Post-transcriptional regulation of cardiac hypertrophy

项目摘要 心力衰竭目前在美国的健康和经济负担中占很大比例。 尽管在开发有效治疗方法方面已经取得了一些进展，但其发病率、发病率和死亡率仍然很低。 心力衰竭的发病率继续上升。因此，重要的是通过药物治疗来寻找新的、更有效的治疗方法。 心脏功能障碍的分子机制研究。适应不良的心脏重塑 通过改变心肌细胞中的基因表达和蛋白质合成。如何转录后 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 还不清楚我们发现，负责m6A在mRNA上形成的甲基化酶-胃L3是一个关键的 是心脏肥大的调节剂，对维持心脏稳态至关重要。但 胃L3影响重塑的机制尚未完全了解。在本提案中，我们 检查胃L3依赖性甲基化在调节mRNA翻译以维持心脏中的作用 在基线和适应压力的功能。利用L3获得和丧失功能的小鼠模型，我们 旨在揭示胃L3调节肥厚性心脏重塑的机制。考虑 这种酶在心脏中的重要性，我们还将讨论调节其功能的机制。 和特异性。这些发现将进一步加深我们对转录后修饰如何控制 心脏基因表达，同时也揭示了新的治疗发展的靶向途径。

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.