ERC FUNDED PROJECTS

At the end of their life, stars spread their inner material into the diffuse interstellar medium. This diffuse medium gets locally denser and form dark clouds (also called dense or molecular clouds) whose innermost part is shielded from the external UV field by the dust, allowing for molecules to grow and get more complex. Gravitational collapse occurs inside these dense clouds, forming protostars and their surrounding disks, and eventually planetary systems like (or unlike) our solar system. The formation and evolution of molecules, minerals, ices and organics from the diffuse medium to planetary bodies, their alteration or preservation throughout this cosmic chemical history set the initial conditions for building planets, atmospheres and possibly the first bricks of life. The current view of interstellar chemistry is based on fragmental works on key steps of the sequence that are observed. The objective of this proposal is to follow the fractionation of the elements between the gas-phase and the interstellar grains, from the most diffuse medium to protoplanetary disks, in order to constrain the chemical composition of the material in which planets are formed. The potential outcome of this project is to get a consistent and more accurate description of the chemical evolution of interstellar matter. To achieve this objective, I will improve our chemical model by adding new processes on grain surfaces relevant under the diffuse medium conditions. This upgraded gas-grain model will be coupled to 3D dynamical models of the formation of dense clouds from diffuse medium and of protoplanetary disks from dense clouds. The computed chemical composition will also be used with 3D radiative transfer codes to study the chemical tracers of the physics of protoplanetary disk formation. The robustness of the model predictions will be studied with sensitivity analyses. Finally, model results will be confronted to observations to address some of the current challenges.

1 166 231 €

Start date: 2013-09-01, End date: 2018-08-31

"High-energy observations of our Galaxy offer a good, albeit not complete, picture of the X-ray source populations, in particular the accreting binary sources. Recent ability to study accreting binaries in nearby galaxies has shown that we would be short-sighted if we restricted ourselves to our Galaxy or to a few nearby ones. I propose an ambitious project that involves a comprehensive study of all the galaxies within 10 Mpc for which we can study in detail their X-ray sources and stellar populations. The study will combine data from a unique suite of observatories (Chandra, XMM-Newton, HST, Spitzer) with state-of-the-art theoretical modelling of binary systems. I propose a novel approach that links the accreting binary populations to their parent stellar populations and surpasses any current studies of X-ray binary populations, both in scale and in scope, by: (a) combining methods and results from several different areas of astrophysics (compact objects, binary systems, stellar populations, galaxy evolution); (b) using data from almost the whole electromagnetic spectrum (infrared to X-ray bands); (c) identifying and studying the different sub-populations of accreting binaries; and (d) performing direct comparison between observations and theoretical predictions, over a broad parameter space. The project: (a) will answer the long-standing question of the formation efficiency of accreting binaries in different environments; and (b) will constrain their evolutionary paths. As by-products the project will provide eagerly awaited input to the fields of gravitational-wave sources, γ-ray bursts, and X-ray emitting galaxies at cosmological distances and it will produce a heritage multi-wavelength dataset and library of models for future studies of galaxies and accreting binaries."

1 242 000 €

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

Obesity and diabetes have reached pandemic proportions and new therapeutic strategies are critically needed. Brown adipose tissue (BAT), a major source of heat production, possesses significant energy-dissipating capacity and therefore represents a promising target to use in combating these diseases. Recently, I discovered a novel link between circadian rhythm and thermogenic stress in the control of the conserved, calorie-burning functions of BAT. Circadian and thermogenic signaling to BAT incorporates blood-borne hormonal and nutrient cues with direct neuronal input. Yet how these responses coordinately shape BAT energy-expending potential through the regulation of cell surface receptors, metabolic enzymes, and transcriptional effectors is still not understood. My primary goal is to investigate this previously unappreciated network of crosstalk that allows mammals to effectively orchestrate daily rhythms in BAT metabolism, while maintaining their ability to adapt to abrupt changes in energy demand. My group will address this question using gain and loss-of-function in vitro and in vivo studies, newly-generated mouse models, customized physiological phenotyping, and cutting-edge advances in next generation RNA sequencing and mass spectrometry. Preliminary, small-scale validations of our methodologies have already yielded a number of novel candidates that may drive key facets of BAT metabolism. Additionally, we will extend our circadian and thermogenic studies into humans to evaluate the translational potential. Our results will advance the fundamental understanding of how daily oscillations in bioenergetic networks establish a framework for the anticipation of and adaptation to environmental challenges. Importantly, we expect that these mechanistic insights will reveal pharmacological targets through which we can unlock evolutionary constraints and harness the energy-expending potential of BAT for the prevention and treatment of obesity and diabetes.

1 497 008 €

Start date: 2015-05-01, End date: 2020-04-30

The gas and dust in the interstellar medium (ISM) drive the chemical evolution of galaxies, the formation of stars and planets, and the synthesis of complex prebiotic molecules. The prime birth places for this interstellar material are the winds of evolved (super)giant stars. These winds are unique chemical laboratories, in which a large variety of gas and dust species radially expand away from the star. Recent progress on the observations of these winds has been impressive thanks to Herschel and ALMA. The next challenge is to unravel the wealth of chemical information contained in these data. This is an ambitious task since (1) a plethora of physical and chemical processes interact in a complex way, (2) laboratory data to interpret these interactions are lacking, and (3) theoretical tools to analyse the data do not meet current needs. To boost the knowledge of the physics and chemistry characterizing these winds, I propose a world-leading multi-disciplinary project combining (1) high-quality data, (2) novel theoretical wind models, and (3) targeted laboratory experiments. The aim is to pinpoint the dominant chemical pathways, unravel the transition from gas-phase to dust species, elucidate the role of clumps on the overall wind structure, and study the reciprocal effect between various dynamical and chemical phenomena. Now is the right time for this ambitious project thanks to the availability of (1) high-quality multi-wavelength data, including ALMA and Herschel data of the PI, (2) supercomputers enabling a homogeneous analysis of the data using sophisticated theoretical wind models, and (3) novel laboratory equipment to measure the gas-phase reaction rates of key species. This project will have far-reaching impact on (1) the field of evolved stars, (2) the understanding of the chemical lifecycle of the ISM, (3) chemical studies of dynamically more complex systems, such as exoplanets, protostars, supernovae etc., and (4) it will guide new instrument development.

2 605 897 €

Start date: 2016-01-01, End date: 2020-12-31

"Understanding the dawn of the first galaxies and how their light permeated the early Universe is at the very frontier of modern astrophysical cosmology. Generous resources, including ambitions observational programs, are being devoted to studying these epochs of Cosmic Dawn (CD) and Reionization (EoR). In order to interpret these observations, we propose to build on our widely-used, semi-numeric simulation tool, 21cmFAST, and apply it to observations. Using sub-grid, semi-analytic models, we will incorporate additional physical processes governing the evolution of sources and sinks of ionizing photons. The resulting state-of-the-art simulations will be well poised to interpret topical observations of quasar spectra and the cosmic 21cm signal. They would be both physically-motivated and fast, allowing us to rapidly explore astrophysical parameter space. We will statistically quantify the resulting degeneracies and constraints, providing a robust answer to the question, ""What can we learn from EoR/CD observations?"" As an end goal, these investigations will help us understand when the first generations of galaxies formed, how they drove the EoR, and what are the associated large-scale observational signatures."

1 468 750 €

Start date: 2015-05-01, End date: 2021-01-31

The aim of this proposal is to understand a novel regulatory signaling network controlling insulin secretion, fat accumulation and energy balance centered around selected components of the TGF-² signaling system, including Activins A and B, GDF-3 and their receptors ALK7 and ALK4. Recent results from my laboratory indicate that these molecules are part of paracrine signaling networks that control important functions in pancreatic islets and adipose tissue through feedback inhibition and feed-forward regulation. These discoveries have open up a new research area with important implications for the understanding of metabolic networks and the treatment of human metabolic syndromes, such as diabetes and obesity. To drive progress in this new research area beyond the state-of-the-art it is proposed to: i) Elucidate the molecular mechanisms by which Activins regulate Ca2+ influx and insulin secretion in pancreatic ²-cells; ii) Elucidate the molecular mechanisms underlying the effects of GDF-3 on adipocyte metabolism, turnover and fat accumulation; iii) Investigate the interplay between insulin levels and fat deposition in the development of insulin resistance using mutant mice lacking Activin B and GDF-3; iv) Investigate tissue-specific contributions of ALK7 and ALK4 signaling to metabolic control by generating and characterizing conditional mutant mice; v) Investigate the effects of specific and reversible inactivation of ALK7 and ALK4 on metabolic regulation using a novel chemical-genetic approach based on analog-sensitive alleles. This is research of a high-gain/high-risk nature. It is posed to open unique opportunities for further exploration of complex metabolic networks. The development of drugs capable of enhancing insulin secretion, limiting fat accumulation and ameliorating diet-induced obesity by targeting components of the ALK7 signaling network will find a strong rationale in the results of the proposed work.

