ERC FUNDED PROJECTS

The goal of this proposal is to establish a new era of stellar cluster evolution research by performing numerical simulations on different scales, and of different stages of a cluster’s life, from the formation of YMCs, the formation and evolution of OB associations, to the evolution of clusters and associations in galaxies. The PI is one of the pioneers of galactic simulations of GMC and star formation was one of the first numericists to perform galactic scale simulations of molecular cloud formation and evolution, and has produced some of the most realistic and sophisticated isolated simulations of galaxies in this field to date. The next challenge is to follow cluster evolution, something which has not yet been attempted numerically. And, with the GaiaAIA instrument set to transform stellar astronomy in our Galaxy, our work will provide a fundamental theoretical counterpart. Key questions we will address include i) how does gas disperse from new clusters and what happens to that gas, ii) how do YMCs form, iii) how do new clustersGiant Molecular Clouds (GMCs) evolve into OB associations, and ivii) how long can clusters survive for as they orbit a galaxy and what causes their destruction.

1 980 385 €

Start date: 2019-06-01, End date: 2024-05-31

The Glioblastoma Multiforme (GBM) is the most common primary brain tumor and it is incurable. Two major challenges affect GBM clinical management: its heterogeneity (which treatment will best fit this very patient?) and its resistance to available treatments (will the patient benefit in any way from the chosen therapy?). Here we approach these questions with a personalized entry point. First, we aim to create “humanized” experimental models of GBM accurately reflecting patients at molecular level. These GBM Subtype Avatars models (GSA) will be exploited as “targeted patients” in personalized biology and intervention studies. Since GBM exists as molecular subtypes with similar histopathology but mutually exclusive genetic lesions and molecular features, we will generate GSA by targeting mutations recurrently associated with Proneural, Classical or Mesenchymal GBM subtypes into adult human neural stem cells (NSC). Evidence supports that these cells can give rise to high-grade gliomas when engineered with the appropriate genetic lesions. Next, engineered NSC will be orthotopically implanted into immunocompromised rats and the resulting tumors profiled for gene expression, DNA methylation and copy number aberrations. These profiles will be compared to those generated in patient-derived xenografts and biopsies. Second, to identify drug targets favoring patients’ response to the current standard of care, we will exploit GSA for state-of-art genetic screens in vivo. Specifically, we will seek for synthetic lethal interactions between DNA damaging agents and the GSA transcriptome using an in vivo CRISPRi screening approach. Third, to investigate the molecular basis of GBM heterogeneity in GSA models, we will combine genetic and immunophenotypic tracing with gene expression and epigenomic profiling. Identifying tumor-specific vulnerabilities in a dismal disease urging for effective therapies and its molecular fingerprinting convey conceivably rapid Translation in Oncology.

1 500 000 €

Start date: 2017-07-01, End date: 2022-06-30

Atherosclerosis is a chronic inflammatory disease of the arterial wall with (auto)immune component, initiated in response to modified (phospho)lipids. Despite important advances in our understanding of the inflammatory response in atherosclerosis, the critical pathways responsible for the breakdown of immune tolerance to lipoproteins and other self-antigens remain largely unknown. An important feature of ruptured/thrombosed atherosclerotic lesions is the accumulation of apoptotic, and secondary necrotic, lipid-laden macrophages and smooth muscle cells due to defective efferocytosis (clearance of apoptotic cells). This leads to the formation of a large ‘necrotic’ lipid core, associated with enhanced vascular inflammation. Interestingly, defective efferocytosis has been associated with the development of autoimmunity, and patients with systemic lupus erythematosus who show increased accumulation of apoptotic material are at very high risk of accelerated atherosclerosis and myocardial infarction. We hypothesize that accumulation of apoptotic/secondary necrotic cells due to defective efferocytosis, together with modified lipids, activate critical immuno-inflammatory pathways in macrophages and B cells, and break immune tolerance in atherosclerosis and post-myocardial infarction. This is consistent with the critical role played by defective efferocytosis and macrophage activation in atherosclerotic lesion progression, and with our recent unsuspected data showing a critical role for B cell activation in driving lesion development in several models of atherosclerosis. We also propose that interactions between macrophages and B cells are essential for the perpetuation of the pathogenic immuno-inflammatory response in cardiovascular disease. Finally, we will harness this knowledge for a better identification of patients at risk of cardiovascular complications, and will target these pathways to limit the progression and complications of cardiovascular disease.

1 499 731 €

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

With this proposed project I will determine whether intermediate-mass black holes (IMBHs) exist. I propose to use ESA's new Gaia mission, the rich Hubble Space Telescope data archive, and state-of-the-art techniques to investigate systems predicted to exist but not yet found hitherto, such as recoiled hyper-compact stellar systems, red-supergiant mass donors to ultra-luminous X-ray sources, and white dwarf tidal disruption events. The latter can only be detected if black holes with masses less than 1E5 Msun are involved. Using these systems and events we can probe the sphere of influence of the IMBH and determine the black hole mass dynamically. Currently, there are strong indications for the existence of IMBHs, but dynamical evidence, the irrefutable proof of their existence, is still lacking. Whereas the unequivocal detection of an IMBH will be a breakthrough discovery in itself, it has also important consequences for searches of dark matter annihilation signals, it will provide a baseline for the rate predictions of gravitational wave radiation events involving IMBHs, and the properties of a population of IMBHs provides important constraints on the growth of supermassive black holes and galaxies. Finally, if we discover IMBHs in hyper-compact star clusters it validates numerical relativity simulations that predict that merging black holes receive a recoil kick. My membership of Gaia's Data Processing and Analysis Consortium gives me a distinct advantage in analysing and interpreting Gaia data that, through the superb angular resolution, immediate spectroscopic observations and all-sky coverage, provides unique capabilities ideally suited for answering the question whether IMBHs exist. My proposed project is the first to recognize the potential of Gaia (WP1&2) as well as the implications of having red supergiant mass donors in some ultra-luminous X-ray sources (WP3) for answering the question on the existence of IMBHs.

1 999 975 €

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

We have previously demonstrated that cellular senescence opposes tumorigenesis thereby opening up new potential opportunities for cancer treatment. Senescence and tumor immunity in cancer are tightly interconnected. Tumor-infiltrating immune cells promote the clearance of senescent tumor cells thereby contributing to the tumor suppressive function of senescence. Moreover, T lymphocytes can drive senescence in cancers by secreting different cytokines in the tumor microenvironment. We have also recently reported that GR1+ myeloid cells antagonize treatment-induced senescence (TIS) and that compounds that block the tumor recruitment of GR1+ cells enhance TIS. Major objective of this proposal is to characterize the immune landscape of different prostate cancer mouse models in order to develop novel treatment modalities that combine pro-senescence compounds with immunotherapy. Using proteomics and bioinformatics approaches, we will assess how the genetic background of prostate tumors, shapes the tumor microenvironment and immune response during TIS. Next, we will define the mechanisms that regulate the recruitment and activation of myeloid derived suppressive cells, macrophages and B-lymphocytes in Pten deficient prostate tumors by focusing on a novel class of secreted factors identified in these tumors. We will also assess in vivo whether the secretome of tumor cells can transmit senescence to TILs and compounds that interfere with the secretome can prevent immunosenescence. Finally, we will develop monoclonal antibodies directed towards senescent tumors cells that we will use as diagnostic and therapeutic tools. These antibodies will be used as biomarkers to detect senescent tumor cells in prostate cancers and will be tested in pre-clinical trials to assess whether they improve tumor clearance during TIS. Our findings will form the basis for future clinical trials in prostate cancer patients.

2 000 000 €

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

"How the immune system controls the partnership established between mammalian hosts and the complex microbial community that colonizes their distal intestine is a fascinating topic with wide implications in physiology and pathology. In order to delineate how the two partners build and maintain mutualistic relationships, we intend to combine bench to bed-site approaches in humans and mechanistic studies in mice. The first part of the proposal aims at dissecting human host pathways mandatory to maintain homeostatic relationships with the microbiota through the analysis of a cohort of young children with colites of early onset likely caused by Mendelian mutations. In this part, we expect to take advantage from recent development of powerful tools in genome analysis to extend our expertise in human intestinal immunopathology, provide novel basic insight into immuno-regulation in the human gut and delineate new tools and strategies for the diagnosis and care of inflammatory bowel diseases in children. In the second part of the proposal, we intend to capitalise on our recent results highlighting the key role of Segmented Filamentous Bacterium in the post-natal maturation of the gut immune system in mice and on very recent evidence of a host-specific version of this bacterium in the human microbiota. First, we want to combine analyses in gnotobiotic mice and molecular approaches to provide a comprehensive view of the mechanisms underlying the outstanding immunostimulatory functions of this unusual symbiont. We hope thereby to identify the bacterial attributes that drive the physiological activation of the host immune system and to gain insight into the rules that govern host-microbiota interactions. Second, we intend to put all possible efforts to characterise the human version of Segmented Filamentous bacterium and to analyse how this bacterium may influence the normal or pathological development of the gut immune system in humans."

