paTCH · Targeting the miR-106b~25 cluster in pathological Cardiac Hypertrophy
FP7 — People (Marie Curie Actions)
- Duration
- 2014-03-01 → 2015-02-28
- EU contribution
- €93,707
- Participants
- 1
- Scheme
- MC-IEF
Lines connect the coordinator with its partners.
Results in brief
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.
Data: CORDIS, © European Union
Project objective
BACKGROUND: There is a tremendous need to develop novel therapies for heart failure. In particular, sustained pathological hypertrophy, a major predictor of this condition, is a complex process, which involves transcriptional and posttranscriptional regulation of the cardiac genome. There is now clear indication that, besides a few known transcriptional regulators, multiple, still poorly understood cardiac factors are involved in hypertrophy; understanding this complexity is expected to pave to the way to innovative therapies. In particular, recent data demonstrate that dysregulated microRNAs (miRs) are associated with heart failure, and that selective modulation of miRs can provide therapeutic benefits. Our pilot-data show that expression of the miR-106b~25 cluster decreases during pathological hypertrophy in mice and that virus-mediated overexpression of this cluster prevents phenylephrine-induced hypertrophic remodeling. Following bioinformatics screens for potential direct downstream targets of the miR-25~106b cluster, we identified a series of transcription factors, which might play a role in pathological cardiac remodeling.AIM: To define the functional implication of the miR-106b~25 cluster in pathological cardiac hypertrophy and to exploit this information towards the development of novel therapeutic approaches.APPROACH: We will identify direct downstream targets of the miR-106b~25 cluster during hypertrophy, by performing Ago2-Immunoprecipitation and by treating neonatal cardiomyocytes with precursors of miR-25, miR-93 and miR-106b, followed by next generation sequencing (Objective 1); We aim to reverse pathological cardiac remodeling and prevent heart failure by delivery of recombinant adeno-associated virus (rAAV9)- miR-106b~25 in mice (Objective 2). The results obtained will generate important intellectual property value and will constitute the basis for further development towards the generation of novel therapies against heart failure.
Original text from CORDIS.
Participants
- INTERNATIONAL CENTRE FOR GENETIC ENGINEERING AND BIOTECHNOLOGY · TriesteCoordinatorItaly
Links
Data: CORDIS, © European Union