ERC FUNDED PROJECTS

The main objective of 4D-PET is to develop an innovative whole-body PET scanner based in a new detector concept that stores 3D position and time of every single gamma interaction with unprecedented resolution. The combination of scanner geometrical design and high timing resolution will enable developing a full sequence of all gamma-ray interactions inside the scanner, including Compton interactions, like in a 3D movie. 4D-PET fully exploits Time Of Flight (TOF) information to obtain a better image quality and to increase scanner sensitivity, through the inclusion in the image formation of all Compton events occurring inside the detector, which are always rejected in state-of-the-art PET scanners. The new PET design will radically improve state-of-the-art PET performance features, overcoming limitations of current PET technology and opening up new diagnostic venues and very valuable physiological information

2 048 386 €

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

The aim of the present proposal is to establish a research team developing and exploiting innovative techniques to study conformal field theories (CFT) analytically. Our approach does not rely on a Lagrangian description but on symmetries and consistency conditions. As such it applies to any CFT, offering a unified framework to study generic CFTs analytically. The initial implementation of this program has already led to striking new results and insights for both Lagrangian and non-Lagrangian CFTs. The overarching aims of my team will be: To develop an analytic bootstrap program for CFTs in general dimensions; to complement these techniques with more traditional methods and develop a systematic machinery to obtain analytic results for generic CFTs; and to use these results to gain new insights into the mathematical structure of the space of quantum field theories. The proposal will bring together researchers from different areas. The objectives in brief are: 1) Develop an alternative to Feynman diagram computations for Lagrangian CFTs. 2) Develop a machinery to compute loops for QFT on AdS, with and without gravity. 3) Develop an analytic approach to non-perturbative N=4 SYM and other CFTs. 4) Determine the space of all CFTs. 5) Gain new insights into the mathematical structure of the space of quantum field theories. The outputs of this proposal will include a new way of doing perturbative computations based on symmetries; a constructive derivation of the AdS/CFT duality; new analytic techniques to attack strongly coupled systems and invaluable new lessons about the space of CFTs and QFTs. Success in this research will lead to a completely new, unified way to view and solve CFTs, with a huge impact on several branches of physics and mathematics.

2 171 483 €

Start date: 2018-12-01, End date: 2023-11-30

Fundamental interactions in nature are well described by quantum gauge fields in 4 space-time dimensions (4d). When the strength of gauge interaction is weak the Feynman perturbation techniques are very efficient for the description of most of the experimentally observable consequences of the Standard model and for the study of high energy processes in QCD. But in the intermediate and strong coupling regime, such as the relatively small energies in QCD, the perturbation theory fails leaving us with no reliable analytic methods (except the Monte-Carlo simulation). The project aims at working out new analytic and computational methods for strongly coupled gauge theories in 4d. We will employ for that two important discoveries: 1) the gauge-string duality (AdS/CFT correspondence) relating certain strongly coupled gauge Conformal Field Theories to the weakly coupled string theories on Anty-deSitter space; 2) the solvability, or integrability of maximally supersymmetric (N=4) 4d super Yang-Mills (SYM) theory in multicolor limit. Integrability made possible pioneering exact numerical and analytic results in the N=4 multicolor SYM at any coupling, effectively summing up all 4d Feynman diagrams. Recently, we conjectured a system of functional equations - the AdS/CFT Y-system – for the exact spectrum of anomalous dimensions of all local operators in N=4 SYM. The conjecture has passed all available checks. My project is aimed at the understanding of origins of this, still mysterious integrability. Deriving the AdS/CFT Y-system from the first principles on both sides of gauge-string duality should provide a long-awaited proof of the AdS/CFT correspondence itself. I plan to use the Y-system to study the systematic weak and strong coupling expansions and the so called BFKL limit, as well as for calculation of multi-point correlation functions of N=4 SYM. We hope on new insights into the strong coupling dynamics of less supersymmetric gauge theories and of QCD.

1 456 140 €

Start date: 2013-11-01, End date: 2018-10-31

Attosecond light pulses are generated when an intense laser interacts with a gas target. These pulses are not only short, enabling the study of electronic processes at their natural time scale, but also coherent. The vision of this proposal is to extend temporal coherent control concepts to a completely new regime of time and energy, combining (i) ultrashort pulses (ii) broadband excitation (iii) high photon energy, allowing scientists to reach not only valence but also inner shells in atoms and molecules, and, when needed, (iv) high spatial resolution. We want to explore how elementary electronic processes in atoms, molecules and more complex systems can be controlled by using well designed sequences of attosecond pulses. The research project proposed is organized into four parts: 1. Attosecond control of light leading to controlled sequences of attosecond pulses We will develop techniques to generate sequences of attosecond pulses with a variable number of pulses and controlled carrier-envelope-phase variation between consecutive pulses. 2. Attosecond control of electronic processes in atoms and molecules We will investigate the dynamics and coherence of phenomena induced by attosecond excitation of electron wave packets in various systems and we will explore how they can be controlled by a controlled sequence of ultrashort pulses. 3. Intense attosecond sources to reach the nonlinear regime We will optimize attosecond light sources in a systematic way, including amplification of the radiation by injecting a free electron laser. This will open up the possibility to develop nonlinear measurement and control schemes. 4. Attosecond control in more complex systems, including high spatial resolution We will develop ultrafast microscopy techniques, in order to obtain meaningful temporal information in surface and solid state physics. Two directions will be explored, digital in line microscopic holography and photoemission electron microscopy.

2 250 000 €

Start date: 2008-12-01, End date: 2013-11-30

T cell engineering with chimeric antigen receptors has opened the door to effective immunotherapy. CARs are fusion genes encoding receptors whose extracellular domain comprises a single chain variable fragment (scFv) antibody that binds to a tumour surface epitope, while the intracellular domain comprises the signalling module of CD3ζ along with powerful costimulatory domains (e.g. CD28 and/or 4-1BB). CARs are a major breakthrough, since they allow bypassing HLA restrictions or loss, and they can incorporate potent costimulatory signals tailored to optimize T cell function. However, solid tumours present challenges, since they are often genetically unstable, and the tumour microenvironment impedes T cell function. The tumour vasculature is a much more stable and accessible target, and its disruption has catastrophic consequences for tumours. Nevertheless, the lack of affinity reagents has impeded progress in this area. The objectives of this proposal are to develop the first potent and safe tumour vascular-disrupting tumour immunotherapy using scFv’s and CARs uniquely available in my laboratory. I propose to use these innovative CARs to understand for the first time the molecular mechanisms underlying the interactions between anti-vascular CAR-T cells and tumour endothelium, and exploit them to maximize tumour vascular destruction. I also intend to employ innovative engineering approaches to minimize the chance of reactivity against normal vasculature. Lastly, I propose to manipulate the tumour damage mechanisms ensuing anti-vascular therapy, to maximize tumour rejection through immunomodulation. We are poised to elucidate critical interactions between tumour endothelium and anti-vascular T cells, and bring to bear cancer therapy of unparalleled power. The impact of this work could be transforming, given the applicability of tumour-vascular disruption across most common tumour types.

2 500 000 €

Start date: 2013-08-01, End date: 2018-07-31

"This is a programme of advanced research with potential for high scientific impact and applications to areas of great strategic importance such as renewable energy and biomolecular technology. The aim is to develop and apply a combination of cutting-edge tools to observe and understand dynamics in molecules and condensed phase matter with attosecond temporal and nanometre spatial resolutions. The programme, will exploit two new types of measurements that my group have already begun to develop: high harmonic generation (HHG) spectroscopy and attosecond absorption pump-probe spectroscopy, and will apply them to the measurement of attosecond electron dynamics in large molecules and the condensed phase. These methods rely upon the emission and transmission of soft X-ray attosecond fields that make accessible measurement not only of larger molecules in the gas phase but also thin (micron to nanometre) samples in the condensed phase. This is a research project that will open new frontiers both experimentally and theoretically. The challenge of this research is high and will be met by a concerted programme that is well matched to my teams experimental and theoretical expertise in attosecond physics, ultrafast intense-field science, soft X-ray techniques and advanced techniques for creating gaseous and condensed phase samples."

2 344 390 €

Start date: 2012-04-01, End date: 2017-03-31

Gauge theories play a central role in particle and condensed matter physics. Heavy-ion collisions explore the strong dynamics of quarks and gluons, which also governs the deep interior of neutron stars, while strongly correlated electrons determine the physics of high-temperature superconductors and spin liquids. Numerical simulations of such systems are often hindered by sign problems. In quantum link models - an alternative formulation of gauge theories developed by the applicant - gauge fields emerge from discrete quantum variables. In the past year, in close collaboration with atomic physicists, we have established quantum link models as a framework for the atomic quantum simulation of dynamical gauge fields. Abelian gauge theories can be realized with Bose-Fermi mixtures of ultracold atoms in an optical lattice, while non-Abelian gauge fields arise from fermionic constituents embodied by alkaline-earth atoms. Quantum simulators, which do not suffer from the sign problem, shall be constructed to address non-trivial dynamics, including quantum phase transitions in spin liquids, the real-time dynamics of confining strings as well as of chiral symmetry restoration at finite temperature and baryon density, baryon superfluidity, or color-flavor locking. New classical simulation algorithms shall be developed in order to solve severe sign problems, to investigate confining gauge theories, and to validate the proposed quantum simulators. Starting from U(1) and SU(2) gauge theories, an atomic physics tool box shall be developed for quantum simulation of gauge theories of increasing complexity, ultimately aiming at 4-d Quantum Chromodynamics (QCD). This project is based on innovative ideas from particle, condensed matter, and computational physics, and requires an interdisciplinary team of researchers. It has the potential to drastically increase the power of simulations and to address very challenging problems that cannot be solved with classical simulation methods.

