the field of heart failure and
cardiac contractility. With the successful completion of this project, our research will elucidate the unknown
mechanism of m6A- and METTL3- mediated cardiac hypertrophy in a mouse model. Our long-term goal is to be
able to target m6A and METTL3 in the heart to improve clinical outcomes for patients with cardiac hypertrophy
and HF.

## Key facts

- **NIH application ID:** 10225518
- **Project number:** 5F30HL145955-03
- **Recipient organization:** OHIO STATE UNIVERSITY
- **Principal Investigator:** Lisa E. Dorn
- **Activity code:** F30 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $51,036
- **Award type:** 5
- **Project period:** 2019-07-22 → 2023-07-21

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10225518

## Citation

> US National Institutes of Health, RePORTER application 10225518, The role of N-6-adenosine and its writer, METTL3, in the cardiac hypertrophic response (5F30HL145955-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10225518. Licensed CC0.

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