mTOR dependent growth control in the myocardium

雷帕霉素复合体1的机制靶点（mTORC1）是蛋白质合成和细胞生长的主要调节因子。mTORC1复合物的激活是心肌梗死或压力过载引起的肥厚以及生理性肥厚后心脏病进展的关键步骤。这一事实激发了人们对心脏中mTORC1复合物治疗靶点的兴趣。mTOR对不同刺激的激活在几分钟内发生，因此可能在mRNA转录发生变化之前通过直接调节mRNA翻译来调节细胞生长。目前尚不清楚这种依赖于mTOR的蛋白质翻译调控是如何影响心脏生长的，以及是否不仅仅是单个mRNA分子，而是翻译调控的mRNA的特定网络如何调节生理或病理生长。本提案的目标是识别和理解mtor依赖的基因表达控制机制，并开发新的治疗心力衰竭的治疗策略。遗传和药理抑制mTORC1可保护心功能，防止压力过载诱发心力衰竭或心肌梗死后的心脏重构。此外，自己的核糖体谱（Ribo-seq）实验在心肌细胞中验证了胞质mtor依赖基因表达控制在体内对心脏应激的反应中的重要作用。本研究将进一步明确mTOR在三种不同策略下心肌生长中的作用。基于心肌细胞的初步数据，将研究1)mTORC1如何调节内皮细胞和成纤维细胞中的基因表达2)特异性mTORC1抑制剂“小调节多肽氨基酸反应（Spar）”如何调节蛋白质翻译和心脏生长3)特异性mTORC1抑制剂“Proline Rich Akt Substrate of 40kDa”（PRAS40）如何调节蛋白质翻译和心脏生长。已建立的体外和体内方法将用于实现这些目标。总的来说，本提案中的研究将为干预方法铺平道路，以调节mTOR活性，以阻断心肌的病理生长和重塑。

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.