Heart failure (HF) is a major cause of morbidity and mortality in the United States. While progress in conventional treatments is making steady and incremental gains, there is a critical need to explore new therapeutic approaches. Over the last five years, there has been a tremendous amount of information about microRNAs (miRs) in cardiac diseases. These small noncoding RNAs regulate protein expression by destabilization and/or translational inhibition of target messenger RNAs (mRNAs). Expression of miRs is abnormally regulated in cardiac hypertrophy and heart failure. In fact, miR expression seems to be more sensitive than mRNA to changes in clinical cardiac function. Single miRs tend to regulate numerous effectors within the same functional pathway, producing a coherent physiological response. Targeting miRs can therefore produce beneficial responses in disease states. Stable miR mimetics (agomiRs) and antagonists (antagomiRs) for specific miRs have been developed to prevent or reverse various diseases including experimental heart failure. Recently, our group found that miR25 is a key microRNA that regulates the cardiac sarcoplasmic reticulum calcium ATPase pump, SERCA2a. We showed antimiR25 treatment enhanced cardiac contractility and function through SERCA2a restoration in murine heart failure models. These early results suggest that inhibition of miR25 expression may be a promising therapeutic approach to enhance cardiac function in HF. Our overall hypothesis is that there are optimized sequences and functional structures of miR25 decoys. These decoys efficiently inhibit miR25 activity and consequently improve SERCA2a expression in cardiac myocytes of HF patients.
Heart failure is a major cause of morbidity and mortality in the United States and there is a critical need for novel therapies. In this proposal, we will investigae the role of noncoding microRNA (miR25) in failing hearts. Modulating miR25 expression may be a promising therapeutic approach to enhance cardiac function in heart failure.
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