Regulation and maintenance of cardiac function by the microRNA, miR-19

心力衰竭（HF）是一种临床综合征，最常由进行性收缩功能障碍引起，是发达国家发病率和死亡率的主要原因之一。无数的信号通路调节心脏功能，但直接控制心脏收缩力的关键调节因子的转录后剂量滴定仍然知之甚少。最近，通过精确滴定节点调节蛋白和假定的疾病调节剂，MicroRNAs成为重要的全球心脏信号转录后调节剂，具有巨大的治疗潜力。我们发现miR-19是一个重要的心脏功能调节剂。miR-19在斑马鱼体内的缺失导致心力衰竭，并伴有心脏必需基因的失调和心脏电生理紊乱。为了进一步评估miR-19在心脏中的具体功能，我们提出了三个不同的实验目标：(1)将利用斑马鱼和小鼠的反向遗传学以及小鼠的靶向耗竭来全面确定miR-19对正常心功能的作用；(2)将在体外和体内鉴定miR-19在心肌细胞中的直接靶向分子和调控途径；(3)最终将评估miR-19作为治疗心力衰竭的靶点的适用性。拟议的研究将为mirna如何调节和维持心脏功能提供新的机制见解，并可能为未来基于mirna的治疗应用开辟新的途径。

Heart failure (HF) describes a clinical syndrome, most frequently caused by progressive contractile dysfunction and represents one of the leading causes for morbidity and mortality in developed countries. A myriad of signaling pathways regulate heart function but the post-transcriptional dose titration of key regulators directly controlling cardiac contractility is still poorly understood. MicroRNAs recently emerged as important global post-transcriptional regulators of cardiac signaling by precisely titrating nodal regulatory proteins and putative disease modifiers, harboring a huge therapeutic potential. We identified miR-19 as an important modulator of heart function. Depletion of miR-19 in zebrafish resulted in heart failure accompanied with dysregulation of essential cardiac genes and disturbed cardiac electrophysiology. To further evaluate the specific function of miR-19 in the heart, three distinct experimental objectives are proposed: (1) reverse genetics in zebrafish and mouse together with targeted depletion in mice will be used to thoroughly define the role of miR-19 for normal heart function, (2) directly targeted molecules and regulated pathways of miR-19 in cardiomyocytes in vitro and in vivo will be identified, (3) and ultimately, the suitability of miR-19 as a therapeutic target to treat heart failure will be evaluated. The proposed research will provide novel mechanistic insights into how miRNAs modulate and maintain cardiac function and could open new avenues for future miRNA-based therapeutic applications.