ERC FUNDED PROJECTS

Our research interests lie in breaking new ground in studying mechanism-based functions of AP-1 (Fos/Jun) in vivo with the aim of obtaining a more global perspective on AP-1 in human physiology and disease/cancer. The unresolved issues regarding the AP-1 subunit composition will be tackled biochemically and genetically in various cell types including bone, liver and skin, the primary organs affected by altered AP-1 activity. I plan to utilize the knowledge gained on AP-1 functions in the mouse and transfer it to human disease. The opportunities here lie in exploiting the knowledge of AP-1 target genes and utilizing this information to interfere with pathways involved in normal physiology and disease/cancer. The past investigations revealed that the functions of AP-1 are an essential node at the crossroads between life and death in different cellular systems. I plan to further exploit our findings and concentrate on utilising better mouse models to define these connections. The emphasis will be on identifying molecular signatures and potential treatments in models for cancer, inflammatory and fibrotic diseases. Exploring genetically modified stem cell-based therapies in murine and human cells is an ongoing challenge I would like to meet in the forthcoming years at the CNIO. In addition, the mouse models will be used for mechanism-driven therapeutic strategies and these studies will be undertaken in collaboration with the Experimental Therapeutics Division and the service units such as the tumor bank. The project proposal is divided into 6 Goals (see also Figure 1): Some are a logical continuation based on previous work with completely new aspects (Goal 1-2), some focussing on in depth molecular analyses of disease models with innovative and unconventional concepts, such as for inflammation and cancer, psoriasis and fibrosis (Goal 3-5). A final section is devoted to mouse and human ES cells and their impact for regenerative medicine in bone diseases and cancer.

2 500 000 €

Start date: 2009-11-01, End date: 2015-10-31

Social bonding success in life impacts on health, survival and fitness. It is proposed that early and later social experience as well as heritable factors determine social bonding abilities in adulthood, although the relative influence of each is unclear. In humans, the resulting uncertainty likely impedes psychological and psychiatric assessment and therapy. One problem hampering progress for human studies is that social bonding success is hard to objectively quantify, particularly in adults. I propose to directly address this problem by determining the key influences on social bonding abilities in chimpanzees, our closest living relative, where social bonding success can be objectively quantified, and is defined as number of affiliative relationships maintained over time with high rates of affiliation. Objectives. This project will quantify the relative impact of early and later social experience as well as heritable factors on social hormone levels, social cognition and social bonding success in 270 wild and captive chimpanzees, using both cohort and longitudinal data. This will reveal the degree of plasticity in social cognition and bonding behaviour throughout life. Finally, it will evaluate the potential for using endogenous hormone levels as non-invasive biomarkers of social bonding success, as well as identifying social contexts that act as strong natural social hormone releasers. Outcomes. This project will expose what makes some better at social bonding than others. Specifically, it will show the extent to which later social experience can compensate for early social experience or heritable factors in terms of adult social bonding success, the latter being a key factor in determining health and happiness in life. This project also offers the potential for using hormonal biomarkers in clincial settings, as objective assessment of changes in relationships over time, and in therapy by engaging in social behaviours that act as strong social hormone releasers.

1 495 000 €

Start date: 2016-04-01, End date: 2021-03-31

Here we propose a first step toward a direct reconstruction of the evolutionary history of human infectious disease agents by obtaining genome wide data of historic pathogens. Through an extensive screening of skeletal collections from well-characterized catastrophe, or emergency, mass burials we plan to detect and sequence pathogen DNA from various historic pandemics spanning at least 2,500 years using a general purpose molecular capture method that will screen for hundreds of pathogens in a single assay. Subsequent experiments will attempt to reconstruct full genomes from all pathogenic species identified. The molecular fossil record of human pathogens will provide insights into host adaptation and evolutionary rates of infectious disease. In addition, human genomic regions relating to disease susceptibility and immunity will be characterized in the skeletal material in order to observe the direct effect that pathogens have made on the genetic makeup of human populations over time. The results of this project will allow a multidisciplinary interpretation of historical pandemics that have influenced the course of human history. It will provide priceless information for the field of history, evolutionary biology, anthropology as well as medicine and will have direct consequences on how we manage emerging and re-emerging infectious disease in the future.

