ERC FUNDED PROJECTS

The interaction of cells with the extracellular matrix or neighboring cells plays a crucial role in many cellular functions, such as motility, differentiation and controlled cell death. Expanding on pioneering studies on defined 2-D model systems, the role of the currently known determinants (geometry, topography, biochemical functionality and mechanical properties) is currently addressed in more relevant 3-D matrices. However, there is a clear lack in currently available approaches to fabricate well defined microenvironments, which are asymmetric or in which these factors can be varied independently. The central objective of ASMIDIAS is the development of a novel route to asymmetric microenvironments for cell-matrix interaction studies. Inspired by molecular self-assembly on the one hand and guided macroscale assembly on the other hand, directed assembly of highly defined microfabricated building blocks will be exploited to this end. In this modular design approach different building blocks position themselves during assembly on pre-structured surfaces to afford enclosed volumes that are restricted by the walls of the blocks. The project relies on two central elements. For the guided assembly, the balance of attractive and repulsive interactions between the building blocks (and its dependence on the object dimensions) and the structured surface shall be controlled by appropriate surface chemistry and suitable guiding structures. To afford the required functionality, new approaches to (i) topographically structure, (ii) biochemically functionalize and pattern selected sides of the microscale building blocks and (iii) to control their surface elastic properties via surface-attached polymers and hydrogels, will be developed.The resulting unique asymmetric environments will facilitate novel insight into cell-matrix interactions, which possess considerable relevance in the areas of tissue engineering, cell (de)differentiation, bacteria-surface interactions and beyond.

1 484 100 €

Start date: 2011-11-01, End date: 2016-10-31

"Sphingolipids are major components of the human cell and are involved in human pathologies ranging from lysosomal storage disorders to type 2 diabetes. Here, we propose to establish an integrated research program for the study of sphingolipid metabolism, in health and disease. We will combine state-of-the-art synthetic organic chemistry, bioorganic chemistry, analytical chemistry, molecular biology and biochemistry techniques and concepts and apply these in an integrated chemical biology approach to study and manipulate sphingolipid metabolism in vivo and in vitro, using human cells and animal models. The program is subdivided in three individual research lines that are interconnected both in terms of technology development and in their biological context. 1) We will develop modified sphinganine derivatives and apply these to study sphingolipid homeostasis in cells derived from healthy and diseased (Gaucher, Fabry, Niemann-Pick A/B disease) individuals/animal models. This question will be addressed in a chemical metabolomics/lipidomics approach. 2) We will develop activity-based probes aimed at monitoring enzyme activity levels of glycosidases involved in (glyco)sphingolipid metabolism, in particular the enzymes that - when mutated and thereby reduced in activity- are responsible for the lysosomal storage disorders Gaucher disease and Fabry disease. 3) We will develop well-defined enzymes and chaperone proteins for directed correction of sphingolipid homeostasis in Gaucher, Fabry and Niemann-Pick A/B patients, via a newly designed semi-synthetic approach that combines sortase-mediated ligation with synthetic chemistry. Deliverables are a better understanding of the composition of the sphingolipid pool that are at the basis of lysosomal storage disorders, effective ways to in situ monitor the efficacy of therapies (enzyme inhibitors, chemical chaperones, recombinant enzymes) to treat these and improved semi-synthetic proteins for enzyme replacement therapy."

2 999 600 €

Start date: 2012-06-01, End date: 2017-05-31

The origins of imperialism, a socio-military system in which hegemony is achieved over alien territories, are poorly investigated. This applies in particular to how imperial strategies affected local communities. This project will investigate the hegemonic practices of one of the earliest stable empires: that of the Assyrians, by focussing on the Late Bronze Age fortified estate at Tell Sabi Abyad, ca. 1230-1180 BC. The Assyrians created a network of strongholds in conquered territories to consolidate their hegemony. The fortified estate at Tell Sabi Abyad is the only extensively investigated of these Assyrian settlements. This settlement is both small and well preserved and has been completely excavated. The complete plan facilitates a study of the spatial properties of this fortress and how it structured interactions. Further, the estate contained a wealth of in situ finds, which allow for a reconstruction of activity patterns in the settlement. Finally, over 400 cuneiform tablets were found which shed light on the local social and economic situation and the broader imperial context. This project will provide a bottom up perspective on the Assyrian Empire. Elements of the Tell Sabi Abyad estate that will be investigated include: spatial characteristics; activity areas; the agricultural economy; and the surrounding landscape. Further, data from the Middle Assyrian Empire at large will be reconsidered, in order to achieve a better understanding of how this empire was constituted. This project is innovative because: it investigates a spatial continuum ranging from room to empire; brings together types of data usually investigated in isolation, such as texts and artifacts; will involve the use of novel techniques; and will investigate the short term normally beyond the scope of archaeology. The research will contribute to the cross-cultural issue of how hegemonic control is achieved in alien territories, and add to our understanding of early empires.

1 191 127 €

Start date: 2012-01-01, End date: 2015-12-31

This proposal addresses currently unresolved fundamental questions concerning the activation and functionalization in homogeneous catalysis of challenging, inherently unreactive substrates like NH3, CO2 or water. Responsive ligands in combination with earth-abundant first row transition metals may hold the key to selective bifunctional activation of these small molecules. This innovative, bioinspired concept, utilizing ligand-metal cooperativity to enhance, tune and control the reactivity of base metals, mimics and circumvents the use of expensive and/or toxic 2nd and 3rd row transition metals. A comprehensive tool-box of readily accessible smart ligand systems with cooperative, redox noninnocent or adaptive features will be used for stoichiometric and ultimately catalytic reactivity studies with Fe, Co, Ni and Cu. This will result in mechanistic understanding of novel pathways for selective N-H and O-H activation on well-defined mono- and dinuclear cooperative complexes. Coupling and insertion reactions with alkenes to yield efficient C-N and C-O bond forming processes and CO2 functionalization will be investigated. This fundamental knowledge is then applied for unprecedented cooperative catalysis with first row transition metals. The project will ultimately result in important leads for the direct intermolecular hydroamination of alkenes, including with ammonia, which is one of the top-ten challenges in catalysis, and the efficient, sustainable production of carboxylic acids from CO2 and alkenes. Also relevant contributions to the oxidative activation of water for hydration reactions with alkynes are foreseen. When successful, my initiatives will enable significant breakthroughs in the design of unique, smart ligand systems for the cooperative activation and functionalization of small molecules with base metals. An ERC starting grant greatly strengthens my position in the emerging field of cooperative homogeneous catalysis.

1 498 471 €

Start date: 2012-01-01, End date: 2016-12-31