ERC FUNDED PROJECTS

The proposed project aims at investigating the molecular mechanisms that activate B cell antigen receptor (BCR) signalling in chronic lymphocytic leukaemia (CLL). While it is widely accepted that the unbroken BCR expression in CLL cells is indicative for a key role in disease development, the mechanisms that induce BCR activation and survival of malignant cells are still elusive. Using a unique reconstitution system, we have recently shown that CLL-derived BCRs possess the exceptional capacity for cell-autonomous signalling independent of external antigen. Crystallographic analyses confirmed our model that CLL-BCRs bind to intrinsic motifs in nearby BCRs on the very same cell. In addition to the BCR, several pathogenic factors influence the biological behaviour of CLL cells, but the functional hierarchy and the effect on BCR signalling are insufficiently understood. Here, we aim at investigating the structural cause of autonomous signalling as well as the characterization of important signalling pathways and their mechanistic action in CLL pathogenesis. By combining crystallography with the measurement of autonomous signalling of wild type and mutated receptors in our unique reconstitution system, we will generate a structure-function relationship for CLL-BCRs. By generating new animal models and by employing classical as well as cutting-edge approaches of biochemistry and molecular/cellular immunology, we will comprehensively characterize the signalling pathways that are activated by autonomous signalling and might be important for CLL pathogenesis. These systematic efforts are necessary to understand how various biological mechanisms operate and ultimately activate downstream pathways that result in a lymphoproliferative disease. In addition, a cohesive model of CLL pathogenesis, which elucidates the hierarchical order of pathogenic factors and their interaction with BCR signalling, may well lead to novel disease-specific preventive or therapeutic intervention.

2 256 250 €

Start date: 2016-11-01, End date: 2021-10-31

Background. We have detailed maps of brain structure and function, yet are lacking understanding of how the highly connected units interact and give rise to mental processes. The Virtual Brain (TVB), a whole brain simulation framework, aims to bridge that gap. Yet it is still developing. We are proposing here breakthrough advances that reveal mechanisms of brain function and foster collaboration between research groups. Vision. Clinical applications that simulate individual patient brains and predict trajectories of recovery or decline or test therapies to select the best one for that person. Goal. Using biologically realistic brain models and multimodal functional and structural imaging data to elucidate control mechanisms of the human brain in aging. A database collects key data and allows identifying most generic models and mechanisms below the spatial and temporal resolution of non-invasive imaging techniques taking into account the complex interaction in the brain that without a model would be impossible to keep track of. Objectives. 1) Parameter optimization for large parameter space search and a library of dynamical regimes linking dynamical regimes and underlying mechanisms to biological (cognitive) age. 2) Identifying the role of intrinsic plasticity for network reconfigurations in the resting state and its age dependency. 3) Model based identification of task related plasticity mechanisms and their functional consequences for network reconfigurations in coordination learning in aging. 4) An interactive tool that provides access to the dynamical regimes library and makes pre-computed simulations easily accessible allowing researchers to benefit and learn from existing work. Impact. Understanding development, aging and brain disorders from the perspective of disruption of information processing architectures provides an opportunity for new interventions that re-establish control in brain pathology hence posing a breakthrough in the health and biotech sector.

1 870 588 €

Start date: 2016-08-01, End date: 2021-07-31

This project aims to develop two arrays of questions at the heart of harmonic analysis, probability and operator theory: Multi-parameter harmonic analysis. Through the use of wavelet methods in harmonic analysis, we plan to shed new light on characterizations for boundedness of multi-parameter versions of classical Hankel operators in a variety of settings. The classical Nehari's theorem on the disk (1957) has found an important generalization to Hilbert space valued functions, known as Page's theorem. A relevant extension of Nehari's theorem to the bi-disk had been a long standing problem, finally solved in 2000, through novel harmonic analysis methods. It's operator analog remains unknown and constitutes part of this proposal. Sharp estimates for Calderon-Zygmund operators and martingale inequalities. We make use of the interplay between objects central to Harmonic analysis, such as the Hilbert transform, and objects central to probability theory, martingales. This connection has seen many faces, such as in the UMD space classification by Bourgain and Burkholder or in the formula of Gundy-Varapoulos, that uses orthogonal martingales to model the behavior of the Hilbert transform. Martingale methods in combination with optimal control have advanced an array of questions in harmonic analysis in recent years. In this proposal we wish to continue this direction as well as exploit advances in dyadic harmonic analysis for use in questions central to probability. There is some focus on weighted estimates in a non-commutative and scalar setting, in the understanding of discretizations of classical operators, such as the Hilbert transform and their role played when acting on functions defined on discrete groups. From a martingale standpoint, jump processes come into play. Another direction is the use of numerical methods in combination with harmonic analysis achievements for martingale estimates.

1 523 963 €

Start date: 2017-01-01, End date: 2021-12-31

Resolution of acute inflammation, involving limiting further leukocyte recruitment, apoptosis and clearance of inflammatory cells via macrophages as well as egress of the inflammatory cells, is operative in acute inflammation but dysfunctional in chronic inflammatory disease. In the latter scenario, the retention and activation of leukocytes in the inflamed tissue linked with failure to resolve inflammation contributes to perpetuation of organ damage and loss of homeostasis. Interestingly, persistent inflammation in insulintarget organs, such as the adipose tissue and the liver in the context of obesity significantly contributes to development of insulin resistance (IR), diabetes and non-alcoholic fatty liver disease (NAFLD). So far, investigations have mainly addressed obesity-related inflammatory mechanisms in the AT and rather less in other metabolic organs, e.g. the liver. Therefore, the aims of this proposal are: (i) To characterize in the context of obesity-related metabolic disease novel processes mediating inflammatory cell retention, especially in the liver. In this context, we will also address the novel hypothesis that adhesive interactions of inflammatory cells (with e.g. parenchymal cells) in the metabolically challenged environment of obese organs may activate them via alterations in their cellular metabolism, thereby contributing to perpetuation of inflammation. (ii) To understand resolution of inflammation including inflammatory cell egress from metabolic organs, especially from the liver in metabolic-inflammatory disease. To this end, we will also utilize models of acute inflammation, which is capable to resolve, in order to understand resolution principles and apply them to non-resolving metabolic-inflammatory disease. In this regard, we will also assess the therapeutic potential of novel inflammation-modulating factors identified by our lab.

1 953 250 €

Start date: 2017-01-01, End date: 2021-12-31