Role of mRNA Modifications in Cardiac Remodeling

与病因无关，心力衰竭涉及心脏结构的变化，收缩功能障碍，以及影响心功能和患者生存的多种遗传和分子改变。这些变化被称为心脏重构。基因表达的变化与特定基因的上调或下调在心力衰竭的发病机制中起着基础性的作用。最近的研究揭示了可逆的mRNA修饰在基因表达调控中的重要性。这项工作表明，除了DNA的表观遗传修饰外，还会发生许多mRNAs的修饰，其中一些直接影响发育、细胞生长、新陈代谢、细胞生存和细胞内信号。最常见的mRNA内部修饰是N6-甲基腺苷(M6A)，但最近发现N1-甲基腺苷(M1A)是另一种调节哺乳动物mRNAs基因表达的mRNA修饰。M6A修改由M6A写入器安装，由橡皮擦反转，并由M6A读取器读取。这使mRNA重新成为细胞内信息的中心枢纽，除了传递来自DNA的信息外，还充当许多生物过程的信息载体、修饰物和衰减器。这一提议的总体目标是表明mRNAs的可逆修饰代表了一种新的表观遗传学标志，在基础心脏生理学和病理生理学中具有广泛的作用。这一建议的创新之处在于首次对心脏不同类型心肌细胞中的mRNA修饰进行了全面的表征。该提案旨在描述心脏中信使核糖核酸甲基化机制的关键重要性，并证明信使核糖核酸甲基化对生长和存活的影响。这些研究的意义在于确定抑制病理性重塑的方法，改善心脏病患者的细胞存活率，从而为心力衰竭的治疗提供新的治疗选择。

Independent of the etiology, heart failure involves changes in cardiac structure, contractile dysfunction, as well as multiple genetic, and molecular alterations that impact heart function and patient survival. These changes have been referred to as cardiac remodeling. Changes in gene expression with up- or down-regulation of specific sets of genes play a fundamental role during the pathogenesis of heart failure. Recent research has unveiled the importance of reversible mRNA modifications on gene expression control. This work has suggested that in addition to epigenetic modifications of DNA, many modifications of mRNAs occur, some of which directly impact development, cell growth, metabolism, cellular survival, and intracellular signaling. The most prevalent internal modification on mRNA is N6-methyladenosine (m6A), but very recently N1-methyladenosine (m1A) was discovered as another mRNA modification regulating gene expression in mammalian mRNAs. m6A modification is installed by m6A writers, is reversed by erasers, and is read by m6A readers. This returns mRNA to a role as a central hub of information within the cell, serving as an information carrier, modifier, and attenuator for many biological processes, in addition to transferring the message from the DNA.The overall goal of this proposal is to show that reversible modifications in mRNAs represent a novel epigenetic hallmark with broad roles in fundamental cardiac physiology and pathophysiology. The innovation of this proposal is based on the first comprehensive characterization of mRNA modifications in different cardiac cell types in the heart. The proposal aims to delineate the critical importance of the mRNA methylation machinery in the heart and to demonstrate the effects of mRNA methylation on growth and survival. The significance of these studies is to define ways to blunt pathological remodeling, to improve cellular survival in cardiac diseases with the goal to delineate new therapeutic options for the treatment of heart failure.