ERC FUNDED PROJECTS

A hot topic in today's debate on global warming is drag reduction in aeronautics. The most beneficial concept for drag reduction is to maintain the major portion of the airfoil laminar. Estimations show that the potential drag reduction can be as much as 15%, which would give a significant reduction of NOx and CO emissions in the atmosphere considering that the number of aircraft take offs, only in the EU, is over 19 million per year. An important element for successful flow control, which can lead to a reduced aerodynamic drag, is enhanced physical understanding of the transition to turbulence process. In previous wind tunnel measurements we have shown that roughness elements can be used to sensibly delay transition to turbulence. The result is revolutionary, since the common belief has been that surface roughness causes earlier transition and in turn increases the drag, and is a proof of concept of the passive control method per se. The beauty with a passive control technique is that no external energy has to be added to the flow system in order to perform the control, instead one uses the existing energy in the flow. In this project proposal, AFRODITE, we will take this passive control method to the next level by making it twofold, more persistent and more robust. Transition prevention is the goal rather than transition delay and the method will be extended to simultaneously control separation, which is another unwanted flow phenomenon especially during airplane take offs. AFRODITE will be a catalyst for innovative research, which will lead to a cleaner sky.

1 418 399 €

Start date: 2010-11-01, End date: 2015-10-31

Spectroscopic binary stars (SB2s) and in particular spectroscopic eclipsing binaries are one of the most useful objects in astrophysics. Their photometric and spectroscopic observations allow one to determine basic parameters of stars and carry out a wide range of tests of stellar structure, evolution and dynamics. Perhaps somewhat surprisingly, they can also contribute to our understanding of the formation and evolution of (extrasolar) planets. We will study eclipsing binary stars by combining the classic - stellar astronomy - and the modern - extrasolar planets - subjects into a cutting edge project. We propose to search for and subsequently characterize circumbinary planets around ~350 eclipsing SB2s using our own novel cutting edge radial velocity technique for binary stars and a modern version of the photometry based eclipse timing of eclipsing binary stars employing 0.5-m robotic telescopes. We will also derive basic parameters of up to ~700 stars (~350 binaries) with an unprecedented precision. In particular for about 50% of our sample we expect to deliver masses of the components with an accuracy ~10-100 times better than the current state of the art. Our project will provide unique constraints for the theories of planet formation and evolution and an unprecedented in quality set of the basic parameters of stars to test the theories of the stellar structure and evolution.

1 500 000 €

Start date: 2010-12-01, End date: 2016-11-30

Humans and other primates possess an exquisite capacity to grasp and manipulate objects. The seemingly effortless interaction with objects in everyday life is subserved by a number of cortical areas of the visual and the motor system. Recent research has highlighted that dorsal stream areas in the posterior parietal cortex are involved in object processing. Because parietal lesions do not impair object recognition, the encoding of object shape in posterior parietal cortex is considered to be important for the planning of actions towards objects. In order to succesfully grasp an object, the complex pattern of visual information impinging on the retina has to be transformed into a motor plan that can control the muscle contractions. The neural basis of visuomotor transformations necessary for directing actions towards objects, however, has remained largely unknown. This proposal aims to unravel the pathways and mechanisms involved in programming actions towards objects - an essential capacity for our very survival. We envision an integrated approach to study the transformation of visual information into motor commands in the macaque brain, combining functional imaging, single-cell recording, microstimulation and reversible inactivation. Our research efforts will be focussed on parietal area AIP and premotor area F5, two key brain areas for visually-guided grasping. Above all, this proposal will move beyond purely descriptive measurements of neural activity by implementing manipulations of brain activity to reveal behavioral effects and interdependencies of cortical areas. Finally the data obtained in this project will pave the way to use the neural activity recorded in visuomotor areas to act upon the environment by grasping objects by means of a robot hand.

