mTOR dependent growth control in the myocardium

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The mechanistic Target Of Rapamycin Complex 1 (mTORC1) is a master regulator of protein synthesis and cellular growth. Activation of the mTORC1 complex is a critical step in the progression of cardiac disease after myocardial infarction or pressure overload induced hypertrophy as well as during physiological hypertrophy. This fact has spurred interest for ways to therapeutic target the mTORC1 complex in the heart. Activation of mTOR in response to different stimuli occurs within minutes and might therefore modulate cellular growth by direct regulation of mRNA translation before changes of the mRNA transcription appear. It is still unclear how this mTOR dependent regulation of protein translation influence the cardiac growth and if not only single mRNAs molecules, but rather specific networks of translational regulated mRNA regulate physiological or pathological growth.The goal of this proposal is to identify and understand mTOR-dependent gene expression control mechanisms and to develop novel therapeutic strategies for the treatment of heart failure. Genetic and pharmacological inhibition of mTORC1 preserves cardiac function and prevents cardiac remodeling after pressure overload induced heart failure or after myocardial infarction. Furthermore, own Ribosomal-profiling (Ribo-seq) experiments validated in cardiomyocytes the important role of cytoplasmic mTOR-dependent gene expression control in vivo in response to cardiac stress.This proposal will further define the role of mTOR in myocardial growth in three different strategies. Based on preliminary data in cardiomyocytes it will be investigated 1) how mTORC1 regulates gene expression in endothelial cells and in fibroblasts 2) how the specific mTORC1 inhibitor “small regulatory polypeptide of amino acid response (Spar)” regulates protein translation and cardiac growth 3) how the specific mTORC1 inhibitor “Proline Rich Akt Substrate of 40kDa” (PRAS40) regulates protein translation and cardiac growth. Established in vitro and vivo methods will be used to achieve these goals. Collectively, the studies in this proposal will pave the way for interventional approaches to regulate mTOR activity in service to block pathological growth and remodeling in the myocardium.