1 975 242 €

Start date: 2014-02-01, End date: 2019-01-31

The prognosis of patients with metastatic pancreatic cancer (PDAC) is very poor. Recent studies have started to elucidate the genetic landscape of this disease to show that PDAC is a genetically complex, unstable, and heterogeneous cancer. However, in-depth analysis of individual patient genomes couple with personalize Avatar mouse models is providing highly effective therapeutic opportunities for the individual patient. Thus, metastatic PDAC appears a candidate disease to implement a genomics-base, personalized treatment approach. In this project, we will conduct an open label, multicenter, randomized phase III study in patients with standard of care resistant metastatic pancreatic cancer aiming to test the hypothesis that an integrated personalized treatment approach improves survival compare to a conventional treatment. Patients randomized to the personalize treatment arm will undergo a biopsy of a metastatic lesion to perform a targeted genome analysis using next generation sequencing. In addition, we will generate a personalize Avatar mouse model from the same patient. We will employ sophisticated bioinformatic analysis as well as mining of drug response-genetic databases to select, for each individual patient, candidate therapeutic targets that will be experimentally tested in the patient´s Avatar model to select the most effective regimen that will ultimately applied to the patient. In addition, based on the genomic data, we will design an individualized monitoring plan for each patient using BEAMing technology to monitor circulating levels of mutated genes. Furthermore, with a discovery goal, we will perform in depth genomic analysis of metastatic PDAC lesions in this cohort of clinically well-annotated patients with Avatar mouse models for therapeutic validation. Overall we expect this work will contribute to our understanding of PDAC and will favourably impact the treatment of this dismal cancer.

2 498 688 €

Start date: 2015-10-01, End date: 2020-09-30

"Prostate cancer is the commonest solid cancer in men in the European Community. There is evidence for genetic predisposition to the development of prostate cancer and our group has found the largest number of such genetic variants described to date worldwide. The next challenge is to harness these discoveries to advance the clinical care of populations and prostate cancer patients to improve screening and target treatments. This proposal, BARCODE, aims to be ground-breaking in this area. BARCODE has two components (1) to profile a population in England using the current 77 genetic variant profile and compare screening outcomes with those from population based screening studies to determine if genetics can target screening more effectively in this disease by identifying prostate cancer that more often needs treatment and (2) genetically profiling men with prostate cancer in the uro-oncology clinic for a panel of genes which predict for worse outcome so that these men can be offered more intensive staging and treatment within clinical trials. This will use next generation sequencing technology using a barcoding system which we have developed to speed up throughput and reduce costs. The PI will spend 35% of her time on this project and she will not charge for her time spent on this grant as she is funded by The University of London UK. The research team at The Institute Of Cancer Research, London, UK is a multidisciplinary team which leads the field of genetic predisposition to prostate cancer and its clinical application and so is well placed to deliver on this research. This application will have a dramatic impact on other researchers as it is ground –breaking and state of the art in its application of genetic findings to public health and cancer care. It will therefore influence the work being undertaken in both these areas to integrate genetic profiling and gene panel analysis into population screening and cancer care respectively."

2 499 123 €

Start date: 2014-10-01, End date: 2019-09-30

The aetiology of many musculoskeletal (MS) diseases is related to biomechanical factors. However, the tools to assess the biomechanical condition of patients used by clinicians and researchers are often crude and subjective leading to non-optimal patient analyses and care. In this project innovations related to imaging, sensor technology and biomechanical modelling are utilized to generate versatile, accurate and objective methods to quantify the (pathological) MS condition of the lower extremity of patients in a unique manner. The project will produce advanced diagnostic, pre-planning and outcome tools which allow clinicians and researchers for detailed biomechanical analysis about abnormal tissue deformations, pathological loading of the joints, abnormal stresses in the hard and soft tissues, and aberrant joint kinematics. The key objectives of this proposal are: 1) Develop and validate image-based 3-D volumetric elastographic diagnostic methods that can quantify normal and pathological conditions under dynamic loading and which can be linked to biomechanical modelling tools. 2) Create an ultrasound (US)-based system to assess internal joint kinematics which can be used as a diagnostic tool for clinicians and researchers and is a validation tool for biomechanical modelling. 3) Generate and validate an ambulant functional (force and kinematic) diagnostic system which is easy to use and which can be used to provide input data for biomechanical models. 4) Create and validate a new modelling approach that integrates muscle-models with finite element models at a highly personalized level. 5) Generate biomechanical models which have personalized mechanical properties of the hard and soft tissues. 6) Demonstrate the applicability of the personalized diagnostic and pre-planning platform by application to healthy individuals and patient subjects. Support from the ERC will open new research fields related to biomechanical patient assessment and modeling of MS pathologies.

2 456 400 €

Start date: 2013-05-01, End date: 2018-04-30

In 2010, 800 billion Euros was spent on brain diseases in Europe and the cost is expected to increase due to the aging population. – Here I propose to exploit our new discovery for research to alleviate this disease burden. In work selected by Nature Medicine among the top 10 ”Notable Advances” and by Science as one of the 10 ”Breakthroughs of the year” 2015, we discovered a meningeal lymphatic vascular system that serves brain homeostasis. We want to reassess current concepts about cerebrovascular dynamics, fluid drainage and cellular trafficking in physiological conditions, in Alzheimer’s disease mouse models and in human postmortem tissues. First, we will study the development and properties of meningeal lymphatics and how they are sustained during aging. We then want to analyse the clearance of macromolecules and protein aggregates in Alzheimer’s disease in mice that lack the newly discovered meningeal lymphatic drainage system. We will study if growth factor-mediated expansion of lymphatic vessels alleviates the parenchymal accumulation of neurotoxic amyloid beta and pathogenesis of Alzheimer’s disease and brain damage after traumatic brain injury. We will further analyse the role of lymphangiogenic growth factors and lymphatic vessels in brain solute clearance, immune cell trafficking and in a mouse model of multiple sclerosis. The meningeal lymphatics could be involved in a number of neurodegenerative and neuroinflammatory diseases of considerable human and socioeconomic burden. Several of our previous concepts have already been translated to clinical development and we aim to develop proof-of-principle therapeutic concepts in this project. I feel that we are just now in a unique position to advance frontline European translational biomedical research in this suddenly emerging field, which has received great attention worldwide.

2 420 429 €

Start date: 2017-08-01, End date: 2022-07-31

Traffic-related air pollution is an important environmental problem that may affect neurodevelopment. Ultrafine particles (UFP) translocate to the brains of experimental animals resulting in local proinflammatory overexpression. As the basic elements for thinking are acquired by developing brains during infancy and childhood, susceptibility may be elevated in early life. We postulate that traffic-related air pollution (particularly UFPs and metals/hydrocarbons content) impairs neurodevelopment in part via effects on frontal lobe maturation, likely increasing attention-deficit/hyperactivity disorder (ADHD). BREATHE objectives are to develop valid methods to measure children's personal UFP exposure and to develop valid neuroimaging methods to assess correlations between neurobehavior, neurostructural alterations and particle deposition in order to reveal how traffic pollution affects children¿s exposure to key contaminants and brain development, and identify susceptible subgroups. We have conducted general population birth cohort studies providing preliminary evidence of residential air pollution effects on prenatal growth and mental development. We aim to demonstrate short and long-term effects on neurodevelopment using innovative epidemiological methods interfaced with environmental chemistry and neuroimaging following 4000 children from 40 schools with contrasting high/low traffic exposure in six linked components involving: repeated psychometric tests, UFP exposure assessment using personal, school and home measurements, gene-environment interactions on inflammation, detoxification pathways and ADHD genome-wide-associated genes, neuroimaging (magnetic resonance imaging/spectroscopy) in ADHD/non-ADHD children, integrative causal modeling using mathematics, and replication in 2900 children with neurodevelopment followed from pregnancy. We believe the expected results will have worldwide global planning and policy implications.

