Role of mRNA Modifications in Cardiac Remodeling

与病因无关，心力衰竭包括心脏结构的改变，收缩功能障碍，以及多种影响心脏功能和患者生存的遗传和分子改变。这些变化被称为心脏重塑。基因表达的变化与特定基因组的上调或下调在心力衰竭的发病过程中起着重要作用。最近的研究揭示了可逆的mRNA修饰对基因表达控制的重要性。这项工作表明，除了DNA的表观遗传修饰外，还发生了许多mrna的修饰，其中一些修饰直接影响发育、细胞生长、代谢、细胞存活和细胞内信号传导。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）是另一种在哺乳动物mRNA中调节基因表达的mRNA修饰。m6A修改由m6A写入器安装，由擦除器反转，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，除了从DNA传递信息外，还在许多生物过程中充当信息载体、修饰剂和衰减器。这项提议的总体目标是表明mrna的可逆修饰代表了一种新的表观遗传标志，在基本的心脏生理学和病理生理学中具有广泛的作用。该提议的创新之处在于首次全面表征了心脏中不同心脏细胞类型的mRNA修饰。该提案旨在描述mRNA甲基化机制在心脏中的关键重要性，并证明mRNA甲基化对生长和生存的影响。这些研究的意义在于明确了抑制病理性重塑的方法，提高了心脏疾病的细胞存活率，目的是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.