2 499 551 €

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

Anti-cancer immunotherapy has provided patients with a promising treatment. Yet, it has also unveiled that the immunosuppressive tumor microenvironment (TME) hampers the efficiency of this therapeutic option and limits its success. The concept that metabolism is able to shape the immune response has gained general acceptance. Nonetheless, little is known on how the metabolic crosstalk between different tumor compartments contributes to the harsh TME and ultimately impairs T cell fitness within the tumor. This proposal aims to decipher which metabolic changes in the TME impede proper anti-tumor immunity. Starting from the meta-analysis of public human datasets, corroborated by metabolomics and transcriptomics data from several mouse tumors, we ranked clinically relevant and altered metabolic pathways that correlate with resistance to immunotherapy. Using a CRISPR/Cas9 platform for their functional in vivo selection, we want to identify cancer cell intrinsic metabolic mediators and, indirectly, distinguish those belonging specifically to the stroma. By means of genetic tools and small molecules, we will modify promising metabolic pathways in cancer cells and stromal cells (particularly in tumor-associated macrophages) to harness tumor immunosuppression. In a mirroring approach, we will apply a similar screening tool on cytotoxic T cells to identify metabolic targets that enhance their fitness under adverse growth conditions. This will allow us to manipulate T cells ex vivo and to therapeutically intervene via adoptive T cell transfer. By analyzing the metabolic network and crosstalk within the tumor, this project will shed light on how metabolism contributes to the immunosuppressive TME and T cell maladaptation. The overall goal is to identify druggable metabolic targets that i) reinforce the intrinsic anti-tumor immune response by breaking immunosuppression and ii) promote T cell function in immunotherapeutic settings by rewiring either the TME or the T cell itself.

1 999 721 €

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

Infant cancer is very distinct to adult cancer and it is progressively seen as a developmental disease. An intriguing infant cancer is the t(4;11) acute lymphoblastic leukemia (ALL) characterized by the hallmark rearrangement MLL-AF4 (MA4), and associated with dismal prognosis. The 100% concordance in twins and its prenatal onset suggest an extremely rapid disease progression. Many key issues remain elusive: Is MA4 leukemogenic? Which are other relevant oncogenic drivers? Which is the nature of the cell transformed by MA4? Which is the leukemia-initiating cell (LIC)? Does this ALL follow a hierarchical or stochastic cancer model? How to explain therapy resistance and CNS involvement? To what extent do genetics vs epigenetics contribute this ALL? These questions remain a challenge due to: 1) the absence of prospective studies on diagnostic/remission-matched samples, 2) the lack of models which faithfully reproduce the disease and 3) a surprising genomic stability of this ALL. I hypothesize that a Multilayer-Omics to function approach in patient blasts and early human hematopoietic stem/progenitor cells (HSPC) is required to fully scrutinize the biology underlying this life-threatening leukemia. I will perform genome-wide studies on the mutational landscape, DNA and H3K79 methylation profiles, and transcriptome on a uniquely available, large cohort of diagnostic/remission-matched samples. Omics data integration will provide unprecedented information about oncogenic drivers which must be analyzed in ground-breaking functional assays using patient blasts and early HSPCs carrying a CRISPR/Cas9-mediated locus/allele-specific t(4;11). Serial xenografts combined with exome-seq in paired diagnostic samples and xenografts will identify the LIC and determine whether variegated genetics may underlie clonal functional heterogeneity. This project will provide a precise understanding and a disease model for MA4+ ALL, offering a platform for new treatment strategies.

2 000 000 €

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

Glucose sensing cells constantly monitor glucose absorption from food and variations in blood glycemic levels. They control the secretion of GLP-1, insulin and glucagon, and the activity of the autonomic nervous system. These hormonal and nervous signals coordinate glucose utilization by liver, fat and muscle, and endogenous glucose production as well as feeding and energy expenditure. Type 2 diabetes, a disease that afflicts an increasing proportion of the world population, is characterized by insufficient insulin production by pancreatic beta-cells, abnormal secretion of GLP-1 and glucagon, and is often associated with imbalance between feeding and energy expenditure. Type 2 diabetes can thus be considered a disease of glucose sensing. Here, I propose a research program using cell biological, genetic, genomic and physiology techniques to investigate three aspects of this integrated glucose sensing network: 1. The identification of novel molecular pathways activated by GLP-1 and that control adult beta-cell proliferation, glucose competence and apoptosis in order to maintain sufficient insulin secretion capacity. 2. The identification and molecular characterization of brain glucose sensors, which share functional similarities with pancreatic beta-cells, and which control glucose homeostasis and pancreatic islet mass and function. 3. The discovery by unbiased genetic-genomic analysis of loci, genes, and gene networks involved in central hypoglycemia detection and the secretion of glucagon, a process whose deregulation is a major limitation in insulin treatment of both type 1 and type 2 diabetes. Together these investigations will bring new knowledge on the integrated control of glucose homeostasis that may lead to novel strategies to control diabetes.

2 499 421 €

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

During evolution the brain has selected glucose as a main source of metabolic energy. This has imposed homeostatic and behavioral constraints. First, the glycemic levels must be maintained at a minimum of ~5 mM to ensure constant energy supply to the brain. Second, a high reward value has to be attributed to glucose-containing foods to increase the motivation to obtain them. These homeostatic and hedonic regulations depend on glucose sensing cells and neuronal circuits in the central nervous system. These cells and circuits regulate the activity of the sympathetic and parasympathetic nerves, which control the function of peripheral organs (liver, fat, muscles) and the secretion of glucagon and insulin by pancreatic islet cells. They also attribute a reward value to glucose-containing foods to control food-seeking behavior, a process that involves the mesolimbic dopaminergic system. Here, we will focus on three interrelated aims: 1. Identify the physiological role of glucose sensing neurons of the ventromedial hypothalamic nucleus (VMN, a key feeding and glucoregulatory center) in glucose homeostasis and food preference; identify their cellular diversity and their molecular make-up; and characterize their deregulations in metabolic diseases. 2. Characterize the molecular physiology of glucose sensing neurons of the paraventricular thalamus, which modulate the activity of the mesolimbic dopaminergic system to control motivated sucrose-seeking behavior; determine their control by other interoceptive signals, including from glucose sensing cells of the VMN. 3. Establish new molecular approaches to characterize, at the molecular and functional levels, the impact of early postnatal nutrition on the development and function of central glucose sensing cells in the control of adult animal physiology. These studies will open-up new perspectives in the understanding of homeostatic and hedonic regulatory pathways, which preserve metabolic health over a lifetime.

2 499 714 €

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

When and how did the first galaxies form across cosmic history? Were they different from present-day ones? This is only a small subset of key cosmological questions that the combination of deep galaxy observations, theoretical modeling, and powerful simulations envisaged here will allow us to answer for the first time. Deep galaxy surveys have provided a first valuable characterization of early galaxies in the Epoch of Reionization (redshift z > 6), mostly in terms of their stellar content. However, almost nothing is known about their internal structure and Interstellar Medium (ISM). This is in striking contrast with galaxies at z < 2, for which ISM observations have enabled a much more complete physical description. Hence, a substantial progress in the study of early galaxies must be based on techniques able to probe their ISM. Conversely, ISM studies will help completing the “stellar” picture. Interstellar will bridge this gap. Its main aim is to understand the internal structure and interstellar medium of galaxies in the Epoch of Reionization by performing theoretical modeling and high fidelity simulations. By post-processing the simulations and calibrating them with local analogs, we will produce mock images/spectra used to (i) interpret available high-redshift observations, and (ii) plan breakthrough experiments with ALMA, JWST and E-ELT. The advent of ALMA, JWST, E-ELT and advances in computational cosmology make the study of high-z ISM one of the most promising areas of development in cosmology. The aim will be achieved through 5 objectives distributed among 3 Work Packages (WPs). WP1 is concerned with theoretical work, a preparatory phase for the cosmological simulations performed in WP2. WP2 represents the production phase of the project and will deliver cutting-edge zoom simulations of a sample of high-z galaxies and their ISM. Finally, WP3 is concerned with the exploitation of the numerical results and their integration with observations.

2 151 875 €

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

Purpose: Cells in a tumor are highly heterogeneous. The role and consequence of having multiple cell types within a cancer is mostly centered towards the function of cancer stem cells (CSCs) since they are the driving forces of tumor growth. However, the exact signaling cues that support CSC function remain to be understood. For instance, what are the roles of immediate descendant tumor cells in relation to CSC support? Do colorectal tumors make their own niche? Preliminary data: To study communication between different cell types (heterocellular signaling) in human colorectal cancers (CRCs), my lab developed movieSTAR technology to mark CSCs in patient-derived CRC organoids (PDOs) for high-resolution live imaging of their dynamics and behavior. Although niche factor dependency decreases along the adenoma-carcinoma transition, we identified a strong interdependency between CSCs and other tumor cells in colorectal PDOs of malignant nature. Hypothesis: We hypothesize a continuous existence of an intratumoral stem cell niche that remains essential for tumor growth and metastasis formation. Which types of heterocellular signaling support CSC function, especially at malignant stages, is unknown. Approach: This project aims to define heterocellular signaling between CSCs and intratumoral niche cells. Therefore, I) we will combine our expertise in human organoid technology for in-depth characterization of the nature of heterocellular communication within the intratumoral niche, II) high-resolution live imaging of PDOs to interrogate heterogeneity of signaling activities at cellular resolution and in real-time, as well as III) in vivo mouse models for validation and further studies of essential intratumoral signaling pathways. Innovation: Our integrative use of novel approaches will provide comprehensive insight into intratumoral niche function during tumorigenesis, establishing novel technologies for future cancer research and new concepts to improve cancer therapy.

