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

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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.