1 499 200 €

Start date: 2010-11-01, End date: 2015-10-31

Devices in wireless networks are no longer used only for communicating binary information, but also for navigation and to sense their surroundings. We are currently approaching fundamental limitations in terms of communication throughput, position information availability and accuracy, and decision making based on sensory data. The goal of this proposal is to understand how the cooperative nature of future wireless networks can be leveraged to perform timekeeping, positioning, communication, and decision making, so as to obtain orders of magnitude performance improvements compared to current architectures. Our research will have implications in many fields and will comprise fundamental theoretical contributions as well as a cooperative wireless testbed. The fundamental contributions will lead to a deep understanding of cooperative wireless networks and will enable new pervasive applications which currently cannot be supported. The testbed will be used to validate the research, and will serve as a kernel for other researchers worldwide to advance knowledge on cooperative networks. Our work will build on and consolidate knowledge currently dispersed in different scientific disciplines and communities (such as communication theory, sensor networks, distributed estimation and detection, environmental monitoring, control theory, positioning and timekeeping, distributed optimization). It will give a new thrust to research within those communities and forge relations between them.

1 500 000 €

Start date: 2011-05-01, End date: 2016-04-30

Current anti-angiogenesis based anti-tumor therapy relies on starving tumors by blocking their vascular supply via inhibition of growth factors. However, limitations such as resistance and toxicity, mandate conceptually distinct approaches. We will explore an entirely novel and long-overlooked strategy to discover additional anti-angiogenic candidates, based on the following innovative concept: ¿rather than STARVING TUMORS BY BLOCKING THEIR VASCULAR SUPPLY, we intend TO STARVE BLOOD VESSELS BY BLOCKING THEIR METABOLIC ENERGY SUPPLY¿, so that new vessels cannot form and nourish the growing tumor. This project is a completely new research avenue in our group, but we expect that it will offer refreshing long-term research and translational opportunities for the field. Because so little is known on endothelial cell (EC) metabolism, we will (i) via a multi-disciplinary systems-biology approach of transcriptomics, proteomics, computational network modeling, metabolomics and flux-omics, draw an endothelio-metabolic map in angiogenesis. This will allow us to identify metabolic regulators of angiogenesis, which will be further validated and characterized in (ii) loss and gain-of-function studies in various angiogenesis models in vitro and (iii) in vivo in zebrafish (knockdown; zinc finger nuclease mediated knockout), providing prescreen data to select the most promising candidates. (iv) EC-specific down-regulation (miR RNAi) or knockout studies of selected candidates in mice will confirm their relevance for angiogenic phenotypes in a preclinical model; and ultimately (v) a translational study evaluating EC metabolism-targeted anti-angiogenic strategies (pharmacological inhibitors, antibodies, small molecular compounds) will be performed in tumor models in the mouse.

2 365 224 €

Start date: 2011-05-01, End date: 2016-04-30

The hypothalamus is essential for our survival and orchestrates every vital function of the body, from defence against predators and energy metabolism to reproduction. Yet, the network mechanisms underlying these actions remain largely hidden in a black box . Here, we will focus on the hypothalamic neuroendocrine system, where we have identified a novel robust network oscillation in the tuberoinfundibular dopamine (TIDA) neurons that control prolactin release. This oscillation is synchronized between neurons via gap junctions, and phasic firing is transformed into tonic discharge by compounds that functionally oppose neuroendocrine dopamine actions. Using this novel preparation, we will investigate the 1) the cellular (conductance) and network (connectivity) mechanisms underlying TIDA rhythmicity; 2) how TIDA activity is affected by hormones and transmitters that affect lactation; 3) the functional significance of phasic vs. tonic discharge in the regulation of dopamine release and lactation; and 4) the generality of TIDA cellular and network properties to other parvocellular neuron populations. These questions will be addressed through several in vitro and in vivo electrophysiological techniques, including slice whole-cell recording, extracellular in vivo recording, voltammetry and optical recording. These experiments will provide novel insight into the link between network interactions and behaviour, and have important clinical implications for e.g. endocrine and reproductive disorders.