2 499 230 €

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

The frontier in cancer therapy of orchestrating the immune system to attack tumors is producing unprecedented survival benefit in some patients. The corollary is lack of efficacy both in ostensibly responsive tumor types as well as others that are mostly non-responsive. The basis lies in pre-existing and adaptive resistance mechanisms that circumvent induction of tumor-reactive cytotoxic T cells (CTLs) capable of infiltrating solid tumors and eliminating cancer cells. A priori, cancers induced by expression of human papillomavirus oncogenes should be responsive to immunotherapy: these cancers encode immunogenic neo-antigens – the oncoproteins E6/7 – necessary for their manifestation. Rather, such tumors are poorly responsive to immunotherapies. Results from my lab and others using mouse models of HPV-induced cancer have established an actionable hypothesis: during tumorigenesis, such tumors erect multiple barriers to the induction, infiltration, and killing of cancer cells by tumor antigen-reactive CTLs. These include overarching systemic antigen-nonspecific immunosuppression mediated by expanded populations of myeloid cells in spleen and lymph nodes, complemented by immune response-impairing barriers operative in the tumor microenvironment. A spectrum of models will probe these barriers, genetically and pharmacologically, establishing their functional importance, alone and in concert. A major focus will be on how oncogene-expressing keratinocytes elicit a marked expansion of immunosuppressive myeloid cells in spleen and lymph nodes, and how these myeloid cells in turn inhibit development and activation of CD8 T cells and antigen-presenting dendritic cells. Then we’ll assess the therapeutic potential of barrier-breaking strategies combined with immuno-stimulatory modalities. This project will deliver new knowledge about multi-faceted barriers to immunotherapy in these refractory cancers, helping lay the groundwork for efficacious immunotherapy.

2 500 000 €

Start date: 2020-01-01, End date: 2024-12-31

The interplay between two of the most important building blocks of nature, quantum mechanics and gravity, has been a great source of inspiration for theoretical physics, leading to discoveries such as the Hawking radiation of black holes and the development of string theory. In turn, the following picture emerged: physics at the most fundamental level is governed by the rules of quantum mechanics while gravity is some effective coarse-grained description of the underlying microscopic theory. Given that the microscopic degrees of freedom are non-local, standard techniques such as the renormalization group and effective field theory a priori do not apply. Nevertheless, we use effective field theories that incorporate general relativity to describe our observations. With the discovery of gravitational waves and the various ongoing and upcoming experiments that will put general relativity to the test, it has become urgent to assess the validity of the standard framework of effective field theory for describing observable quantum gravity effects. Recent developments in resolving the information loss paradox and the quantum nature of black holes concluded that effective field theory must be modified in a way that uniquely incorporates quantum gravity. The main purpose of this proposal is to describe this modification in a precise and quantitative way, ultimately connecting it to potential experimental discoveries. In order to achieve this goal, I will approach the problem using a combination of thermodynamics, hydrodynamics and quantum information theory, mostly in the context of the AdS/CFT correspondence, where a precise description of quantum gravity is available. As a by-product of identifying observational features of quantum gravity, I will also make substantial progress in several foundational problems. My broad track record and expertise, and the fact that I have already obtained promising preliminary results, makes me uniquely qualified to lead this endeavor.

2 500 000 €

Start date: 2019-09-01, End date: 2024-08-31

We envisage a new generation of dynamic holographic laser tweezers and stretching tools with unprecedented spatial control of gradient and scattering light forces, to unravel functional mysteries of cell biology and genetics: Based on our recently developed, highly successful and widely recognized amplitude and phase shaping techniques with cascaded spatial light modulators (SLM), we will create new holographic optical manipulators consisting of a line-shaped trap with balanced net scattering forces and controllable local phase-gradients. Combining these line stretchers with spiral phase contrast imaging or nonlinear optical microscopy will allow quantitative study of functional shape changes. The novel tool is hugely more versatile than standard optical tweezers, since direction and magnitude of the scattering force can be designed to precisely follow the structure. In combination with conventional multi-spot traps the line stretcher acts as a sensitive and adaptable local force sensor. In collaboration with local experts we want to tackle hot topics in Genetics, e.g. search for force profile signatures in regions with Copy Number Variations. Possibly the approach may shed light on basic physical characteristics such as, for example, chromosomal fragility in Fra(X) syndrome, the most common monogenic cause of mental retardation. The new design intrinsically offers enhanced microscopic resolution, as SLM-synthesized apertures and waveforms can enlarge the number of spatial frequencies forming the image. Ultimately, nonlinear holography can be implemented, sending phase shaped wavefronts to target samples. This can, e.g., be used to push the sensitivity of nonlinear chemical imaging, or for controlled photo-activation of targeted regions in neurons.

1 987 428 €

Start date: 2010-05-01, End date: 2015-04-30

Given a quantum system, how can one ensure that it (i) is entangled? (ii) random? (iii) secure? (iv) performs a computation correctly? The concept of quantum certification embraces all these questions and CERQUTE’s main goal is to provide the tools to achieve such certification. The need of a new paradigm for quantum certification has emerged as a consequence of the impressive advances on the control of quantum systems. On the one hand, complex many-body quantum systems are prepared in many labs worldwide. On the other hand, quantum information technologies are making the transition to real applications. Quantum certification is a highly transversal concept that covers a broad range of scenarios –from many-body systems to protocols employing few devices– and questions –from theoretical results and experimental demonstrations to commercial products–. CERQUTE is organized along three research lines that reflect this broadness and inter-disciplinary character: (A) many-body quantum systems: the objective is to provide the tools to identify quantum properties of many-body quantum systems; (B) quantum networks: the objective is to characterize networks in the quantum regime; (C) quantum cryptographic protocols: the objective is to construct cryptography protocols offering certified security. Crucial to achieve these objectives is the development of radically new methods to deal with quantum systems in an efficient way. Expected outcomes are: (i) new methods to detect quantum phenomena in the many-body regime, (ii) new protocols to benchmark quantum simulators and annealers, (iii) first methods to characterize quantum causality, (iv) new protocols exploiting simple network geometries (v) experimentally-friendly cryptographic protocols offering certified security. CERQUTE goes at the heart of the fundamental question of what distinguishes quantum from classical physics and will provide the concepts and protocols for the certification of quantum phenomena and technologies.

1 735 044 €

Start date: 2020-01-01, End date: 2024-12-31

In the gastrointestinal tract, the balance between activation of the mucosal immune system and tolerance should be tightly regulated to maintain immune homeostasis to prevent chronic inflammation and tissue damage. Recently, the new concept was introduced that the vagus nerve plays an important role in modulating immune homeostasis as part of a so-called inflammatory reflex. We provided evidence for this concept in the gastrointestinal tract and showed that vagus nerve stimulation (VNS) reduced inflammation of the intestinal muscle layer. Moreover, we showed that this effect was mediated by activation of enteric cholinergic neurons (cholinergic tone) interacting with intestinal macrophages in the muscle layer. Of interest, we have collected exciting data that the vagus nerve (and thus the cholinergic tone) also significantly contributes to mucosal immune homeostasis. Mice that underwent vagotomy lost their ability to develop tolerance to oral feeding of an antigen, whereas VNS reduced mucosal inflammation in a model of food allergy. Based on these data, we hypothesize that the cholinergic tone is a major determinant of the tolerogenic microenvironment of the mucosal immune system, and want to further explore the immune-modulatory effect of the vagal innervation and enteric neurons on the macrophages residing in the lamina propria. In addition, we will further explore the therapeutic potential and the mechanisms involved of chronic VNS in colitis and food allergy. Finally, we will translate our preclinical findings to the human situation. The anti-inflammatory effect of VNS (applied during surgery) will be studied in human intestinal tissue whereas the therapeutic potential of chronic VNS in Crohn’s disease will be studied in a pilot trial. The outcome of this project will be ground-breaking and will have an immense impact on clinical management as it will provide new therapeutic opportunities for the treatment of immune-mediated gastrointestinal disorders.

2 495 200 €

Start date: 2014-04-01, End date: 2019-03-31

Background: Therapeutic angiogenesis with vascular endothelial growth factors (VEGFs) has great potential to become a novel, minimally invasive new treatment for a large number of patients with severe myocardial ischemia. However, this requires development of new technology. Advancing state-of-the-art: We propose a paradigm shift in gene therapy for chronic ischemia by activating endogenous VEGF-A,-B and -C genes and angiogenic transcription programs from the native promoters instead of gene transfer of exogenous cDNA to target tissues. We will develop a new platform technology (endogenetherapy) based on our novel concept of the release of promoter pausing and new promoter-targeted upregulating short hairpinRNAs, tissue-specific superenhancerRNAs activating specific transcription centers involving gene clusters in different chromosomal regions, small circularRNAs formed from self-splicing exons-introns that can be regulated with oligonucleotides and small molecules such as metabolites, nuclear RNAi vectors and specific CRISPR/gRNAmutatedCas9-VP16 technology with an ability to target integration into genomic safe harbor sites. After preclinical studies in mice and in a newly developed chronic cardiac ischemia model in pigs with special emphasis on the analysis of clinically relevant blood flow, metabolic and functional outcomes based on MRI, ultrasound, photoacoustic and PET imaging, the best construct will be taken to a phase I clinical study in patients with severe myocardial ischemia. Since endogenetherapy also involves epigenetic changes, which are reversible and long-lasting, we expect to efficiently activate natural angiogenic programs. Significance: If successful, this approach will begin a new era in gene therapy. Since there is a clear lack of technology capable of targeted upregulation of endogenous genes, the novel endogenetherapy approach may become widely applicable beyond cardiovascular diseases also in other areas of medicine and biomedical research.