1 500 000 €

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

Mucus-Penetrating Microbiota: Characterization, Mechanism and Therapeutic in Metabolic Disease Humanity is facing an epidemic of inter-related metabolic disorders, including obesity, insulin resistance, hyperglycemia, hyperlipidemia, and hepatic steatosis, that altogether have major impact on the promotion of cardiovascular diseases. The increasing incidence of these complex metabolic disorders and their highly morbid, chronic and costly downstream diseases threatens to overwhelm the world’s health care systems and economies, making it a top public health priority in dire need of investigation. The intestinal tract is inhabited by a large and diverse community of bacteria, collectively referred to as the intestinal microbiota. When stably maintained at an appropriately safe distance from the epithelial cell monolayer, the microbiota provides important benefits to its host. However, disturbance of the microbiota-host relationship, promoted by genetic or non-genetic factors, can alter intestinal homeostasis and drive chronic low-grade intestinal inflammation, ultimately leading to metabolic abnormalities. We previously reported that a ubiquitous class of food additives, emulsifiers, detrimentally impact the microbiota resulting in its encroachment into the mucus layer that associated with low-grade inflammation and development of metabolic disorders. The central goal of this proposal is to investigate the hypothesis that bacteria that penetrate the inner part of the mucus layer, referred as invaders, promote development of metabolic alterations. We herein propose to identify mucus-invaders, in preclinical models and clinical conditions, and investigate mechanisms by which they promote inflammatory and metabolic abnormalities. Furthermore, we propose to define original approaches to modulate the intestinal microbiota in order to counteract microbiota encroachment and protect against associated metabolic abnormalities.

1 850 000 €

Start date: 2019-10-01, End date: 2024-09-30

Severe sepsis remains a poorly understood systemic inflammatory condition with high mortality rates and limited therapeutic options outside of infection control and organ support measures. Based on our recent discovery that anthracycline drugs prevent organ failure without affecting the bacterial burden in a model of severe sepsis, we propose that strategies aimed at target organ protection have extraordinary potential for the treatment of sepsis and possibly for other inflammation-driven conditions. However, the mechanisms of organ protection and disease tolerance are either unknown or poorly characterized. The central goal of the current proposal is to identify and characterize novel cytoprotective mechanisms, with a focus on DNA damage response dependent protection activated by anthracyclines as a window into stress-induced genetic programs conferring disease tolerance. To that end, we will carry out a combination of candidate and unbiased approaches for the in vivo identification of ATM-dependent and independent mechanisms of tissue protection. We will validate the leading candidates through adenovirus-mediated delivery of constructs for overexpression (gain-of-function) or shRNA for gene silencing (loss-of-function) to the lung, based on our recent finding that rescuing this organ is essential and perhaps sufficient in anthracycline-induced protection against severe sepsis. The candidates showing the most promise will be characterized using a combination of in vitro and in vivo genetic, biochemical, cell biological and physiological methods. The results arising from the current proposal are likely not only to inspire the design of transformative therapies for sepsis but also to open a completely new field of opportunity to molecularly understand core surveillance mechanisms of basic cellular processes with a critical role in the homeostasis of organ function and whose activation can ultimately promote quality of life during aging and increase lifespan.

1 985 375 €

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

The project aims at unraveling the molecular pathophysiology of recessive ataxias, a heterogeneous set of severely disabling neurodegenerative disorders due to loss of function of proteins involved either in mitochondrial/metabolic pathways or DNA repair. Friedreich ataxia, the most common form, is due to partial loss of function of frataxin, a mitochondrial protein involved in iron-sulfur cluster (ISC) biogenesis. Furthermore, the rare X-linked sideroblastic anemia with cerebellar ataxia is caused by mutation in ABCb7, an ATP-binding cassette transporter of the mitochondrial inner membrane necessary for cytosolic ISC export. ISC are versatile co-factors of proteins involved in electron transport, enzyme catalysis and regulation of gene expression. The synthesis and insertion of ISC into apoproteins involve complex machineries that are still poorly understood in the mammalian cell. The objectives of this proposal are: 1) to elucidate ISC biogenesis and metabolism in the mammalian cell, with an emphasis on the role of frataxin and ABCb7; 2) to better understand the molecular pathways that are involved in neuronal dysfunction due to defects in mitochondrial ISC metabolism. These objectives will be accomplished by a multidisciplinary approach combining molecular and biochemical approaches to study the ISC assembly machineries, bioinformatic and proteomic studies to identify new Fe-S proteins, the development and pathological analysis of animal and cellular models to dissect the molecular mechanisms, and transcriptomic analysis to uncover the common pathways among recessive ataxias. A specific focus of the proposal will be the involvement of DNA damage response pathways in neuronal dysfunction, as several DNA repair enzymes have recently been identified as Fe-S proteins and thus might be directly affected by frataxin and ABCb7 deficiency. This proposal should lead to the identification of different pathways for therapeutic intervention for these devastating disorders.

1 449 924 €

Start date: 2008-07-01, End date: 2013-06-30

Many reports indicate the number of people with diabetes will exceed 350 million by the year 2030. Both type 1 and type 2 diabetes are characterized by the deterioration and impaired function of pancreatic b-cells. While transplantation is a promising strategy to replace lost tissue, several obstacles remain in the pathway to its clinical application. Whether b-cells are derived from patient samples or differentiated from embryonic stem cells, a major concern facing these strategies is how a recipient will respond to transplanted foreign tissue. Since the native environment for pancreatic islets is comprised of neural and vascular networks, successful integration may depend upon signals received from these neighboring cell types. Using a multidisciplinary approach, the principal investigator plans to elucidate molecular mechanisms underlying the interactions between pancreatic islet cells and their neighboring endothelial cells. Developing an understanding of how these interactions change during the pathogenesis of disease will provide insight into how islet growth and insulin release is dependent upon signals received from adjacent cell types. Emphasis will be placed on genetic mouse models to measure changes in gene expression in both isolated pancreatic b-cells and endothelial cells to identify genes that mediate the interaction between these cell types. In addition, it is of great interest to identify secreted factors that may constitute autocrine or paracrine signalling mechanisms that influence growth and function between these cell types. Furthermore, it will be determined whether current protocols for the differentiation of mouse stem cells into insulin producing cells are improved by restoring the expression of genes which facilitate communication to endothelial cells. This project aims to identify genes essential to the vascular context of pancreatic b-cells to improve transplantation protocols and facilitate the development of therapeutic strategies for diabetes.

1 496 257 €

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

We are currently experiencing a fast-growing diabetes pandemic. Both type 2 diabetes and rare monogenic forms of diabetes, such as neonatal diabetes, are characterised by impaired insulin secretion. This project seeks to resolve the fundamental mechanisms underlying insulin secretion and its failure in diabetes. We have shown that activating mutations in the ATP-sensitive potassium (KATP) channel cause neonatal diabetes, which has enabled children with this disease to switch from insulin injections to oral sulphonylurea drugs (which block their open KATP channels and stimulate insulin release). The most severe mutations also cause neurological symptoms that, for unknown reasons, are less well treated by sulphonylureas. We aim to: obtain a detailed mechanistic understanding of how nucleotides and drugs regulate KATP channel activity by combining state-of-the-art structural and functional approaches; define how drug therapy affects glucose homeostasis in neonatal diabetes; and explore how activating KATP channel mutations affect glucagon release from pancreatic alpha-cells. We will also investigate how severe KATP channel mutations cause neurological symptoms (such as developmental delay, reduced sensitivity to general anaesthetics and impaired eye movements) and determine how these might be alleviated by drug therapy. While underpinned by my previous work, this project takes my research in new directions, including structural analysis of eukaryotic membrane proteins, stimulus-secretion coupling in other types of islet cell, and neurological studies in humans as well as animal models. It involves a broad multidisciplinary approach, addresses questions of fundamental scientific importance, and has a strong translational element. We expect our studies will be of direct benefit to patients with neonatal or type 2 diabetes.

2 478 420 €

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

Supermassive black holes (SMBHs) with masses in the range ~10^6-10^10 M⊙ are found at the centres of all massive galaxies in the Local Universe. In the ΛCDM picture of structure formation galaxies grow bottom-up through mergers and gas accretion, leading to multiple SMBHs in the same stellar system. Current simulation codes are unable to resolve in a single simulation the full SMBH merging process, which involves dynamical friction, three-body interactions and finally gravitational wave (GW) emission. KETJU will provide a significant breakthrough in SMBH research by following for the first time accurately global galactic-scale dynamical and gaseous astrophysical processes, while simultaneously solving the dynamics of SMBHs, SMBH binaries and surrounding stellar systems at sub-parsec scales. Our code KETJU (the word for 'chain' in Finnish) is built on the GADGET-3 code and it includes regions around every SMBH in which the dynamics of SMBHs and stellar particles is modelled using a non-softened Post-Newtonian algorithmic chain regularisation technique. The remaining simulation particles far from the SMBHs are evolved using softened GADGET-3. Using KETJU we can study at unprecedented accuracy the dynamics of SMBHs to separations of ~10 Schwarzschild radii, the formation of cores in massive galaxies, the formation of nuclear stellar clusters and finally provide a realistic prediction for the amplitude and frequency distribution of the cosmological gravitational wave background. The UH theoretical extragalactic team is ideally suited for this project, as it has an unusually versatile background in modelling the dynamics, feedback and merging of SMBHs. KETJU is also particularly timely, as the spectacular direct detection of GWs in 2016 is paving the way for a new era in gravitational wave astronomy. Future space-borne GW observatories, such as the European Space Agency's LISA, require accurate global GW predictions in order to fully realise their science goals.