1 493 958 €

Start date: 2011-01-01, End date: 2015-12-31

At the dawn of the 21st century, our knowledge of the molecular mechanism of mammalian fertilization remains very limited. Different lines of evidence indicate that initial gamete recognition depends on interaction between a few distinct proteins on sperm and ZP3, a major component of the extracellular coat of oocytes, the zona pellucida (ZP). On the other hand, recent findings suggest an alternative mechanism in which cleavage of another ZP subunit, ZP2, regulates binding of gametes by altering the global structure of the ZP. Progress in the field has been hindered by the paucity and heterogeneity of native egg-sperm recognition proteins, so that novel approaches are needed to reconcile all available data into a single consistent model of fertilization. Following our recent determination of the structure of the most conserved domain of sperm receptor ZP3 by X-ray crystallography, we will conclusively establish the basis of mammalian gamete recognition by performing structural studies of homogeneous, biologically active recombinant proteins. First, we will combine crystallographic studies of isolated ZP subunits with electron microscopy analysis of their filaments to build a structural model of the ZP. Second, structures of key egg-sperm recognition protein complexes will be determined. Third, we will investigate how proteolysis of ZP2 triggers overall conformational changes of the ZP upon gamete fusion. Together with functional analysis of mutant proteins, these studies will provide atomic resolution snapshots of the most crucial step in the beginning of a new life, directly visualizing molecular determinants responsible for species-restricted gamete interaction at fertilization. The progressive decrease of births in the Western world and inadequacy of current contraceptive methods in developing countries underscore an urgent need for a modern approach to reproductive welfare. This research will not only shed light on a truly fundamental biological problem, but also constitute a solid foundation for the reproductive medicine of the future.

1 499 282 €

Start date: 2011-01-01, End date: 2015-12-31

Although several therapies target cellular pathways, current small molecules drug discovery is based on identification of inhibitors to single proteins, without knowledge of whether they are the most advantageous target. The objective of this proposal is to develop a novel method for drug discovery, combining phenotypic cell based screens with functional genetic networks to determine the molecular mechanisms of numerous small molecule inhibitors. This method will enable identification of numerous distinct inhibitors of a particular pathway, as well as providing their molecular mechanism. Cancer cells harbour gene mutations that make them more reliant on other cellular pathways for survival. Such cellular pathways can be targeted to selectively kill the cancer cells using the concept of synthetic lethality. In this project we want to identify inhibitors of homologous recombination to target cancer using synthetic lethality. To establish a functional genetic network for homologous recombination, we will first identify all recombination proteins using multiple genome-wide RNAi screens. Then the synthetic sick or lethal interaction map between all recombination proteins is determined by co-depletion of these. Such synthetic sick or lethal network will identify numerous putative targets for anti-cancer treatment. Importantly, using this network for chemical-genetic functional interactions will assist in determinating of the molecular mechanisms of inhibitors. Chemical-genetic networks based on synthetic sickness or lethality can potentially change future drug discovery methods as well as providing new mechanistic insights into the field of toxicology.

2 500 000 €

Start date: 2011-03-01, End date: 2016-02-29

Halogen bonding is an electron density donation-based weak interaction that has so far almost exclusively been investigated in computational and crystallographic studies. It shows high similarities to hydrogen bonding; however, its applicability for molecular recognition processes long remained unappreciated and has not been thoroughly explored. The main goals of this project are (1) to take the major leap from solid state/computational to /solution/ investigations of halogen bonding by developing novel NMR methods, using these (2) perform the first ever systematic physicochemical study of halogen bonding in solutions, and (3) to apply the gained knowledge in structural biology through elucidation of the anaesthetic binding site of native proteins. This in turn is of direct clinical relevance by providing a long-sought understanding of the disease malignant hyperthermia. Model compounds will be prepared using solution-phase and solid-supported organic synthesis; NMR methods will be developed for physicochemical studies of molecular recognition processes and applied in structural biology through the study of the interaction of anaesthetics with proteins involved in cellular calcium regulation. Using a peptidomimetic model system and an outstandingly sensitive NMR technique I will systematically study the impact of halogen bond donor and acceptor sites, and of electronic and solvent effects on the strength of the interaction. The proposed method will quantify relative stability of a strategically-designed, cooperatively folding model system. A second NMR technique will utilize paramagnetic effects and permit simultaneous characterization of bond strength and geometry of weak intermolecular complexes in solution. The technique will first be validated on small, organic model compounds and subsequently be transferred to weak, protein-ligand interactions. It will be exploited to gain an atomic level understanding of anaesthesia.