1 474 560 €

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

"A conventional assumption in dynamic models is that agents form their expectations in a very sophisticated manner. In particular, that they have Rational Expectations (RE). We develop some tools to relax this assumption while retaining fully optimal behaviour by agents. We study implications for asset pricing and macro policy. We assume that agents have a consistent set of beliefs that is close, but not equal, to RE. Agents are ""Internally Rational"", that is, they behave rationally given their system of beliefs. Thus, it is conceptually a small deviation from RE. It provides microfoundations for models of adaptive learning, since the learning algorithm is determined by agents’ optimal behaviour. In previous work we have shown that this framework can match stock price and housing price fluctuations, and that policy implications are quite different. In this project we intend to: i) develop further the foundations of internally rational (IR) learning, ii) apply this to explain observed asset price price behavior, such as stock prices, bond prices, inflation, commodity derivatives, and exchange rates, iii) extend the IR framework to the case when agents entertain various models, iv) optimal policy under IR learning and under private information when some hidden shocks are not revealed ex-post. Along the way we will address policy issues such as: effects of creating derivative markets, sovereign spread as a signal of sovereign default risk, tests of fiscal sustainability, fiscal policy when agents learn, monetary policy (more specifically, QE measures and interest rate policy), and the role of credibility in macro policy."

1 970 260 €

Start date: 2013-06-01, End date: 2018-08-31

Deregulated apoptotic signaling in hematopoietic stem and progenitor cells (HSPCs) strongly contributes to the pathogenesis and phenotypes of congenital bone marrow failure and myelodysplastic syndromes (MDS) and their progression to acute myeloid leukemia (AML). HSPCs are highly susceptible to apoptosis during bone marrow failure and early MDS, but AML evolution selects for apoptosis resistance. Little is known about the main apoptotic players and their regulators. ApoptoMDS will investigate the impact of apoptotic deregulation for pathogenesis, correlate apoptotic susceptibility with the kinetics of disease progression and characterize the mechanism by which apoptotic susceptibility turns into resistance. ApoptoMDS will draw on a large collection of patient-derived samples and genetically engineered mouse models to investigate disease progression in serially transplanted and xenotransplanted mice. How activated DNA damage checkpoint signaling contributes to syndrome phenotypes and HSPC hypersusceptibility to apoptosis will be assessed. Checkpoint activation confers a competitive disadvantage, and HSPCs undergoing malignant transformation are under high selective pressure to inactivate it. Checkpoint abrogation mitigates the hematological phenotype, but increases the risk of AML evolution. ApoptoMDS aims to analyze if inhibiting apoptosis in HSPCs from bone marrow failure and early-stage MDS can overcome the dilemma of checkpoint abrogation. Whether inhibiting apoptosis is sufficient to improve HSPC function will be tested on several levels and validated in patient-derived samples. How inhibiting apoptosis in the presence of functional checkpoint signaling influences malignant transformation kinetics will be assessed. If, as hypothesized, inhibiting apoptosis both mitigates hematological symptoms and delays AML evolution, ApoptoMDS will pave the way for novel therapeutic approaches to expand the less severe symptomatic period for patients with these syndromes.

1 372 525 €

Start date: 2015-06-01, End date: 2020-05-31

Apoptotic cell death is essential for development, immune function or tissue homeostasis, and it is often deregulated in disease. Mitochondrial outer membrane permeabilization (MOMP) is central for apoptosis execution and plays a key role in its inflammatory outcome. Knowing the architecture of the macromolecular machineries mediating MOMP is crucial for understanding their function and for the clinical use of apoptosis. Our recent work reveals that Bax and Bak dimers form distinct line, arc and ring assemblies at specific apoptotic foci to mediate MOMP. However, the molecular structure and mechanisms controlling the spatiotemporal formation and range of action of the apoptotic foci are missing. To address this fundamental gap in our knowledge, we aim to unravel the composition, dynamics and structure of apoptotic foci and to understand how they are integrated to orchestrate function. We will reach this goal by building on our expertise in cell death and cutting-edge imaging and by developing a new analytical pipeline to: 1) Identify the composition of apoptotic foci using in situ proximity-dependent labeling and extraction of near-native Bax/Bak membrane complexes coupled to mass spectrometry. 2) Define their contribution to apoptosis and its immunogenicity and establish their assembly dynamics to correlate it with apoptosis progression by live cell imaging. 3) Determine the stoichiometry and structural organization of the apoptotic foci by combining single molecule fluorescence and advanced electron microscopies. This multidisciplinary approach offers high chances to solve the long-standing question of how Bax and Bak mediate MOMP. APOSITE will provide textbook knowledge of the mitochondrial contribution to cell death and inflammation. The implementation of this new analytical framework will open novel research avenues in membrane and organelle biology. Ultimately, understanding of Bax and Bak structure/function will help develop apoptosis modulators for medicine.

