This project aims at identifying therapeutic molecules for stimulating regeneration in the mammalian heart. Intervention will target the most important populations in the heart, i.e. cardiomyocytes and cardiac fibroblasts. Regeneration will be achieved via direct cell reprogramming. Conceptually, cardiomyocytes will be reprogrammed into proliferating cells following dedifferentiation whereas cardiac fibroblasts will be reprogrammed into cardiac precursor cells and subsequently into cardiomyocytes. We will target a newly discovered layer of regulatory molecules, long noncoding RNAs (lncRNAs). LncRNAs can regulate gene expression both at the site of transcription, and at remote locations in the nucleus and cytoplasm, making them ideal regulators of epigenomic and post-transcriptional remodeling, which are key determinants of cellular reprogramming.

 

The project is interdisciplinary and involves three partner institutions in Switzerland and Italy. A number of advanced technologies will be applied. Deep understanding of the cellular mechanisms dictating the response of the heart to stress, primary cardiac cell isolation, advanced computational and bioinformatics capability, use of robotic stations for high throughput library screening, cutting-edge methods for the analysis of gene expression and chromatin remodeling, platforms for ultra-deep genomic sequencing, use of original transgenic mouse models and isolation, cloning and expression of long-non-coding RNAs in vivo using viral vectors are all components that are necessary for the success of the project.