Description:
<jats:p>There is an urgent need for therapies that reverse the course of ventricular dysfunction in heart failure, which is a leading cause of morbidity and mortality. We have performed high throughput chemical and functional genomics screens probing cardiomyocyte differentiation and contractility, and used the results to construct protein‐protein interaction networks controlling these complex biological processes. To measure cardiac contractility in high throughput, we have used an automated microscopy platform (Vala Sciences) that optically measures heart muscle cell action potential and calcium transient kinetics and morphology. By screening static and kinetic endpoint assays against whole genome microRNA libraries, we have reconstructed microRNA:protein networks that control myocyte differentiation and contractility. This approach has revealed a number of microRNAs that direct differentiation and modulate physiological function, including microRNAs that adversely affect heart function in vivo. Targeting one of microRNAs with an antisense RNA is able to enhance echocardiographic and hemodynamic indices of heart function in vivo and halt the progression of established heart failure in a mouse pressure overload model.</jats:p>