1 953 569 €

Start date: 2019-07-01, End date: 2024-06-30

This project aims at exploring the roles or KRAB/KAP1-mediated gene regulation in mammalian physiology and the possible impact of its dysfunctions on human health. The proper control of gene expression is paramount to all biological events, and is orchestrated through a sophisticated balance of activating and repressing influences. The mouse and human genomes contain around four hundred genes encoding KRAB-containing zinc finger proteins (KRAB-ZFPs), a family of tetrapod-restricted sequence-specific DNA-binding transcriptional repressors. Even though these KRAB-ZFPs represent the single largest group of transcriptional regulators encoded by higher vertebrates, their functions remain largely unknown. Nevertheless, it has been established that they share an essential cofactor, the histone methyltransferase- and histone deacetylase-recruiting KAP1, and act by triggering the formation of heterochromatin. KAP1 is ubiquitous, and KRAB-ZFPs are present in most if not all cells, albeit along distinctly cell type-, stage- and state-specific patterns, suggesting that KRAB/KAP1 gene regulation influences a very large number of physiological events. A few years ago, we launched a program aimed at addressing this hypothesis through a combination of genetic, functional and molecular studies focused on two paradigmatic organs, the lympho-hematopoietic system and the liver. Our preliminary results confirm that KRAB/KAP1-mediated transcriptional control is a master regulator of mammalian homeostasis. Accordingly, we now propose to dissect the regulatory networks orchestrated by KAP1 and KRAB-ZFPs in these two systems, to identify their gene targets and the mechanisms of their control, and to probe their possible implication in human pathologies targeting these organs.

2 499 996 €

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

In general relativity and other relativistic theories of gravity, space and time are combined to form ``space-time'' which is curved in the presence of mass. As masses move, for instance like the two components in a binary system, ripples in space-time are created that propagate through the Universe, very much like waves caused by a stone falling into a pond. These ``gravitational waves'' (GWs) are known to exist from the effect that they have on a system of two orbiting stars. After inferring their existence indirectly, the next great challenge is the {\em direct} detection of GWs. While this is the aim of a number of gravitational wave detectors around the world, a detection has not been made. Fortunately, a method exists that allows us today to detect GWs directly, in a frequency range that is much lower but complementary to those covered by ground-based detectors. This method utilises the radio astronomical observations of a special type of star known as radio pulsars. We propose an experiment to achieve the ground-breaking goal of GW detection with the help of an innovative approach. At the heart of this approach, named LEAP, lies the goal to combine the collective power of Europe's biggest radio-telescopes to form the biggest fully-steerable telescope on Earth, providing a ``leap'' in our sensitivity to go beyond the threshold that delivers the first direct detection of GWs. While the rewards for a successful detection of GWs are immense, we demonstrate that this is possible by harvesting the experience and resources uniquely available in Europe.

2 455 285 €

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

Over the past decade, redshift surveys and multi-wavelength imaging campaigns have drawn up an empirical picture of how many stars had formed in which types of galaxies over the history of the universe. However, we have yet to unravel the individual pathways along which galaxies evolve, and the physical processes that drive them. Continuing with the previous approach -- larger and deeper photometric samples -- is not adequate to achieve this goal. A change of focus is required. In this ERC project I will embark on a new way to address the question of galaxy evolution. I will do so as Principle Investigator of the recently approved LEGA-C observing program that has been allocated 128 nights of observation time over the next 4 years with ESO's flagship facility the Very Large Telescope. This new survey will produce for 2500 distant (at z~1) galaxies with, for the first time, sufficient resolution and S/N to measure ages and chemical compositions of their stellar populations as well as internal velocity dispersions and dynamical masses. This will provide an entirely new physical description of the galaxy population 7 Gyr ago, with which I will finally be able solve long-standing questions in galaxy formation that were out of reach before: what is the star-formation history of individual galaxies, why and how is star-formation ``quenched'' in many galaxies, and to what extent do galaxies grow subsequently through merging afterward? LEGA-C is worldwide the largest spectroscopic survey of distant galaxies to date, and ERC funding will be absolutely critical in harvesting this unparallelled database. I am seeking to extend my research group to realize the scientific potential of this substantial investment (6.5M Eur) of observational resources by the European astronomy community. Timing of the execution of the VLT program is perfectly matched with the timeline of this ERC program.

1 884 875 €

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

Acute myeloid leukemia (AML) is the most common malignant myeloid disorder in adults and strongly associated in incidence to advanced age. AML arises from immature hematopoietic progenitor cells via a sequential multistep process, but the nature of these steps remains to a large extent unknown. Therefore, while significant efforts have previously been invested in characterizing the molecular properties of late-stage AML, as diagnosed in patients, less information is available on the events that underlie leukemia initiation and progression. This includes the identity of potential mechanisms that restrict or eradicate developing leukemic cells; hurdles evaded at some point in time for AML to occur. We have developed an inducible transgenic mouse model of AML that, when combined with high-resolution cell fractionation of primitive hematopoietic progenitor cells, offers a unique opportunity to track development of AML from the very first stages of cancer development. Using this, I propose to: 1) Identify and functionally validate molecular determinants that underlie why only some hematopoietic progenitor cells progress into AML, 2) To explore the extent and identity of immune surveillance/editing that accompany progression into AML, and 3) By building on my previous work on hematopoietic aging, to explore AML progression in the context of aging. I anticipate the LEUKEMIABARRIER project to generate novel basic knowledge, not excluding with clinical relevance, with the potential to open up several new fields for further studies. This includes identification of novel cell-intrinsic regulators and immune responses, their underlying mechanisms, and their relationship to the increased incidence of AML with age.

1 999 714 €

Start date: 2014-07-01, End date: 2019-06-30

"Despite impressive progress in cosmology over the last decade, our understanding of the universe is still limited particularly in some Dark Areas: Dark Matter, Dark Energy & Dark Ages, where progress is particularly difficult. I propose to build a focused research group in a unique environment at the crossroad of astrophysics, cosmology and fundamental physics. The goal is to shade new “Light on the DArk” (LIDA) using new analysis techniques and new observations coming from two complementary surveys. The first survey will target the fifty most massive strong lensing galaxy clusters and will shade new lights: i) on the nature of the Dark Matter through constraints coming from: the detailed mass distribution, the importance of substructures, and possible measurement of Dark Matter particle decay or self-annihilation, ii) on the most distant galaxies and the identification of the nature of the sources participating in the cosmic-reionization and ending the Dark Ages, iii) on the nature of the Dark Energy, through the accurate modeling of numerous multiple images in the best lensing clusters. Second, with wide field imaging and spectroscopic surveys of the galaxy distribution we will probe new cosmological tests: i) the combination of galaxy-galaxy weak lensing and galaxy clustering in the framework of the halo model, ii) the measurement of the angle distribution of galaxy pairs, and thanks to the huge volume probed by the BOSS survey, iii) the test of the isotropy principle at various location of the surveyed volume. Finally we will prepare for the next generation of cosmological surveys by conducting an emission line galaxies redshift survey (e-BOSS) similar as those planned by the future facilities such as BigBOSS and EUCLID. The LIDA project can started now, and will benefit from: new data collected by both space and ground-based telescopes over the next five years, as well as an active and vibrant work location in one of the best ranked university in Europe."

2 499 935 €

Start date: 2012-09-01, End date: 2017-08-31

This project will investigate the hypothesis that dust clouds are a major source of charge separation and discharge processes in very low mass, extrasolar objects like M-dwarfs, Brown-Dwarfs, and planets. The aim is to model charging, dust formation and sedimentation in dusty media to understand how the atmospheric ionisation mechanisms change at the border from stars to planets in the M-dwarf--Brown-Dwarf transition region where radio emission starst to exceed X-ray emission, and to investigate the physics and the occurrence of intra-cloud lightning outside our solar system. Lightning is suggested to have triggered the occurrence of life on Earth. Dusty media are generally very common on Earth and in space, for example in volcano plumes that influence the local climate on Earth, on Mars where it blocks Mars-Rover's wheels, in dust-clouds in Brown Dwarfs and planets which determine their chemistry and their detectability, or in planet-forming disks. All have in common that dust of mixed composition is abundant in a turbulent environment in a variety of sizes. This project will perform a characterisation of dusty astrophysical plasma, systemically study charge separation processes and draw comparison to known scenarios in volcanos and Martian plasmas. The project determines stellar parameter and dust cloud characteristics (e.g. cloud height) for which dust cloud charging becomes important, and under which conditions lightning can occur. A charge conservation model will be coupled to a non-equilibrium chemistry to search for discharge-related molecules and for pre-biotic molecules that might occur during lightning. Applications to standard model atmospheres will be carried out to study the influence on the spectral energy distribution and the object's albedo. The long-term aim of this project is to solve the dust and charge conservation equations together with the magnetic field equations in order to study the development of radio emission in low-mass objects.

1 500 000 €

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

"Changes in lifestyle have resulted in a dramatic epidemic of type 2 diabetes and obesity. Among associated complications, Nonalcoholic Fatty Liver Disease (NAFLD) is emerging as the most common chronic liver disease and is gaining increasing recognition as a component of the epidemic of obesity. NAFLD is generally asymptomatic, although a minority of patients may present progressive liver injury with complications of Nonalcoholic steatohepatitis (NASH), cirrhosis and HCC. Excessive accumulation of fatty acids (FA) stored as triglycerides (TGs) in hepatocytes is the hallmark of NAFLD, which is strongly associated with insulin resistance (IR). However, despite the existing correlation between fatty liver and insulin resistance, it remains unclear whether insulin resistance causes the excessive accumulation of TG in the liver, or whether the increase in TG itself or other lipid intermediates such as diacylglycerols (DAG) and/or ceramides may trigger the development of hepatic or systemic insulin resistance. While some studies support the concept that intrahepatic accumulation of lipids precedes insulin resistance, others suggest that hepatic TG may in fact protect the liver from lipotoxicity by buffering the accumulation of FA. Such discrepancy might be explained since different pools of lipids exist within cells and only certain pools regulate insulin signaling. Consistent with such hypothesis, recent results by our group strongly support that specific FA species may influence hepatic TG storage, insulin signaling and/or inflammation. Therefore, the global aim of our proposal is to better understand the regulation of hepatic fatty acid synthesis and partitioning in addition to its impact on the detailed lipid profile. Using state-of-art technology and key genetically modified mouse models combined with original nutritional approaches and lipidomic analysis, our project aims at providing new information on the molecular basis of the pathogenesis of NAFLD."