2 000 000 €

Start date: 2019-04-01, End date: 2024-03-31

AppSAM will unlock the synthetic capability of S-adenosyl¬methionine (SAM)-dependent methyltransferases and radical SAM enzymes for application in environmentally friendly and fully sustainable reactions. The biotechnological application of these enzymes will provide access to chemo-, regio- and stereoselective methylations and alkylations, as well as to a wide range of complex rearrangement reactions that are currently not possible through traditional approaches. Methylation reactions are of particular interest due to their importance in epigenetics, cancer metabolism and the development of novel pharmaceuticals. As chemical methylation methods often involve toxic compounds and rarely exhibit the desired selectivity and specificity, there is an urgent need for new, environmentally friendly methodologies. The proposed project will meet these demands by the provision of modular in vitro and in vivo systems that can be tailored to specific applications. In the first phase of AppSAM, efficient in vitro SAM-regeneration systems will be developed for use with methyltransferases as well as radical SAM enzymes. To achieve this aim, enzymes from different biosynthetic pathways will be combined in multi-enzyme cascades; methods from enzyme and reaction engineering will be used for optimisation. The second phase of AppSAM will address the application on a preparative scale. This will include the isolation of pure product from the in vitro systems, reactions using immobilised enzymes and extracts from in vivo productions. In addition to E. coli, the methylotrophic bacterium Methylobacter extorquens AM1 will be used as a host for the in vivo systems. M. extorquens can use C1 building blocks such as methanol as the sole carbon source, thereby initiating the biotechnological methylation process from a green source material and making the process fully sustainable, as well as being compatible with an envisaged “methanol economy”.

1 499 219 €

Start date: 2017-10-01, End date: 2022-09-30

This project aims to detect magnetic fields with high spatial and temporal resolution and unprecedented sensitivity using ultra-cold atoms as interferometric sensors. The project will, on the one hand, test and demonstrate the most advanced concepts in the dynamic field of quantum metrology, and on the other hand, develop measurement techniques with the potential to transform existing fields and open new ones to study. Quantum metrology is in an exciting phase: on the one hand, a long-held goal of improving gravita- tional wave detection appears near at hand. At the same time, atomic instruments including atomic clocks, atomic gravimeters and atomic magnetometers are setting records in detection of time, ac- celeration, and fields, with revolutionary potential in several areas. This has stimulated new theory, including remarkable proposals suggesting that long-established “ultimate” limits can in fact be sur- passed. This project will study quantum metrology applied to atomic sensors by developing a versatile and highly sensitive cold atom magnetometer. We set an ambitious goal: to demonstrate record sensi- tivity, and then to improve on that sensitivity using quantum entanglement. This ground-breaking accomplishment will show the way to super-precise measurements in many fields. Fundamental topics in quantum metrology will be explored using the advanced magnetometry sys- tem. Nonlinear quantum metrology proposes to surpass the Heisenberg limit using inter-particle interactions. Compressed sensing aims to surpass the Nyquist limit, obtaining more information than normally allowed.

1 387 000 €

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

"Archaea constitute the third domain of life and are believed to be close to the origin of life. They comprise a diverse group of micro-organisms that combine bacterial and eukaryotic features, but also employ many novel mechanisms. They possess a unique cell envelope with a cytoplasmic membrane of ether lipids surrounded by a proteinaceous S-layer and various cell appendages such as flagella, pili and more unusual structures. Studies have shown that the archaeal flagellum is an unique structure as it functionally resembles the bacterial flagellum, but structurally it is a simple type IV pilus. Moreover, we have shown that this type IV pilus can rotate. Therefore I propose to name the archaeal flagellum, the archaellum, as it is fundamentally different from the bacterial flagellum. In this proposal I aim to understand the assembly and mechanism of rotation of the archaellum of the thermocacidophilic crenarchaen Sulfolobus acidocaldarius by using biochemical, genetic and biophysical methods. The main milestons are: - Biochemical and structural characterization of all archaellum subunits - To understand the assembly pathway of the archaellum and the interactions of its different subunits - To understand how rotation of the filament is achieved and which subunits are important for this movement This work will identify a new, relatively simple motor complex that has evolved from primordial type IV pili assembly machineries and therefore uncover general principles of macromolecular assemblies at cellular surfaces and a novel mechanism to generate mechanical force that can be translated into movement."