2 462 154 €

Start date: 2009-04-01, End date: 2014-03-31

New neurons are continuously generated in certain regions of adult mammalian brain. One of those regions is the dentate gyrus, a subregion of hippocampus, which is essential for memory formation. Although these new neurons in the adult dentate gyrus are thought to have an important role in learning and memory, it is largely unclear how new neurons are involved in information processing and storage underlying memory. Because new neurons constitute a minor portion of intermingled local neuronal population, simple application of conventional techniques such as multi-unit extracellular recording and pharmacological lesion are not suitable for the functional analysis of new neurons. In this proposed research program, I will combine multi-unit recording and behavioral analysis with virus mediated, cell-type-specific genetic manipulation of neuronal activity, to investigate computational roles of new neurons in learning and memory. Specifically, I will determine: 1) specific memory processes that require new neurons, 2) dynamic patterns of activity that new neurons express during memory-related behavior, 3) influence of new neurons on their downstream structure. Further, based on the information obtained by these three lines of studies, we will establish causal relationship between specific memory-related behavior and specific pattern of activity in new neurons. Solving these issues will cooperatively provide important insight into the understanding of computational roles performed by adult neurogenesis. The information on the function of new neurons in normal brain could contribute to future development of efficient therapeutic strategy for a variety of brain disorders.

1 991 743 €

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

Blood and lymphatic vessels have been the subject of intense investigation due to their important role in cancer development and in cardiovascular diseases. The significant advance in the methods used to modify and analyse gene function have allowed us to obtain a much better understanding of the molecular mechanisms involved in the regulation of the biology of blood vessels. However, there are two key aspects that significantly diminish our capacity to understand the function of gene networks and their intersections in vivo. One is the long time that is usually required to generate a given double mutant vertebrate tissue, and the other is the lack of single-cell genetic and phenotypic resolution. We have recently performed an in vivo comparative transcriptome analysis of highly angiogenic endothelial cells experiencing different VEGF and Notch signalling levels. These are two of the most important molecular mechanisms required for the adequate differentiation, proliferation and sprouting of endothelial cells. Using the information generated from this analysis, the overall aim of the proposed project is to characterize the vascular function of some of the previously identified genes and determine how they functionally interact with these two signalling pathways. We propose to use novel inducible genetic tools that will allow us to generate a spatially and temporally regulated fluorescent cell mosaic matrix for quantitative analysis. This will enable us to analyse with unprecedented speed and resolution the function of several different genes simultaneously, during vascular development, homeostasis or associated diseases. Understanding the genetic epistatic interactions that control the differentiation and behaviour of endothelial cells, in different contexts, and with high cellular definition, has the potential to unveil new mechanisms with high biological and therapeutic relevance.

1 481 375 €

Start date: 2015-03-01, End date: 2020-02-29

Angiogenesis research has focused on the sprouting of new capillaries. The mechanisms of vessel maturation are much less well understood. Yet, the maintenance of a mature, quiescent, and organotypically-differentiated layer of endothelial cells (ECs) lining the inside of all blood vessels is vital for human health. The goal of ANGIOMATURE is to identify, validate, and implement novel mechanisms of vascular maturation and organotypic EC differentiation that are active during development, maintenance of vascular stability in adults, and undergo changes in aging. We recently identified previously unrecognized gene expression signatures of vascular maturation in a genome-wide screen of ECs isolated from newborn and adult mice. Epigenetic mechanisms were identified that control the EC transcriptome through gain and loss of DNA methylation as well as EC differentiation and signaling specification. These findings pave the way for groundbreaking novel opportunities to study vascular maturation. By characterizing functionally diverse types of blood vessels, including continuous ECs in lung and brain and sinusoidal ECs in liver and bone marrow, the ANGIOMATURE project will (1) determine up to single cell resolution the transcriptional and epigenetic program(s) of vascular maturation and organotypic differentiation during adolescence, (2) analyze the functional consequences of such program(s) in differentiated ECs and their adaptation to challenge, and (3) study changes of maturation and differentiation program(s) and vascular responses during aging. We will towards this end employ an interdisciplinary matrix of approaches involving omics, systems biology, conditional gene targeting, organoid cell culture, and experimental pathology to create a high-resolution structural and functional organotypic angioarchitectural map. The project will thereby yield transformative mechanistic insights into vital biological processes that are most important for human health and healthy aging.

2 338 918 €

Start date: 2018-08-01, End date: 2023-07-31

Despite improved therapy, cardiovascular diseases remain the most prevalent diseases in the European Union and the incidence is rising due to increased obesity and ageing. The fine-tuned regulation of vascular functions is essential not only for preventing atherosclerotic diseases, but also after tissue injury, where the coordinated growth and maturation of new blood vessels provides oxygen and nutrient supply. On the other hand, excessive vessel growth or the generation of immature, leaky vessels contributes to pathological angiogenesis. Thus, the regulation of the complex processes governing vessel growth and maturation has broad impacts for several diseases ranging from tumor angiogenesis, diabetic retinopathy, to ischemic cardiovascular diseases. MicroRNAs (miRs) are small noncoding RNAs, which play a crucial role in embryonic development and tissue homeostasis. However, only limited information is available regarding the role of miRs in the vasculature. MiRs regulate gene expression by binding to the target mRNA leading either to degradation or to translational repression. Because miRs control patterns of target genes, miRs represent an attractive and promising therapeutic target to interfere with complex processes such as neovascularization and repair of ischemic tissues. Therefore, the present application aims to identify miRs in the vasculature, which regulate vessel growth and vessel remodelling and may, thus, serve as therapeutic targets in ischemic diseases. Since ageing critically impairs endothelial function, neovascularization and vascular repair, we will specifically identify miRs, which are dysregulated during ageing in endothelial cells and pro-angiogenic progenitor cells, in order to develop novel strategies to rescue age-induced impairment of neovascularization. Beyond the specific scope of the present application, the principle findings may have impact for other diseases, where deregulated vessel growth causes or accelerates disease states.

2 375 394 €

Start date: 2009-03-01, End date: 2014-02-28

Dysregulation of capillary permeability is a severe problem in critically ill patients, but the mechanisms involved are poorly understood. Further, there are no targeted therapies to stabilize leaky vessels in various common, potentially fatal diseases, such as systemic inflammation and sepsis, which affect millions of people annually. Although a multitude of signals that stimulate opening of endothelial cell-cell junctions leading to permeability have been characterized using cellular and in vivo models, approaches to reverse the harmful process of capillary leakage in disease conditions are yet to be identified. I propose to explore a novel autocrine endothelial permeability regulatory system as a potentially universal mechanism that antagonizes vascular stabilizing ques and sustains vascular leakage in inflammation. My group has identified inflammation-induced mechanisms that switch vascular stabilizing factors into molecules that destabilize vascular barriers, and identified tools to prevent the barrier disruption. Building on these discoveries, my group will use mouse genetics, structural biology and innovative, systematic antibody development coupled with gene editing and gene silencing technology, in order to elucidate mechanisms of vascular barrier breakdown and repair in systemic inflammation. The expected outcomes include insights into endothelial cell signaling and permeability regulation, and preclinical proof-of-concept antibodies to control endothelial activation and vascular leakage in systemic inflammation and sepsis models. Ultimately, the new knowledge and preclinical tools developed in this project may facilitate future development of targeted approaches against vascular leakage.

1 999 770 €

Start date: 2018-05-01, End date: 2023-04-30

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

1 372 525 €

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

"The deregulation of transcription is an important driver of leukemia development. Typically, transcription in leukemia cells is altered by the ectopic expression of transcription factors, by modulation of signaling pathways or by epigenetic changes. In addition to these factors that affect the production of RNAs, also changes in the processing of RNA (its splicing, transport and decay) may contribute to determine steady-state RNA levels in leukemia cells. Indeed, acquired mutations in various genes encoding RNA splice factors have recently been identified in myeloid leukemias and in chronic lymphocytic leukemia. In our study of T-cell acute lymphoblastic leukemia (T-ALL), we have identified mutations in RNA decay factors, including mutations in CNOT3, a protein believed to function in deadenylation of mRNA. It remains, however, unclear how mutations in RNA processing can contribute to the development of leukemia. In this project, we aim to further characterize the mechanisms of RNA regulation in T-cell acute lymphoblastic leukemia (T-ALL) to obtain insight in the interplay between RNA generation and RNA decay and its role in leukemia development. We will study RNA decay in human T-ALL cells and mouse models of T-ALL, with the aim to identify the molecular consequences that contribute to leukemia development. We will use new technologies such as RNA-sequencing in combination with bromouridine labeling of RNA to measure RNA transcription and decay rates in a transcriptome wide manner allowing unbiased discoveries. These studies will be complemented with screens in Drosophila melanogaster using an established eye cancer model, previously also successfully used for the studies of T-ALL oncogenes. This study will contribute to our understanding of the pathogenesis of T-ALL and may identify new targets for therapy of this leukemia. In addition, our study will provide a better understanding of how RNA processing is implicated in cancer development in general."

