mTOR dependent growth control in the myocardium

mTOR 依赖性心肌生长控制

• 批准号: 265635433
• 负责人: Professor Dr. Mirko Völkers
• 金额: --
• 依托单位: Klinik für Kardiologie, Angiologie und Pulmologie
• 依托单位国家: 德国
• 项目类别: Independent Junior Research Groups
• 财政年份: 2015
• 资助国家: 德国
• 起止时间: 2014-12-31 至 2022-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/265635433?language=en
• 关键词: mTOR; dependent; growth; control; myocardium

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.

雷帕霉素复合体的机械靶点1(MTORC1)是蛋白质合成和细胞生长的主要调节因子。在心肌梗死或压力超负荷引起的肥厚以及生理性肥厚过程中，mTORC1复合体的激活是心脏病进展的关键步骤。这一事实激发了人们对以心脏中mTORC1复合体为靶点的治疗方法的兴趣。MTOR对不同刺激的激活在几分钟内就会发生，因此可能在mRNA转录发生变化之前通过直接调节mRNA的翻译来调节细胞的生长。目前尚不清楚这种mTOR依赖的蛋白质翻译调控如何影响心脏生长，以及是否不仅单个mRNAs分子，而是特定的翻译调控的mRNA网络调控生理或病理生长。本研究的目的是识别和了解mTOR依赖的基因表达调控机制，并开发治疗心力衰竭的新治疗策略。基因和药物抑制mTORC1可以保护心脏功能，防止压力超负荷引起的心力衰竭或心肌梗死后的心脏重构。此外，自己的核糖体分析(Ribo-seq)实验在心肌细胞中验证了细胞质mTOR依赖的基因表达控制在体内响应心脏应激的重要作用。这一建议将进一步确定mTOR在三种不同策略中在心肌生长中的作用。基于心肌细胞的初步数据，我们将研究1)mTORC1如何调控内皮细胞和成纤维细胞中的基因表达2)特异性mTORC1抑制剂“氨基酸反应小调节多肽(Spar)”如何调控蛋白质翻译和心脏生长3)特异性mTORC1抑制剂“40 kDa富含Pro的Akt底物”(PRAS40)如何调控蛋白质翻译和心脏生长。建立在体外和体内的方法将被用来实现这些目标。总之，这项建议中的研究将为介入方法调节mTOR活性以阻止心肌病理性生长和重塑铺平道路。

项目成果

N6-Methyladenosine in the Heart

• DOI: 10.1007/978-3-030-71612-7_11
• 发表时间: 2021
• 期刊: Epitranscriptomics
• 作者: V. Kmietczyk;Ellen Malovrh;M. Völkers

m6A-mRNA methylation regulates cardiac gene expression and cellular growth

• DOI: 10.26508/lsa.201800233
• 发表时间: 2019-04-01
• 期刊: LIFE SCIENCE ALLIANCE
• 影响因子: 4.4
• 作者: Kmietczyk, Vivien;Riechert, Eva;Voelkers, Mirko
• 通讯作者: Voelkers, Mirko

PRAS40 suppresses atherogenesis through inhibition of mTORC1-dependent pro-inflammatory signaling in endothelial cells

• DOI: 10.1038/s41598-019-53098-1
• 发表时间: 2019-11
• 期刊: Scientific Reports
• 影响因子: 4.6
• 作者: K. S. Zhang;J. Schecker;A. Krull;Eva Riechert;L. Jürgensen;V. Kamuf-Schenk;Jana Burghaus;Leon Kiper;Thanh Cao Ho;Kerstin Wöltje;V. Stangl;H. Katus;K. Stangl;M. Völkers;Till F. Althoff

Identification of dynamic RNA-binding proteins uncovers a Cpeb4-controlled regulatory cascade during pathological cell growth of cardiomyocytes.

• DOI: 10.1016/j.celrep.2021.109100
• 发表时间: 2021-05
• 期刊: Cell reports
• 影响因子: 8.8
• 作者: Eva Riechert;V. Kmietczyk;F. Stein;T. Schwarzl;T. Sekaran;L. Jürgensen;V. Kamuf-Schenk;E. Varma;C. Hofmann;Mandy Rettel;Kira Gür;Julie Ölschläger;Friederike Kühl;Judit Martin;Marta Ramirez-Pedraza;Mercedes Fernandez;Shirin Doroudgar;R. Méndez;H. Katus;M. Hentze;M. Völkers

Transient inhibition of translation improves long-term cardiac function after ischemia/reperfusion by attenuating the inflammatory response

• DOI: 10.1101/2022.07.25.501397
• 发表时间: 2022-07
• 期刊: bioRxiv
• 作者: C. Hofmann;Adrian Serafin;Ole M Schwerdt;Fereshteh Younesi;Florian Sicklinger;I. S. Meyer;Ellen Malovrh;Clara Sandmann;L. Jürgensen;V. Kamuf-Schenk;C. Stroh;Zoe Löwenthal;Mandy Rettel;F. Stein;H. Katus;Tobias Jakobi;N. Frey;F. Leuschner;M. Völkers