Post-transcriptional regulation of cardiac hypertrophy

心脏肥大的转录后调控

基本信息

批准号：
10655127
负责人：
Federica Accornero
金额：
$ 5.12万
依托单位：
OHIO STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-04-01 至 2023-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10655127
关键词：
3&apos Untranslated Regions Achievement Address Affect Binding Proteins Cardiac Cardiac Myocytes Cell Nucleus Cells Complex Economic Burden Electron Transport Enzymes Event Gene Expression Gene Proteins Health Heart Heart Diseases Heart Hypertrophy Heart failure Homeostasis Hypertrophy Incidence Knowledge Maintenance Mass Spectrum Analysis Medical Messenger RNA Metabolic Metabolism Methylation Methyltransferase Mitochondria Mitochondrial Proteins Modeling Modification Molecular Morbidity - disease rate Multiprotein Complexes Mus Myocardial dysfunction Nuclear Nucleotides Operative Surgical Procedures Outcome Pathologic Pathway interactions Phenotype Play Post-Transcriptional Regulation Protein Biosynthesis Proteins Proteome Regulation Research Ribosomes Role Site Specificity Stress Stretching System Testing Tissues Transcript Translations United States Work effective therapy gain of function genetic manipulation heart function heart metabolism loss of function mRNA Translation mitochondrial metabolism mortality mouse model nanopore novel novel therapeutics posttranscriptional pressure protein complex protein protein interaction ribosome profiling therapeutic development therapeutically effective translational impact

项目摘要

Project Summary Heart failure currently drives a significant proportion of health and economic burden in the United States. Although steps have been made in developing effective treatments, the incidence, morbidity, and mortality of heart failure continues to rise. Thus, it is important to seek out new, more effective therapeutics through the study of molecular mechanisms responsible for cardiac dysfunction. Maladaptive cardiac remodeling is driven by changes in gene expression and protein synthesis in cardiomyocytes. How post-transcriptional modifications control the outcome of gene expression to regulate the synthesis of specific proteins in the heart is unclear. We found that METTL3, the methylase responsible for m6A formation on mRNAs, is a critical regulator of cardiac hypertrophy and is essential for the maintenance of cardiac homeostasis. However, the mechanisms through which METTL3 impacts remodeling has yet to be fully understood. In this proposal we examine the role of METTL3-dependent methylation in regulating mRNA translation for maintenance of heart function at baseline and in adaptation to stress. Utilizing METTL3 gain- and loss-of-function mouse models, we aim to uncover the mechanisms through which METTL3 regulates hypertrophic heart remodeling. Considering the critical importance of this enzyme in the heart we will also address the mechanisms regulating its function and specificity. These findings will further our understanding on how post-transcriptional modifications control cardiac gene expression, while also uncovering new targetable pathways for therapeutic development.

项目概要目前，心力衰竭在美国造成很大一部分健康和经济负担。尽管已经采取措施开发有效的治疗方法，但该病的发病率、发病率和死亡率心力衰竭继续上升。因此，通过以下途径寻找新的、更有效的治疗方法非常重要：研究心脏功能障碍的分子机制。驱动适应不良的心脏重塑通过心肌细胞中基因表达和蛋白质合成的变化。转录后如何修饰控制基因表达的结果，以调节心脏中特定蛋白质的合成尚不清楚。我们发现 METTL3（负责 mRNA 上 m6A 形成的甲基化酶）是一个关键的酶。心脏肥大的调节剂，对于维持心脏稳态至关重要。然而， METTL3 影响重塑的机制尚未完全了解。在这个提案中我们检查 METTL3 依赖性甲基化在调节 mRNA 翻译以维持心脏中的作用基线和压力适应功能。利用 METTL3 功能获得和丧失的小鼠模型，我们旨在揭示 METTL3 调节肥厚心脏重塑的机制。考虑到这种酶在心脏中至关重要，我们还将探讨调节其功能的机制和特异性。这些发现将进一步我们对转录后修饰如何控制的理解心脏基因表达，同时还揭示了治疗开发的新靶向途径。