1 500 000 €

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

Cachexia is a complex syndrome characterized by massive loss of body weight due to uncontrolled loss of adipose tissue and skeletal muscle. The wasting occurs during late stages of many unrelated chronic diseases and frequently leads to the death of affected individuals. Cachexia is most common in cancer, where an estimated 25% of patients die from cancer-associated cachexia (CAC) rather than from the cancer. Despite the tremendous impact of CAC on morbidity and mortality, the underlying molecular mechanisms are poorly understood. Recently, we demonstrated that lipase-catalyzed triacylglycerol (TG) catabolism is required for the pathogenesis of CAC. Mice lacking adipose triglyceride lipase, the rate-limiting enzyme for TG hydrolysis (lipolysis), were completely protected from loss of both adipose tissue and muscle in two forms of cancer. This implies an essential role of the lipolytic process in the pathogenesis of CAC. Here we propose to elucidate the causal role of lipases and their coregulators in CAC development. We will determine mechanisms involved and pursue novel treatment strategies. Our objectives are to: - Investigate how different cancers in mice regulate tissue-specific lipolysis; - Elucidate the functional role of lipases and their coregulators in the pathogenesis of CAC; - Assess whether pharmacological inhibition of specific lipases prevents or delays CAC; - Study the effects of cancer-induced lipolysis on energy dissipating pathways and epigenetic control. The project enters a largely unexplored field: the role of lipid metabolism in the pathogenesis of CAC. The work will heavily rely on the characterization of induced mutant mouse models with CAC and require extensive collaboration with experts in pathology and large-scale systems analytics. The results are expected to yield new mechanisms of disease development and provide novel therapeutic targets to prevent the devastating and prevalent consequences of CAC.

2 499 446 €

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

Observing the process of planetary accretion is crucial to inform models of planet formation. Most of the key action is expected to happen in the gaps of protostellar disks – a spatial realm over which aperture masking interferometry has demonstrated a unique ability to deliver incisive imaging. Masking offers twin advantages of higher dynamic range at the diffraction limit (lambda/D) than differential imaging, while at the same time giving nearly complete Fourier coverage compared to long baseline interferometry. The founding objective of this proposal is to create expertise and technology to understand the astrophysical phenomena so far only glimpsed in faint detections in stellar gaps such as those published in T Cha (Huelamo et al. 2011), HD142527 (Biller et al. 2012) and FL Cha (Cieza et al. 2013). But the central goal of this project is to further advance the experimental technique. Reaching even higher dynamic range for fainter detections is essential for probing planetary birth. The way to improve the dynamic range is clear: increase the accuracy of the primary closure phase observable. To do so, we will follow two paths. The first will use laboratory experimentations to analyse and understand the sources of bias to the closure phase. The resulting end-product will be better software offered to the community, and better techniques for a next generation of aperture masking devices. The second path is to amplify the closure phase signal by combining nulling with closure phase (Lacour et al. 2014). This second path is the most challenging, but will be an important breakthrough to the field. Nulling is to aperture masking what coronagraphy is to classical imaging. Without a first level of nulling, the aperture masking technique will always be limited by the photon noise due to the stellar light. We propose to build on our experience of Lithium Niobate integrated optics devices to bring aperture masking to a new level of performance in high dynamic range imaging.

1 851 881 €

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

The goal of this proposal is to revolutionize our understanding of star formation in nearby galaxies, using numerical simulations. Traditionally, research in star formation has considered the contraction of a giant molecular cloud (GMC), or more commonly a star forming core, under gravity. However there has been relatively little research on molecular clouds themselves, even though they provide the initial conditions for star formation, and thus determine the main assumptions for theories of star formation. The proposed research will focus on the scales of giant molecular clouds, the clouds of molecular hydrogen (H2) where most star formation takes place in nearby galaxies. These objects link galactic scale physics with the small scale physics of star formation. Only now are the computational resources becoming available to study the interstellar medium (ISM) numerically on galactic scales, and model the complex processes involved in GMC and star formation. Simultaneously observational programs (e.g. ALMA, Herschel, CARMA) are starting to resolve GMCs in nearby galaxies. Our research will involve performing calculations on scales from individual GMCs to interacting galaxies, and comparing to forthcoming observations to answer some of the most fundamental questions in star formation, such as why star formation is inefficient, how do GMCs form and what are their lifetimes.

1 169 586 €

Start date: 2011-11-01, End date: 2017-05-31

Clusters of galaxies are a unique cosmological probe. Beyond the potential wells of individual clusters the vast filamentary cosmic web which binds them together contains two thirds of the baryonic matter in the Universe and represents a rich scientific resource. In order to use such resources correctly it is essential to understand the energetics, dynamics and redshift dependence of the intra/inter-cluster media. Absolutely fundamental to this understanding is a detailed knowledge of the strength, morphology and evolution of their magnetic fields. In addition, using clusters of galaxies and cosmic large scale structure as a laboratory in which to probe these fields is also the key to unlocking the more fundamental long standing problems of magnetic evolution and structure, and ultimately to determining the very origins of cosmic magnetism itself. To tackle these fundamental questions I will use a combination of two different observational approaches, effectively unifying the radio spectrum from meter to millimeter wavelengths: Rotation Measure Synthesis and the resolved Sunyaev–Zel’dovich Effect. Individually these approaches both offer unique insights; combined they provide an almost complete picture of the internal baryonic dynamics of clusters and large scale structure. I will use a set of leading and next generation radio telescopes around the globe. These telescopes span the radio spectrum, but are united by my leading role in the magnetism and/or cluster science case for each one. I will build an infrastructure which combines their operations to achieve a scientific outcome much greater than the individual instruments can produce independently. This will include development of world leading image reconstruction techniques; novel approaches to data combining; and state of the art analysis methods - as well as building a program which integrate disparate communities in astronomy. This program is called LODESTONE, to reflect the aligning nature of magnetism.

1 928 369 €

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

Black holes (BHs) and ultra-high energy cosmic rays (UHECRs) are two extremes of the universe that link particle physics and astrophysics. BHs are the most efficient power generators in the universe while UHECRs are the most energetic particles ever detected. As we showed previously, a major fraction of the power of BHs is channeled into radio-emitting plasma jets, which are also efficient particle accelerators. Are BHs also responsible for UHECRs? This long-standing question could be answered soon, through the dawn of cosmic ray astronomy. The giant Auger observatory has now shown for the first time that the arrival directions of UHECRs are non-isotropic, potentially pointing back to their sources of origin. BHs turned out to be major suspects, but other sources could still also be responsible. To address this conclusively and to establish cosmic ray astronomy as a productive new field in the coming years, we need to increase statistics, expand current observatories, and have complementary all-sky radio surveys available to identify sources, since radio emission traces particle acceleration sites. Here, techniques pioneered by the Low-Frequency Array (LOFAR) promise major advances. First of all, working on LOFAR we uncovered a new technique to detect UHECRs with radio antennas and verified it experimentally. The technique promises to increase the number of high-quality events by almost an order of magnitude and provides much improved energy and direction resolution. We now want to implement this technique in Auger, combining LOFAR and AUGER know-how. Secondly, LOFAR and soon other SKA pathfinders will significantly improve all-sky radio surveys with high sensitivity, resolution, and image quality. Hence, we will use LOFAR to understand the astrophysics of UHECR source candidates and compile a radio-based catalog thereof. We start with jets from BHs and move later to other sources. Together this will allow us to identify UHECR sources and study them in detail.

3 460 000 €

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

Despite clinical advances, diseases of the cardiovascular system are the most common cause of morbidity and mortality in the EU with currently 50 million people suffering from heart failure. These important challenges call for a better understanding of underlying mechanisms to enable development of innovative, effective diagnostic and therapeutic strategies for heart failure. Cardiac stress such as myocardial infarction or hypertension leads to cellular “remodeling” of the left ventricle resulting in heart failure. Protein-coding genes originate from only 1.5% of the genome, whereas the larger remaining portion is often transcribed to non-coding RNAs, of which functional importance is still ill understood. We pioneered a role of small microRNAs as diagnostics and therapeutic targets for heart failure (Nature, 2008; Nature Comm, 2012, J Clin Invest, 2014). We now will focus on the larger fraction of long non-coding RNAs (lncRNAs) and their functional roles, as well as diagnostic and therapeutic use in heart failure. The proposal has the following interconnected objectives: a) identify novel functional relevant cardiac remodeling-associated lncRNAs; b) characterise key lncRNA cardiac targetomes; c) investigate lncRNA-paracrine mechanisms and the diagnostic and prognostic potential of cardiac-derived extracellular lncRNAs using large clinical cohorts; and d) discover their therapeutic potential to prevent cardiac remodeling in clinically relevant animal models. Innovative molecular and cell-based methods, a unique lncRNA-shRNA library, genetic animal models and availability of large clinical biobanks will form the basis for a successful strategy. LONGHEART will lead to ground-breaking new insight into the role of lncRNAs in the heart. These findings will firmly establish lncRNA-based mechanisms to identify fundamentally novel diagnostic and therapeutic entry points for a most serious clinical important disorder in dire need for new diagnostic and therapeutic paradigms.

