ERC FUNDED PROJECTS

Developing new therapeutic strategies for heart regeneration is a major goal for cardiac biology and medicine. While cardiomyocytes can be generated from human pluripotent stem (hPSC) cells in vitro, it has proven difficult to use these cells to generate a large scale, mature human heart ventricular muscle graft on the injured heart in vivo. The central objective of this proposal is to optimize the generation of a large-scale pure, fully functional human ventricular muscle patch in vivo through the self-assembly of purified human ventricular progenitors and the localized expression of defined paracrine factors that drive their expansion, differentiation, vascularization, matrix formation, and maturation. Recently, we have found that purified hPSC-derived ventricular progenitors (HVPs) can self-assemble in vivo on the epicardial surface into a 3D vascularized, and functional ventricular patch with its own extracellular matrix via a cell autonomous pathway. A two-step protocol and FACS purification of HVP receptors can generate billions of pure HVPs- The current proposal will lead to the identification of defined paracrine pathways to enhance the survival, grafting/implantation, expansion, differentiation, matrix formation, vascularization and maturation of the graft in vivo. We will captalize on our unique HVP system and our novel modRNA technology to deliver therapeutic strategies by using the in vivo human ventricular muscle to model in vivo arrhythmogenic cardiomyopathy, and optimize the ability of the graft to compensate for the massive loss of functional muscle during ischemic cardiomyopathy and post-myocardial infarction. The studies will lead to new in vivo chimeric models of human cardiac disease and an experimental paradigm to optimize organ-on-organ cardiac tissue engineers of an in vivo, functional mature ventricular patch for cardiomyopathy

2 149 228 €

Start date: 2017-12-01, End date: 2022-11-30

What is the origin of cosmic rays, what are the dominant acceleration mechanisms in relativistic shocks, how do cosmic rays self-consistently influence the shock dynamics, how are relativistic collisionless shocks formed are longstanding scientific questions, closely tied to extreme plasma physics processes, and where a close interplay between the micro-instabilities and the global dynamics is critical. Relativistic shocks are closely connected with the propagation of intense streams of particles pervasive in many astrophysical scenarios. The possibility of exciting shocks in the laboratory will also be available very soon with multi-PW lasers or intense relativistic particle beams. Computational modeling is now established as a prominent research tool, by enabling the fully kinetic modeling of these systems for the first time. With the fast paced developments in high performance computing, the time is ripe for a focused research programme on simulation-based studies of relativistic shocks. This proposal therefore focuses on using self-consistent ab initio massively parallel simulations to study the physics of relativistic shocks, bridging the gap between the multidimensional microphysics of shock onset, formation, and propagation and the global system dynamics. Particular focus will be given to the shock acceleration mechanisms and the radiation signatures of the various physical processes, with the goal of solving some of the central questions in plasma/relativistic phenomena in astrophysics and in the laboratory, and opening new avenues between theoretical/massive computational studies, laboratory experiments and astrophysical observations.

1 588 800 €

Start date: 2011-06-01, End date: 2016-07-31

Space exploration is one of boldest and most exciting endeavors that humanity has undertaken, and it holds enormous promise for the future. Our next challenges for the spatial conquest include bringing back samples to Earth by means of robotic missions and continuing the manned exploration program, which aims at sending human beings to Mars and bring them home safely. Inaccurate prediction of the heat-flux to the surface of the spacecraft heat shield can be fatal for the crew or the success of a robotic mission. This quantity is estimated during the design phase. An accurate prediction is a particularly complex task, regarding modelling of the following phenomena that are potential “mission killers:” 1) Radiation of the plasma in the shock layer, 2) Complex surface chemistry on the thermal protection material, 3) Flow transition from laminar to turbulent. Our poor understanding of the coupled mechanisms of radiation, ablation, and transition leads to the difficulties in flux prediction. To avoid failure and ensure safety of the astronauts and payload, engineers resort to “safety factors” to determine the thickness of the heat shield, at the expense of the mass of embarked payload. Thinking out of the box and basic research are thus necessary for advancements of the models that will better define the environment and requirements for the design and safe operation of tomorrow’s space vehicles and planetary probes for the manned space exploration. The three basic ingredients for predictive science are: 1) Physico-chemical models, 2) Computational methods, 3) Experimental data. We propose to follow a complementary approach for prediction. The proposed research aims at: “Integrating new advanced physico-chemical models and computational methods, based on a multidisciplinary approach developed together with physicists, chemists, and applied mathematicians, to create a top-notch multiphysics and multiscale numerical platform for simulations of planetary atmosphere entries, crucial to the new challenges of the manned space exploration program. Experimental data will also be used for validation, following state-of-the-art uncertainty quantification methods.”

1 494 892 €

Start date: 2010-09-01, End date: 2015-08-31

Sex differences in life span and aging are ubiquitous across the animal kingdom and represent a long-standing challenge in evolutionary biology. In most species, including humans, sexes differ not only in how long they live and when they start to senesce, but also in how they react to environmental interventions aimed at prolonging their life span or decelerating the onset of aging. Therefore, sex differences in life span and aging have important implications beyond the questions posed by fundamental science. Both evolutionary reasons and medical implications of sex differences in demographic, reproductive and physiological senescence are and will be crucial targets of present and future research in the biology of aging. Here I propose a two-step approach that can provide a significant breakthrough in our understanding of the biological basis of sex differences in aging. First, I propose to resolve the age-old conundrum regarding the role of sexspecific mortality rate in sex differences in aging by developing a series of targeted experimental evolution studies in a novel model organism – the nematode, Caenorhabditis remanei. Second, I address the role of intra-locus sexual conflict in the evolution of aging by combining novel methodology from nutritional ecology – the Geometric Framework – with artificial selection approach using the cricket Teleogryllus commodus and the fruitfly Drosophila melanogaster. I will directly test the hypothesis that intra-locus sexual conflict mediates aging by restricting the adaptive evolution of diet choice. By combining techniques from evolutionary biology and nutritional ecology, this proposal will raise EU’s profile in integrative research, and contribute to the training of young scientists in this rapidly developing field.

1 391 904 €

Start date: 2010-12-01, End date: 2016-05-31