Post-transcriptional regulation of cardiac hypertrophy

项目总结/摘要 心力衰竭对美国来说是一个巨大的健康和经济负担。尽管目前的治疗， 心力衰竭的发病率-沿着其相关的发病率和死亡率-持续上升。鉴于这些 临床观察，新的治疗策略是迫切需要的，并了解分子 负责应激诱导的心脏肥大和功能障碍的机制将是开发 必要的医学治疗。病理性心脏重塑是通过增加合成特异性 心肌细胞中的蛋白质。尽管在理解转录调控方面已经取得了重大进展， 在重塑心脏发生的变化，很少有人知道如何转录后事件控制 应激心肌中适应不良蛋白的合成。在本提案中，我们将审查 胃L3介导的心脏m6 A mRNA甲基化是调节心脏肥大的新途径我们 假设胃L3依赖性mRNA甲基化通过促进心肌肥厚， 特异性促肥大mRNA的翻译。第一次，利用增益和损失的功能 方法，我们将描述这种新的促肥大程序，建立分子机制， 其中m6 A调节选择mRNA的寿命，并检查其在临床相关动物模型中的作用。的 实现拟议的目标将有助于发现一个新的机制，负责员额， 转录调控的心脏肥大与明显的治疗分歧。

PROJECT SUMMARY/ABSTRACT Heart failure represents a substantial health and economic burden on the US. Despite current treatments, the incidence of heart failure - along with its associated morbidity and mortality - continues to rise. Given these clinical observations, new therapeutic strategies are urgently needed and understanding the molecular mechanisms responsible for stress-induced cardiac hypertrophy and dysfunction will be key to develop the necessary medical therapies. Pathologic cardiac remodeling is mediated by increased synthesis of specific proteins in cardiomyocytes. Although significant progress has been made in understanding the transcriptional changes occurring in the remodeling heart, very little is known about how post-transcriptional events control the synthesis of maladaptive proteins in the stressed myocardium. In this proposal we will examine the role of METTL3-mediated m6A mRNA methylation in the heart as a novel pathway regulating cardiac hypertrophy. We hypothesize that METTL3-dependent mRNA methylation regulates cardiac hypertrophy by favoring the translation of specific pro-hypertrophic mRNAs. For the first time, utilizing gain- and loss-of-function approaches we will characterize this novel pro-hypertrophic program, establish the molecular mechanism by which m6A regulates the life of select mRNAs and examine its role in clinically relevant animal models. The achievement of the proposed aims will allow the uncovering of a novel mechanism responsible for post- transcriptional regulation of cardiac hypertrophy with obvious therapeutics ramifications.