Final Report Summary - PATCH (Targeting the miR-106b~25 cluster in pathological Cardiac Hypertrophy)
Heart Failure is a serious clinical disorder that represents the primary cause of hospitalization and death in Europe and in the United States. In humans, sustained pathological hypertrophy is a major predicator of heart failure and sudden cardiac death.
Recent studies established essential roles for microRNAs (miRs) in heart development and heart failure. MicroRNAs are 18-24 nucleotide single-stranded RNAs, encoded by the genome, which and inhibit gene expression by translational repression. Recent data demonstrate that the selective modulation of microRNA activity can provide therapeutic benefit in rodents and primates. These exciting data strengthen the idea for microRNA modulators as candidate therapeutics. MicroRNAs target many gene transcripts and predictive bioinformatics approaches allow the identification of target genes mechanistically linked to microRNA-driven pathogenesis. Recently, it was shown that loss of the microRNA clusters miR-106b~25 and miR-17~92 leads to embryonic death associated with severe cardiac defects and widespread apoptosis, indicating that these clusters have an essential role during the process of cardiogenesis. Our pilot-data show that the expression of the miR-106b~25 cluster is decreased in the failing heart. Following bioinformatics screens for the miR-106b, miR-93 and miR-25 binding sites in the 3’UTR of potential direct downstream targets, we surprisingly identified a network of genes known to play a role in pathological hypertrophy, but also a series of new genes, suggesting a role for the miR-106b~25 cluster in pathological hypertrophic remodeling, by re-activating these sets of genes, resulting in heart failure.
Recent studies established essential roles for microRNAs (miRs) in heart development and heart failure. MicroRNAs are 18-24 nucleotide single-stranded RNAs, encoded by the genome, which and inhibit gene expression by translational repression. Recent data demonstrate that the selective modulation of microRNA activity can provide therapeutic benefit in rodents and primates. These exciting data strengthen the idea for microRNA modulators as candidate therapeutics. MicroRNAs target many gene transcripts and predictive bioinformatics approaches allow the identification of target genes mechanistically linked to microRNA-driven pathogenesis. Recently, it was shown that loss of the microRNA clusters miR-106b~25 and miR-17~92 leads to embryonic death associated with severe cardiac defects and widespread apoptosis, indicating that these clusters have an essential role during the process of cardiogenesis. Our pilot-data show that the expression of the miR-106b~25 cluster is decreased in the failing heart. Following bioinformatics screens for the miR-106b, miR-93 and miR-25 binding sites in the 3’UTR of potential direct downstream targets, we surprisingly identified a network of genes known to play a role in pathological hypertrophy, but also a series of new genes, suggesting a role for the miR-106b~25 cluster in pathological hypertrophic remodeling, by re-activating these sets of genes, resulting in heart failure.