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The Role of RNA Modifications in Heart Failure

RNA 修饰在心力衰竭中的作用

基本信息

批准号：
10589848
负责人：
Christopher Lee Holley
金额：
$ 36.23万
依托单位：
DUKE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-04-20 至 2025-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10589848
关键词：
Affect Animal Model Animals Cardiac Cardiac Myocytes Cardiovascular Diseases Cardiovascular Pathology Cell model Complex Data Development Disease susceptibility Enzymes Gene Expression Gene Expression Regulation Genes Genetic Goals Guide RNA Health Health Care Costs Heart Heart Diseases Heart Hypertrophy Heart failure Hospitalization Hypertrophy In Vitro Link Maps Measures Mediating Messenger RNA Methods Methylation Modeling Modification Mus Neonatal Oxidative Stress Pathologic Physiological Play Post-Transcriptional Regulation Proteins Proteomics RNA RNA Splicing RNA immunoprecipitation sequencing RNA methylation Rattus Reactive Oxygen Species Reporting Resistance Ribosomal RNA Role Site Small Nucleolar RNA Testing Time Tissues Translations United States antisense nucleic acid aorta constriction cardiovascular health crosslinking and immunoprecipitation sequencing differential expression fibrillarin in vivo knock-down mRNA Expression mRNA Translation mouse model new therapeutic target novel overexpression peroxidasin protein complex protein expression recruit ribosome profiling targeted treatment transcriptome

项目摘要

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.

摘要一个新的证据表明，mRNA甲基化在转录后调控中起着关键作用。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尚未研究。现在，在一个小鼠模型中，心肌肥大和心力衰竭，我们已经确定了mRNA 2 '-O-甲基化（Nm）的第一个例子影响心血管病理学根据我们的研究结果，我们建议通过以下方式来描述具体的机制：其中mRNA的Nm修饰影响心脏肥大和心力衰竭。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。该提议的目的是具体确定Rpl 13 a snoRNA的丢失如何影响细胞的功能。导致防止心脏肥大和心力衰竭。我们的中心假设是Rpl 13 a snoRNA 引导心脏中多个mRNA靶点的Nm修饰，并且这些修饰调节生理学以及在mRNA丰度和蛋白质翻译水平上的病理生理基因表达。我们建议我们的实验目的是：（1）明确Rpl 13 a snoRNA如何调节心脏的功能，肥大和心力衰竭。(2)确定snoRNA引导的Nm修饰在心脏上的体内网络 mRNA。(3)确定snoRNA引导的Nm对mRNA的修饰如何改变两种正常人中的蛋白质表达。发育和病理性肥大。成功实现这些目标将首次确定如何 snoRNA引导的mRNA甲基化有助于心血管健康和疾病。因此，我们预计，我们的发现将为心脏肥大和心力衰竭的研究开辟新的途径。最后，由于snoRNA- 指导的Nm修饰的mRNA还没有以前的报道，这些结果也将是广泛的信息在RNA修饰领域。