Aging poses the largest risk for cardiovascular disease (CVD) and is orchestrated, to some extent, by epigenetic changes. Despite the significant progress on many fronts in the cardiovascular field, non-inherited epigenetic regulation in cardiac aging and CVD remains unexplored. Dilated Cardiomyopathy (DCM) is a major contributor to healthcare costs and it is the leading indication for heart transplantation. We have recently discovered that adult cardiac-specific deletion of epigenetic regulator Bmi1 in mice induces DCM and heart failure. These unprecedented data support the idea that inadequate epigenetic regulation in adulthood is critical in CVD. In addition, our studies with parabiotic pairing of healthy and DCM-diagnosed mice show that the circulation of a healthy mouse significantly improve the cardiac performance of mouse with DCM. These ground-breaking discoveries suggest that DCM regression, or cardiac rejuvenation, is feasible in terms of epigenetic states. Therefore, YOUNGatHEART will unveil significant breakthrough on (1) how non-inherited epigenetic deregulation induces DCM and (2) how epigenetic remodeling reversed this process. For that, our challenges are: 1A. To decipher how aged-linked cardiac dysfunction contributes to CVD by identifying the epigenetic landscape regulating cardiac aging among species; 1B. To decode how epigenetic deregulation induces DCM by integrating clinical data and samples from DCM-transplanted patients with imaging, transcriptomic, proteomic, and functional approaches from DCM model; and, 2A. To identified systemic factors with anti-cardiomyopathic effects by systematic proteomic screenings after parabiosis and epigenome of the DCM hearts. In sum, YOUNGatHEART puts forward an ambitious but feasible and pioneering program to tackle the epigenetic hallmark in cardiac aging with the final aim (2B) of setting the molecular basis for future therapeutic interventions in CVD.

Cardiovascular disease (CVD) incidence continues to rise at an alarming rate largely as a consequence of behavioural risk factors. The only way to tackle this epidemic is to implement preventive strategies before the disease appears. Current evidence suggests that conventional approaches are inadequate for promoting healthier lifestyles, and therefore implementation of novel methods is desperately needed. The research proposed under the acronym of CLIP (Comprehensive Lifestyle Intervention Project) will tackle novel approaches to CVD prevention based on the Personalized Medicine concept, considering the interactions between genetic and environmental factors of disease development. During the outgoing phase (24 months), the young Experienced Researcher (ER) will perform extensive and multidisciplinary training on innovative strategies for effective lifestyle modification in adults and children, and will undertake a specific study to identify genomic factors able to predict adult subjects who will benefit most from novel lifestyle interventions, thus permitting future tailored approaches. During the incoming phase (12 months) the ER will transfer the new methodology to Europe by carrying out a pilot lifestyle modification and genomic study program in adults in Spain. This experience will be enriched by the secondment in a private multinational company. Thus, the new abilities the ER will acquire from various areas will enable him to implement new programmes to attain primary CVD prevention, including the use of genomic-driven personalized approaches; and to become an independent group leader upon my return to Europe at the host institution. The long term impact of the CLIP will help to reduce the huge economic burden to society and healthcare systems associated with CVD treatment as it will directly contribute to Europe’s aim of fighting the CVD epidemic.

Blood and lymphatic vessels have been the subject of intense investigation due to their important role in cancer development and in cardiovascular diseases. The significant advance in the methods used to modify and analyse gene function have allowed us to obtain a much better understanding of the molecular mechanisms involved in the regulation of the biology of blood vessels. However, there are two key aspects that significantly diminish our capacity to understand the function of gene networks and their intersections in vivo. One is the long time that is usually required to generate a given double mutant vertebrate tissue, and the other is the lack of single-cell genetic and phenotypic resolution. We have recently performed an in vivo comparative transcriptome analysis of highly angiogenic endothelial cells experiencing different VEGF and Notch signalling levels. These are two of the most important molecular mechanisms required for the adequate differentiation, proliferation and sprouting of endothelial cells. Using the information generated from this analysis, the overall aim of the proposed project is to characterize the vascular function of some of the previously identified genes and determine how they functionally interact with these two signalling pathways. We propose to use novel inducible genetic tools that will allow us to generate a spatially and temporally regulated fluorescent cell mosaic matrix for quantitative analysis. This will enable us to analyse with unprecedented speed and resolution the function of several different genes simultaneously, during vascular development, homeostasis or associated diseases. Understanding the genetic epistatic interactions that control the differentiation and behaviour of endothelial cells, in different contexts, and with high cellular definition, has the potential to unveil new mechanisms with high biological and therapeutic relevance.