Transcriptional control of cardiomyocyte stress response

Pathological cardiac remodeling is a major risk factor for heart failure. It occurs in response to pathological stimuli such as chronic pressure overload (i.e. arterial hypertension). Cardiac remodeling is characterized by cardiomyocyte hypertrophy and interstitial fibrosis. Previously, we identified transcription factor EB (TFEB) and TFE3 as potent regulators of protein and energy homeostasis in cardiomyocytes and the heart contributing to cardiac stress response. Both transcription factors bind to highly conserved 10bp palindromic E-box elements in the promoter of their target genes, regulate similar gene sets and display partially redundant functions. Although the function of TFEB and TFE3 in non-muscle cells is well described, their individual and coordinate functions in cardiomyocytes are not well described. Here, we aim to investigate the function of TFEB and TFE3 in vitro in ardiomyocytes and in vivo in the heart. We will use adeno-associated viral vector of serotype 9 (AAV9)-mediated delivery of an RNA hairpin TFEB/TFE3-decoy oligonucleotide to attenuate their effects in mouse hearts. Cardiac hypertrophy will be induced by chronic pressure overload due to transverse aortic constriction (TAC) surgery. We will focus on cardiac stress response by performing phenotypical, functional, and molecular analyses. This will be complemented by in-vitro "proof-of-concept" approaches in cardiomyocytes. For that, we will generate AAV6 to overexpress and diminish TFEB and/or TFE3 in stressed and unstressed neonatal rat cardiomyocytes.