1 998 300 €

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

Massive stars dominate their surroundings during their short lifetimes, while their explosive deaths impact the chemical evolution and spatial cohesion of their hosts. After birth, their evolution is largely dictated by their ability to remove layers of hydrogen from their envelopes. Multiple lines of evidence are pointing to violent, episodic mass-loss events being responsible for removing a large part of the massive stellar envelope, especially in low-metallicity galaxies. Episodic mass loss, however, is not understood theoretically, neither accounted for in state-of-the-art models of stellar evolution, which has far-reaching consequences for many areas of astronomy. We aim to determine whether episodic mass loss is a dominant process in the evolution of the most massive stars by conducting the first extensive, multi-wavelength survey of evolved massive stars in the nearby Universe. The project hinges on the fact that mass-losing stars form dust and are bright in the mid-infrared. We plan to (i) derive physical parameters of a large sample of dusty, evolved targets and estimate the amount of ejected mass, (ii) constrain evolutionary models, (iii) quantify the duration and frequency of episodic mass loss as a function of metallicity. The approach involves applying machine-learning algorithms to existing multi-band and time-series photometry of luminous sources in ~25 nearby galaxies. Dusty, luminous evolved massive stars will thus be automatically classified and follow-up spectroscopy will be obtained for selected targets. Atmospheric and SED modeling will yield parameters and estimates of time-dependent mass loss for ~1000 luminous stars. The emerging trend for the ubiquity of episodic mass loss, if confirmed, will be key to understanding the explosive early Universe and will have profound consequences for low-metallicity stars, reionization, and the chemical evolution of galaxies.

1 128 750 €

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

The Milky Way is a complex system, with dynamical and chemical substructures, where several competing processes such as mergers, internal secular evolution, gas accretion and gas flows take place. To study in detail how such a giant spiral galaxy was formed and evolved, we need to reconstruct the sequence of its main formation events with high (~10%) temporal resolution. Asterochronometry will determine accurate, precise ages for tens of thousands of stars in the Galaxy. We will take an approach distinguished by a number of key aspects including, developing novel star-dating methods that fully utilise the potential of individual pulsation modes, coupled with a careful appraisal of systematic uncertainties on age deriving from our limited understanding of stellar physics. We will then capitalise on opportunities provided by the timely availability of astrometric, spectroscopic, and asteroseismic data to build and data-mine chrono-chemo-dynamical maps of regions of the Milky Way probed by the space missions CoRoT, Kepler, K2, and TESS. We will quantify, by comparison with predictions of chemodynamical models, the relative importance of various processes which play a role in shaping the Galaxy, for example mergers and dynamical processes. We will use chrono-chemical tagging to look for evidence of aggregates, and precise and accurate ages to reconstruct the early star formation history of the Milky Way’s main constituents. The Asterochronometry project will also provide stringent observational tests of stellar structure and answer some of the long-standing open questions in stellar modelling (e.g. efficiency of transport processes, mass loss on the giant branch, the occurrence of products of coalescence / mass exchange). These tests will improve our ability to determine stellar ages and chemical yields, with wide impact e.g. on the characterisation and ensemble studies of exoplanets, on evolutionary population synthesis, integrated colours and thus ages of galaxies.

1 958 863 €

Start date: 2018-04-01, End date: 2023-03-31

ASTROFLOW aims to make ground-breaking progress in our physical understanding of exoplanetary mass loss, by quantifying the influence of stellar outflows on atmospheric escape of close-in exoplanets. Escape plays a key role in planetary evolution, population, and potential to develop life. Stellar irradiation and outflows affect planetary mass loss: irradiation heats planetary atmospheres, which inflate and more likely escape; outflows cause pressure confinement around otherwise freely escaping atmospheres. This external pressure can increase, reduce or even suppress escape rates; its effects on exoplanetary mass loss remain largely unexplored due to the complexity of such interactions. I will fill this knowledge gap by developing a novel modelling framework of atmospheric escape that will, for the first time, consider the effects of realistic stellar outflows on exoplanetary mass loss. My expertise in stellar wind theory and 3D magnetohydrodynamic simulations is crucial for producing the next-generation models of planetary escape. My framework will consist of state-of-the-art, time-dependent, 3D simulations of stellar outflows (Method 1), which will be coupled to novel 3D simulations of atmospheric escape (Method 2). My models will account for the major underlying physical processes of mass loss. With this, I will determine the response of planetary mass loss to realistic stellar particle, magnetic and radiation environments and will characterise the physical conditions of the escaping material. I will compute how its extinction varies during transit and compare synthetic line profiles to atmospheric escape observations from, eg, Hubble and our NASA cubesat CUTE. Strong synergy with upcoming observations (JWST, TESS, SPIRou, CARMENES) also exists. Determining the lifetime of planetary atmospheres is essential to understanding populations of exoplanets. ASTROFLOW’s work will be the foundation for future research of how exoplanets evolve under mass-loss processes.

1 999 956 €

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

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

2 500 000 €

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

Cosmic Rays (ionized atomic nuclei) are the only matter from beyond our solar system or even from extragalactic space, that we can directly investigate. Up to energies of 10^17 eV they most likely originate in our Galaxy. The highest-energy cosmic rays (>10^18 eV) cannot be magnetically bound any more to the Galaxy and are most likely of extragalactic origin. The pure existence of these particles raises the question about their origin – how and where are they accelerated? How do they propagate through the universe and interact? How can we directly probe extragalactic matter and how can we locate its origin? A key to understand the origin of cosmic rays is to measure the particle species (atomic mass). A precise mass measurement will allow discriminating astrophysical models and will clarify the reason for the observed suppression of the cosmic-ray flux at the highest energies, namely the maximum energy of the accelerators or the energy losses during propagation. I address these questions by employing a new technique to precisely measure the cosmic-ray mass composition, which my group pioneered, the radio detection of air showers (induced by high-energy cosmic rays in the atmosphere) on very large scales, detecting horizontal air showers with zenith angles from 60° to 90°. The new set-up will be the world-largest radio array, operated together with the well-established Auger surface and fluorescence detectors, forming a unique set-up to measure the properties of cosmic rays with unprecedented precision for energies above 10^17.5 eV. The radio technique is a cost-effective and robust method to measure the cosmic-ray energy and mass, complementary to established techniques. The energy scale of the radio measurements is established from first principles. The proposed detectors will also enhance the detection capabilities for high-energy neutrinos and the search for new physics through precision measurements of the electromagnetic and muonic shower components.

3 499 249 €

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

This project focuses on Sun-like stars, which possess convective envelopes and universally exhibit magnetic activity (in the mass range 0.1 to 1.3 MSun). The rotation of these stars influences their internal structure, energy and chemical transport, and magnetic field generation, as well as their external magnetic activity and environmental interactions. Due to the huge range of timescales, spatial scales, and physics involved, understanding how each of these processes relate to each other and to the long-term evolution remains an enormous challenge in astrophysics. To face this challenge, the AWESoMeStars project will develop a comprehensive, physical picture of the evolution of stellar rotation, magnetic activity, mass loss, and accretion. In doing so, we will (1) Discover how stars lose the vast majority of their angular momentum, which happens in the accretion phase (2) Explain the observed rotation-activity relationship and saturation in terms of the evolution of magnetic properties & coronal physics (3) Characterize coronal heating and mass loss across the full range of mass & age (4) Explain the Skumanich (1972) relationship and distributions of spin rates observed in young clusters & old field stars (5) Develop physics-based gyrochronology as a tool for using rotation rates to constrain stellar ages. We will accomplish these goals using a fundamentally new and multi-faceted approach, which combines the power of multi-dimensional MHD simulations with long-timescale rotational-evolution models. Specifically, we will develop a next generation of MHD simulations of both star-disk interactions and stellar winds, to model stars over the full range of mass & age, and to characterize how magnetically active stars impact their environments. Simultaneously, we will create a new class of rotational-evolution models that include external torques derived from our simulations, compute the evolution of spin rates of entire star clusters, & compare with observations.

2 206 205 €

Start date: 2016-07-01, End date: 2021-06-30

Massive black hole binaries (MBHBs) are the most extreme, fascinating yet elusive astrophysical objects in the Universe. Establishing observationally their existence will be a milestone for contemporary astronomy, providing a fundamental missing piece in the puzzle of galaxy formation, piercing through the (hydro)dynamical physical processes shaping dense galactic nuclei from parsec scales down to the event horizon, and probing gravity in extreme conditions. We can both see and listen to MBHBs. Remarkably, besides arguably being among the brightest variable objects shining in the Cosmos, MBHBs are also the loudest gravitational wave (GW) sources in the Universe. As such, we shall take advantage of both the type of messengers – photons and gravitons – they are sending to us, which can now be probed by all-sky time-domain surveys and radio pulsar timing arrays (PTAs) respectively. B MASSIVE leverages on a unique comprehensive approach combining theoretical astrophysics, radio and gravitational-wave astronomy and time-domain surveys, with state of the art data analysis techniques to: i) observationally prove the existence of MBHBs, ii) understand and constrain their astrophysics and dynamics, iii) enable and bring closer in time the direct detection of GWs with PTA. As European PTA (EPTA) executive committee member and former I International PTA (IPTA) chair, I am a driving force in the development of pulsar timing science world-wide, and the project will build on the profound knowledge, broad vision and wide collaboration network that established me as a world leader in the field of MBHB and GW astrophysics. B MASSIVE is extremely timely; a pulsar timing data set of unprecedented quality is being assembled by EPTA/IPTA, and Time-Domain astronomy surveys are at their dawn. In the long term, B MASSIVE will be a fundamental milestone establishing European leadership in the cutting-edge field of MBHB astrophysics in the era of LSST, SKA and LISA.

