Heart failure represents a substantial health and economic burden on the US. Despite current treatments, the incidence of heart failure - along with its associated morbidity and mortality - continues to rise. Given these clinical observations, new therapeutic strategies are urgently needed and understanding the molecular mechanisms responsible for stress-induced cardiac hypertrophy and dysfunction will be key to develop the necessary medical therapies. Pathologic cardiac remodeling is mediated by increased synthesis of specific proteins in cardiomyocytes. Although significant progress has been made in understanding the transcriptional changes occurring in the remodeling heart, very little is known about how post-transcriptional events control the synthesis of maladaptive proteins in the stressed myocardium. In this proposal we will examine the role of METTL3-mediated m6A mRNA methylation in the heart as a novel pathway regulating cardiac hypertrophy. We hypothesize that METTL3-dependent mRNA methylation regulates cardiac hypertrophy by favoring the translation of specific pro-hypertrophic mRNAs. For the first time, utilizing gain- and loss-of-function approaches we will characterize this novel pro-hypertrophic program, establish the molecular mechanism by which m6A regulates the life of select mRNAs and examine its role in clinically relevant animal models. The achievement of the proposed aims will allow the uncovering of a novel mechanism responsible for post- transcriptional regulation of cardiac hypertrophy with obvious therapeutics ramifications.
Heart failure is a growing medical problem for which current medical therapies offer no cure. This proposal will uncover a novel mechanism of regulation of pathologic cardiac remodeling through identifying how the synthesis of specific maladaptive proteins is regulated during cardiac stress. The achievement of the proposed aims should open exciting new therapeutic avenues.
| Dorn, Lisa E; Lasman, Lior; Chen, Jing et al. (2018) The m6A mRNA Methylase METTL3 Controls Cardiac Homeostasis and Hypertrophy. Circulation : |
| Dorn, Lisa E; Petrosino, Jennifer M; Wright, Patrick et al. (2018) CTGF/CCN2 is an autocrine regulator of cardiac fibrosis. J Mol Cell Cardiol 121:205-211 |
| Accornero, Federica; Schips, Tobias G; Petrosino, Jennifer M et al. (2017) BEX1 is an RNA-dependent mediator of cardiomyopathy. Nat Commun 8:1875 |
| Ackermann, Maegen A; Petrosino, Jennifer M; Manring, Heather R et al. (2017) TGF-?1 affects cell-cell adhesion in the heart in an NCAM1-dependent mechanism. J Mol Cell Cardiol 112:49-57 |