1 464 317 €

Start date: 2013-02-01, End date: 2018-01-31

Arl (Arf-like) proteins, GTP-binding proteins of the Ras superfamily, are molecular switches that cycle between a GDP-bound inactive and GTP-bound active state. There are 16 members of the Arl subfamily in the human genome whose basic mechanistic function is unknown. The interactome of Arl2/3 includes proteins involved in retinopathies and other ciliary diseases such as Leber¿s Congenital Amaurosis (LCA) and kidney diseases such as nephronophthisis. Arl6 has been found mutated in Bardet Biedl Syndrome, another pleiotropic ciliary disease. In the proposed interdisciplinary project I want to explore the function of the protein network of Arl2/3 and Arl6 by a combination of biochemical, biophysical and structural methods and use the knowledge obtained to probe their function in live cells. As with other subfamily proteins of the Ras superfamily which have been found to mediate similar biological functions I want to derive a basic understanding of the function of Arl proteins and how it relates to the development and function of the ciliary organelle and how they contribute to ciliary diseases. The molecules in the focus of the project are: the GTP-binding proteins Arl2, 3, 6; RP2, an Arl3GAP mutated in Retinitis pigmentosa; Regulators of Arl2 and 3; PDE¿ and HRG4, effectors of Arl2/3, which bind lipidated proteins; RPGR, mutated in Retinitis pigmentosa, an interactor of PDE¿; RPGRIP and RPGRIPL, interactors of RPGR mutated in LCA and other ciliopathies; Nephrocystin, mutated in nephronophthisis, an interactor of RPGRIP and Arl6, mutated in Bardet Biedl Syndrome, and the BBS complex. The working hypothesis is that Arl protein network(s) mediate ciliary transport processes and that the GTP switch cycle of Arl proteins is an important element of regulation of these processes.

2 434 400 €

Start date: 2011-04-01, End date: 2016-03-31

Adoptive T cell therapy (ACT) is a powerful approach to treat even advanced cancer diseases where poor prognosis calls for innovative treatments. However ACT is critically limited by insufficient T cell infiltration into the tumor, T cell activation at the tumor site and local T cell suppression. Few advances have been made in the field to tackle these limitations besides increasing T cell activation. My group has focussed on these unaddressed issues but came to realise that tackling these one by one will not be sufficient. I have developed a panel of unpublished chemokine receptors and innovative modular antibody-activated receptors which have the potential to overcome the limitations of ACT against solid tumors. This ground-breaking portfolio places my group in the unique position to address combination of synergistic receptors and enable cellular therapies in previously unsuccessful indications. My project will provide the rationale for provision of an effective cancer treatment. The goal is to develop the next generation of ACT through T cell engineering both by forced expression of migratory and activating receptors and simultaneous deletion of immune suppressive molecules by gene editing. ARMOR-T will provide the basis for further preclinical and clinical development of a pioneering cellular product devoid of the limitations of available products to date. I will prove 1) synergy between migratory and modular activating receptors, 2) feasibility to integrate gene editing into a T cell expansion protocol, 3) synergy between gene editing, migratory and modular receptors and 4) efficacy, safety and mode of action. The main work of the project will be carried out in models of pancreatic cancer. The ARMOR-T platform will subsequently be translated to other cancer entities where response to ACT is likely such as melanoma, breast or colon cancer, providing less toxic and more effective therapies to otherwise untreatable disease.

1 636 710 €

Start date: 2018-03-01, End date: 2023-02-28

Osteoarthritis (OA) is the most common form of arthritis of the joints, affecting over 70 million EU citizens. At present, no cure for OA is available; only symptomatic therapies may help to ameliorate this painful disorder. OA affects the integrity of the cartilage and progresses to an increased damage in its surrounding tissues, inclusive bone, and to inflammation of the synovial tissue. The latter reaction is caused by an accumulation of bone splinters. The therapy of choice would be – if available – bidirectional: first, regeneration of the damaged cartilage (by implants) and second, dissolution of the bone fragments (by injections). This proposal presents for the first time this two-fold solution. Within my ERC Advanced Grant “BIOSILICA” (No. 268476) we disclosed that biosilica elicits morphogenetic activity in cells involved in connective tissue formation. The effect of silica is augmented by another natural inorganic polymer, by polyphosphate (polyP), which is synthesized in most animal cells, especially blood platelets that accumulate in damaged bone and cartilage. polyP acts as “metabolic fuel” for the synthesis of the extracellular inorganic and organic skeletal and cartilage tissues. Our strategy is to combine and to amplify the beneficial properties of these two polymers, biosilica and polyP, their morphogenetic activity with their structure-forming/guiding activity, by applying hybrid microparticles, consisting of silica and polyP. The proposed project will provide the proof-of-concept of this dual strategy, using silica and the amorphous Mg2+/Ca2+ salt of polyP together with hyaluronic acid, to dissolve firstly existing bone splinters in the synovial fluid (by injection), reducing the painful joint burden in osteoarthritis, and secondly to repair damaged cartilage with polyP/silica implants. This innovative material, injectable and implantable, will be developed to commercializable products for the benefit of the aging society.