1 816 250 €

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

The solar system beyond Neptune’s contains largely unaltered material from the primordial circum-solar disk. It also kept the memory of the early planetary migrations, and thus contains essential information on the origin and evolution of our planetary system. Here I propose to study the Trans-Neptunian Objects (TNOs) using the stellar occultation technique. It consists in observing the passage of remote TNOs in front of those “Lucky Stars”, that reveal shapes, atmosphere and rings of bodies from sub-km to thousand-km in size. Very few teams in the world master this method. The European-led network that I coordinate is now leader in predictions, instrumentation, observations and analysis related to stellar occultations, with innovative approaches and unprecedented results. In the last decade, our group led the field by discovering rings around the asteroid-like object Chariklo, detecting sub-km TNOs and drastic variations of Pluto’s atmospheric pressure. Based on those noteworthy discoveries and unique skills of ours, I will coordinate the following work packages: (1) Rings around small bodies - Understand the newly found Chariklo’s rings, tackle the theory of rings’ origins and evolutions around small bodies, discover new ring systems around other bodies. (2) Very small, sub-km TNOs and Oort Cloud objects - Constrain the collisional history of our early outer solar system, and possibly detect Oort Cloud objects. (3) Pluto’s atmosphere – Explore Pluto’s atmosphere and its atypical seasonal cycle, search for atmospheres around other TNOs. (4) Explore specific, large TNOs – Provide their sizes, shapes, albedos and densities. These programs are timely in view of NASA/New Horizons Pluto flyby in July 2015, and the ESA/GAIA mission expected to provide a greatly improved astrometric catalog release in 2016. Most of the budget will be dedicated to human power to conduct observations and their analysis, plus the associated travel and telescope time expenses.

2 423 750 €

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

Tumors often engage the lymphatic system to invade and metastasize. The tumor-draining lymph node (dLN) may be an immune privileged site that protects the tumor from host immunity, and lymph flow draining tumors is often increased, enhancing communication between the tumor and the sentinel node. In addition to increasing transport of tumor antigens and regulatory cytokines to the lymph node, increased lymph flow in the tumor margin causes mechanical stress-induced changes in stromal cells that stiffen the matrix and alter the immune microenvironment of the tumor. In this proposed project, we will investigate the interplay between lymphatic drainage and flow-induced mechanotransduction in the tumor stroma that may synergize to promote tumor immune escape by appropriating lymphatic mechanisms of peripheral tolerance. We will address the hypothesis that lymphatic drainage and flow-induced mechanotransduction in the tumor stroma synergistically promote tumor immune escape by altering the immune microenvironment, and that targeting lymphatic drainage from the tumor may represent a new avenue for tumor immunotherapy. For the latter, we will develop strategies to limit or block lymphatic flow in the tumor microenvironment and characterize their ability to improve the efficacy of tumor immunotherapy by dampening local immunosuppression in the tumor stroma and tumor-draining lymph node (dLN). We will combine in vivo mouse models and intravital imaging with engineered in vitro microenvironments and nanoparticle-based targeting strategies in three broad aims designed to constitute several PhD and postdoctoral projects.

2 217 582 €

Start date: 2013-05-01, End date: 2016-12-31

Lymphoid cancers are among the most common human malignancies and characteristically harbour genomic aberrations. Although databases will soon be flooded with genome sequences from thousands of tumours, interpretation and validation of these data is limited by the genetic variability and uncontrolled environmental exposures inherent to human studies. There is therefore a growing need in complementary approaches that would provide understanding of how and which genomic aberrations underlie tumour genesis. It has become apparent that the generation of DNA double strand breaks during the process of antigen receptor diversification, including RAG1/2 protein-generated DNA breaks during V(D)J recombination, are key intermediates in the appearance of lymphoid neoplasm. In this project, we propose to elucidate the molecular mechanisms, the genomic lesions and the oncogenic pathways underlying B and T cell cancers using a combination of mouse models and cutting-edge cytogenetic, genomic and transcriptomic technologies. We aim (i) to define the major genomic lesions and oncogenic pathways underlying the rapid onset of T-cell lymphomas in a unique mouse model that carries exacerbated RAG-induced genomic instability; (ii) to decipher the genomic lesions and pathways underlying B versus T lymphoma tropism; (iii) to investigate the functional interactions between RAG- and DNA damage response / DNA repair-complexes in suppressing genomic instability and lymphomagenesis; and (iv) to identify and validate lesions and genes underlying human B and T cell cancers using a cross-species oncogenomic comparative approach. In doing so, this study will also 1) increase our understanding of the fundamental mechanisms maintaining genome stability during lymphocyte development; 2) greatly improve interpretation and validation of whole genome sequencing analysis of human leukaemia and lymphoma; and 3) provide well-characterized animal models for developing and testing targeted therapeutics.

1 498 940 €

Start date: 2013-02-01, End date: 2019-01-31

Primary cancers can induce lymphatic vessel growth (lymphangiogenesis), enhancing metastasis to draining lymph nodes (LNs). We found that tumors also induce lymphangiogenesis in draining LNs, leading to increased cancer spread to distal LNs and beyond. Very recently, we found that lymphatic vessel activation in peripheral tissues and draining LNs also plays a previously unanticipated role in the control of chronic inflammatory diseases. This proposal aims at a comprehensive characterization of the function of lymphatic vessels in inflammation, using a variety of genetic mouse models for enhanced or reduced lymphatic function, novel quantitative techniques for the in vivo imaging of lymphatic function, and a miniaturized 3-dimensional in vitro platform for the high-throughput phenotypic screening of libraries of small, drug-like molecules for modulators of lymphatic function. A genome-wide analysis of the gene expression profile shall be made from lymphatic vessels isolated by high-speed cell sorting and by immuno-laser capture microdissection from tumors and their lymph node metastases, inflamed tissue and its draining lymph nodes, and normal tissues, followed by functional characterization of potential therapeutic targets and diagnostic markers. Finally, we will establish novel genetically fluorescent mouse models for the in vivo real-time imaging of lymphatic activation, and we will develop an innovative approach for the in vivo detection of early micrometastases, using antibody-based PET and near-infrared imaging of tumor-induced stromal changes. These studies will improve our understanding of lymphatic involvement in inflammation and cancer metastasis, and will provide the basis for completely novel approaches to treat and detect inflammation and cancer metastasis.

2 493 300 €

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

Chromosomal instability (CIN), the inability to correctly segregate sister chromatids during mitosis, is a hallmark of cancer cells. Overexpression of the mitotic checkpoint protein Mad2, commonly found in human tumors, leads to CIN and the development of aneuploid tumors in mouse models. However, recent observations from various laboratories suggest that aneuploidy can promote or suppress tumorigenesis. Therefore understanding the relationship between aneuploidy and tumor formation, identifying in what context aneuploidy acts oncogenically and those in which it acts as a tumor suppressor, is thus vital if we want to make progress in battling cancer. We propose to generate regulatable mouse models that recapitulate the aneuploidy state of human tumors, using state-of–the–art mouse genetic strategies, to investigate the role of CIN in promoting or suppressing tumorigenesis. Moreover, CIN has been shown to facilitate escape from oncogene addiction (the dependence of tumor cells on their initiating lesion for survival) and may be responsible for tumor relapse after targeted therapies. Due to the clinical relevance of these findings, this proposal aims to investigate how CIN potentiates oncogene independence. It is possible that some CIN cells in the primary tumor are already independent of the initiating oncogene prior to treatment. Alternatively, CIN cells are more susceptible of acquiring additional mutations and evolve to become independent of the initiating lesion. We propose to develop a highly innovative three-dimensional in vitro culture system to isolate and characterize these surviving cells to further eliminate them. It is necessary to understand the molecular mechanisms that lead to CIN and the consequences it has in tumor initiation, suppression and relapse, hoping that the genes or proteins identified could be targeted therapeutically. We believe that answers to these specific aims will have important consequences for the treatment of human tumors.

1 500 000 €

Start date: 2012-02-01, End date: 2018-01-31

The birth of a neutron star with an extremely strong magnetic field, called a magnetar, has emerged as a promising scenario to power a variety of outstanding explosive events. This includes gamma-ray bursts, among the most luminous events observed up to high redshift and therefore useful as cosmological probes, but also supernovae with extreme kinetic energies called hypernovae and other classes of super-luminous supernovae. Simple phenomenological models, where the magnetar rotation period and magnetic field are adjusted, can explain many of these observations but lack a sound theoretical basis. The goal of this proposal is to develop an ab initio description of magnetar powered explosions in order to delineate the role they play for the production of gamma-ray bursts and super-luminous supernovae. This is urgently needed to interpret the growing diversity of explosions observed with ongoing transient surveys (iPTF, CRTS, Pan-STARRS) and in the perspective of future programs of observations such as SVOM and LSST. By using state-of-the-art numerical simulations, the following outstanding questions will be addressed: 1) What is the origin of the gigantic magnetic field observed in magnetars? The physics of the magnetic field amplification in a fast-rotating nascent neutron star will be investigated thoroughly from first principles. By developing the first global protoneutron star simulations of this amplification process, the magnetic field strength and geometry will be determined for varying rotation rates. 2) What variety of explosion paths can be explained by the birth of fast-rotating magnetars? Numerical simulations of the launch of a hypernova explosion and a relativistic GRB jet will provide the first self-consistent description of both events from a millisecond magnetar. Furthermore, the new understanding of magnetic field amplification will be used to improve the realism of these simulations.

