miR-301b inhibits autophagy by directly targeting RAB5A

University Of Colorado Denver, Aurora CO

Investigators

Abstract

PROJECT SUMMARY End-stage heart failure (HF) due to dilated cardiomyopathy (DCM) is the most common indication for cardiac transplantations in children over the age of 1 year. Though DCM affects both adults and children the causes can be different, with ischemic heart disease being the most frequent cause of HF in adults whereas in children the most common cause of DCM is idiopathic. However, the therapeutic strategies in children with heart failure are based on adult clinical studies and are less effective in managing HF in children. This suggests that understanding the mechanisms of heart failure in children is critical to identify novel age-specific therapeutic targets in this population and improve the translational barrier roadblock in pediatric DCM patients. My preliminary data suggests that miR-301b is highly expressed in pediatric DCM hearts and its predicted target genes are implicated in autophagy. In addition, primary cardiomyocytes over-expressing miR-301b demonstrate inhibited phagosome formation associated with reduced RAB5A protein expression. RAB5A is known to be highly expressed in the heart and is a miR-301b predicted target gene. In this application, I propose to determine the expression level of autophagy-related proteins in the heart tissue of pediatric DCM patients (Aim1), establish the effect of miR-301b over-expression on autophagy and apoptosis in primary cardiomyocytes (Aim2) and Determine in vivo regulation of cardiac autophagy by miR-301b and its consequence on cardiac function in neonatal mouse model. These studies will confirm the negative effect of miR-301b on autophagy, apoptosis and most importantly on cardiac function by directly targeting Rab5A and contribute to the development of novel age-specific therapies in children with heart failure addressing the translational barrier roadblock in this population.