1 495 630 €

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

Owing to the increase in obesity, life expectancy may start to decrease in developed countries for the first time in recent history. In humans the generation of fat cells (adipocytes) is a major factor behind the growth of adipose tissue during childhood. The factors determining the fat mass in adults, however, are not fully understood. Increased fat storage in fully differentiated adipocytes, resulting in enlarged fat cells, is well documented and thought to be the most important mechanism whereby fat depots increase in adults. Very little is known about the maintenance of fat cells (adipocytes) in humans, how different fat depots are maintained and how (or if) this is altered in obesity. Recently I developed a method that is based on the incorporation of 14C from nuclear bomb tests into genomic DNA, which allows for the analysis of cell and tissue turnover in humans. Using this novel methodology we now have a strategy for studying cell turnover in humans. One tissue of great interest and significant clinical relevance is adipose tissue. Excess adipose tissue, resulting in obesity, is currently one of the most serious threats to human health on a global level. The current proposal aims to determine the dynamics of human adipose tissue maintenance and investigate any differences in regulation of the fat mass in lean and obese individuals. Understanding the dynamics of adipocyte turnover may shed new light on potential treatments for obesity.

1 500 000 €

Start date: 2011-04-01, End date: 2017-03-31

The Principal Investigator and his team will open up new horizons in the field of laser spectroscopy through basic research on silicon-photonics-based Spectroscopic Systems-On-Chip (SpecSOC’s). The key question being addressed is: how can the powerful concepts of high-index-contrast nanophotonics be combined with the extreme accuracy of silicon technology and with the performance of hybrid silicon/III-V integration in order to create system-on-chip functionalities for advanced (bio-)spectroscopy. We will first focus research on integrated lasers or Laser Systems-on-Chip (LaSOC’s) capable of providing very wide wavelength tuning in the infrared, mid-infrared or visible. These lasers will have an unprecedented combination of properties. They will differ from existing semiconductor lasers in the sense that they combine the best of III-V semiconductor technology and silicon technology in unique cavity structures exploiting high index contrast in three dimensions. In the second phase of the project we will shift the focus from laser-oriented novelty to spectroscopy-oriented novelty and investigate SpecSOC’s with an unprecedented system performance that matches the requirements of mainstream real-life spectroscopy. We will explore coherent optical detection techniques for sensitivity enhancement, microporous coatings for on-chip gas sensing and implant-oriented tissue spectroscopy. Our research will lead to a paradigm shift in laser spectroscopy, in the sense that it will turn an advanced spectroscopy system into a small form-factor commodity system. This will have an enormous impact on applications such as point-of-care medical diagnosis and medical implants, monitoring of air, water and food quality. Furthermore the on-chip spectroscopy systems will be highly valuable for fundamental research.

2 183 000 €

Start date: 2011-04-01, End date: 2017-03-31

The objective with this proposal is to provide design tools and algorithms for model management in robust, adaptive and autonomous engineering systems. The increasing demands on reliable models for systems of ever greater complexity have pointed to several insufficiencies in today's techniques for model construction. The proposal addresses key areas where new ideas are required. Modeling a central issue in many scientific fields. System Identification is the term used in the Automatic Control Community for the area of building mathematical models of dynamical systems from observed input and output signals, but several other research communities work with the same problem under different names, such as (data-driven) learning. We have identified five specific themes where progress is both acutely needed and feasible: 1. Encounters with Convex Programming Techniques: How to capitalize on the remarkable recent progress in convex and semidefinite programming to obtain efficient, robust and reliable algorithmic solutions. 2. Fundamental Limitations: To develop and elucidate what are the limits of model accuracy, regardless of the modeling method. This can be seen as a theory rooted in the Cramer-Rao inequality in the spirit of invariance results and lower bounds characterizing, e.g., Information Theory. 3. Experiment Design and Reinforcement Techniques: Study how well tailored and ``cheap'' experiments can extract essential information about isolated model properties. Also study how such methods may relate to general reinforcement techniques. 4. Potentials of Non-parametric Models: How to incorporate and adjust techniques from adjacent research communities, e.g. concerning manifold learning and Gaussian Processes in machine learning. 5. Managing Structural Constraints: To develop structure preserving identification methods for networked and decentralized systems. We have ideas how to approach each of these themes, and initial attempts are promising.