1 500 000 €

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

"Understanding star formation remains one of the greatest challenges of modern astronomy. Indeed in this field the progresses have been limited due, first, to the huge dynamics of spatial and temporal relevant scales and, second, the great variety and non-linearity of the physical processes involved in the formation of stars. The present proposal will contribute to provide a complete and coherent picture of the star formation process by self-consistently following the evolution of the interstellar matter from the very diffuse gas up to the protostars. This will be achieved by performing a series of heavy MHD numerical simulations with an adaptive mesh refinement code while subdivising the problem in three major steps namely the formation of large scale molecular clouds, the formation of star forming cores and the collapse of protostellar cores. In particular, the impact of the magnetic field and the radiative processes will be self-consistently treated using appropriate schemes. At each step, comparisons with both analytical models and observations will be performed by using existing models or developing new ones and calculating synthetic observations. The simulation results will also be used to test and improve the methods and the algorithms used by observers to extract the physical information from their data. An existing database, where the simulation results are available, will be further developed. The present proposal pursues two aims: i) achieving a global understanding of the star formation process, in particular by elucidating the link between the physical properties of the large scale ISM and the characteristics of the protostars, such as their mass, magnetisation and angular momentum ii) provide a better insight of the structure, nature and role of the magnetic field and the turbulence from the diffuse to the dense parts of the ISM."

1 312 267 €

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

"Rotation and angular momentum transport play a critical role in the formation and evolution of astrophysical objects, including the fundamental bricks of astrophysical structures: stars. Stars like our Sun form when rotating dense cores, in the interstellar medium, collapse until they eventually reach temperatures at which nuclear fusion begins; while planets, including the Earth, form in the rotationally supported disks around these same young stars. One of the major challenges of modern astrophysics is the “angular momentum problem"": observations show that a typical star-forming cloud needs to reduce its specific angular momentum by 5 to 10 orders of magnitude to form a typical star such as our Sun. It is also crucial to solve the angular momentum problem to understand the formation of protoplanetary disks, stellar binaries and the initial mass function of newly formed stars. Magnetic fields are one of the key ways of transporting angular momentum in astrophysical structures: understanding how angular momentum is transported to allow star formation requires characterizing the role of magnetic fields in shaping the dynamics of star-forming structures. The MagneticYSOs project aims at characterizing the role of magnetic field in the earliest stage of star formation, during the main accretion phase. The simultaneous major improvements of instrumental and computational facilities provide us, for the first time, with the opportunity to confront observational information to magnetized models predictions. Polarization capabilities on the last generation of instrument in large facilities are producing sensitive observations of magnetic fields with a great level of detail, while numerical simulations of star formation are now including most of the physical ingredients for a detailed description of protostellar collapse at all the relevant scales, such as resistive MHD, radiative transfer and chemical networks. These new tools will undoubtedly lead to major discovery in the fields of planets and star formation in the coming years. It is necessary to conduct comprehensive projects able to combine theory and observations in a detailed fashion, which in turn require a collaboration with access to cutting edge observational datasets and numerical models. Through an ambitious multi-faceted program of dedicated observations probing magnetic fields (polarized dust emission and Zeeman effect maps), gas kinematics (molecular lines emission maps), ionization rates and dust properties in Class 0 protostars, and their comparison to synthetic observations of MHD simulations of protostellar collapse, we aim to transform our understanding of: 1) The long-standing problem of angular momentum in star formation 2) The origin of the stellar initial mass function 3) The formation of multiple stellar systems and circumstellar disks around young stellar objects (YSOs) Not only this project will enable a major leap forward in our understanding of low-mass star formation, answering yet unexplored questions with innovative methods, but it will also allow to spread the expertise in interpreting high-angular resolution (sub-)mm polarization data. Although characterizing magnetic fields in astrophysical structures represents the next frontier in many fields (solar physics, evolved stars, compact objects, galactic nuclei are a few examples), only a handful of astronomers in the EU community are familiar with interferometric polarization data, mostly because of the absence of large european facilities providing such capabilities until the recent advent of ALMA. It is now crucial to strengthen the European position in this research field by training a new generation of physicists with a strong expertise on tailoring, analyzing and interpreting high angular resolution polarization data."

1 500 000 €

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

With the CoRoT & Kepler data analysed, the time is optimal to move from observational asteroseismology to innovative stellar modelling of the steal factories of the Universe. With MAMSIE, we follow the footsteps of helioseismologists some 30 years after them, but this time we shall be developing inversion methods for stellar structure based on gravity-mode oscillations that probe the deep stellar interior. MAMSIE will lead to new models for a variety of single and binary stars with masses between 3 and 30 M⊙ whose space photometry and high-resolution spectroscopy reveal sufficient seismic information on their gravity modes to invert the frequencies and compute the stars’ structure. In contrast to the conventional theoretical approach to stellar evolution, the data-driven approach of MAMSIE will allow us to include angular momentum transport due to internal gravity waves, as well as mixing prescriptions for turbulent entrainment, from coupling of the output of 3D hydrodynamical simulations of these phenomena to specialised seismic observables of relevance for massive stars. Our sample includes slow and fast rotators, with and without a magnetic field, with and without a stellar wind. The new models will be placed in an evolutionary context for optimal assessment of the evolution of internal rotation, angular momentum, and chemical mixing throughout stellar life of massive stars. The output of the stellar modelling will provide fundamentals for all topics in modern astrophysics that rely on massive star models. MAMSIE is overarching and will require a multidisciplinary team led by an expert in gravity-mode oscillations working in close collaboration with a 3D hydrodynamics expert; it will offer a highly competitive environment for PhD and postdoctoral research on the astrophysics of massive stars.

2 498 941 €

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

Over the past decades, the robotic exploration of the planet Mars has produced a wealth of geological observations. They show that Mars has not always been the desert planet of today. It has seen eras conducive to rivers and lakes, ice ages, and even periods with a collapsed atmosphere. These different epochs are the reason why Mars remains the objective of space agencies, as they evoke the possibility of past habitability and spectacular climate changes. Yet, in spite of all the data, the climatic processes that have shaped Mars’ surface through time remain largely unknown. What happened on Mars? Was the Red Planet suitable for life? What explains its evolution? The objective of this project is to develop numerical models to simulate the past environments of Mars.A completely new “Mars Evolution Model” will be created by asynchronously coupling hydrology, glacial flows and ground ice models with a new generation 3D Global Climate Model (GCM). This GCM will be derived from the one that we have previously designed to simulate present day Mars. We will radically update it using new technologies to represent the details of the surface as well as all the processes that affected Mars when its environment evolved because of the oscillations of its orbit and obliquity, during changes in the atmospheric composition, or through events like meteoritic impacts or volcanic eruptions. Notably, we will highlight the last ten millions years that have been recorded in the polar layered deposits, whose formation will be simulated for the first time realistically. These new tools will address numerous enigmas found in Mars sciences. They will also offer a new platform to study specific processes such as the atmospheric escape through time or the chemical alteration of the soil. Furthermore, the project will test our capacity to model planetary environments and climate changes, as well as provide lessons on the evolution of terrestrial planets and the possibility of life elsewhere.

2 493 836 €

Start date: 2019-10-01, End date: 2024-09-30

The ambition of this research program is to challenge the nature of gravity, provide an alternative to dark energy, and pave the way towards a potential resolution of one the most tantalizing problems of physics today: The Old Cosmological Constant Problem. As General Relativity celebrates its centennial, its predictive successes and its status as our most elegant theory of gravity are incontrovertible. Nevertheless, while the recent discovery of the late-time acceleration of the Universe is in perfect agreement with observations, the 120 orders of magnitude discrepancy between expectations and observations is one of today's most challenging puzzles and may be the sign of new physics to uncover. This conundrum has driven the development of dark energy models as alternative sources for acceleration, but many of them suffer from a similar discrepancy and require an unnatural tuning of their parameters. Despite decades of attempts, the Old Cosmological Constant Problem remains yet unsolved. This program proposes a distinct direction to address this problem and to explain the acceleration of the Universe where the graviton, the particle carrier of gravity, has a mass, or is effectively massive. Not only will this open a new panorama for cosmology, it will also answer the fundamental question of the nature of the graviton. Signatures and constraints will be derived through astrophysical and cosmological probes. While striving to address these fundamental challenges, the program will also elucidate new aspects of massive gravity by establishing its theoretical viability and embedding as an effective field theory. These developments will feed into new breakthroughs that have recently emerged from massive gravity. As major missions and experiments are underway to probe dark energy and to detect gravitational waves, there is no better time to question gravity at the fundamental level, to provide alternatives to dark energy and to determine their unique signatures.

1 975 829 €

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

Chronic inflammation may result from failure of the host response to engage pro-resolving pathways. The current treatment armamentarium for chronic inflammatory conditions may lead to immune suppression. Thus, identification of novel therapeutics that control inflammation without immune suppression will provide an attractive alternative approach. This is especially important since incidence of these conditions increases with an ageing global population. In planaria, mice, human peripheral blood and milk I recently uncovered a new family of endogenous molecules, named Maresin Conjugates in Tissue Regeneration (MCTR). These potently regulate white blood cell responses, promote the resolution of acute inflammation and accelerate tissue regeneration. The aim of this Starting Grant is to identify pathways that lead to failed resolution in inflammatory arthritis, as a prototypical chronic inflammatory condition. The hypothesis is that MCTR biosynthesis is dysregulated in inflammatory arthritis, leading to an unbridled host response, chronic inflammation and tissue destruction. This proposal will employ a multipronged approach to test this hypothesis by 1) Determining MCTR regulation in self-resolving and delayed-resolving arthritis; 2) Investigating the host protective and tissue regenerative actions of MCTRs in inflammatory arthritis; 3) Establishing the MCTR biosynthetic pathway and 4) Determining the regulation if its components during self-limited and delayed-resolving arthritis. Anticipated results will uncover novel pathways that become dysregulated during failed resolution. Results from this Starting Grant will also identify targets and new therapeutic approaches that will engage pro-resolution programs as well as tissue regeneration in conditions characterised by persistent inflammation and hence failed resolution. This will lay the basis for informed structure-activity based studies and the design of therapeutics for treatment of chronic inflammatory conditions.