2 437 500 €

Start date: 2015-11-01, End date: 2020-10-31

CODIR proposes a new configuration of fundamental and applied biomedical and engineering multidisciplinary research to explore and characterise colon behavior necessary for the project and wider objectives. Scope and focus is on novel robotic hydro-colonoscopy (RHC), which stems from two considerations: (i) replacement of the flexible colonosocope with a patient-friendly system for inspection of the mucosal surface colon and (ii) the very recent concept of hydro-colonoscopy whereby water is used instead of traditional air insufflation. RHC can enable a breakthrough in patient-compliant complete endoscopic examination and biopsy of the colon for the further study of life threatening disorders of the colon commonly categorized as inflmmatory bowel disease, all of unknown aetilogy despite intensive research. CODIR will provide new insights for biomedical investigation and research applicable to many biomedical fields: biologic [absorption of water and electrolyte from the colon, characterisation of surface topograpgy of the colon, mechanical properties of colonic wall], imaging, mechatronics robot functionality and a novel colonic irrigation and filling system. The ambition is to develop a one-stop holistic system which cleans the colon of faecal debris and then introduces a tethered swimming/ submerging robot for inspection of the mucosal aspect of colon under the control of a clinician operating the endoluminal mini-robot from a control console. A secondary, very important outcome of CODIR is to increase patient compliance (currently 50%) for screening colonoscopy in early diagnosis of colorectal cancer, the worlds second commonest cancer. RHC can overcome major disadvantages of existing colonoscopy examination: discomfort, sedation, thus increasing compliance and enabling future research.

2 999 948 €

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

In a quantum engineering approach we aim to create strongly correlated molecular quantum gases for polar molecules confined in an optical lattice to two-dimensional geometry with full quantum control of all de-grees of freedom with single molecule control and detection. The goal is to synthesize a high-fidelity molec-ular quantum simulator with thousands of particles and to carry out experiments on phases and dynamics of strongly-correlated quantum matter in view of strong long-range dipolar interactions. Our choice of mole-cule is the KCs dimer, which can either be a boson or a fermion, allowing us to prepare and probe bosonic as well as fermionic dipolar quantum matter in two dimensions. Techniques such as quantum-gas microscopy, perfectly suited for two-dimensional systems, will be applied to the molecular samples for local control and local readout. The low-entropy molecular samples are created out of quantum degenerate atomic samples by well-established coherent atom paring and coherent optical ground-state transfer techniques. Crucial to this pro-posal is the full control over the molecular sample. To achieve near-unity lattice filling fraction for the mo-lecular samples, we create two-dimensional samples of K-Cs atom pairs as precursors to molecule formation by merging parallel planar systems of K and Cs, which are either in a band-insulating state (for the fermions) or in Mott-insulating state (for the bosons), along the out-of-plane direction. The polar molecular samples are used to perform quantum simulations on ground-state properties and dy-namical properties of quantum many-body spin systems. We aim to create novel forms of superfluidity, to investigate into novel quantum many-body phases in the lattice that arise from the long-range molecular dipole-dipole interaction, and to probe quantum magnetism and its dynamics such as spin transport with single-spin control and readout. In addition, disorder can be engineered to mimic real physical situations.

2 356 117 €

Start date: 2019-01-01, End date: 2023-12-31

Low temperature matter exhibits a spectacular variety of highly ordered states that occur through phase transitions. In quantum systems, phase transitions and associated critical phenomena constitute a central issue of modern physics. Wilson’s theory of renormalization showed that very different physical systems could be unified under the same universality class characterized by critical exponents. The high degree of control offered by ultracold atom experiments sets them as an ideal platform for the investigation of phase transitions and critical phenomena. CRITISUP2 aims at exploring criticality in superfluid spin ½ Fermi gases where the interplay between temperature spin polarization and interactions is at the origin of a rich phase diagram and a variety of phase transitions. We will measure the corresponding static and dynamic critical exponents, and search for the long-sought Fulde-Ferrell-Larkin-Ovchinnikov (FFLO) phase predicted over 50 years ago. We will also study the phase diagram and critical counterflow of dual Bose-Fermi superfluids which have emerged as a new paradigm of quantum matter. Cutting-edge Bold Diagrammatic Monte Carlo and new resummation methods, developed in-house, will be confronted to the experiments on the one hand, and provide answers to debated questions on the other. The expected outcomes of CRITISUP2 will constitute a major leap forward relevant for several fields of modern physics, ranging from condensed-matter to astrophysics, nuclear physics, and high energy physics.

2 246 536 €

Start date: 2017-05-01, End date: 2022-04-30

The clinical phenotype and the outcome of Crohn's disease (CD) and ulcerative colitis (UC), the opposite ends of chronic inflammatory bowel diseases (IBD), are heterogeneous and represent the result of a complex interplay of the gut microbiome with the immune system in genetically predisposed individuals. Disease management is much less heterogeneous as all patients are treated using non-specific anti-inflammatory agents, and only 30-50% achieve clinical and mucosal remission -the goal of therapy nowadays- therefore leaving large margins for improvement. The advances in knowledge about the factors triggering disease onset should be translated to approach the disease from a molecular angle. Key cellular pathways have emerged including bacterial recognition, autophagy, endoplasmic reticulum stress and intestinal barrier function. Functional/molecular characterization of these pathways in a given patient, correlation with meaningful clinical outcomes, and tailoring an individual therapeutic approach has never been attempted and will represent a breakthrough in the current paradigm of treating multifactorial inflammatory conditions. This project aims to functionally characterize patients with CD/UC for the major pathways by using integrated (epi)genetic, transcriptomic, immunologic, barrier integrity and metagenomic studies. From these readouts we will construct an index [the Crohn’s and Ulcerative Colitis Characterization and Intervention trial (CrUCCial) index], reflecting the proportional contribution of each of the pathogenic mechanisms in a given patient. We will next study the correlation of this index and its components to meaningful clinical outcomes and finally, the index will be tested in a pilot study of newly diagnosed patients in whom the disease will be targeted individually based on the components of the CrUCCial index. Our approach, from diagnosis over prognosis to therapy, will revolutionize the paradigm of disease management.

2 494 500 €

Start date: 2016-09-01, End date: 2021-08-31

In physiological situations, the extracellular matrix (ECM) sequesters cytokines, localizes them, and modulates their signaling. Thus, physiological signaling from cytokines occurs primarily when the cytokines are interacting with the ECM. In therapeutic use of cytokines, however, this interaction and balance have not been respected; rather the growth factors are merely injected or applied as soluble molecules, perhaps in controlled release forms. This has led to modest efficacy and substantial concerns on safety. Here, we will develop a protein engineering design for second-generation cytokines to lead to their super-affinity binding to ECM molecules in the targeted tissues; this would allow application to a tissue site to yield a tight association with ECM molecules there, turning the tissue itself into a reservoir for cytokine sequestration and presentation. To accomplish this, we have undertaken preliminary work screening a library of cytokines for extraordinarily high affinity binding to a library of ECM molecules. We have thereby identified a small peptide domain within placental growth factor-2 (PlGF-2), namely PlGF-2123-144, that displays super-affinity for a number of ECM proteins. Also in preliminary work, we have demonstrated that recombinant fusion of this domain to low-affinity binding cytokines, namely VEGF-A, PDGF-BB and BMP-2, confers super-affinity binding to ECM molecules and accentuates their functionality in vivo in regenerative medicine models. In the proposed project, based on this preliminary data, we will push forward this protein engineering design, pursuing super-affinity variants of VEGF-A and PDGF-BB in chronic wounds, TGF-beta3 and CXCL11 in skin scar reduction, FGF-18 in osteoarthritic cartilage repair and CXCL12 in stem cell recruitment to ischemic cardiac muscle. Thus, we seek to demonstrate a fundamentally new concept and platform for second-generation growth factor protein engineering.

2 368 170 €

Start date: 2014-05-01, End date: 2019-04-30

Dark matter (DM) is a ubiquitous yet invisible presence in our universe. It dictated how galaxies formed in the first place, and now moves stars around them at puzzling speeds. The DM mass in the universe is known to be five times that of ordinary matter; yet its true nature remains elusive. Weakly interacting massive particles (WIMPs), relics from the early universe, are a compelling explanation chased by sensitive experiments in deep underground laboratories. However, searches for heavy WIMPs (≈100 times the proton mass), the most theoretically natural candidates, have been so far unsuccessful. Nor has evidence for such heavy particles yet been found at the CERN Large Hadron Collider. Alternative scenarios are now under scrutiny, such as the existence of a hidden sector of lighter DM particles that interact, differently than WIMPs, also with electrons. DAMIC-M (Dark Matter In CCDs at Modane) will search beyond the heavy WIMP paradigm by detecting nuclear recoils and electrons induced by light DM in charge-coupled devices (CCDs). The 0.5 kg detector will be installed at the Laboratoire Souterrain de Modane, France. In this novel and unconventional use of CCDs, which are commonly employed for digital imaging in astronomical telescopes, the ionization charge will be detected in the most massive CCDs ever built with exquisite spatial resolution (15 μm x 15 μm pixel). The crucial innovation in these devices is the non-destructive, repetitive measurement of the pixel charge, which results in the high-resolution detection of a single electron and unprecedented sensitivity to light DM (≈ eV energies are enough to free an electron in silicon). By counting individual charges in a detector with extremely low leakage current – a combination unmatched by any other DM experiment – DAMIC-M will take a leap forward of several orders of magnitude in the exploration of the hidden sector, a jump that may be rewarded by serendipitous discovery.

