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

microRNA、miR-19 对心脏功能的调节和维持

• 批准号: 226338204
• 负责人: Professor Dr. David Hassel
• 金额: --
• 依托单位: Klinik für Kardiologie, Angiologie und Pulmologie
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2012
• 资助国家: 德国
• 起止时间: 2011-12-31 至 2016-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/226338204?language=en
• 关键词: Regulation; maintenance; cardiac; function; microRNA

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.

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，但直接控制心肌收缩力的关键调节因子的转录后剂量滴定仍然知之甚少。microRNA最近成为重要的全球心脏信号转导的转录后调节因子，通过精确滴定节点调节蛋白和假定的疾病修饰剂，具有巨大的治疗潜力。我们将miR-19鉴定为心脏功能的重要调节剂。斑马鱼中miR-19的缺失会导致心力衰竭，并伴有心脏必需基因的失调和心脏电生理学紊乱。为了进一步评估miR-19在心脏中的特异性功能，提出了三个不同的实验目标：（1）斑马鱼和小鼠中的反向遗传学以及小鼠中的靶向消除将用于彻底确定miR-19对正常心脏功能的作用，（2）将鉴定miR-19在体外和体内心肌细胞中的直接靶向分子和调节途径，（3）最终，将评估miR-19作为治疗心力衰竭的治疗靶标的适用性。拟议的研究将为miRNAs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miRNAs的治疗应用开辟新途径。

项目成果

Essential light chain S195 phosphorylation is required for cardiac adaptation under physical stress.

心脏在身体压力下的适应需要必需的轻链 S195 磷酸化

• DOI: 10.1093/cvr/cvw066
• 发表时间: 2016
• 期刊: Cardiovascular research
• 影响因子: 10.8
• 作者: Scheid LM;Mosqueira M;Hein S;Kossack M;Juergensen L;Mueller M;Meder B;Fink RHA;Katus HA;Hassel D
• 通讯作者: Hassel D