2 500 000 €

Start date: 2011-01-01, End date: 2015-12-31

Molecular simulation has become a standard tool for studying the function of biomolecules, such as proteins, nucleic acids and lipids. Due to increasing computer power and decreasing length scales in engineering, molecular simulation is also increasingly used in microfluidics and the study of, for instance, small water droplets. All these applications would benefit strongly from simulations that are several orders of magnitude longer than the current state of art. Although currently Moore's law still holds, the performance of processor cores no longer doubles every 18 months, but rather the number of cores increases. Therefore to improve the performance and to scale to a million cores, each core should do less work. With the classical single-program multiple-data parallelism the communication time will quickly become a bottleneck. To advance the molecular simulation field and efficiently use upcoming million core computers, a switch to multiple-program multiple-data parallelism (MPMD) is required. Domain decomposition should be applied over the nodes, whereas within a node MPMD parallelism should be used. This requires workloads being divided and dispatched efficiently to different threads. To hide the communication times, calculation should be overlapped with communication. Because simulation time steps will soon take in the order of 100 microseconds, global communication will become a bottleneck. However,global communication is required for, among other things, full electrostatics algorithms. Thus new algorithms need to be derived to ensure parallel scaling. Only with such efforts we will be able to fully utilize the potential of upcoming hardware to solve current and future scientific problems.

899 448 €

Start date: 2011-05-01, End date: 2017-04-30

Alzheimer's Disease (AD) is a major health problem in aging societies. Remarkable progress in the study of the rare genetic forms of the disease has lead to the identification of several key players like APP and the secretases, but the molecular basis of sporadic AD remains largely unresolved. The convergence of several factors (multicausality) has to be considered. miRNAs are crucially involved in normal brain functioning and integrity. Evidence obtained from analyzing a limited number of brains indicates that miRNA expression is affected in sporadic AD. We propose the hypothesis that such changes can affect normal functioning of neurons increasing their susceptibility to AD. We will document in 3 brain regions in >100 sporadic AD patients and in >100 controls alterations in miRNA expression and explore whether similar alterations can be detected in cerebrospinal fluid. This part of the study will firmly establish which miRNAs are altered in AD. We will then investigate the functional relevance of those miRNAs by gain and loss of function experiments in brains of zebra fish and mice. We will determine the target genes of the miRNA with genetic and proteomic approaches, and establish the functional networks controlled by those miRNA. We anticipate that this will lead to complete novel insights in the role of miRNAs in AD and in maintenance of brain integrity. Our work is likely to have diagnostic relevance for AD and will identify novel drug targets for the disease.

2 500 000 €

Start date: 2011-05-01, End date: 2016-04-30

Non-invasive imaging techniques allow visualization of the dynamics and biochemical activity of pathological processes in real-time. By having proper molecular tools, a complete picture of pathologic conditions can be acquired at resolutions from the molecular level to the full body scale. Hence, smart multimodal imaging tools can be utilized for a diversity of applications, ranging from fundamental understanding of disease related events to molecular diagnostics of specific diseases. Secondly, molecular scaffolds used for imaging can also be explored as therapeutics for specific diseases, since such scaffolds are directed towards targets involved in the pathological mechanism of the disease. This project aims at developing an alternative concept for molecular imaging, diagnostics and therapy based on the chemical design of luminescent conjugated oligomeric thiophene derivatives (LCOs) which recognize distinct structural motifs instead of specific biomolecules. The LCO can for instance be utilized for specific labelling of protein aggregates, the pathological hallmark of Alzheimer’s, Parkinson’s and prion diseases, and for differentiation of distinct cell types, such as stem cells or cancer cells. By combining the LCO technique with other technology platforms, multimodal molecular imaging tools that can be used to gain novel insights regarding fundamental disease related biological mechanisms from the nanoscopic to the macroscopic level will be achieved. The LCO molecular scaffolds will also be evaluated as therapeutically active agents towards pathologic molecular process underlying protein aggregation diseases, bacterial infection and cancer. The main objectives of the project are; • To synthesize a diverse library of novel LCOs specific for disease related molecular targets • To develop novel LCO-hybrid materials for multimodal real time in vivo imaging of biological and pathological processes from the nanoscopic (molecular, cellular) to the macroscopic level (body, organ) • To utilize the novel real-time imaging probes for studying the pathological or biological processes associated with certain diseases, including protein aggregation diseases, such as Alzheimer’s and Parkinson’s diseases, bacterial infection and cancer. • To explore LCO and LCO-based pharmacophores as therapeutics towards pathological molecular process involved in protein aggregation diseases, bacterial infection and cancer. The main focus of the project is to synthesize novel molecular tools but the project has a multidisciplinary research approach and involves research disciplines such as organic chemistry, physics, biochemistry and medicine. The purpose is to provide real-time in vivo imaging agents that can be utilized for studying both the nanoscopic molecular mechanism and the macro-pathology of a diversity of biological events. In addition, the same molecular scaffold will be explored for the development of therapeutic agents. We foresee that the novel multimodal tools will be of relevance to a wide community of researchers and also of great interest to the European health care industry.