1 964 303 €

Start date: 2016-03-01, End date: 2021-02-28

MYC proteins like MYC and MYCN are transcription factors that are mis-regulated in more than half of all types of human cancer including medulloblastoma, the most common brain malignancy in children. The two main challenges that can guide research in the field of pediatric brain tumors is improving survival and reducing long-term detriments due to treatment toxicities, especially from craniospinal radiotherapy. Medulloblastoma is suggested to originate from specific cells in the small brain, cerebellum. These brain tumors have recently been classified into four distinct molecular subgroups and subgroup-specific driver genes have been suggested. However, the precise role of such drivers in tumor initiation and their importance in specifying particular subgroups has not been sufficiently evaluated in proper cells of medulloblastoma origin. We have generated clinically relevant animal models that carefully resemble some of the defined subgroups of medulloblastoma. In this proposal we intend to use the models to identify the specific cell type these brain tumors originates from. We also aim to refine our medulloblastoma models and develop novel models to define and study cells involved in brain metastasis and tumor recurrence; the main cause of death in brain tumor patients. We have managed to culture normal human cerebellar stem cells and we now plan to model human medulloblastoma development by overexpressing oncogenes or silencing suppressor genes that are defined as clinically relevant medulloblastoma drivers. We will use a forward genetics screen to identify novel drivers and specifiers of various subtypes of medulloblastoma. We hope these combined efforts will help us better model human medulloblastoma formation and we expect to generate tumors that correlate well, both pathologically and molecularly, with primary cell cultures derived from medulloblastoma patients.

1 497 059 €

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

In most western countries, life expectancy is increasing by 3 months a year. As the average age of the population increases, so too does the prevalence of age-related diseases such as cancer, cardiovascular and metabolic diseases, and neurodegenerative disorders. An essential component of ageing research is to understand the biological mechanisms that contribute to the ageing process at the cellular and molecular levels. This has major implications not only for the treatment of age-associated diseases but also for the promotion of healthy ageing. Studies of experimental animals and observations in humans have identified an array of genes and nutritional conditions that increase lifespan. However, these manipulations (genetic or nutritional) often have detrimental effects on other biological processes; for example, reproduction, metabolism, immunity or growth. This is an area of ageing research that has largely been ignored but that is critical to the success of strategies intended to slow ageing and thus the onset of disease. The primary goal of this research proposal is to understand how lifespan extension is linked to reproduction. We will use the nematode Caenorhabditis elegans as a model organism to identify novel conserved genes, molecules, and metabolic networks that link reproduction and longevity through nutrition. The proposed study is based on a unique set of preliminary data that identifies the first clear molecular links between these traits: a steroid hormone receptor and a reproduction-responsive lipase, both of which modulate lifespan extension achieved through changes in nutrition. Understanding the regulation and function of these genes and pathways will clarify at the molecular level how reproduction is linked to longevity. This may ultimately lead to interventions that optimise metabolic activity to promote healthy ageing.

1 941 499 €

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

The last decade has seen an explosion of research into the epigenetic regulation of cell biology. Indeed, great efforts have been made to elucidate epigenetic regulation in stem cell biology, development, and within the plastic states of cancer. Current estimates place the prevalence of obesity in the range of 300 million to beyond 1 billion by the year 2030. As a critical risk factor for heart disease, diabetes and stroke, obesity currently represents one of the world’s chief economic and health care challenges. While studies have established a genetic framework for our current understanding of obesity, the contribution of several critical regulatory layers, in particular epigenetic regulation, remains poorly understood. We recently performed the first genome-wide RNAi screen for obesity regulators in the adult fly. Intriguingly, developmental regulators scored among the most enriched pathways (Pospisilik, Cell 2010). Systematic interrogation of the 500 candidate obesity genes by tissue-specific knockdown has now identified the Polycomb-Trithorax system (PcG-Trx) as the most enriched obesity-altering pathway. Here, we propose to translate these findings to the mammalian context through completion of three aims: i. generation and characterization of 8 PcG conditional knockout mouse lines, ii. dissection of the functional roles of PcG in adipose tissue differentiation, function and disease, and iii. building of a functionally interrogated unbiased epigenetic map of the PcG-system for murine and human obesity. To achieve these goals we will combine targeted mouse genetics, complex phenotyping and state-of-the-art integrative bioinformatics. Using this unique functional-genetics-to-epigenomics approach we will provide an unprecedented functionally validated genomics resource for obesity research worldwide, unravel an entire regulatory niveau in obesity, and if we are lucky, highlight novel therapeutic strategies for metabolic disease.

1 654 430 €

Start date: 2011-12-01, End date: 2016-11-30

This proposal aims to clarify mitochondrial contribution to obesity and thinness, using carefully characterized mitochondrial disease and obese patient materials, and genetically modified disease models. Manifestations of mitochondrial respiratory chain (RC) defects range from infantile multisystem disorders to adult-onset myopathies or neurodegeneration, and even aging-related wasting. Why defects in oxidative ATP production can lead to such variety of manifestations and tissue specificity is unknown. We have previously identified a number of gene defects that lead to RC disorders. In addition to neurological symptoms, these patients often show various metabolic manifestations: specific gene defects associate with short stature and thinness, whereas others with metabolic syndrome or obesity. This implies that specific mitochondrial defects can have opposing effects for fat storage or utilization. The involved pathways may contribute to mitochondrial disease progression, but are unknown. We propose to a) undertake a major clinical study on genetically defined, obese or thin, mitochondrial patients, and examine their metabolic phenotype in finest detail. These data will be compared to those from normal obesity, to search for common mechanisms between mitochondrial and general obesity. b) generate a set of disease models for mitochondrial disorders associated with obesity, and knock-out models for specific signallers for crossing with the disease models. c) identify in detail the involved regulatory pathways, and utilize these for searching chemical compounds that could modulate the response, and have therapeutic potential. The project has potential for major breakthroughs in the fields of mitochondrial disease pathogenesis and treatment, neurodegeneration and obesity.

2 500 000 €

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

Ageing is a complex physiological process that affects almost all species, including humans. Despite its importance for all of us, the biology of ageing is insufficiently understood. To uncover the molecular underpinnings of ageing, I propose an interdisciplinary research program that will identify and investigate metabolic and genetic regulators of ageing. Progressive loss of cellular homeostasis causes ageing and an age-associated decline in protein quality control has been implicated in numerous diseases, including neurodegeneration. Seeking for ways to improve protein quality, I have identified a novel longevity pathway in Caenorhabditis elegans. In a forward genetic screen, I found a link between metabolites in the hexosamine pathway and cellular protein quality control. Hexosamine pathway activation extends C. elegans lifespan, suggesting modulation of ageing by endogenous molecules. In a first step, I will explore the mechanism by which hexosamine metabolites improve protein quality control in mammals, using cultured mammalian cells and a mouse model for neurodegeneration. Preliminary data show that hexosamine pathway metabolites enhance proteolytic capacity in cells and reduce protein aggregation, suggesting conservation. Second, I will investigate molecular mechanisms that activate the hexosamine pathway to promote protein homeostasis and counter ageing. Third, I will perform a direct forward genetic screen for modulators of ageing in C. elegans. For the first time, mutagenesis and next generation sequencing can be paired in forward genetic screens to interrogate the whole genome for lifespan-extending mutations in a truly unbiased manner. This innovative approach has the potential to reveal novel modulators of the ageing process. Taken together, this work aims to understand molecular mechanisms that maintain cellular homeostasis to slow the ageing process, and to develop a new technology to identify yet unknown genetic modulators of ageing.

1 500 000 €

Start date: 2015-08-01, End date: 2020-07-31

Blood vessels form a versatile transport network and provide inductive signals called angiocrine factors to regulate tissue-specific functions. Blood vessels in bone are heterogeneous with distinct capillary subtypes that exhibit remarkable alterations with age. Bone is the most prevalent site of metastasis, and ageing is linked to the reactivation of dormant tumor cells (dorTCs) and metastatic relapse. Bone remodeling processes are also associated with metastatic relapse. Here, I will define the role of distinct vascular niches in regulating the fate of DTCs in bone. Finally, I will unravel the age-related angiocrine factors and identify key angiocrine signals that drive the reactivation of dorTCs. I will employ a powerful combination of advanced 3D, intravital, and whole body imaging, cell specific-inducible mouse genetics, transcriptional profiling and bioinformatics in an unprecedented manner to achieve my goals. New cutting-edge techniques such as advanced 3D and 4D bone imaging are important aspects of my proposal. I will also define the role of highly promising novel candidate age-related angiocrine signals with sophisticated inducible endothelial-specific humanised mouse models. My work will break new ground by unraveling a repertoire of age-related angiocrine factors and will contribute to a wider scientific community in bone, blood, and age-related diseases. This interdisciplinary work at the frontiers of bone, cancer and vascular biology will provide the first conceptual link between vascular ageing and bone metastasis and will contribute towards the development of therapeutic strategies for targeting DTCs in bone.

1 496 613 €

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