3 349 563 €

Start date: 2018-09-01, End date: 2023-08-31

The transition from quantum to classical is an essential issue in physics. At a practical level, quantum information thrives to build large quantum systems for tasks in communication or computing beyond the reach of classical devices. At the fundamental level, the question is whether there exists, in addition to environment-induced decoherence, another mechanism responsible for the disappearance of state superpositions at the macroscopic scale. Harmonic oscillators coupled to qubits are ideal to probe the limits of the quantum domain. Among various versions of this system, microwave Cavity Quantum Electrodynamics coupling Rydberg atoms to superconducting cavities has developed tools of un-matched sensitivity and precision. Building on these advances and on the development of deterministic atomic sources, DECLIC proposes to explore the dynamics of fields trapped in cavities and to study their decoherence under various perspectives. It will implement novel ways to generate non-classical states with large photon numbers stored in one cavity or non-locally split between two. DECLIC will record the gradual evolution of these states towards classicality and locality. Along this way, it will explore promising processes such as quantum random walks and collective photonic effects leading to non-classical interferometry breaking the standard quantum limit. Beyond witnessing decoherence, DECLIC will investigate ways to manipulate and control it, either by implementing feedback procedures steering the field towards targeted states, or by engineering artificial environments protecting against decoherence specific states of light. These experiments will provide invaluable clues for the understanding of other oscillator-qubit systems exploring the quantum to classical boundary.

2 500 000 €

Start date: 2010-02-01, End date: 2016-01-31

Hematopoietic stem cells (HSC) are used in clinical therapies for leukemia and blood-related genetic disorders. Whereas the number of patients requiring treatment continues to increase, HSC transplantations are limited due to insufficient patient-matched donor HSCs. The current challenge is to create more matched HSCs. As evidenced by the Nobel Prize award this year, reprogramming of somatic cells to pluripotent stem cells (iPS) is one of the most important breakthroughs of recent times. This innovative advance contributes to our ability to reprogram patient-specific cells not only to pluripotency, but also to directly program them to other desired cell lineages. The study of healthy and diseased patient cells in this context will have huge impact on the development of new drug and cell-based treatments. My research is uniquely positioned at the interface of fundamental and translational research at the University of Edinburgh Centre for Inflammation Research and Centre for Regenerative Medicine. Through more than a decade of HSC developmental research, my group has shown that HSCs arise from endothelial cells in a natural reprogramming event. We are one of the few groups worldwide that can isolate these special endothelial cells and show that they yield robust transplantable HSCs (the gold-standard for clinically relevant HSCs). Using our unique expertise I aim to foster new translational strategies to de novo generate human HSCs from patient somatic cells. My aims are to 1) mark and manipulate the program for HSC generation during the endothelial to HSC transition (EHT); 2) define extrinsic molecules affecting EHT and engineer novel niches; 3) reprogram human somatic cells or endothelial derived iPS cells directly to HSCs. These aims will be realized through novel multi-color reporter mouse and ES/iPS lines indicating EHT in real-time, allowing for the isolation and functional validation of de novo HSC generation. These novel models and cultures will significantly advance research and technology, to have major impact on the field.

2 500 000 €

Start date: 2015-01-01, End date: 2019-12-31

"Catabolism of amino acids is an ancient survival strategy that also controls immune responses in mammals. Indoleamine 2,3-dioxygenase (IDO), a tryptophan catabolizing enzyme, is recognized as an authentic regulator of immunity in several physiopathologic conditions, including autoimmune diseases, in which it is often defective, and neoplasia, in which it promotes immune unresponsiveness. The PI’s group recently revealed that IDO does not merely degrade tryptophan and produce immunoregulatory kynurenines but also acts as a signal-transducing molecule independently of its enzyme activity. IDO’s signaling function relies on the presence of phosphorylable motifs in a region (small IDO domain) distant from the catalytic site (large IDO domain). Preliminary data indicate that IDO, depending on microenvironmental conditions, can move among distinct cellular compartments. Thus IDO may be considered a ‘moonligthing’ protein, i.e., an ancestral metabolic molecule that, during evolution, has acquired the DYNAMIC feature of moving intracellularly and switching among distinct functions by changing its conformational state. By means of computational studies, Macchiarulo’s group (team member) has identified distinct conformations of IDO, some of which are associated with optimal catalytic activity of the enzyme whereas others may favor tyrosine phosphorylation of IDO’s small domain. A switch between distinct conformations can be induced by the use of ligands that bind either the catalytic site or an accessory pocket outside the IDO catalytic site. The first aim of DIDO is to decipher the relationships between IDO conformations and multiple functions of the enzyme. A second aim is to identify small molecules with drug-like properties capable of modulating distinct IDO’s molecular conformations in order to either potentiate (a new therapeutic approach in autoimmune diseases) or inhibit (more efficient anti-tumor therapeutic strategy) immunoregulatory signaling ability of IDO."

2 442 078 €

Start date: 2014-02-01, End date: 2019-01-31

We propose to build a two-dimensional (2D) discrete quantum simulator based on ensembles of ultracold neutral atoms. In this system all degrees of freedom will be controlled at the quantum limit: the number and positions of the atoms, as well as their internal (qubit) and vibrational states. The dynamics is implemented by discrete steps of spin-dependent transport combined with controlled cold collisions of the atoms. Although numerous theoretical studies have considered this architecture as the most promising route to quantum simulation, it has not yet been realized experimentally in all essential aspects. This simulator allows us to study dynamical properties of single-particle and many-body systems in engineered 2D environments. In single particle discrete systems, also known as quantum walks, we plan to investigate transport properties connected to graphene-like Dirac points, and localization phenomena associated with disorder. In the many-particle setting we will realize 2D cluster states as needed for measurement-based quantum computation, as well as simple quantum cellular automata.

2 575 573 €

Start date: 2012-04-01, End date: 2017-03-31

This proposal intends to develop and apply a new-generation theoretical toolbox for understanding the rich dynamics of strongly-interacting many-body quantum sytems subjected to destabilizing manipulations bringing them very far from equilibrium. In atomic systems, condensed matter and nanophysics settings, quantum matter is nowadays routinely pushed beyond the traditional low-energy/linear response/thermal equilibrium paradigms. Some experiments even clearly highlight the need to revise basic fundamental quantum statistical mechanics notions such as ergodicity, relaxation and thermalization in order to explain their behaviour. Theory must thus urgently revise its textbooks and develop new interpretations and capabilities for offering concrete, quantitative phenomenology. This proposal is focused on a set of systems at the very center of this strongly-correlated, experimentally realizable far-from-equilibrium spectacle: integrable models of quantum spin chains, interacting gases confined to one spatial dimension, and quantum dots. Building up on recent theoretical breakthroughs in dynamical correlations and post-quench steady states, this proposal aims to shed a new light on the fundamental principles at the heart of many-body quantum dynamics. It will implement a broad and ambitious research agenda consisting of synergetic projects from mathematically formal thought experiments all the way to phenomenologically applied practical calculations. The types of protocols to be studied include probes creating high-energy excitations, pulses inducing changes beyond linear response, quenches causing sudden global reorganizations, all the way to drivings completely metamorphozing the physical states. The result will be to provide reliable, experimentally relevant and urgently-needed theoretical `anchoring points' in our general understanding of the physics underlying far-from-equilibrium strongly-interacting quantum matter.

2 444 446 €

Start date: 2017-09-01, End date: 2022-08-31

"Questions about the origins of electroweak symmetry breaking and of the striking hierarchies ob-served in the spectrum of fermion masses and mixing angles are among the most pressing problems in fundamental physics. While the Large Hadron Collider at CERN was built to explore the physics of electroweak symmetry breaking on tiny distance scales of an attometer, the absence of clear hints for new particles in existing high-energy physics experiments suggests that new phenomena might only occur at distances still smaller than this. What if the LHC discovers a Higgs boson and nothing else? It has recently been realized that significantly shorter distances of only a few zeptometer (10^-21 m) can be probed indirectly in precision measurements of rare weak decay processes and of the couplings of the Higgs boson. Exploring nature at these scales never before accessible to mankind requires breakthrough advances in theory. I propose a broad theoretical approach to precision physics in and beyond the Standard Model based on effective field-theory tools. In the context of warped extra-dimension models, the genuine quantum structure of fundamental physics will be probed in loop-mediated processes, including Higgs-boson production and decay as well as rare flavour-changing neutral current processes. These explorations will be complemented by highest-precision calculations of important collider-physics processes, such as Higgs, top, and electroweak gauge-boson production in association with jets, which for the first time will be performed without recourse to phenomenological models. The multi-loop anomalous dimensions required for these calculations will also provide a deeper understanding of the structure of infrared singularities of scattering amplitudes in non-abelian gauge theories. The results obtained from the research described in this proposal are likely to reveal the deep common origins of the flavour structure and electroweak symmetry breaking."