1 498 800 €

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

The long-term goal of this research is to establish the chain of molecular events associated with (1) neurotransmitter release at the single cell and subcellular level and (2) with cell differentiation and reprogramming. These are incredibly important goals for which there are few analytical chemistry methods that are available and useful. The immediate goal therefore includes development of three chemical methodologies at the cutting edge of analytical chemistry: 1) the development of arrays of nanometer electrodes that can be used to spatially measure the release of easily oxidized substances across the cell surface; 2) to improve the combination of MALDI and cluster SIMS ion sources on an orthogonal QStar instrument to enable protein and glycoprotein analysis at the single whole cell level, lipid domain analysis at the subcellular level, and importantly, depth profiling; and 3) the application of information discovered at single cells and of the methods developed in goals 1 and 2 to an in vitro model of cell-to-cell communication and regeneration. I intend to build on my expertise in both electrochemistry and SIMS imaging to develop these approaches. The work described here constitutes two new directions of research in my group as well as new analytical chemistry, and, if successful, will lead to researchers being able to gather incredibly important new data about cell-to-cell communication and cell differentiation and reprogramming as well as to a better understanding the role of lipids in exocytosis and endocytosis.

2 491 881 €

Start date: 2011-01-01, End date: 2015-12-31

Locomotion is an essential motor act that for the most part is controlled by neuronal circuits in the spinal cord itself, called central pattern generators (CPGs), although their activity is turned on from centers in the brainstem. Understanding the operation of CPG circuits in mammals has been a significant challenge to neuroscientists over the last 50 years. The CPG for walking generates rhythm, as well as the precise patterns of muscular activity. The neural assembly that is directly involved in generating the locomotor rhythm is completely unknown. There is strong evidence from pharmacological and lesion studies showing that glutamatergic neurons are responsible for this function. Here, I propose to identify these key glutamatergic neuronal CPG circuits. As a first step we will use state-of-the-art RNA-sequencing to obtain the complete transcriptome of glutamatergic subpopulations in the ventral spinal cord of the mouse to define new postnatally expressed molecular markers. To link glutamatergic neuronal subpopulations to the locomotor behavior we will use transgenic mouse systems to incorporate light-activated switches in a cell specific way. These tools will provide a new basis for functional and network studies needed to understand the CPG operation. We also propose to use mouse models with optogenetic switches to provide a molecular identification of the glutamatergic locomotor command systems and their integration in the CPG. Our analysis will provide a unified characterization of the neuronal organization of the mammalian CPG and its immediate control from the brain. Understanding the locomotor CPG and its control in mammals is of outmost importance for improving rehabilitation of spinal cord injured patients and designing new repair strategies.

2 500 000 €

Start date: 2011-08-01, End date: 2016-07-31

This project aims at revisiting the economics of poverty by using recent advances in welfare economics. First, poverty measurement theory will be enriched by taking account of individual preferences over the several dimensions of poverty. New poverty indices will be defined. They will be applied using panel data of material standard of living and subjective satisfaction to study the recent evolution of poverty in developed societies. Second, the ethical value of poverty reduction will be added to theories of social welfare based on equality of opportunities. New evaluation criteria of taxation policies will be derived. These criteria will be applied to the design of fiscal reforms.