1 532 750 €

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

The standard model of cosmology, the ɅCDM model, is remarkably successful at explaining a wide range of observations of our Universe. However, it is now being subjected to much more stringent tests than ever before, and recent large-scale structure (LSS) measurements appear to be in tension with its predictions. Is this tension signalling that new physics is required? For example, time-varying dark energy, or perhaps a modified theory of gravity? A contribution from massive neutrinos? Before coming to such bold conclusions we must be certain that all of the important systematic errors in the LSS tests have been accounted for. Presently, the largest source of systematic uncertainty is from the modelling of complicated astrophysical phenomena associated with galaxy formation. In particular, energetic feedback processes associated with star formation and black hole growth can heat and expel gas from collapsed structures and modify the large-scale distribution of matter. Furthermore, the LSS field is presently separated into many sub-fields (each using different models, that usually neglect feedback), preventing a coherent analysis. Cosmological hydrodynamical simulations (are the only method which) can follow all the relevant matter components and self-consistently capture the effects of feedback. I have been leading the development of large-scale simulations with physically-motivated prescriptions for feedback that are unrivalled in their ability to reproduce the observed properties of massive systems. With ERC support, I will build a team to exploit these developments, to produce a suite of simulations designed specifically for LSS cosmology applications with the effects of feedback realistically accounted for and which will allow us to unite the different LSS tests. My team and I will make the first self-consistent comparisons with the full range of LSS cosmology tests, and critically assess the evidence for physics beyond the standard model.

1 725 982 €

Start date: 2018-06-01, End date: 2023-05-31

In the bone-enclosed CNS, increased vascular permeability may cause life-threatening tissue swelling, and/or ischemia and inflammation which compromise tissue repair after trauma or stroke. The brain vasculature possesses several unique features collectively named the blood-brain barrier (BBB) in which passive permeability is almost completely abolished and replaced by a complex of specific transport mechanisms. The BBB is necessary to uphold the specific milieu necessary for neuronal function. Whereas breakdown of the BBB is part of many CNS diseases, including stroke, neuroinflammation, trauma and neurodegenerative disorders, its molecular mechanisms and consequences are unclear and debated. Conversely, the intact BBB is a huge obstacle for drug delivery to the brain. Research on the BBB therefore has two seemingly opposing aims: 1) to seal a damaged BBB and protect the brain from toxic blood products, and 2) to open the BBB “on demand” for drug delivery. A major problem in the BBB field has been the lack of in vivo animal models for molecular and functional studies. So far, available in vitro models are not recapitulating the in vivo BBB. Our recent work on mouse models lacking pericytes, a BBB-associated cell type, demonstrates a specific role for pericytes in the development and regulation of the mammalian BBB. These animal models are the first ones showing a general and significant BBB impairment in adulthood, and as such they provide a unique opportunity to address molecular mechanisms of BBB disruption in disease and in drug transport across the BBB. Importantly, the new models and tools that we have developed allow us to search for relevant druggable mechanisms and molecular targets in the BBB. The long-term goals of this proposal are to develop molecular strategies and tools to open and close the BBB “on demand” for drug delivery to the CNS, and to explore the importance and mechanisms of BBB dysfunction in neurodegenerative diseases and stroke.

2 499 427 €

Start date: 2012-08-01, End date: 2017-07-31

BEACON aims at performing an ambitious multi-disciplinary (optical, radio astronomy and theoretical physics) study to enable a fundamentally improved understanding of gravitation and space-time. For almost a century Einstein's general relativity has been the last word on gravity. However, superstring theory predicts new gravitational phenomena beyond relativity. In this proposal I will attempt to detect these new phenomena, with a sensitivity 20 times better than state-of-the-art attempts. A successful detection would take physics beyond its current understanding of the Universe. These new gravitational phenomena are emission of dipolar gravitational waves and the violation of the strong equivalence principle (SEP). I plan to look for them by timing newly discovered binary pulsars. I will improve upon the best current limits on dipolar gravitational wave emission by a factor of 20 within the time of this proposal. I also plan to develop a test of the Strong Equivalence Principle using a new pulsar/main-sequence star binary. The precision of this test is likely to surpass the current best limits within the time frame of this proposal and then keep improving indefinitely with time. This happens because this is the cleanest gravitational experiment ever carried out. In order to further these goals, I plan to build the ultimate pulsar observing system. By taking advantage of recent technological advances in microwave engineering (particularly sensitive ultra-wide band receivers) digital electronics (fast analogue-to-digital converters and digital spectrometers) and computing, my team and me will be able to greatly improve the sensitivity and precision for pulsar timing experiments and exploit the capabilities of modern radio telescopes to their limits. Pulsars are the beacons that will guide me in these new, uncharted seas.

1 892 376 €

Start date: 2011-09-01, End date: 2016-08-31

Planets orbiting both stars of a binary system -circumbinary planets- are challenging our understanding about how planets assemble, and how their orbits subsequently evolve. Long confined to science-fiction, circumbinary planets were confirmed by the Kepler spacecraft, in one of its most spectacular, and impactful result. Despite Kepler’s insights, a lot remains unknown about these planets. Kepler also suffered from intractable biases that the BEBOP project will solve. BEBOP will revolutionise how we detect and study circumbinary planets. Conducting a Doppler survey, we will vastly improve the efficiency of circumbinary planet detection, and remove Kepler’s biases. BEBOP will construct a clearer picture of the circumbinary planet population, and free us from the inherent vagaries, and important costs of space-funding. Thanks to the Doppler method we will study dynamical effects unique to circumbinary planets, estimate their multiplicity, and compute their true occurrence rate. Circumbinary planets are essential objects. Binaries disturbe planet formation. Any similarity, and any difference between the population of circumbinary planets and planets orbiting single stars, will bring novel information about how planets are produced. In addition, circumbinary planets have unique orbital properties that boost their probability to experience transits. BEBOP’s detections will open the door to atmospheric studies of colder worlds than presently available. Based on already discovered systems, and on two successful proofs-of-concept, the BEBOP team will detect 15 circumbinary gas-giants, three times more than Kepler. BEBOP will provide an unambiguous measure of the efficiency of gas-giant formation in circumbinary environments. In addition the BEBOP project comes with an ambitious programme to combine three detection methods (Doppler, transits, and astrometry) in a holistic approach that will bolster investigations into circumbinary planets, and create a lasting legacy.

1 186 313 €

Start date: 2018-11-01, End date: 2023-10-31

The challenge in cell physiology/pathology today is to translate in vitro findings to the living organism. We have developed a unique approach where signal-transduction can be investigated in vivo non-invasively, longitudinally at single cell resolution, using the anterior chamber of the eye as a natural body window for imaging. We will use this approach to understand how the universally important and highly complex signal Ca2+ is regulated in the pancreatic beta-cell, while localized in the vascularized and innervated islet of Langerhans, and how that affects the insulin secretory machinery in vivo. Engrafted islets in the eye take on identical innervation- and vascularization patterns as those in the pancreas and are proficient in regulating glucose homeostasis in the animal. Since the pancreatic islet constitutes a micro-organ, this imaging approach offers a seminal model system to understand Ca2+ signaling in individual cells at the organ level in real life. We will test the hypothesis that the Ca2+-signal has a key role in pancreatic beta-cell function and survival in vivo and that perturbation in the Ca2+-signal serves as a common denominator for beta-cell pathology associated with impaired glucose homeostasis and diabetes. Of special interest is how innervation impacts on Ca2+-dynamics and the integration of autocrine, paracrine and endocrine signals in fine-tuning the Ca2+-signal with regard to beta-cell function and survival. We aim to define key defects in the machinery regulating Ca2+-dynamics in association with the autoimmune reaction, inflammation and obesity eventually resulting in diabetes. Our imaging platform will be applied to clarify in vivo regulation of Ca2+-dynamics in both healthy and diabetic human beta-cells. To define novel drugable targets for treatment of diabetes, it is crucial to identify similarities and differences in the molecular machinery regulating the in vivo Ca2+-signal in the human and in the rodent beta-cell.