2 109 600 €

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

The study of black hole physics and string theory are leading to a novel perspective on gravity and space-time. The old frameworks are replaced by a new paradigm in which gravity is understood as an emergent phenomenon. A central role in this revolution is played by the holographic principle put forward by ‘t Hooft. It states that the microscopic information associated with the physical world can be stored on the boundary of space. From this holographic viewpoint I have recently derived the familiar laws of Newton and Einstein using only first principles. Gravity appears as an entropic force caused by changes in information associated with matter. With this ERC proposal I am aiming to build a research group that will further develop this new entropic view on gravity. The powerful string theoretic tools, such as the holographic correspondence between gauge theory and gravity, will be used to illuminate and further clarify gravity’s entropic origin. In addition, I plan to investigate the implications of the emergence of the gravitational force for the areas in which gravity plays a crucial role, in particular cosmology. For instance, the entropic viewpoint is expected to shed new light on the nature of dark energy and possibly dark matter. It may also lead to a new perspective on the other fundamental forces, since the notions of inertia and mass need to be reconsidered as well. The understanding of gravity as an emergent phenomenon will also influence and benefit from the conceptual ideas developed in condensed matter physics, such as the recently discovered connection between quantum critical electron systems and black hole horizons. The university of Amsterdam and the Netherlands provide an excellent environment for a successful completion of these goals.

2 033 983 €

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

Immunotherapy with checkpoints blockers is transforming the treatment of advanced cancers. Colorectal cancer (CRC), a cancer with 1.4 million new cases diagnosed annually worldwide, is refractory to immunotherapy (with the exception of a minority of tumors with microsatellite instability). This is somehow paradoxical as CRC is a cancer for which we have shown that it is under immunological control and that tumor infiltrating lymphocytes represent a strong independent predictor of survival. Thus, there is an urgent need to broaden the clinical benefits of immune checkpoint blockers to CRC by combining agents with synergistic mechanisms of action. An attractive approach to sensitize tumors to immunotherapy is to harness immunogenic effects induced by approved conventional or targeted agents. Here I propose a new paradigm to identify molecular determinants of resistance to immunotherapy and develop personalized in silico and in vitro models for predicting response to combination therapy in CRC. The EPIC concept is based on three pillars: 1) emphasis on antitumor T cell activity; 2) systematic interrogation of tumor-immune cell interactions using data-driven modeling and knowledge-based mechanistic modeling, and 3) generation of key quantitative data to train and validate algorithms using perturbation experiments with patient-derived tumor organoids and cutting-edge technologies for multidimensional profiling. We will investigate three immunomodulatory processes: 1) immunostimulatory effects of chemotherapeutics, 2) rewiring of signaling networks induced by targeted drugs and their interference with immunity, and 3) metabolic reprogramming of T cells to enhance antitumor immunity. The anticipated outcome of EPIC is a precision immuno-oncology platform that integrates tumor organoids with high-throughput and high-content data for testing drug combinations, and machine learning for making therapeutic recommendations for individual patients.

2 460 500 €

Start date: 2018-10-01, End date: 2023-09-30

Early detection is crucial for the outcome of most cancers. Prevention of cancer development is even more desirable. To facilitate these ultimate goals we aim to construct a comprehensive view of the stepwise process through which common human cancers, such as colorectal cancer, arise. In particular, we aim to identify novel mechanisms of cancer susceptibility by focusing on the epigenome, whose alterations may underlie several phenomena related to chronic adult-onset disease that are not explained by genetics alone. The stepwise process of carcinogenesis can be accelerated or halted for various reasons, including inherited susceptibility and diet. The human multi-organ cancer syndromes hereditary nonpolyposis colorectal cancer (HNPCC) and familial adenomatous polyposis (FAP) as well as their murine counterparts, the Mlh1+/- mouse and the ApcMin/+ mouse, will be used as shortcuts to study the interplay between the epigenome and genome in tumorigenesis and to identify biomarkers of cancer susceptibility, malignant transformation, and tumor progression. This will be achieved by molecular profiling of normal and tumor tissues, cell line studies, in vitro functional assays, and in silico approaches. Additionally, the role that the epigenome plays to mediate the effects of the Western type diet on colorectal tumorigenesis will be examined in the mouse. Unlike genetic changes, epigenetic alterations are potentially reversible, which makes them promising targets for preventive and therapeutic interventions.

2 500 000 €

Start date: 2009-04-01, End date: 2014-09-30

Motivated by the overwhelming success of symmetry concepts in formulating basic laws of physics, the present proposal (eQG) seeks to develop a new symmetry based approach to the problem of reconciling Quantum Mechanics and Einstein’s General Relativity into a consistent theory of Quantum Gravity, regarded by many as the greatest challenge of contemporary theoretical physics. The need for such a theory is most pressing for the resolution of black hole singularities and the Big Bang, but it is equally crucial to the search for a consistent UV completion of the Standard Model of Particle Physics and the unification of the fundamental interactions. eQG aims to tackle this problem from a new perspective, bringing together very different strands of development: on the one hand, by paying particular attention to recent advances in our understanding of cosmological singularities and the evidence for novel infinite-dimensional duality symmetries near the singularity that has emerged in supergravity and string theory, and to recent progress in formulating ‘exceptional geometries’ transcending Riemannian geometry; on the other hand, by exploiting insights from modern canonical quantisation towards a better understanding of the basic degrees of freedom and the dynamics of quantum space-time. The main focus of eQG will be the ‘maximally extended’ exceptional hyperbolic Kac–Moody symmetry E10, whose uniquely distinguished status makes it a prime candidate symmetry for unifying the known dualities of string and M theory, for a conceptually precise scenario of emergent (quantum) space and time near the singularity, and finally, for replacing supersymmetry as a guiding principle for unification. Consequently, the principal goal of eQG will be to explore how this symmetry can define a theory of quantum gravity, how it acts on its fundamental degrees of freedom, what the special features are of the quantised theory, and what physical predictions can be derived from it.

1 918 750 €

Start date: 2017-12-01, End date: 2022-11-30

I propose to leverage the unique properties of optical fiber Fabry-Perot (FFP) microcavities pioneered by my group to advance the field of quantum engineering. We will take quantum-enhanced measurement from its current proof-of-principle state to a true metrological level by applying cavity-based spin squeezing to a compact atomic clock, aiming to improve the clock stability beyond one part in 10^-13 in one second. In a new experiment, we will generate multiparticle entangled states with high metrological gain by applying cavity-based entanglement schemes to alkaline earth-like atoms, the atomic species used in today’s most precise atomic clocks. In a second phase, a miniature quantum gas microscope will be added to this experiment, creating a rich new situation at the interface of quantum information, metrology, and cutting-edge quantum gas research. Finally, we will further improve the FFP microcavity technology itself to enable novel atom-light interfaces with a currently unavailable combination of strong coupling, efficient fiber coupling, and open access. This will open new horizons for light-matter interfaces not only in our experiments, but also in our partner groups working with trapped ions, diamond color centers, semiconductor quantum dots, carbon nanotubes and in quantum optomechanics.

2 422 750 €

Start date: 2015-10-01, End date: 2020-09-30

Femtosecond lasers can now provide intensities such that the light field induces relativistic motion of large ensembles of electrons. The ultimate goal of this Ultra-High Intensity (UHI) Physics is the control of relativistic motion of matter with light, which requires a deep understanding of this extreme regime of laser-matter interaction. Such a control holds the promise of major scientific and societal applications, by providing ultra-compact laser-driven particle accelerators and attosecond X-ray sources. Until now, advances in UHI Physics have relied on a quest for the highest laser intensities, pursued by focusing optimally-compressed laser pulses to their diffraction limit. In contrast, the goal of the ExCoMet project is to establish a new paradigm, by demonstrating the potential of driving UHI laser plasma-interactions with sophisticated structured laser beams–i.e. beams whose amplitude, phase or polarization are shaped in space-time. Based on this new paradigm, we will show that unprecedented experimental insight can be gained on UHI laser-matter interactions. For instance, by using laser fields whose propagation direction rotates on a femtosecond time scale, we will temporally resolve the synchrotron emission of laser-driven relativistic electrons in plasmas, and thus gather direct information on their dynamics. We will also show that such structured laser fields can be exploited to introduce new physics in UHI experiments, and can provide advanced degrees of control that will be essential for future light and particles sources based on these interactions. Using Laguerre-Gauss beams, we will in particular investigate the transfer of orbital angular momentum from UHI lasers to plasmas, and its consequences on the physics and performances of laser-plasma accelerators. This project thus aims at bringing conceptual breakthroughs in UHI physics, at a time where major projects relying on this physics are being launched, in particular in Europe.

