Alternative mRNA processing in cardiac hypertrophy

描述（由申请人提供）：选择性mRNA加工事件，如选择性剪接（AS）和选择性聚腺苷酸化（阿帕），有助于哺乳动物细胞中转录组的复杂性，并在心脏发育和疾病中发挥重要作用。心脏肥大是心脏对增加的机械负荷的反应，其涉及心肌细胞大小的生长和心脏生理学方面的重塑。在肥大过程中，多种信号通路受到调节，导致许多基因的转录改变。最近的报道也暗示microRNA在肥大过程中的转录后基因调控。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。我们这个项目有3个具体目标：1）检查心脏肥大中的替代mRNA加工事件; 2）比较心脏肥大中的替代mRNA加工谱与早期发育中的替代mRNA加工谱; 3）阐明心脏肥大中替代mRNA加工的机制。这个探索性/发展性项目将使用计算分析和实验测定系统地研究心脏肥大中的替代mRNA加工。这一结果将极大地丰富我们对心肌肥厚中转录后基因调控的认识，并为心力衰竭的潜在治疗提供线索。 公共卫生相关性：心脏肥大是心脏对机械负荷增加的反应，通常导致心力衰竭。心力衰竭是美国的主要死亡原因之一。了解心肌肥厚的分子机制将有助于我们设计有效的治疗方法来减轻或治愈这种疾病。

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.