2 499 590 €

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

A fundamental challenge of pancreas biology is to understand and manipulate the determinants of beta cell mass. The homeostatic maintenance of adult beta cell mass relies largely on replication of differentiated beta cells, but the triggers and signaling pathways involved remain poorly understood. Here I propose to investigate the physiological and molecular mechanisms that control beta cell replication. First, novel transgenic mouse tools will be used to isolate live replicating beta cells and to examine the genetic program of beta cell replication in vivo. Information gained will provide insights into the molecular biology of cell division in vivo. Additionally, these experiments will address critical unresolved questions in beta cell biology, for example whether duplication involves transient dedifferentiation. Second, genetic and pharmacologic tools will be used to dissect the signaling pathways controlling the entry of beta cells to the cell division cycle, with emphasis on the roles of glucose and insulin, the key physiological input and output of beta cells. The expected outcome of these studies is a detailed molecular understanding of the homeostatic maintenance of beta cell mass, describing how beta cell function is linked to beta cell number in vivo. This may suggest new targets and concepts for pharmacologic intervention, towards the development of regenerative therapy strategies in diabetes. More generally, the experiments will shed light on one of the greatest mysteries of developmental biology, namely how organs achieve and maintain their correct size. A fundamental challenge of pancreas biology is to understand and manipulate the determinants of beta cell mass. The homeostatic maintenance of adult beta cell mass relies largely on replication of differentiated beta cells, but the triggers and signaling pathways involved remain poorly understood. Here I propose to investigate the physiological and molecular mechanisms that control beta cell replication. First, novel transgenic mouse tools will be used to isolate live replicating beta cells and to examine the genetic program of beta cell replication in vivo. Information gained will provide insights into the molecular biology of cell division in vivo. Additionally, these experiments will address critical unresolved questions in beta cell biology, for example whether duplication involves transient dedifferentiation. Second, genetic and pharmacologic tools will be used to dissect the signaling pathways controlling the entry of beta cells to the cell division cycle, with emphasis on the roles of glucose and insulin, the key physiological input and output of beta cells. The expected outcome of these studies is a detailed molecular understanding of the homeostatic maintenance of beta cell mass, describing how beta cell function is linked to beta cell number in vivo. This may suggest new targets and concepts for pharmacologic intervention, towards the development of regenerative therapy strategies in diabetes. More generally, the experiments will shed light on one of the greatest mysteries of developmental biology, namely how organs achieve and maintain their correct size.

1 445 000 €

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

Massive stars play many key roles in Astrophysics. As COSMIC ENGINES they transformed the pristine Universe left after the Big Bang into our modern Universe. We use massive stars, their explosions and products as COSMIC PROBES to study the conditions in the distant Universe and the extreme physics inaccessible at earth. Models of massive stars are thus widely applied. A central common assumption is that massive stars are non-rotating single objects, in stark contrast with new data. Recent studies show that majority (70% according to our data) will experience severe interaction with a companion (Sana, de Mink et al. Science 2012). I propose to conduct the most ambitious and extensive exploration to date of the effects of binarity and rotation on the lives and fates of massive stars to (I) transform our understanding of the complex physical processes and how they operate in the vast parameter space and (II) explore the cosmological implications after calibrating and verifying the models. To achieve this ambitious objective I will use an innovative computational approach that combines the strength of two highly complementary codes and seek direct confrontation with observations to overcome the computational challenges that inhibited previous work. This timely project will provide the urgent theory framework needed for interpretation and guiding of observing programs with the new facilities (JWST, LSST, aLIGO/VIRGO). Public release of the model grids and code will ensure wide impact of this project. I am in the unique position to successfully lead this project because of my (i) extensive experience modeling the complex physical processes, (ii) leading role in introducing large statistical simulations in the massive star community and (iii) direct involvement in surveys that will be used in this project.

1 926 634 €

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

The detection of primordial gravity waves created during the Big Bang ranks among the greatest potential intellectual achievements in modern science. During the last few decades, the instrumental progress necessary to achieve this has been nothing short of breathtaking, and we today are able to measure the microwave sky with better than one-in-a-million precision. However, from the latest ultra-sensitive experiments such as BICEP2 and Planck, it is clear that instrumental sensitivity alone will not be sufficient to make a robust detection of gravitational waves. Contamination in the form of astrophysical radiation from the Milky Way, for instance thermal dust and synchrotron radiation, obscures the cosmological signal by orders of magnitude. Even more critically, though, are second-order interactions between this radiation and the instrument characterization itself that lead to a highly non-linear and complicated problem. I propose a ground-breaking solution to this problem that allows for joint estimation of cosmological parameters, astrophysical components, and instrument specifications. The engine of this method is called Gibbs sampling, which I have already applied extremely successfully to basic CMB component separation. The new and ciritical step is to apply this method to raw time-ordered observations observed directly by the instrument, as opposed to pre-processed frequency maps. While representing a ~100-fold increase in input data volume, this step is unavoidable in order to break through the current foreground-induced systematics floor. I will apply this method to the best currently available and future data sets (WMAP, Planck, SPIDER and LiteBIRD), and thereby derive the world's tightest constraint on the amplitude of inflationary gravitational waves. Additionally, the resulting ancillary science in the form of robust cosmological parameters and astrophysical component maps will represent the state-of-the-art in observational cosmology in years to come.

1 999 205 €

Start date: 2018-04-01, End date: 2023-03-31

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

1 500 000 €

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

Autophagy is a fundamental cellular catabolic process deputed to the degradation and recycling of a variety of intracellular materials. Autophagy plays a significant role in multiple human physio-pathological processes and is now emerging as a critical regulator of skeletal development and homeostasis. We have discovered that during postnatal development in mice, the growth factor FGF18 induces autophagy in the chondrocyte cells of the growth plate to regulate the secretion of type II collagen, a major component of cartilaginous extracellular matrix. The FGF signaling pathways play crucial roles during skeletal development and maintenance and are deregulated in many skeletal disorders. Hence our findings may offer the unique opportunity to uncover new molecular mechanisms through which FGF pathways regulate skeletal development and maintenance and to identify new targets for the treatment of FGF-related skeletal disorders. In this grant application we propose to study the role played by the different FGF ligands and receptors on autophagy regulation and to investigate the physiological relevance of these findings in the context of skeletal growth, homeostasis and maintenance. We will also investigate the intracellular machinery that links FGF signalling pathways to the regulation of autophagy. In addition, we generated preliminary data showing an impairment of autophagy in chondrocyte models of Achondroplasia (ACH) and Thanathoporic dysplasia, two skeletal disorders caused by mutations in FGFR3. We propose to study the role of autophagy in the pathogenesis of FGFR3-related dwarfisms and explore the pharmacological modulation of autophagy as new therapeutic approach for achondroplasia. This application, which combines cell biology, mouse genetics and pharmacological approaches, has the potential to shed light on new mechanisms involved in organismal development and homeostasis, which could be targeted to treat bone and cartilage diseases.

1 586 430 €

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

More than 30 million people are living with diabetes in the EU, with a prevalence expected to grow to over 10% of the adult population by the year 2030. Type 2 diabetes is a major cause of cardiovascular disease related death and disability, substantially increasing the risk of myocardial infarction, stroke and peripheral arterial disease. Recent landmark trials, showing that intensive glucose control does not improve cardiovascular outcomes and may increase mortality in some circumstances, provide a compelling rationale for intense research aimed at developing novel therapeutic strategies. Type 2 diabetes is underpinned by resistance to the effects of insulin, which I have shown in endothelial cells causes reduced bioavailability of the anti-atherosclerotic molecule nitric oxide and leads to accelerated atherosclerosis. The cellular effects of insulin are mirrored by insulin-like growth factor factor-1, the bioavailability of which at its receptor is in turn is regulated by a family of high affinity binding proteins (IGFBP). Epidemiological studies demonstrate and inverse association between one of these binding proteins, IGFBP1, and diabetes-related cardiovascular risk. I have recently demonstrated that IGFBP1 when expressed in mice can ameliorate insulin resistance, obesity and atherosclerosis. In endothelial cells, I showed that IGFBP1 upregulates the production of nitric oxide indepenedently of IGF. These findings suggest that IGFBP1 may be a ‘protective’ endogenous protein and that increasing circulating levels may be a therapeutic strategy to prevent development of diabetes and cardiovascular disease. In this proposal I will address this hypothesis by employing state of the art studies in cells and novel gene modified mice to unravel the molecular basis of the protective effects of IGFBP1 and to investigate the possibility of exploiting the IGF-IGFBP axis to prevent cardiovascular disease in the setting of diabetes and obesity.

1 493 543 €

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

"The dynamic nature of the brain operates at disparate time scales ranging from milliseconds to months. How do single neurons change over such long time scales? This question remains stubborn to answer in the field of brain plasticity mainly because of limited tools to study the physiology of single neurons over time in the complex environment of the brain. The research aim of this proposal is to reveal the physiological changes of single neurons in the mammalian brain over disparate time scales using time-lapse optical imaging. Specifically, we aim to establish a new team that will develop genetic and optical tools to probe the physiological activity of single neurons, in vivo. As a model system, we will study a unique neuronal population in the mammalian brain; the adult-born local neurons in the olfactory bulb. These neurons have tremendous potential to reveal how neurons develop and maintain in the intact brain because they are accessible both genetically and optically. By following the behavior of adult-born neurons in vivo we will discover how neurons mature and maintain over days and weeks. If our objectives will be met, this study has the potential to significantly ""raise the bar"" on how neuronal plasticity is studied and reveal some basic secrets of the ever changing mammalian brain."