150 000 €

Start date: 2017-09-01, End date: 2019-02-28

The bottom-up assembly of tissue from cellular building blocks constitutes a promising, yet highly challenging approach to engineer complex tissues. The challenge lies in controlling cell-cell interactions, which determine how cells organize with respect to each other, how they work together and consequently whether such a multicellular architecture will be functional. The limited spatial and temporal control over cell-cell interactions current biological and chemical approaches provide severely restricts bottom-up tissue engineering. Here, I propose a new way to control cell-cell interactions. I aim to regulate cell-cell interactions with visible light using proteins that reversibly homo- or heterodimerize under blue or red light. These photoswitchable cell-cell interactions provide sustainable, non-invasive, dynamic and reversible control over cell-cell interactions with unprecedented spatial and temporal resolution. First of all, we will focus on various light dependent protein interactions to mediate cell-cell contacts. The detailed characterization (strength, dynamics, interaction modes and orthogonality) of these new photoswitchable cell-cell interactions will provide the framework for the bottom-up construction of tissue-like structures. Secondly, we will use these photoswitchable cell-cell interactions to assemble cells into multicellular architectures with predictable and programmable organization. The dynamic and reversible nature of the photoswitchable contacts will allow us to locally alter interactions at any point in time, to rearrange and obtain asymmetric multicellular structures, which are typical of tissues. Finally, we will also explore how the photoswitchable cell-cell interactions alter cell behavior and signaling. Ultimately, this will pave the way for the bottom-up assembly of multicellular architectures, enabling us to control precisely and dynamically their organization in space and time as well as regulate how cells work together.

1 937 000 €

Start date: 2018-07-01, End date: 2023-06-30

The objective of the present scientific proposal is the implementation of a novel approach in selective and asymmetric heterogeneous catalysis. We aim to exploit the structure and chirality of small, supported metal and bimetal clusters for triggering selective and enantioselective reactions. Our Ansatz is beyond doubt of fundamental nature. Although chemistry and in particular catalysis evolved on a largely empirical basis in the past, we strongly believe the complexity of the challenges at hand to make this a less ideal approach. In consequence, developing selective and asymmetric cluster catalysis will be based on a detailed molecular understanding and will not only require intense methodological developments for the synthesis and characterization of asymmetric catalysts and the detection of chiral and isomeric product molecules but also make use of innovative basic science in the fields of surface chemistry, cluster science, spectroscopy and kinetics. As complex as the involved challenges are, we aim at mastering the following ground-breaking steps: (a) development of cutting-edge spectroscopic methodologies for the isomer and enantiomer sensitive in situ detection of product molecules. (b) preparation and characterization of isomer- and enantioselective heterogeneous catalysts based on chiral metal clusters or molecule-cluster-complexes. (c) investigations of the selectivity and enantioselectivity of cluster based heterogeneous catalysts and formulation of concepts for understanding the observed selective and asymmetric chemistry. Besides the importance of the science carried out within this proposal, the proposed experimental methodology will also open up opportunities in other fields of chemistry like catalysis, analytical chemistry, spectroscopy, surface science, and nanomaterials.

2 301 600 €

Start date: 2010-04-01, End date: 2015-03-31

"The objective of this proposal is to tackle two of the greatest challenges in quantum chemistry: (i) extending the applicability of highly accurate wave function methods to large molecular systems, and (ii) developing accurate and robust multi-reference methods that can be used for studying important but very difficult problems in transition metal chemistry, catalysis, and photochemistry. Solutions to these problems have now come within reach due to three advances we recently reported: first, the steep scaling of the computational cost with molecular size can be reduced to linear by exploiting the short-range character of electron correlation (local correlation methods). Second, the accuracy, efficiency, and robustness of these local correlation methods can be strongly improved by new tensor decomposition approaches and the inclusion of terms depending explicitly on the inter-electronic distances (F12 methods). Third, the development of highly complex electronic structure theories can be greatly facilitated and accelerated by new automated tensor network evaluation techniques. We are certain that by combining and generalizing these advances the long-standing problems (i) and (ii) can be solved. We will focus especially on highly scalable algorithms in order to use massively parallel computer systems efficiently. For linear-scaling methods this means that the size of the molecules that can be treated in a fixed time will grow linearly with the number of available processors. We will furthermore explore new multi-reference ansätze and implement analytical energy gradients and response properties for local methods. Hybrid and embedding methods to account for solvent and environment effects will also be investigated. It is our priority to make our new methods as easy to use, robust, and widely applicable as possible. We believe that they will open entirely new horizons for innumerable applications in chemistry, physics, biology, and materials science."