1 350 000 €

Start date: 2011-06-01, End date: 2017-05-31

Protein misfolding is implicated as a pathogenetic mechanism in several neurodegenerative disorders, including Parkinson¿s disease (PD). In prion disease, the misfolded protein spreads between cells and acts as a ¿permissive template¿, causing protein in the recipient cell to misfold. In 2008 we reported that classical neuropathological changes gradually propagate from a PD patient¿s brain to a graft of healthy neurons, over one decade after surgery. These groundbreaking findings suggest that the protein ¿-synuclei may transfer between cells and propagate protein aggregation in a ¿prion-like¿ fashion in PD. This molecular disease mechanism might explain how protein aggregates gradually spread throughout the nervous system and promote progression of disease symptoms. This highly novel concept represents a hitherto poorly explored route of intercellular communication and might have far-reaching implications well beyond PD. Little is known about how various forms of ¿-synuclein are taken up; if they seed aggregation in the recipient cell; how they affect proteostasis in the recipient cells; if they are transported axonally; and, finally, whether they can cause spreading of PD-like pathology in the nervous system. In a multidisciplinary project will now examine the molecular mechanisms underlying translocation of ¿-synuclein across a lipid membrane, from the outside to the inside of a cell; what the molecular and functional consequences are of importing ¿-synuclein; what the dynamics of ¿-synuclein transfer are in vivo; whether aggregates of misfolded ¿-synuclein can spread from one region of the nervous system to another; what genes influence the likelihood for ¿-synuclein transfer to take place; and, finally if small molecules that inhibit ¿-synuclein can be identified. Our studies will shed light on what appears to be a new principle for pathogenesis of neurodegenerative disorders and can open up avenues for new therapeutic strategies.

2 499 998 €

Start date: 2011-06-01, End date: 2016-05-31

Propagation of a species requires periodic cell renewal to avoid clonal senescence. My laboratory has described a new mechanism for such cell renewal in yeast, in which damaged protein aggregates are transported out of the daughter buds along actin cables to preserve youthfulness. Such spatial protein quality control (SQC) is a Sir2p-dependent process and by establishing the global genetic interaction network of SIR2, we identified the polarisome as the machinery required for mitotic segregation and translocation of protein aggregates. In addition, we found that the fusion of smaller aggregates into large inclusion bodies, a process that has been suggested to reduce the toxicity of such aggregates, requires actin cables and their nucleation at the septin ring. Sir2p controls damage segregation by affecting deacetylation and the activity of the chaperonin CCT, enhancing actin folding and polymerization. Considering that CCT has been implicated in mitigating aggregation/toxicity of polyglutamine proteins, e.g. huntingtin, and that actin cables is affecting formation, fusion, and resolution of aggregates, we hypothesize that CCT deacetylation may underlie Sirt1¿s (mammalian orthologues of Sir2p) documented beneficial effects in several neurodegenerative disorders caused by proteotoxic aggregates. This project is aimed at approaching this hypothesis and to elucidate, on a genome-wide scale, how the cell tether, sort, fuse, and detoxify aggregates with the help of CCT, actin cables, and the polarity machinery. This will be accomplished by combining the power of synthetic genetic array analysis, high-content imaging, genome wide proximity ligand assays, and microfluidics. Using such approaches, the project seeks to decipher the machineries of the spatial quality control network as a means to identify new therapeutic targets that may retard or postpone the development of age-related maladies, including neurodegenerative disorders.

2 371 262 €

Start date: 2011-06-01, End date: 2016-05-31

The aim of this research project is to outline a conceptual genealogy and a critical typology of the theoretical arguments that have been advanced, in the name of democracy, against the dominant human rights discourse of contemporary societies. In light of the prolific literature on human rights in general, we might expect the counter arguments made since the Declarations of 1776 and 1789 to have been widely explored as an area of interest. This is not, however, the case. Whereas the reactionary critique of human rights dates far back and is well known, its modern equivalent which often draws in important ways from the liberal tradition is far less familiar terrain to political theorists. However, the central hypothesis running through this project is that challenges to human rights discourse must not be confused with antiliberal or antidemocratic stances. The main types of critique will be outlined, with an emphasis on their complexity and diverse nature, thus resisting the temptation to generalise them as part of a tradition of opposition to legal-political modernity. This typology will then be supplemented with historical contextualisation. Contemporary examples of the democratic critique of the primacy of human rights will be compared with historical examples of thinkers who criticised human rights as such, notably Bentham, Burke, Marx, De Maistre, Comte and Schmitt. The key research question is whether a common critical aim can be articulated from different intellectual starting points that are otherwise far apart; and whether or not the structure of the arguments that run through these approaches significantly changes the type of critique advanced.