1 750 000 €

Start date: 2008-08-01, End date: 2013-07-31

The human genome carries genetic information in two distinct forms: Transcribed genes and regulatory DNA elements (rDEs). rDEs control the magnitude and pattern of gene expression, and are indispensable for organismal development and cellular homeostasis. Nevertheless, while large-scale functional genetic screens greatly advanced our knowledge in studying mammalian genes, such tools to study rDEs were lacking, impeding scientific progress. Interestingly, recent advance in genome editing technologies has not only expanded the available screening toolbox to examine genes, but also opened up novel opportunities in studying rDEs. We distinguish two types of rDEs: Transcriptional rDEs that recruit transcription factors to enhancers, and structural rDEs that maintain chromatin 3D structure to insulate transcriptional activities, a feature postulated to be essential for gene expression regulation by enhancers. Recently, we developed a CRISPR strategy to target enhancers. We showed its scalability and effectivity in identifying potential oncogenic and tumour-suppressive enhancers. Here, we will exploit this line of research and develop novel strategies to target structural rDEs (e.g. insulators). By setting up functional genetic screens, we will identify key players in cell proliferation, differentiation, and survival, which are related to cancer development, metastasis induction, and acquired therapy resistance. We will validate key insulators and decipher underlying mechanisms of action that control phenotypes. In a parallel approach, we will analyse whole genome sequencing datasets of cancer to identify and characterize genetic aberrations occurring in the identified regions. Altogether, the outlined research plan forms a natural extension of our successful functional approaches to study gene regulation. Our results will setup the foundation to better understand principles of chromatin architecture in gene expression regulation in development and cancer.

2 497 000 €

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

Brown adipocytes can dissipate energy in a process called adaptive thermogenesis. Whilst the classical brown adipose tissue (BAT) depots disappear during early life in humans, cold exposure can promote the appearance of brown-like adipocytes within the white adipose tissue (WAT), termed brite (brown-in-white). Increased BAT activity results in increased energy expenditure and has been correlated with leanness in humans. Hence, recruitment of brite adipocytes may constitute a promising therapeutic strategy to treat obesity and its associated metabolic diseases. Despite the beneficial metabolic properties of brown and brite adipocytes, little is known about the molecular mechanisms underlying their specification and activation in vivo. This proposal focuses on understanding the complex biology of thermogenic adipocyte biology by studying the epigenetic and transcriptional aspects of WAT britening and BAT recruitment in vivo to identify pathways of therapeutic relevance and to better define the brite precursor cells. Specific aims are to 1) investigate epigenetic and transcriptional states and heterogeneity in human and mouse adipose tissue; 2) develop a novel time-resolved method to correlate preceding chromatin states and cell fate decisions during adipose tissue remodelling; 3) identify and validate key (drugable) epigenetic and transcriptional regulators involved in brite adipocyte specification. Experimentally, I will use adipose tissue samples from human donors and mouse models, to asses at the single-cell level cellular heterogeneity, transcriptional and epigenetic states, to identify subpopulations, and to define the adaptive responses to cold or β-adrenergic stimulation. Using computational methods and in vitro and in vivo validation experiments, I will define epigenetic and transcriptional networks that control WAT britening, and develop a model of the molecular events underlying adipocyte tissue plasticity.

1 552 620 €

Start date: 2019-03-01, End date: 2024-02-29

Deep galaxy surveys are the most valuable asset to understand the history of our Universe. They are key to test galaxy formation models which, based on the Cold Dark Matter framework, are successful at reproducing general aspects of galaxy evolution with cosmic time. However, important discrepancies still exist between models and observations, most notably at high redshifts. This Project will reconstruct the history of galaxy buildup from the first billion years of cosmic time through the peak activity epoch of the Universe, which occurred 10 billion years ago, providing a fundamental constraint for galaxy formation models. I am leading the largest ultra-deep galaxy survey that will ever be conducted with the Spitzer Space Telescope. In this Project, I will exploit my new Spitzer program to do a groundbreaking study of galaxy buildup in the young Universe, paving the way for further galaxy evolution studies with the forthcoming James Webb Space Telescope (JWST). My main objectives are: 1) quantifying galaxy stellar mass assembly beyond the peak activity epoch, through the study of the galaxy stellar mass function up to z~7; 2) measuring, for the first time, galaxy clustering with stellar mass information up to such high redshifts; 3) linking galaxy growth to dust-obscured star formation using Spitzer and new APEX/AMKID sub-millimetre data; 4) unveiling the first steps of galaxy buildup at z>7 with JWST; 5) optimizing the official JWST Mid Infrared Instrument (MIRI) data reduction pipeline for the analysis of deep galaxy surveys. The delivery of an optimized MIRI pipeline is an important added value to the scientific outcome of this Project, which will benefit the general Astronomical community. This is the right time for this Project to make a maximum impact. We are now in a turning point for IR Astronomy, and this opportunity should not be missed. This Project will have a long-lasting legacy, bridging current and next generations of IR galaxy surveys.

1 902 235 €

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

Gastric bypass surgery results in massive weight loss and diabetes remission. The effect is superior to intensive medical treatment, showing that there are mechanisms within the body that can cure diabetes and obesity. Revealing the nature of these mechanisms could lead to new, cost-efficient, similarly effective, non-invasive treatments of these conditions. The hypothesis is that hyper-secretion of a number of gut hormones mediates the effect of surgery, as indicated by a series of our recent studies, demonstrating that hypersecretion of GLP-1, a hormone discovered in my laboratory and basis for the antidiabetic medication of millions of patients, is essential for the improved insulin secretion and glucose tolerance. But what are the mechanisms behind the up to 30-fold elevations in secretion of these hormones following surgery? Constantly with a translational scope, all elements involved in these responses will be addressed in this project, from detailed analysis of food items responsible for hormone secretion, to identification of the responsible regions of the gut, and to the molecular mechanisms leading to hypersecretion. Novel approaches for studies of human gut hormone secreting cells, including specific expression analysis, are combined with our advanced and unique isolated perfused gut preparations, the only tool that can provide physiologically relevant results with a translational potential regarding regulation of hormone secretion in the gut. This will lead to further groundbreaking experimental attempts to mimic and engage the identified mechanisms, creating similar hypersecretion and obtaining similar improvements as the operations in patients with obesity and diabetes. Based on our profound knowledge of gut hormone biology accumulated through decades of intensive and successful research and our successful elucidation of the antidiabetic actions of gastric bypass surgery, we are in a unique position to reach this ambitious goal.

2 500 000 €

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

Some of the primary questions in extragalactic astronomy concern the formation and evolution of galaxies in the distant Universe. In particular, little is known about the less luminous (and therefore less massive) galaxy populations, which are currently missed from large observing surveys and could contribute significantly to the overall star formation happening at early times. One way to overcome the current observing limitations prior to the arrival of the future James Webb Space Telescope or the European Extremely Large Telescopes is to use the natural magnification of strong lensing clusters to look at distant sources with an improved sensitivity and resolution. The aim of CALENDS is to build and study in great details a large sample of accurately-modelled, strongly lensed galaxies at high redshift (1<z<5) selected in the fields of massive clusters, and compare them with the more luminous or lower redshift populations. We will develop novel techniques in this process, in order to improve the accuracy of strong-lensing models and precisely determine the mass content of these clusters. By performing a systematic modelling of the cluster sample we will look into the relative distribution of baryons and dark matter as well as the amount of substructure in cluster cores. Regarding the population of lensed galaxies, we will study their global properties through a multiwavelength analysis covering the optical to millimeter domains, including spectroscopic information from MUSE and KMOS on the VLT, and ALMA. We will look for scaling relations between the stellar, gas and dust parameters, and compare them with known relations for lower redshift and more massive galaxy samples. For the most extended sources, we will be able to spatially resolve their inner properties, and compare the results of individual regions with predictions from simulations. We will look into key physical processes: star formation, gas accretion, inflows and outflows, in these distant sources.

