The Role of RNA Modifications in Heart Failure

摘要 新出现的大量证据表明，mRNA甲基化在转录后转录中起着关键作用。 基因表达的调控。甲基化可以调节mRNA的剪接、稳定性和翻译，但健康 MRNA修饰在心血管疾病中的意义还没有研究。现在，在一个老鼠模型中 心肌肥厚和心力衰竭，我们已经确定了第一例2‘-O-甲基化(Nm) 影响心血管病理。基于我们的发现，我们建议通过以下方式描述具体的机制 哪些Nm基因修饰会影响心肌肥厚和心力衰竭。我们的长期目标是 确定mRNA Nm甲基化在心脏病易感性中的总体重要性，并确定 相关机制。这项建议的目标是具体确定Rpl13a snoRNAs的丢失 可预防心肌肥大和心力衰竭。我们的中心假设是Rpl13a snoRNAs 引导心脏中多个信使核糖核酸靶点的Nm修饰，并且这些修饰调节生理 病理生理基因在mRNA丰度和蛋白质翻译水平上的表达。我们建议 用以下具体目标验证我们的假设：(1)定义Rpl13a snoRNAs如何调节心脏 肥大和心力衰竭。(2)确定snoRNA引导的Nm修饰心脏的体内网络 MRNA.(3)确定snoRNA引导的Nm对mRNA的修饰如何改变两种正常动物的蛋白质表达 发展和病理性肥大。这些目标的成功实现将第一次确定如何 SnoRNA引导的信使核糖核酸甲基化有助于心血管健康和疾病。因此，我们预计 我们的发现将为研究心肌肥厚和心力衰竭开辟新的途径。最后，由于snoRNA- 以前还没有报道过引导Nm基因的修饰，这些结果也将提供广泛的信息 在RNA修饰领域。

ABSTRACT An emerging body of evidence suggests that mRNA methylation plays a key role in the post-transcriptional regulation of gene expression. Methylation can regulate mRNA splicing, stability, and translation, but the health significance of mRNA modification has not been studied in cardiovascular disease. Now, in a mouse model of cardiac hypertrophy and heart failure, we have identified the first example of mRNA 2'-O-methylation (Nm) affecting cardiovascular pathology. Based on our findings, we propose to delineate the specific mechanisms by which Nm modification of mRNA influences cardiac hypertrophy and heart failure. Our long-term goals are to determine the overall importance of mRNA Nm methylation in cardiac disease susceptibility, and to define the relevant mechanisms. The objective of this proposal is to determine specifically how loss of Rpl13a snoRNAs leads to protection from cardiac hypertrophy and heart failure. Our central hypothesis is that Rpl13a snoRNAs guide Nm modification of multiple mRNA targets in the heart, and that these modifications regulate physiologic and pathophysiologic gene expression at the level of mRNA abundance and protein translation. We propose to test our hypothesis with the following Specific Aims: (1) Define how Rpl13a snoRNAs regulate cardiac hypertrophy and heart failure. (2) Determine the in vivo network of snoRNA-guided Nm modifications on cardiac mRNA. (3) Determine how snoRNA-guided Nm modifications on mRNA alter protein expression in both normal development and pathologic hypertrophy. Successful completion of these Aims will define, for the first time, how snoRNA-guided mRNA methylation contributes to cardiovascular health and disease. As a result, we expect that our findings will open new avenues in the study of cardiac hypertrophy and heart failure. Finally, since snoRNA- guided Nm modification of mRNA has not been previously reported, these results will also be broadly informative in the field of RNA modifications.