ERC FUNDED PROJECTS

Cardiac connective tissue is regarded as passive in terms of cardiac electro-mechanics. However, recent evidence confirms that fibroblasts interact directly with cardiac muscle cells in a way that is likely to affect their beat-by-beat activity. To overcome limitations of traditional approaches to exploring these interactions in native tissue, we will build and explore murine models that express functional reporters (membrane potential, Vm; calcium concentration, [Ca2+]i) in fibroblasts, to identify how they are functionally integrated in native heart (myocyte => fibroblast effects). Next, we will express light-gated ion channels in murine fibroblast, to selectively interfere with their Vm (fibroblast => myocyte effects). Fibroblast-specific observation and interference will be conducted in normal and pathologically remodelled tissue, to characterise fibroblast relevance for heart function in health & disease. Based on these studies, we will generate 2 transgenic rabbits (fibroblast Vm reporting / interfering). Rabbit cardiac structure-function is more amenable to translational work, e.g. to study fibroblast involvement in normal origin & spread of excitation across the heart, in pathological settings such as arrhythmogenicity of post-infarct scars (a leading causes of sudden death), or as a determinant of therapeutic outcomes such as in healing of atrial ablation lines (interfering with a key interventions to treat atrial fibrillation). The final ‘blue-skies’ study will assess whether modulation of cardiac activity, from ‘tuning’ of biological pacemaker rates to ‘unpinning’ / termination of re-entrant excitation waves, can be achieved by targeting not myocytes, but fibroblasts. The study integrates basic-science-driven discovery research into mechanisms and dynamics of biophysical myocyte-fibroblast interactions, generation of novel transgenic models useful for a broad range of studies, and elucidation of conceptually new approaches to heart rhythm management.

2 498 612 €

Start date: 2013-07-01, End date: 2019-06-30

The impressive progress in synthetic organic chemistry during the past century has propelled this discipline to its current central place as the key enabling technology in the physical and life sciences. Despite these remarkable advances, our ability to construct molecules of even moderate structural complexity remains unsatisfactory, since these syntheses continue to be inefficient, rely on a high number of reaction steps, and generate undesired, often toxic waste. These features led to the general need for greener transformations that will stimulate the development of more sustainable chemical industries. Conventional approaches in synthetic organic chemistry make use of starting materials displaying specific functional groups, the installation of which results in costly reaction and purification steps. Therefore, an environmentally-sound and economically-attractive alternative is represented by the direct functionalization of ubiquitous carbon-hydrogen (C–H) bonds. These transition-metal-catalyzed processes avoid prefunctionalization strategies, prevent the formation of undesired waste, and thus enable an overall streamlining of organic synthesis. While considerable recent progress has been accomplished in C–H bond functionalizations, available methodologies continue to be limited in scope, and key challenges are still to be overcome. Establishing a full set of sustainable C–H bond functionalization protocols will undeniably have a tremendous impact on various applied areas, such as drug discovery, chemical industries or material sciences.

1 499 338 €

Start date: 2012-10-01, End date: 2017-09-30

"Spatially distributed multi-agent networks have been used successfully to model a wide range of natural, social and engineered complex systems, such as animal groups, online communities and electric power grids. In various contexts, it is crucial to introduce control actions into such networks to either achieve desired collective dynamics or test the understanding of the systems’ behavior. However, controlling such systems is extremely challenging due to agents’ complicated sensing, communication and control interactions that are distributed in space. Systematic methodologies to attack this challenge are in urgent need, especially when vast efforts are being made in multiple disciplines to apply the model of complex multi-agent networks. The goal of the project is twofold. First, understand whether a complex multi-agent network can be controlled effectively when the agents can only sense and communicate locally. Second, provide methodologies to implement distributed control in typical spatially distributed complex multi-agent networks. The project requires integrated skills since both rigorous theoretical analysis and novel empirical explorations are necessary. The research methods that I plan to adopt have two distinguishing features. First, I use tools from algebraic graph theory and complex network theory to investigate the impact of network topologies on the systems’ controller performances characterized by mathematical control theory. Second, I utilize a homemade robotic-fish testbed to implement various multi-agent control algorithms. The unique combination of theoretical and empirical studies is expected to lead to breakthroughs in developing an integrated set of principles and techniques to control effectively spatially distributed multi-agent networks. The expected results will make original contributions to control engineering and robotics, and inspire innovative research methods in theoretical biology and theoretical sociology."

1 495 444 €

Start date: 2013-01-01, End date: 2017-12-31

"DNA in higher organisms is organized in a nucleoprotein complex called chromatin. The structure of chromatin is responsible for compacting DNA to fit within the nucleus and for governing its access in nuclear processes. Epigenetic information is encoded chiefly via chromatin modifications. Readout of the genetic code depends on chromatin remodeling, a process actively altering chromatin structure. An understanding of the hierarchical structure of chromatin and of structurally based, remodeling mechanisms will have enormous impact for developments in medicine. Following our high resolution structure of the nucleosome core particle, the fundamental repeating unit of chromatin, we have endeavored to determine the structure of the chromatin fiber. We showed with our X-ray structure of a tetranucleosome how nucleosomes could be organized in the fiber. Further progress has been limited by structural polymorphism and crystal disorder, but new evidence on the in vivo spacing of nucleosomes in chromatin should stimulate more advances. Part A of this application describes how we would apply these new findings to our cryo-electron microscopy study of the chromatin fiber and to our crystallographic study of a tetranucleosome containing linker histone. Recently, my laboratory succeeded in providing the first structurally based mechanism for nucleosome spacing by a chromatin remodeling factor. We combined the X-ray structure of ISW1a(ATPase) bound to DNA with cryo-EM structures of the factor bound to two different nucleosomes to build a model showing how this remodeler uses a dinucleosome, not a mononucleosome, as its substrate. Our results from a functional assay using ISW1a further justified this model. Part B of this application describes how we would proceed to the relevant cryo-EM and X-ray structures incorporating dinucleosomes. Our recombinant ISW1a allows us to study in addition the interaction of the ATPase domain with nucleosome substrates."

2 500 000 €

Start date: 2013-01-01, End date: 2017-12-31