1 450 992 €

Start date: 2013-09-01, End date: 2019-08-31

This project will be aimed at obtaining a deeper insight into the physical processes taking place in astrophysical magnetized plasmas. To study these scenarios I will employ different numerical codes as virtual tools that enable me to experiment on computers (virtual labs) with distinct initial and boundary conditions. Among the kind of sources I am interested to consider, I outline the following: Gamma-Ray Bursts (GRBs), extragalactic jets from Active Galactic Nuclei (AGN), magnetars and collapsing stellar cores. A number of important questions are still open regarding the fundamental properties of these astrophysical sources (e.g., collimation, acceleration mechanism, composition, high-energy emission, gravitational wave signature). Additionally, there are analytical issues on the formalism in relativistic dynamics not resolved yet, e.g., the covariant extension of resistive magnetohydrodynamics (MHD). All these problems are so complex that only a computational approach is feasible. I plan to study them by means of relativistic and Newtonian MHD numerical simulations. A principal focus of the project will be to assess the relevance of magnetic fields in the generation, collimation and ulterior propagation of relativistic jets from the GRB progenitors and from AGNs. More generally, I will pursue the goal of understanding the process of amplification of seed magnetic fields until they become dynamically relevant, e.g., using semi-global and local simulations of representative boxes of collapsed stellar cores. A big emphasis will be put on including all the relevant microphysics (e.g. neutrino physics), non-ideal effects (particularly, reconnection physics) and energy transport due to neutrinos and photons to account for the relevant processes in the former systems. A milestone of this project will be to end up with a numerical tool that enables us to deal with General Relativistic Radiation Magnetohydrodynamics problems in Astrophysics.

1 497 000 €

Start date: 2011-03-01, End date: 2017-02-28

Even at their earliest stages, human cancers are more than just cells with malignant potential. Cells and extracellular matrix components that normally support and protect the body are coerced into a tumour microenvironment that is central to disease progression. My hypothesis is that recent advances in tissue engineering, biomechanics and stem cell biology make it possible to engineer, for the first time, a complex 3D human tumour microenvironment in which individual cell lineages of malignant, haemopoietic and mesenchymal origin will communicate, evolve and grow in vitro. The ultimate aim is to build this cancerous tissue with autologous cells: there is an urgent need for models in which we can study the interaction of human immune cells with malignant cells from the same individual in an appropriate 3D biomechanical microenvironment. To achieve the objectives of the CANBUILD project, I have assembled a multi-disciplinary team of collaborators with international standing in tumour microenvironment research, cancer treatment, tissue engineering, mechanobiology, stem cell research and 3D computer-assisted imaging. The goal is to recreate the microenvironment of high-grade serous ovarian cancer metastases in the omentum. This is a major clinical problem, my lab has extensive knowledge of this microenvironment and we have already established simple 3D models of these metastases. The research plan involves: Deconstruction of this specific tumour microenvironment Construction of artificial scaffold, optimising growth of cell lineages, assembly of the model Comparison to fresh tissue Investigating the role of individual cell lineages Testing therapies that target the tumour microenvironment My vision is that this project will revolutionise the practice of human malignant cell research, replacing misleading systems based on cancer cell monoculture on plastic surfaces and allowing us to better test new treatments that target the human tumour microenvironment.

2 431 035 €

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

Introduction: Current anti-cancer treatments are often inefficient, while many patients initially benefit from anti-cancer drugs eventually experience relapse of resistant tumors throughout the body. Current clinical strategies mainly aim at inducing tumor cell death, but this induction may have unintentional and unwanted side effects on surviving tumor cells. Preliminary data: We show that after chemotherapy-induced initial regression, PyMT mammary tumors reappear. During regression, we observe an increased number of cells that have undergone epithelial-mesenchymal transition (EMT) and become migratory. We show that migration can be induced upon uptake of extracellular vesicles (e.g. apoptotic bodies). Our findings suggest that EMT is induced upon chemotherapy, through e.g. EV uptake, potentially leading to migration and growth of surviving cells. Hypothesis and main aim: Based on preliminary data, we hypothesize that tumor cell death induces migration and growth of the surviving tumor cells. We aim to identify the key cell types and mechanisms that mediate this effect, and establish whether interference with these cells and mechanisms can reduce recurrence of tumors after chemotherapy. Approach: We have developed unique intravital imaging tools and genetically engineered fluorescent mice to visualize and characterize if and how dying tumor cells can affect surrounding surviving tumor and stromal cells. We will test whether dying tumor cells can influence the growth, migration, dissemination and metastasis of surviving tumor cells directly or indirectly through stromal cells. We will identify potential targets to block the influence of the dying tumor cells, and test whether this blockade inhibits the unintended side-effects of tumor cell death. Conclusion: With the studies proposed in this grant, we will gain fundamental insights on how induction of tumor cell death, the universal aim of therapy, could play a role in growth and spread of surviving tumor cells.

2 000 000 €

Start date: 2015-09-01, End date: 2020-08-31

The actual view of cellular transformation and cancer progression supports the notion that cancer cells must undergo metabolic reprogramming in order to survive in a hostile environment. This field has experienced a renaissance in recent years, with the discovery of cancer genes regulating metabolic homeostasis, in turn being accepted as an emergent hallmark of cancer. Prostate cancer presents one of the highest incidences in men mostly in developed societies and exhibits a significant association with lifestyle environmental factors. Prostate cancer recurrence is thought to rely on a subpopulation of cancer cells with low-androgen requirements, high self-renewal potential and multidrug resistance, defined as cancer-initiating cells. However, whether this cancer cell fraction presents genuine metabolic properties that can be therapeutically relevant remains undefined. In CancerMetab, we aim to understand the potential benefit of monitoring and manipulating metabolism for prostate cancer prevention, detection and therapy. My group will carry out a multidisciplinary strategy, comprising cellular systems, genetic mouse models of prostate cancer, human epidemiological and clinical studies and bioinformatic analysis. The singularity of this proposal stems from the approach to the three key aspects that we propose to study. For prostate cancer prevention, we will use our faithful mouse model of prostate cancer to shed light on the contribution of obesity to prostate cancer. For prostate cancer detection, we will overcome the consistency issues of previously reported metabolic biomarkers by adding robustness to the human studies with mouse data integration. For prostate cancer therapy, we will focus on a cell population for which the metabolic requirements and the potential of targeting them for therapy have been overlooked to date, that is the prostate cancer-initiating cell compartment.

1 498 686 €

Start date: 2013-11-01, End date: 2019-10-31

Recent ground-breaking studies by my team and others demonstrated that latent heart regeneration machinery can be awakened even in adult mammals. My lab’s main contribution is the identification of two, apparently different, molecular mechanisms for augmenting cardiac regeneration in adult mice. The first requires transient activation of ErbB2 signalling in cardiomyocytes and the second involves extra cellular matrix-driven signalling by the proteoglycan agrin. Impressively, both mechanisms promote a major regenerative response that, in turn, enhances cardiac repair. In CardHeal we will use the two powerful regenerative models to obtain a holistic view of cardiac regeneration and repair mechanisms in mammals (mice and pigs). In Aim 1, we will explore the molecular mechanisms underlying our discovery that transient activation of ErbB2 in adult cardiomyocytes results in massive cardiomyocyte dedifferentiation and proliferation followed by new vessels formation, scar resolution and functional cardiac repair. Specific objectives focus on ErbB2-Yap/Hippo signalling during cardiac regeneration; ErbB2 activation in a chronic heart failure model; ErbB2-induced regenerative EMT-like process; and cardiomyocyte re-differentiation. In Aim 2, we will investigate the therapeutic effects of agrin, whose administration into injured hearts of mice and pigs elicits a significant regenerative response. Specific objectives are matrix-related cardiac regenerative cues, modulation of the immune response, angiogenesis, matrix remodeling, and developing a preclinical, large animal model to study agrin efficacy for cardiac repair. Interrogating the differences and similarities between our two regenerative models should give us a detailed roadmap for cardiac regenerative medicine by providing deeper knowledge of the regenerative process in the heart and pointing to novel targets for cardiac repair in human patients.

2 268 750 €

Start date: 2018-06-01, End date: 2023-05-31

Heart failure (HF) is the ultimate outcome of many cardiovascular diseases. Re-expression of fetal genes in the adult heart contributes to development of HF. Two mechanisms involved in the control of gene expression are epigenetics and microRNAs (miRs). We propose a project on epigenetic and miR-mediated mechanisms leading to HF. Epigenetics refers to heritable modification of DNA and histones that does not modify the genetic code. Depending on the type of modification and on the site affected, these chemical changes up- or down-regulate transcription of specific genes. Despite it being a major player in gene regulation, epigenetics has been only partly investigated in HF. miRs are regulatory RNAs that target mRNAs for inhibition. Dysregulation of the cardiac miR signature occurs in HF. miR expression may itself be under epigenetic control, constituting a miR-epigenetic regulatory network. To our knowledge, this possibility has not been studied yet. Our specific hypothesis is that the profile of DNA/histone methylation and the cross-talk between epigenetic enzymes and miRs have fundamental roles in defining the characteristics of cells during cardiac development and that the dysregulation of these processes determines the deleterious nature of the stressed heart’s gene programme. We will test this first through a genome-wide study of DNA/histone methylation to generate maps of the main methylation modifications occurring in the genome of cardiac cells treated with a pro-hypertrophy regulator and of a HF model. We will then investigate the role of epigenetic enzymes deemed important in HF, through the generation and study of knockout mice models. Finally, we will test the possible therapeutic potential of modulating epigenetic genes. We hope to further understand the pathological mechanisms leading to HF and to generate data instrumental to the development of diagnostic and therapeutic strategies for this disease.

