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.
Cardiac hypertrophy is a strong risk factor for heart failure and results in both structural and functional changes in the heart. This study will explore a novel mechanism involving mRNA modification by which hypertrophic changes during heart failure are mediated. The understanding of this process may lead to new therapeutic opportunities for heart failure patients.