793 999 €

Start date: 2010-10-01, End date: 2016-03-31

All kingdoms possess a large fraction of RNA-based regulation. We identified several small non-coding regulatory RNAs (ncRNAs) in the human bacterial pathogen Listeria monocytogenes that controlled virulence by a direct RNA:RNA interaction. My group have also identified several 5´-untranslated RNAs (5´-UTRs) known to control expression of their downstream mRNA by a switch mechanism triggered by certain metabolites, specific compartments of the host or by different temperatures. In the suggested project, we will analyze the mechanism by how various RNA-species function on a molecular level by biochemical and genetic approaches. By constructing mutations (deletion and base-substitutions), the role of the regulatory RNAs and their targets during pathogenesis will be pin-pointed using different virulence model organisms. For 5´-UTRs binding specific metabolites, we will add non-metabolic analogs to examine if such molecules can block the function of the 5´-UTRs and hence infection. The core structure of one identified ncRNA will be used as a scaffold to develop an RNA interference system in bacteria. At least one RNA-helicase has been shown to be essential for bacterial motility and growth at 4°C. It is being purified to test its in vitro properties at mRNA targets and at different temperatures. Its in vivo role will be analyzed by genetic techniques. Bacterial resistance against different antibiotics is an increasing problem worldwide. We have identified one pyridine molecule specifically targeting listerial virulence gene expression and its mechanism of action will be revealed by genetic and biochemical techniques. A diffusible, although yet unknown molecule, with bacteriostatic activity was observed and its nature and mechanism will be revealed mainly by biochemical experiments. Our work will give important knowledge of how the bacterium uses RNA to sense its surroundings, but will also identifiy new types of antibacterial agents.

999 996 €

Start date: 2010-10-01, End date: 2015-09-30

Today's state-of-the-art methods for data processing are model based. We propose a fundamentally new approach that does not depend on an explicit model representation and can be used for model-free data processing. From a theoretical point of view, the prime advantage of the newly proposed paradigm is conceptual unification of existing methods. From a practical point of view, the proposed paradigm opens new possibilities for development of computational methods for data processing. The underlying computational tool in the proposed setting is low-rank approximation. Recent work by the applicant, co-workers, and others has demonstrated advantages of computational methods based on low-rank approximation over classical methods, based on solution of linear systems of equations. In this proposal, we will further advance the theory and algorithms for low-rank approximation by developing robust and efficient local optimisation methods and methods based on convex relaxations. Low-rank approximation has applications in systems and control, signal processing, computer algebra, and machine learning, to name a few. Generic examples in system theory and signal processing are model reduction and system identification. Dimensionality reduction, classification, and information retrieval problems in machine learning can be formulated and solved as low-rank approximation problems, thus benefiting from the theory, algorithms, and numerical software tools developed in this research proposal. Beyond the scope of the proposal, we envisage that the newly proposed paradigm will catalyse cross-disciplinary research, leading to selection of the best theoretical tools and computational methods available as well as development of new ones by a synergy of ideas from different application domains.

782 960 €

Start date: 2011-01-01, End date: 2015-12-31

Synaptic transmission is of paramount importance for neuronal circuit integrity; if synapses fail, circuits fail. Transmission of electrical pulses in our brain is critical for normal but also higher brain functions such as learning, memory formation and thought, and understanding the regulatory processes of synaptic transmission may provide insight into neurological and psychiatric disorders, such as Parkinson‟s disease, bipolar disorder and drug addiction that arise from defects in specific neuronal circuits in the brain. Here, we propose to study novel regulatory mechanisms that operate at the synapse and have the capacity to be major regulators of synaptic plasticity. Our work will include studies of novel synaptic organelles and alternative pathways of synaptic vesicle endocytosis (e.g. clathrin-dependent or kiss-and-run), with a clear link to human disease (e.g. Parkinson‟s Disease). We will use innovative genetic screen approaches in flies and bacteria and study processes that regulate synaptic vesicle trafficking employing imaging, electrophysiology and electron microscopy with the ultimate hope of elucidating mechanisms of normal but also diseased brain function

1 498 522 €

Start date: 2011-01-01, End date: 2015-12-31