Role of Cand2 in cardiac pathophysiology

Cand2 在心脏病理生理学中的作用

• 批准号: 455752792
• 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: Research Grants
• 资助国家: 德国
• 项目状态: 未结题
• 来源: https://gepris.dfg.de/gepris/projekt/455752792?language=en
• 关键词: Role; Cand2; cardiac; pathophysiology

Pathological cardiac hypertrophy predisposes to the development of heart failure (HF) and is frequently a consequence of ventricular pressure overload, myocardial infarction, or inherited cardiomyopathies. Pathological hypertrophy is associated with strong increases in protein synthesis that lead to enlargement of the heart within days after pressure overload.The mechanistic Target of Rapamycin Complex 1 (mTORC1) is a master regulator of protein synthesis. Importantly, previous studies have emphasized the central role of mTORC1 for translational regulation and for HF development and progression. mTORC1 activation enhances mRNA translation by induction of rRNA transcription, stimulation of ribosomal protein biosynthesis, by phosphorylation of translation initiation factors, but also controls translational of specific networks of mRNAs that are required to stress adaptation. The mTORC1-dependent induction of cellular remodeling underlines its significance in HF and importance as a therapeutic target. Since a pharmacological inhibitor of mTOR, rapamycin, improves cardiac function, but also causes side effects it is a great of importance to identify specific mTORC1 targets for innovative treatment options. A newly developed experimental procedure has been used to perform a cardiac myocyte genome-wide analysis of mTORC1-dependent post-transcriptional gene expression control at the level of mRNA translation. This approach identified Cullin-associated NEDD8-dissociated protein 2 (Cand2) as a translationally upregulated gene dependent on the activity of mTORC1 during pathological stress both in vitro and in vivo. Cand2 is a muscle specific protein, but its function in differentiated cardiac myocytes is still unknown. The overall goal of this proposal is to delineate the critical importance of the mTORC1-dependent translational control of Cand2 expression during pathological cell growth with significant impact on cardiac function. Specific aims are designed to comprehensively understand Cand2 expression regulation and its contribution to HF, both in vitro in cultured cardiac myocytes and in vivo in adult murine hearts. We aim to characterize the molecular mechanisms of mTORC1-dependent translational control of Cand2 expression during pathological cell growth. We propose that cellular remodeling and cardiac function is regulated by Cand2 expression and we will develop therapeutic strategies. In the last aim, we will define the molecular function of Cand2.

病理性心脏肥大易导致心力衰竭（HF）的发生，通常是心室压力超负荷、心肌梗死或遗传性心肌病的结果。病理性肥大与蛋白质合成的强烈增加有关，导致压力超负荷后数天内心脏增大。雷帕霉素复合物1（mTORC 1）的机械靶标是蛋白质合成的主要调节剂。重要的是，以前的研究强调了mTORC1在翻译调控和HF发展和进展中的核心作用。mTORC 1激活通过诱导rRNA转录、刺激核糖体蛋白生物合成、通过翻译起始因子磷酸化来增强mRNA翻译，而且还控制应激适应所需的特定mRNA网络的翻译。mTORC1依赖性诱导细胞重塑强调了其在HF中的意义和作为治疗靶点的重要性。由于mTOR的药理学抑制剂雷帕霉素可改善心脏功能，但也会引起副作用，因此确定特定的mTORC1靶点以用于创新治疗方案非常重要。一个新开发的实验程序已被用来进行心肌细胞全基因组分析的mTORC1依赖的转录后基因表达控制在mRNA翻译的水平。该方法鉴定了Cullin相关的NEDD8解离蛋白2（Cand2）作为在体外和体内病理应激期间依赖于mTORC 1活性的特异性上调基因。Cand2是一种肌肉特异性蛋白，但其在分化的心肌细胞中的功能尚不清楚。本提案的总体目标是阐明病理细胞生长过程中Cand2表达的mTORC1依赖性翻译控制对心脏功能的重要性。具体的目的是全面了解Cand2的表达调控及其对HF的贡献，无论是在体外培养的心肌细胞和体内成年小鼠心脏。我们的目的是表征mTORC1依赖的Cand2表达在病理细胞生长的翻译控制的分子机制。 我们提出细胞重塑和心脏功能受Cand2表达的调节，我们将开发治疗策略。最后，我们将确定Cand2的分子功能。