2 250 000 €

Start date: 2016-10-01, End date: 2021-09-30

Pancreatic islet transplantation is essential for diabetes treatment. Outcome varies due to transplantation site, quality of islets and the fact that transplanted islets are affected by the same challenges as in situ islets. Tailor-making islets for transplantation by tissue engineering combined with a more favorable transplantation site that allows for both monitoring and local modulation of islet cells is thus instrumental. We have established the anterior chamber of the eye (ACE) as a favorable environment for long term survival of islet grafts and the cornea as a natural body window for non-invasive, longitudinal optical monitoring of islet function. ACE engrafted islets are able to maintain blood glucose homeostasis in diabetic animals. In addition to studies in non-human primates we are performing human clinical trials, the first patient already being transplanted. Tissue engineering of native islets is technically difficult. We will therefore apply genetically engineered islet organoids. This allows us to generate i) standardized material optimized for transplantation, function and survival, as well as ii) islet organoids suitable for monitoring (sensor islet organoids) and treating (metabolic islet organoids) insulin-dependent diabetes. We hypothesize that genetically engineered islet organoids transplanted to the ACE are superior to native pancreatic islets to monitor and treat insulin-dependent diabetes. Our overall aim is to create a platform allowing monitoring and treatment of insulin-dependent diabetes in mice that can be transferred to large animals for validation. The objective is to combine tissue engineering of islet cell organoids, transplantation to the ACE, synthetic biology, local pharmacological treatment strategies and the development of novel micro electronic/micro optical readout systems for islet cells. This regenerative medicine approach will follow our clinical trial programs and be transferred into the clinic to combat diabetes.

2 500 000 €

Start date: 2020-01-01, End date: 2024-12-31

The complex interplay between Coulomb repulsion and Fermi statistics in two dimensional systems is responsible for some of the most dramatic phenomena encountered in solid state physics (High critical temperature superfluidity, Fractional Quantum Hall Effect,..). However, despite decades of efforts, many questions regarding these systems are still unsolved. In FERLODIM, we plan to take advantage of recent progress in ultracold gases, to simulate several fundamental Hamiltonians describing these many-body systems in 1 and 2 dimensions. We will realize two ultra-cold atom machines allowing for a full characterization of the many-body wave function of an ensemble of interacting fermions in periodic potentials, called optical lattices. Our experiments will rely on a high resolution imaging system allowing both for single atom detection and the possibility of tailoring optical potentials of arbitrary shape and geometry. This unique design will allow us to address a variety of physical situations, depending on the geometry of the light induced potentials. One-dimensional problems will be addressed, from spin chains to Luttinger liquids. In pure two dimensional configurations, we will investigate the link between the repulsive Hubbard model, superfluidity and the Mott insulator transition, as well as frustration effects in periodic potentials. Finally we will explore the physics of interacting fermions under rotation in the lowest Landau level, and the connection with fractional Quantum Hall systems.

2 050 000 €

Start date: 2009-01-01, End date: 2013-12-31

Since a few decades, human patients who suffer from severe illnesses or multiple trauma, conditions that were previously lethal, are being treated in intensive care units (ICUs). Modern intensive care medicine bridges patients from life-threatening conditions to recovery with use of mechanical devices, vasoactive drugs and powerful anti-microbial agents. By postponing death, a new unnatural condition, intensive-care-dependent prolonged (>1 week) critical illness, has been created. About 25% of ICU patients today require prolonged intensive care, sometimes for weeks or months, and these patients are at high risk of death while consuming 75% of resources. Although the primary insult was adequately dealt with, many long-stay patients typically suffer from hypercatabolism, ICU-acquired brain dysfunction and polyneuropathy/myopathy leading to severe muscle weakness, further increasing the risk of late death. As hypercatabolism was considered the culprit, several anabolic interventions were tested, but these showed harm instead of benefit. We previously showed that fasting early during illness is superior to forceful feeding, pointing to certain benefits of catabolic responses. In healthy humans, fasting activates catabolism to provide substrates essential to protect and maintain brain and muscle function. This proposal aims to investigate whether evolutionary conserved catabolic fasting pathways, specifically lipolysis and ketogenesis, can be exploited in the search for prevention of brain dysfunction and muscle weakness in long-stay ICU patients, with the goal to identify a new metabolic intervention to enhance their recovery. The project builds further on our experience with bi-directional translational research - using human material whenever possible and a validated mouse model of sepsis-induced critical illness for objectives that cannot be addressed in patients - and aims to close the loop, from a novel concept to a large randomized controlled trial in patients.

2 500 000 €

Start date: 2018-10-01, End date: 2023-09-30

Recent experimental results in flavor physics exhibit deviations from the Standard Model predictions that are growing with time, both as far as statistical significance and as far as internal consistency. Understanding the origin of this phenomenon, the so-called “flavor anomalies”, is of paramount importance for a deeper understanding of fundamental interactions. As recently shown by the PI and collaborators, this phenomenon is likely to be intimately related to the long-standing “flavor problem”, or the origin of the hierarchical pattern of quark and lepton mass matrices observed in Nature. The goal of this project is to shed light on both these issues, providing a solution to old and recent puzzles in flavor physics. We propose to address these questions via an original bottom-up approach, based on Effective Field Theory methods and simplified models, combined with new top-down ideas about the ultraviolet completion of the Standard Model. On the phenomenological side, the proposed bottom-up approach will allow us to exploit with the highest accuracy all the available and expected experimental data. It will allow us to take into account both low- and high-energy observables, as well as both quark and lepton sectors. These results will constitute the basis for the theoretical investigation of a new class of Standard Model extensions not considered so far. The latter are based on new ideas, such as flavor non-universal gauge interactions, that imply a change of paradigm in theoretical high-energy physics: the origin of the flavor hierarchies plays a central role in revealing the ultraviolet completion of the Standard Model. Combining a bottom-up approach to flavor-physics data with top-down ideas on the origin of the flavor hierarchies, this project has the potential to lead to a major advancement in fundamental physics.

2 318 750 €

Start date: 2019-09-01, End date: 2024-08-31

The Mexican influenza A virus (H1N1) reminds us that the threat of an influenza pandemic is real. The 1918 Spanish flu virus, also started as a low pathogenic virus that mutated into a highly pathogenic virus within months, causing more than 50 million deaths. The Mexican influenza A virus (H1N1) may follow the same path. FLUPLAN will expand our knowledge of the packaging signals that govern reassortment events between influenza A viruses in general and between the Mexican influenza A virus (H1N1) and circulating human, porcine and highly pathogenic avian influenza A viruses in particular. FLUPLAN will thus lead to fundamental insights in the mechanisms that govern reassortment phenomena, providing a risk assessment concerning the pandemic potential of circulating avian and mammalian influenza A viruses. This will provide us with a panel of possible reassortant viruses of potentially pandemic nature. The MVA vaccine vector system that efficiently induced broad protective immunity against HPAI-H5N1 viruses in macaques, will be used for the preparation of a repository of MVA-H based pandemic vaccine seed viruses.The selection will be based on the reassortant viruses mentioned above, and on a repository of avian influenza viruses of the 16HA subtypes including the Mexican influenza A virus (H1N1) of avian/swine origin. The added value of including a relevant MVA-NP in the immunization schedule to obtain broader and longer protection will be determined in a macaque infection model. Collectively these studies will provide us with a highly versatile system that anticipates on future pandemic events by having seed viruses for vaccine development ready to go on the shelf, for the rapid production of broadly protective pandemic vaccines, which will save time and thus lives.

2 187 758 €

Start date: 2010-06-01, End date: 2015-05-31

Humans have evolved intimate symbiotic relationships with a consortium of gut microbes (including fungi) and individual variations in the microbiome influence host health and disease. The fact that fungi are capable of colonizing almost every niche within the human body suggests that they must possess particular immune adaptation mechanisms, the breakdown of which may result in fatal fungal infections and severe fungal diseases. Traditional reductionist approaches of the past have not been sufficient to address these new challenges in the pathogenesis of fungal diseases. Here, I propose an integrated, systems biology approach to understand the role of L-tryptophan (trp) metabolic pathways in multilevel host−fungus interactions. Present in mammals as well as in fungi, pathways of trp metabolic pathways are exploited by the host and the fungal biota for survival and immune adaptation. A variety of indole derivatives, generated through conversion from dietary trp by symbiotic bacteria, activate the aryl hydrocarbon receptor/IL-22 pathway that provides antifungal resistance and tissue repair. Harmful inflammatory responses to fungi are instead tamed by kynurenines generated via the enzyme indoleamine 2,3–dioxygenase (IDO) of the trp pathway. Through high-throughput wet-lab ‘omics’ techniques combined with computational techniques, the project aims at defining the molecular basis of mammalian and fungal IDO activity and a metabolic network linking the metabolic phenotype (metabotype) to immune adaptations and its possible breakdown in experimental and human fungal infections. The project will provide ideal post-graduate training focussed on the development of metabolomics for diagnosis of fungal diseases and optimization of current antifungal therapy and diet that are of relevance to public health care solutions.

