Alternative mRNA processing in cardiac hypertrophy

描述(由申请人提供)：选择性剪接(AS)和选择性多聚腺苷酸化(APA)等选择性信使核糖核酸加工事件导致哺乳动物细胞转录组的复杂性，并在心脏的发育和疾病中发挥重要作用。心肌肥厚是心脏对机械负荷增加的反应而增大，包括心肌细胞大小的增长和心脏生理方面的重构。在肥大过程中，几条信号通路受到调节，导致许多基因的转录发生变化。最近的报道还表明，在肥大过程中，microRNAs参与了转录后基因调控。我们的长期目标是了解心肌肥厚的转录和转录后基因表达机制。我们对这个项目有三个特别的目标：1)研究心肌肥厚中不同的mRNA加工事件；2)比较心肌肥厚和早期发育中的不同的mRNA加工模式；3)阐明心肌肥厚中不同的mRNA加工机制。这一探索性/发展性项目将利用计算分析和实验分析，系统地研究心肌肥厚中的替代mRNA处理。这一结果将极大地丰富我们对心肌肥厚转录后基因调控的认识，并为心力衰竭的潜在治疗方法提供帮助。 公共卫生相关性：心肌肥大是指心脏因机械负荷增加而增大，这通常会导致心力衰竭。在美国，心力衰竭是主要的死亡原因之一。了解心肌肥大的分子机制将有助于我们设计有效的治疗方法来缓解或治愈这种疾病。

DESCRIPTION (provided by applicant): Alternative mRNA processing events, such as alternative splicing (AS) and alternative polyadenylation (APA), contribute to the complexity of transcriptome in mammalian cells, and play significant roles in development and disease of the heart. Cardiac hypertrophy is enlargement of heart in response to increased mechanical load, which involves growth of cardiac myocytes in size, and remodeling of aspects of cardiac physiology. Several signaling pathways are regulated during hypertrophy, leading to change of transcription for many genes. Recent reports also implicated microRNAs in post-transcriptional gene regulation during hypertrophy. Our long term goal is to understand transcriptional and post-transcriptional gene expression mechanisms in cardiac hypertrophy. We have 3 specific aims for this project: 1) To examine alternative mRNA processing events in cardiac hypertrophy; 2) To compare the alternative mRNA processing profiles in cardiac hypertrophy with those in early development; 3) To elucidate the mechanisms of alternative mRNA processing in cardiac hypertrophy. This exploratory/developmental project will systematically examine alternative mRNA processing in cardiac hypertrophy using computational analyses and experimental assays. The results will significantly enrich our knowledge about post-transcriptional gene regulation in cardiac hypertrophy, and shed light on potential therapeutics for heart failure. PUBLIC HEALTH RELEVANCE: Cardiac hypertrophy is enlargement of the heart in response to increased mechanical load, which often leads to heart failure. Heart failure is one of the leading causes of death in the United States. Understanding the molecular mechanism underlying cardiac hypertrophy will help us design effective therapies to mitigate or cure the disease.