Investigating long non-coding RNA regulated pathways

Recent advances in the treatment of myocardial infarction have resulted in marked improvement in the survival of patients. However, many patients develop heart failure because the initial loss of cardiomyocytes cannot be compensated, resulting in chronic deterioration of the heart. Thus, ischemic heart disease and its consequences remain the leading cause of death worldwide. Major efforts are underway to develop strategies for myocardial recovery and thus improve cardiac regeneration. Recently, complete cardiac regeneration has been demonstrated in fish and newborn mice following apex resection or cardiac infarctions. We could demonstrate that the mouse model can be translated to the human heart by studying a newborn baby that experienced a severe perinatal myocardial infarction and completely regenerated within a few weeks. In the mouse heart the window of cardiac regeneration closes within the first week of life. Whereas neonatal mouse hearts fully regenerate, 7-days-old murine hearts show severe scarring following ischemic injury. The critical question remains: What are the mechanism? Thus, the thorough elucidation of the underlying mechanism for neonatal cardiac regeneration is of paramount interest. We focus on the transcriptional changes within the first week of life. In the described project, INNOVATION, we analyse a novel class of non-coding RNAs: the long-non coding RNAs (lncRNAs). In general little is known about this promising class of macromolecules but some scientific results in the heart hint at significant roles of lncRNAs in several cell types. We hypothesis that the differential expression of lncRNAs regulate the process of cardiac growth and regeneration. We will apply state-of-the-art in vitro and in-vivo models to generate cell type- and sex specific lncRNA expression profiles during myocardial physiological growth and cardiac regeneration. Promising target lncRNAs will then be tested for their therapeutic potential in vitro and in vivo. Taken together, the overall aim of INNOVATION is the introduction of novel innovative lncRNA based therapeutic approaches to induce cardiac regeneration in adult mice and humans.

Recent advances in the treatment of myocardial infarction have resulted in marked improvement in the survival of patients. However, many patients develop heart failure because the initial loss of cardiomyocytes cannot be compensated, resulting in chronic deterioration of the heart. Thus, ischemic heart disease and its consequences remain the leading cause of death worldwide. Major efforts are underway to develop strategies for myocardial recovery and thus improve cardiac regeneration. Recently, complete cardiac regeneration has been demonstrated in fish and newborn mice following apex resection or cardiac infarctions. In the mouse heart the window of cardiac regeneration closes within the first week of life. Whereas neonatal mouse hearts fully regenerate, 7-days-old murine hearts show severe scarring following ischemic injury. The critical question remains: What are the mechanism? Thus, the thorough elucidation of the underlying mechanism for neonatal cardiac regeneration is of paramount interest. As part of the international project, INNOVATION, we paid particular attention to non-coding RNAs, especially long non-coding RNAs (lncRNA). We used state-of-the-art in vitro and in vivo methods for lncRNA expression analysis during cardiac regeneration. The resulting interesting candidate RNAs were and will be further investigated for their importance in the regeneration process. Promising new approaches for future regeneration therapies have been established. In summary, observations in newborn mammalian hearts give us hope of finding new approaches for the therapy of myocardial diseases. LncRNAs are a large, partly still unexplored group of non-coding transcripts with great potential for future therapeutic approaches, including in the field of heart regeneration.