2 454 000 €

Start date: 2013-02-01, End date: 2018-01-31

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

"One of the greatest challenges these days in condensed matter physics is the fundamental understanding of the mechanisms leading to high-Tc superconductivity and ultimately, as a result of that, the discovery of a material system exhibiting a superconducting state with a transition temperature Tc above room temperature. While several different classes of high-Tc materials have been discovered in the past decades, including the well-known CuO-based superconductors (cuprates) or the more recently discovered class of Fe-based superconductors (pnictides), the mechanisms behind high-Tc superconductivity remain controversial. Up to date, no theory exists which would allow for a rational design of a superconducting material with a transition temperature above room temperature. On the other hand, experiments on rather complex material systems often suffer from material imperfections or from a lack of tunability of materials’ properties within a wide range. Our experimental studies within this project therefore will focus on model-type systems which can be prepared and thoroughly characterized with atomic level precision. The growth of the model-type samples will be controlled vertically one atomic layer at a time and laterally by making use of single-atom manipulation techniques. Atomic-scale characterization at low energy-scales will be performed by low-temperature spin-resolved elastic and inelastic scanning tunnelling microscopy (STM) and spectroscopy (STS) as well as by non-contact atomic force microscopy and spectroscopy based techniques. Transport experiments will be conducted by a four-probe STM setup under well-defined ultra-high vacuum conditions. By having access to the electronic and spin, as well as to the vibrational degrees of freedom down to the atomic level, we hope to be able to identify the nature of and the conditions for inducing superconductivity at high temperatures, which could ultimately lead a knowledge-based design of high-Tc superconductors."

2 170 696 €

Start date: 2014-01-01, End date: 2018-12-31

Despite considerable efforts aimed at prevention and treatment, the prevalence of obesity and type 2 diabetes has increased at an alarming rate worldwide over recent decades. Given the urgent need to develop safe and efficient anti-obesity drugs, the scientific community has to intensify efforts to better understand the mechanisms involved in the pathogenesis of obesity. Based on human genome-wide association studies and targeted mouse mutagenesis models, it has recently emerged that the brain controls most aspects of systemic metabolism and that obesity may be a brain disease. I have recently shown that like neurons, astrocytes also respond to circulating nutrients, and they cooperate with neurons to efficiently regulate energy metabolism. So far, the study of brain circuits controlling energy balance has focused on neurons, ignoring the presence and role of astrocytes. Importantly, our studies were the first to describe that exposure to a high-fat, highsugar (HFHS) diet triggers hypothalamic astrogliosis prior to significant body weight gain, indicating a potentially important role in promoting obesity. Overall, my recent findings suggest a novel model in which astrocytes are actively involved in the central nervous system (CNS) control of metabolism, likely including active crosstalk between astrocytes and neurons. To test this hypothetical model, I propose to develop a functional understanding of astroglia-neuronal communication in the CNS control of metabolism focusing on: 1) dissecting the ability of astrocytes to release gliotransmitters to neurons, 2) assessing how astrocytes respond to neuronal activity, and 3) determining if HFHS-induced astrogliosis interrupts this crosstalk and contributes to the development of obesity and type 2 diabetes. These studies aim to uncover the molecular underpinnings of astrocyte-neuron inputs regulating metabolism in health and disease so as to inspire and enable novel therapeutic strategies to fight diabetes and obesity.