2 299 200 €

Start date: 2012-04-01, End date: 2018-03-31

A foremost health problem stems from the burden of degenerative diseases, including heart failure, neurodegeneration, retinal degeneration and diabetes, essentially linked to the aging of the human population and the incapacity of post-mitotic tissues to undergo efficient repair. This is an ambitious, highly innovative project aimed at developing an in vivo selection procedure, based on gene transfer of two genetic libraries cloned into Adeno-Associated Virus (AAV)-based vectors, for the identification of novel secreted factors or microRNAs providing benefit against various degenerative diseases. Two arrayed libraries will be generated, one coding for ~1,300 cDNAs from the mouse secretome, the other for all known microRNAs (~800 genes). Pools of vectors from each library will be obtained with serotypes suitable for in vivo transduction of different organs. The vectors will be injected in a series of mouse models of degenerative disorders involving damage to cardiomyocytes,, neurodegeneration, retinal degeneration and loss of beta-cells in the pancreas. The degenerative conditions will drive the selection for secreted factors or miRNA putatively preventing cell apoptosis, enhancing residual cell function or, in the best possible scenario, promoting tissue regeneration. This in vivo selection approach, which is supported by very encouraging preliminary results, has never been attempted before and is rendered possible by the property of AAV vectors to be produced at high titers, infect tissues at high multiplicity, persist in the transduced cells for prolonged period of times and efficiently express their transgenes in vivo. In addition to its final goal of identifying novel biotherapeutics, the project entails the successful achievement of several intermediate objectives and is expected to extend both technology and knowledge beyond the state-of-the art.

1 824 000 €

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

Background: Poor angiogenesis and collateral vessel formation lead to coronary heart disease, claudication, infarctions and amputations while malignant glioma is one of the most aggressive proangiogenic tumors leading to death in a few months. For these diseases either stimulation or blocking, respectively, of angiogenesis may provide novel treatment options. Advancing State-of-the-Art: Our hypothesis is that in ischemia it will be possible to support natural growth of blood vessels with Therapeutic angiogenesis and lymphangiogenesis by using local gene transfer of the new members of vascular endothelial growth factor (VEGF) family and their receptors. New co-receptors, designer mutants and PCR suffling products of VEGFs will be used. New vector technology will be used to achieve long-lasting effects of VEGFs. We aim to develop novel site-specifically integrating, targeted, regulated vectors to precisely express the new VEGFs, their soluble decoy receptors and single-chain therapeutic antibodies (scFv) for pro- and anti-angiogenic purposes. As novel approaches, we have developed metabolically biotinylated lenti- and adenoviruses suitable for targeting and Epigenetherapy where siRNA/miRNAs and short nuclear RNAs regulate endogenous gene expression at the VEGF promoter level via modification of histone code. scFv library for endothelial cells and lentivirus-siRNA library directed to all human and mouse kinases will be screened to identify new mediators of angiogenesis in order to develop next generation pro- and antiangiogenic therapies. Based on our strong track record in Clinical applications, the best new pro- and antiangiogenic approaches will be taken to phase I clinical studies in myocardial ischemia and malignant glioma. Significance: This work should lead to significant advances and new therapies for severe ischemia and malignant glioma. Epigenetherapy and new site-specifically integrating, regulated vectors should be widely applicable in medicine.

2 200 000 €

Start date: 2010-06-01, End date: 2015-05-31

The observation that matter dominates over anti-matter in the Universe is one of the most critical open questions in physics. A natural explanation of this asymmetry postulates neutrinos as their own anti-particles, usually referred to as Majorana particles. The only practical way to establish the Majorana character of neutrinos is the experimental search for neutrinoless double-beta decay (NDBD). This decay violates lepton-number conservation and would establish new physics beyond the Standard Model of particle physics. The Germanium eXploration (GemX) project will focus on cutting-edge research towards a ton-scale NDBD decay experiment based on germanium detectors enriched in 76Ge, and thereby sustain a European leadership also in the next-generation worldwide experimental competition. With its superior energy resolution and lowest background, a one-ton 76Ge experiment has potentially the highest sensitivity for discovering NDBD decay amongst the next-generation experiments. A discovery would be groundbreaking in the fields of particle physics, astrophysics and cosmology. The goal of GemX is to develop and evaluate novel HPGe detectors enriched in 76Ge, test their performance in LEGEND-200 and inform the design decisions of the future flagship 1000-kg experiment LEGEND-1000, which the PI leads as elected European spokesperson. GemX will (1) investigate new Ge detector designs with increased mass and improved pulse shape discrimination to enhance background reduction; (2) develop a crystal growth process from germanium material enriched in 76Ge for large high-purity Ge crystals with suitable net-impurity concentrations in Europe; (3) develop the production of large Ge detectors enriched in 76Ge with minimal activation by cosmic radiation and with full control of surface contaminations from alpha contaminations; (4) deploy, test and operate the novel detectors in the TUM underground liquid argon test stand and in LEGEND-200 at the LNGS, Italy.

3 355 460 €

Start date: 2018-10-01, End date: 2023-09-30

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

There is an urgent need to develop vaccines for the induction of CD8+ T-cell immunity to treat cancer and infectious diseases. Dendritic Cells (DC) have shown potential to induce antigen specific CD8+ T-cell responses with the help of CD4+ T cells, yet the efficacy by which the induction is achieved still has its limitations. The main challenge is: (a) to increase targeting efficacy to the complete repertoire of DC subsets; (b) to trigger T-cell responses by the DC that is powerful enough to eliminate a tumour (c) to implement novel human read-out systems, that mimic he human body response to evaluate vaccine efficacy. The aim of this research project is to develop new glycan-based nanomedicines targeted to DC to induce powerful T-cell responses. Within the scope of this research project these new glycan-based nanomedicines will be tested to (i) trigger a strong T-cell response to pathogens, (ii) induce a powerful and adequate T-cell response to self antigen in a tumour induced immune suppressive environment and (iii) render fundamental insights to establish a vaccine platform relevant for the treatment of cancer and infectious diseases. GlycoTreat employs an unconventional, novel glycan biotechnology approach to target a multitude of DC subsets in the human skin to validate the groundbreaking hypothesis that the local administration and molecular size and glycan valency of the targeting compound affect the efficiency of the T-cell stimulating vaccine. This research project joins the chemical design of glyco-nanomedical vaccines with immunological outcomes in our advanced in-vitro, in-situ human skin and in-vivo mouse DC model systems. While crossing the established disciplinary boundaries between chemistry, biology and medicine, Prof. van Kooyk will generate a new field of expertise in vaccine development applied in the field of cancer treatment.

2 498 736 €

Start date: 2014-02-01, End date: 2019-07-31

States of matter in which the interactions between the microscopic constituents are both strong and quantum mechanical lie at the frontier of our understanding of nature. Such states appear in a wide variety of settings including high temperature superconductors, gases of cold atoms and the quark- gluon plasma created in the high-energy collisions of nuclei. Understanding the properties of such strongly coupled quantum matter poses huge conceptual challenges because standard perturbative techniques break down at strong coupling. In a remarkable development, the mathematical framework of string theory has provided a fundamentally new way to study strongly coupled quantum field theories using a dual, weakly coupled gravitational description. Furthermore, this duality states that the phase structure of the quantum field at finite temperature is precisely described by black hole geometries. The principal thrust of the proposal is to develop our understanding of these gravitational techniques in order to make contact with real world systems, particularly in condensed matter physics. The proposal focuses on four main topics in this emerging, rapidly developing and interdisciplinary field. The first is to extend our understanding of known strongly coupled quantum critical ground states using gravitational solutions and also to search for new ones. The second is to map out the phase structure of strongly coupled quantum field theories at finite temperature by constructing a wide variety of new black hole solutions. Superconducting and spatially modulated phases will be a particular focus. Thirdly, fermion spectral functions will be calculated to extend our understanding of non-Fermi liquids, which are known to arise in many materials. The fourth topic is to explore the behaviour of strongly coupled systems in situations far from thermal equilibrium by studying the dynamical process of black hole formation.

1 963 542 €

Start date: 2014-03-01, End date: 2019-02-28

Targeting therapeutic genes selectively into the central nervous system (CNS) is a crucial precondition for translation of gene therapy strategies into human trials. The current multidisciplinary proposal integrates expertise identified as essential in the effective acceleration of research to overcome bottlenecks in the field including: 1) Inefficiency of therapy delivery to the CNS because of factors like the blood-brain barrier (BBB); 2) Poor understanding of disease mechanisms at the molecular and cellular levels. These problems must be overcome to develop fully effective treatments for neurological disorders. Currently the adeno-associated (AAV)-based system is one of the most refined and effective gene delivery systems for neuronal cells. In contrast to all other systems, it has been possible to engineer AAV9 to deliver genes through the BBB to the CNS by intravascular (IV) administration. However, following IV delivery, these vectors also target liver and other tissues, with significant potential for untoward effects. This has prompted us to adopt two major strategies: i) targeting of AAV9 vectors at the level of transcription by insertion of hybrid motor neuron specific promoters into the vector genome; ii) development of a CNS-targeted delivery approach based on state-of-the art nanoparticle-mediated encapsulation of AAV9 vectors. We anticipate that engineering strategies with the ability to restrict transgene expression to CNS tissue will significantly overcome various existing hurdles in CNS gene therapy development. Our objectives are to: 1) explore mechanisms leading to penetration of scAAV9 vectors through BBB since the exact mechanism of AAV9 diffusion through BBB is unknown; 2) design novel targeted strategies with enhanced tropism to CNS; 3) use CNS targeted vectors to investigate mechanisms of motor neuron death linked to mutations in RNA processing genes; 4) utilise CNS-targeted systems to test therapeutic strategies for motor neuron diseases.

2 499 959 €

Start date: 2012-03-01, End date: 2017-10-31