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：
9918955
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 2024-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9918955
关键词：
Affect Animal Model Animals Cardiac Cardiac Myocytes Cardiovascular Diseases Cardiovascular Pathology Cardiovascular system Cell model Complex Data Development Disease susceptibility Enzymes Gene Expression Gene Expression Regulation Genes Genetic Genetic Translation Germ Lines Goals Guide RNA Health Health Care Costs Heart Heart Diseases Heart Hypertrophy Heart failure Hospitalization Hypertrophy In Vitro Link 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 base cardiovascular health constriction crosslinking and immunoprecipitation sequencing differential expression fibrillarin in vivo knock-down mRNA Expression 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.

抽象的新兴的证据表明，mRNA甲基化在转录后起着关键作用基因表达的调节。甲基化可以调节mRNA剪接，稳定性和翻译，但健康在心血管疾病中尚未研究mRNA修饰的重要性。现在，在鼠标模型中心脏肥大和心力衰竭，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。根据我们的发现，我们建议通过 mRNA的NM修饰会影响心脏肥大和心力衰竭。我们的长期目标是确定mRNA NM甲基化在心脏病敏感性中的总体重要性，并定义相关机制。该建议的目的是确定RPL13A snornas的损失导致免受心脏肥大和心力衰竭的保护。我们的中心假设是RPL13A snornas 指导心脏中多个mRNA靶标的NM修饰，并且这些修饰调节生理在mRNA丰度和蛋白质翻译水平上的病理生理基因表达。我们建议用以下特定目的测试我们的假设：（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修饰的体内网络 mRNA。（3）确定在两个正常的mRNA改变蛋白表达上的SNORNA引导的NM修饰发育和病理肥大。这些目标的成功完成将首次定义 SNORNA引导的mRNA甲基化有助于心血管健康和疾病。结果，我们期望我们的发现将在心脏肥大和心力衰竭的研究中开放新的途径。最后，自snorna- 以前尚未报告指导的NM修改mRNA，这些结果也将是广泛的信息在RNA修饰领域。