2 500 000 €

Start date: 2012-10-01, End date: 2018-09-30

"We want to determine how oxidants are sensed and transduced into a biological effect within the cardiovascular system. The proposed work will focus on thiol-based redox sensors, defining their role in heart and blood vessel function during health and disease. Although this laboratory has studied the molecular basis of redox signaling for more than a decade, the subject is still in its relative infancy with considerable scope for major advances. Oxidant signaling remains a ‘hot topic’ with high profile studies confirming a fundamental role for redox control of protein and cellular function continuing to emerge. The molecular basis of redox sensing is the reaction of an oxidant with target proteins. This gives rise to oxidative post-translational modifications, most commonly of cysteinyl thiols, potentially altering the activity of proteins to regulate cell or tissue function. One of the reasons there are so many unanswered questions about redox sensing and signaling is the diversity of oxidant molecules produced by cells that can interact with sensor proteins to alter their function. This application is aimed at extending our knowledge of redox sensing and signalling, allowing us to define its importance in cardiovascular health and disease."

2 255 659 €

Start date: 2013-12-01, End date: 2018-11-30

Contraction and relaxation of cardiac myocytes, and thus the whole heart, are critically dependent on dyads. These functional junctions between t-tubules, which are invaginations of the surface membrane, and the sarcoplasmic reticulum allow efficient control of calcium release into the cytosol, and also its removal. Dyads are formed gradually during development and break down during disease. However, the precise nature of dyadic structure is unclear, even in healthy adult cardiac myocytes, as are the triggers and consequences of altering dyadic integrity. In this proposal, my group will investigate the precise 3-dimensional arrangement of dyads and their proteins during development, adulthood, and heart failure by employing CLEM imaging (PALM and EM tomography). This will be accomplished by developing transgenic mice with fluorescent labels on four dyadic proteins (L-type calcium channel, ryanodine receptor, sodium-calcium exchanger, SERCA), and by imaging tissue from explanted normal and failing human hearts. The signals responsible for controlling dyadic formation, maintenance, and disruption will be determined by performing high-throughput sequencing to identify novel genes involved with these processes in several established model systems. Particular focus will be given to investigating left ventricular wall stress and stretch-dependent gene regulation as controllers of dyadic integrity. Candidate genes will be manipulated in cell models and transgenic animals to promote dyadic formation and maintenance, and reverse dyadic disruption in heart failure. The consequences of dyadic structure for function will be tested experimentally and with mathematical modeling to examine effects on cardiac myocyte calcium homeostasis and whole-heart function. The results of this project are anticipated to yield unprecedented insight into dyadic structure, regulation, and function, and to identify novel therapeutic targets for heart disease patients.

2 000 000 €

Start date: 2015-07-01, End date: 2020-06-30

The proposed project will significantly improve the insight in the processes that have changed a comet nucleus or asteroid since their formation. These processes typically go along with activity, the observable release of gas and/or dust. Understanding the evolutionary processes of comets and asteroids will allow us to answer the crucial question which aspects of these present-day bodies still provide essential clues to their formation in the protoplanetary disc of the early solar system. Ground-breaking progress in understanding these fundamental questions can now be made thanks to the huge and unprecedented data set returned between 2014 and 2016 by the European Space Agency’s Rosetta mission to comet 67P/Churyumov-Gerasimenko, and by recent major advances in the observational study of active asteroids facilitated by the increased availability of sky surveys and follow-on observations with world-class telescopes. The key aims of this proposal are to - Obtain a unified quantitative picture of the different erosion processes active in comets and asteroids, - Investigate how ice is stored in comets and asteroids, - Characterize the ejected dust (size distribution, optical and thermal properties) and relate it to dust around other stars, - Understand in which respects comet 67P can be considered as representative of a wider sample of comets or even asteroids. We will follow a highly multi-disciplinary approach analyzing data from many Rosetta instruments, ground- and space-based telescopes, and connect these through numerical models of the dust dynamics and thermal properties.

1 484 688 €

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

Whereas the human heart cannot regenerate cardiac muscle after myocardial infarction, certain fish efficiently repair their hearts. Astyanax mexicanus, a close relative of the zebrafish, is a single fish species comprising cave-dwelling and surface river populations. Remarkably, while surface fish regenerate their heart after injury, cavefish cannot and form a permanent fibrotic scar, similar to the human heart. Using transcriptomics analysis and immunohistochemistry, we have identified key differences in the scarring and inflammatory response between the surface and cavefish heart after injury. These differences include extracellular matrix (ECM) proteins, growth factors and macrophage populations present in one, but not the other population, suggesting properties unique to the surface fish scar that promote heart regeneration. The objective of the proposed project is to characterise and utilise these findings to identify therapeutic targets to heal the human heart after myocardial infarction. First, we will analyse the identified differences in scarring and immune response between the fish in detail, before testing the role of the most interesting proteins and macrophage populations during regeneration using CRISPR mutagenesis and clodronate liposomes. Next, we will link the key scarring and inflammatory differences directly to both the genome and the ability for heart regeneration using new and prior Quantitative Trait Loci analyses. This will allow to find the most fundamental molecular mechanisms directing the wound healing process towards regeneration versus scarring. Together with an in vitro and in vivo small molecule screen directed specifically at influencing scarring towards a more ‘fish-like’ regenerative phenotype in the cavefish and mouse heart after injury, this will provide targets for therapeutic strategies to maximise the endogenous regenerative potential of the mammalian heart, with the aim to find a cure for myocardial infarction.

1 499 429 €

Start date: 2017-03-01, End date: 2022-02-28

"Our research group has worked over the years at the interface between cancer and ageing, with a strong emphasis on mouse models. More recently, we became interested in cellular reprogramming because we hypothesized that understanding cellular plasticity could yield new insights into cancer and ageing. Indeed, during the previous ERC Advanced Grant, we made relevant contributions to the fields of cellular reprogramming (Nature 2013), cellular senescence (Cell 2013), cancer (Cancer Cell 2012), and ageing (Cell Metabolism 2012). Now, we take advantage of our diverse background and integrate the above processes. Our unifying hypothesis is that cellular plasticity lies at the basis of tissue regeneration (“adaptive cellular plasticity”), as well as at the origin of cancer (“maladaptive gain of cellular plasticity”) and ageing (“maladaptive loss of cellular plasticity”). A key experimental system will be our “reprogrammable mice” (with inducible expression of the four Yamanaka factors), which we regard as a tool to induce cellular plasticity in vivo. The project is divided as follows: Objective #1 – Cellular plasticity and cancer: role of tumour suppressors in in vivo de-differentiation and reprogramming / impact of transient de-differentiation on tumour initiation / lineage tracing of Oct4 to determine whether a transient pluripotent-state occurs during cancer. Objective #2 – Cellular plasticity in tissue regeneration and ageing: impact of transient de-differentiation on tissue regeneration / contribution of the damage-induced microenvironment to tissue regeneration / impact of transient de-differentiation on ageing. Objective #3: New frontiers in cellular plasticity: chemical manipulation of cellular plasticity in vivo / new states of pluripotency / characterization of in vivo induced pluripotency and its unique properties. We anticipate that the completion of this project will yield new fundamental insights into cancer, regeneration and ageing."

2 488 850 €

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

We propose to carry out a project which will produce a decisive step towards improving the accuracy of the Hubble constant as determined from the Cepheid-SN Ia method to 1%, by using 28 extremely rare eclipsing binary systems in the LMC which offer the potential to determine their distances to 1%. To achieve this accuracy we will reduce the main error in the binary method by interferometric angular diameter measurements of a sample of red clump stars which resemble the stars in our binary systems. We will check on our calibration with similar binary systems close enough to determine their orbits from interferometry. We already showed the feasibility of our method which yielded the best-ever distance determination to the LMC of 2.2% from 8 such binary systems. With 28 systems and the improved angular diameter calibration we will push the LMC distance uncertainty down to 1% which will allow to set the zero point of the Cepheid PL relation with the same accuracy using the large available LMC Cepheid sample. We will determine the metallicity effect on Cepheid luminosities by a) determining a 2% distance to the more metal-poor SMC with our binary method, and by b) measuring the distances to LMC and SMC with an improved Baade-Wesselink (BW) method. We will achieve this improvement by analyzing 9 unique Cepheids in eclipsing binaries in the LMC our group has discovered which allow factor- of-ten improvements in the determination of all basic physical parameters of Cepheids. These studies will also increase our confidence in the Cepheid-based H0 determination. Our project bears strong synergy to the Gaia mission by providing the best checks on possible systematic uncertainties on Gaia parallaxes with 200 binary systems whose distances we will measure to 1-2%. We will provide two unique tools for 1-3 % distance determinations to individual objects in a volume of 1 Mpc, being competitive to Gaia already at a distance of 1 kpc from the Sun.

2 360 500 €

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