1 499 938 €

Start date: 2018-01-01, End date: 2022-12-31

The main goal of ASTRUm is to employ stored and cooled radioactive ions for forefront nuclear astrophysics research. Four key experiments are proposed to be conducted at GSI in Darmstadt, which holds the only facility to date capable of storing highly charged radionuclides in the required element and energy range. The proposed experiments can hardly be conducted by any other technique or method. The weak decay matrix element for the transition between the 2.3 keV state in 205Pb and the ground state of 205Tl will be measured via the bound state beta decay measurement of fully ionized 205Tl81+. This will provide the required data to determine the solar pp-neutrino flux integrated over the last 5 million years and will allow us to unveil the astrophysical conditions prior to the formation of the solar system. The measurements of the alpha-decay width of the 4.033 MeV excited state in 19Ne will allow us to constrain the conditions for the ignition of the rp-process in X-ray bursters. ASTRUm will open a new field by enabling for the first time measurements of proton- and alpha-capture reaction cross-sections on radioactive nuclei of interest for the p-process of nucleosynthesis. Last but not least, broad band mass and half-life measurements in a ring is the only technique to precisely determine these key nuclear properties for nuclei with half-lives as short as a millisecond and production rates of below one ion per day. To accomplish these measurements with highest efficiency, sensitivity and precision, improved detector systems will be developed within ASTRUm. Possible applications of these systems go beyond ASTRUm objectives and will be used in particular in accelerator physics. The instrumentation and experience gained within ASTRUm will be indispensable for planning the future, next generation storage ring projects, which are launched or proposed at several radioactive ion beam facilities.

1 874 750 €

Start date: 2016-04-01, End date: 2021-03-31

The Large Hadron collider (LHC) at CERN will be a milestone for the understanding of fundamental interactions and for the future of high energy physics. Four large experiments at the LHC are complementarily addressing the question of the origin of our Universe by searching for so-called New Physics. The world of particles and their interactions is nowadays described by the Standard Model. Up to now there is no single measurement from laboratory experiments which contradicts this theory. However, there are still many open questions, thus physicists are convinced that there is a more fundamental theory, which incorporates New Physics. It is expected that at the LHC either New Physics beyond the Standard Model will be discovered or excluded up to very high energies, which would revolutionize the understanding of particle physics and require completely new experimental and theoretical concepts. The LHCb (Large Hadron Collider beauty) experiment is dedicated to precision measurements of B hadrons (B hadrons are all particles containing a beauty quark). The analysis proposed here is the measurement of asymmetries between B_s particles and anti-B_s particles at the LHCb experiment. Any New Physics model will change the rate of observable processes via additional quantum corrections. Particle antiparticle asymmetries are extremely sensitive to these corrections thus a very powerful tool for indirect searches for New Physics contributions. In the past, most of the ground-breaking findings in particle physics, such as the existence of the charm quark and the existence of a third quark family, have first been observed in indirect searches. First - still statistically limited - measurements of the asymmetry in the B_s system indicate a 2 sigma deviation from the Standard Model prediction. A precision measurement of this asymmetry is potentially the first observation for New Physics beyond the Standard Model at the LHC. If no hint for New Physics will be found, this measurement will severely restrict the range of potential New Physics models.

1 059 240 €

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

Atherosclerosis is characterized by chronic inflammation of the arterial wall. Mononuclear cell recruitment is driven by chemokines that can be deposited e.g. by activated platelets on inflamed endothelium. Chemokines require oligomerization and immobilization for efficient function, and recent evidence supports the notion that heterodimer formation between chemokines constitutes a new regulatory principle amplifying specific chemokine activities while suppressing others. Although crucial to inflammatory disease, this has been difficult to prove in vivo, primarily as chemokine heterodimers exist in equilibrium with their homodimer counterparts. We introduce the paradigm that heteromerization of chemokines provides the combinatorial diversity for functional plasticity and fine-tuning, coining this interactome. Given the relevance of chemokine heteromers in vivo, we aim to exploit this in an anti-inflammatory approach to selectively target vascular disease. In a multidisciplinary project, we plan to generate covalently-linked heterodimers to establish their biological significance. Obligate heterodimers of CC and CXC chemokines will be designed using computer-assisted modeling, chemically synthesized and cross-linked, structurally assessed using NMR spectroscopy and crystallography, and subjected to functional characterization in vitro and reconstitution in vivo. Conversely, we will develop cyclic beta-sheet-based peptides binding chemokines to specifically disrupt heteromers and we will generate mice with conditional deletion or knock-in of chemokine mutants with defects in heteromerization or proteoglycan binding to be analyzed in models of atherosclerosis. Peptides will be used for molecular imaging and chemokine heteromers will be quantified in cardiovascular patients.

2 500 000 €

Start date: 2010-04-01, End date: 2016-03-31

The ongoing miniaturization in nanotechnology and functional materials puts an ever increasing focus on the development of three-dimensional (3D) nanostructures, such as quantum dot arrays, structured nanowires, or non-trivial topological magnetic textures such as skyrmions, which permit a better performance of logical or memory devices in terms of speed and energy efficiency. To develop and advance such technologies and to improve the understanding of the underlying fundamental solid state physics effects, the nondestructive and quantitative 3D characterization of physical, e.g., electric or magnetic, fields down to atomic resolution is indispensable. Current nanoscale metrology methods only inadequately convey this information, e.g., because they probe surfaces, record projections, or lack resolution. AToM will provide a ground-breaking tomographic methodology for current nanotechnology by mapping electric and magnetic fields as well as crucial properties of the underlying atomic structure in solids, such as the chemical composition, mechanical strain or spin configuration in 3D down to atomic resolution. To achieve that goal, advanced holographic and tomographic setups in the Transmission Electron Microscope (TEM) are combined with novel computational methods, e.g., taking into account the ramifications of electron diffraction. Moreover, fundamental application limits are overcome (A) by extending the holographic principle, requiring coherent electron beams, to quantum state reconstructions applicable to electrons of any (in)coherence; and (B) by adapting a unique in-situ TEM with a very large sample chamber to facilitate holographic field sensing down to very low temperatures (6 K) under application of external, e.g., electric, stimuli. The joint development of AToM in response to current problems of nanotechnology, including the previously mentioned ones, is anticipated to immediately and sustainably advance nanotechnology in its various aspects.

1 499 602 €

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

Quantum information science and atom optics are among the most active fields in modern physics. In recent years, many theoretical efforts have been made to combine these two fields. Recent experimental progresses have shown the in-principle possibility to perform scalable quantum information processing (QIP) with linear optics and atomic ensembles. The main purpose of the present project is to use atomic qubits as quantum memory and exploit photonic qubits for information transfer and processing to achieve efficient linear optics QIP. On the one hand, utilizing the interaction between laser pulses and atomic ensembles we will experimentally investigate the potentials of atomic ensembles in the gas phase to build quantum repeaters for long-distance quantum communication, that is, to develop a new technological solution for quantum repeaters making use of the effective qubit-type entanglement of two cold atomic ensembles by a projective measurement of individual photons by spontaneous Raman processes. On this basis, we will further investigate the advantages of cold atoms in an optical trap to enhance the coherence time of atomic qubits beyond the threshold for scalable realization of quantum repeaters. Moreover, building on our long experience in research on multi-photon entanglement, we also plan to perform a number of significant experiments in the field of QIP with particular emphasis on fault-tolerant quantum computation, photon-loss-tolerant quantum computation and cluster-state based quantum simulation. Finally, by combining the techniques developed in the above quantum memory and multi-photon interference experiments, we will further experimentally investigate the possibility to achieve quantum teleportation between photonic and atomic qubits, quantum teleportation between remote atomic qubits and efficient entanglement generation via classical feed-forward. The techniques that will be developed in the present project will lay the basis for future large scale

1 435 000 €

Start date: 2008-07-01, End date: 2013-12-31

Collective electron motion can unfold on attosecond time scales in nanoplasmonic systems, as defined by the inverse spectral bandwidth of the plasmonic resonant region. Similarly, in dielectrics or semiconductors, the laser-driven collective motion of electrons can occur on this characteristic time scale. Until now, such collective electron dynamics has not been directly observed on its natural, attosecond timescale. In ATTOCO, the attosecond, sub-cycle dynamics of strong-field driven collective electron dynamics in clusters and nanoparticles will be explored. Moreover, we will explore field-dependent processes induced by strong laser fields in nanometer sized matter, such as the metallization of dielectrics, which has been recently proposed theoretically. In order to map the collective electron motion we will apply the attosecond nanoplasmonic streaking technique, which has been proposed and developed theoretically. In this approach, the temporal resolution is achieved by limiting the emission of high energetic, direct photoelectrons to a sub-cycle time window using attosecond XUV pulses phase-locked to a driving few-cycle near-infrared field. Kinetic energy spectra of the photoelectrons recorded for different delays between the excitation field and the ionizing XUV pulse will allow extracting the spatio-temporal electron dynamics. ATTOCO offers the capability to measure field-induced material changes in real-time and to gain novel insight into collective electron dynamics. In particular, we aim to learn from ATTOCO in detail, how the collective electron motion is established, how the collective motion is driven by the strong external field and over which pathways and timescale the collective motion decays. ATTOCO provides also a major step in the development of lightwave (nano-)electronics, which may push the frontiers of electronics from multi-gigahertz to petahertz frequencies. If successfully accomplished, this development will herald the potential scalability of electron-based information technologies to lightwave frequencies, surpassing the speed of current computation and communication technology by many orders of magnitude.

1 498 500 €

Start date: 2013-06-01, End date: 2018-05-31