Data-Gouv-ML/pcri-erc-participations-et-projets-laureats huggingface dataset:
Projet ERC : CARBOCENTRE (Horizon 2020, appel 2020, Synergy grants)
Entité participante : Leiden University — Pays : Pays-Bas — Rôle : CO-PI
Type d'entité : Enseignement supérieur ou secondaire
Financement ERC de l'entité : 3768875.0 €

Enzymes that produce and degrade oligosaccharides and glycoconjugates are present in all kingdoms of life. The ability to visualize, modulate and understand these carbohydrate-active enzymes (CAZymes) therefore offers great potential for human health and sustainable industries. To provide a “disruptive” shift in our understanding, we adopt in this proposal a multidisciplinary approach combining structural biology, enzymology, computational chemistry, organic synthesis, and chemical biology, with major leaders in these fields part of our CARBOCENTRE Synergy Team. Three fundamental strands will specifically target and ‘capture’ glycoprocessing enzyme active sites. Biochemical and 3-D structural analyses will inform computational dissection of the reaction coordinate of key enzymes for human health and biotechnology processes. Building on our founding work on retaining glycosidases we will also target inverting glycosidases and glycosyltransferases. Following fundamental analyses, our probes will feed research in two major application domains of human health and biotechnology: 1. To provide visualization, diagnosis, and inhibitor assays and clinical lead compounds for enzymes in cancers and genetic diseases (lysosomal storage disorders). 2. To explore the natural diversity of CAZymes and to discover, quantify and optimize new enzymes for food and household applications and for biomass conversion to biofuels. In an iterative cycle, structural biology and enzymology (Davies, York), will inform, through structures of enzymes and enzyme-inhibitor complexes, theoretical and computational chemistry (Rovira, Barcelona), which in turn will guide the design and synthesis (Overkleeft, Leiden), of inhibitors and activity-based probes for ensuing chemical biology studies in the domains of biomedicine and biotechnology.

Mots-clés : carbohydrate active enzymes,activity based protein profiling,carbohydrate chemistry,enzymology,biofuels,computational design,glycobiology,glycochemistry
Projet ERC : CHROMABOLISM (Horizon 2020, appel 2017, Consolidator grants)
Domaine scientifique : Life Science
Panel : Cellular, Developmental and Regenerative Biology
Entité participante : Austrian Academy of Sciences — Pays : Autriche — Rôle : PI
Acronyme de l'entité : OAW
Type d'entité : Organismes privés (hors enseignement)
Financement ERC de l'entité : 1980916.0 €

Epigenetics research has revealed that in the cell’s nucleus all kinds of biomolecules–DNA, RNAs, proteins, protein posttranslational modifications–are highly compartmentalized to occupy distinct chromatin territories and genomic loci, thereby contributing to gene regulation and cell identity. In contrast, small molecules and cellular metabolites are generally considered to passively enter the nucleus from the cytoplasm and to lack distinct subnuclear localization. The CHROMABOLISM proposal challenges this assumption based on preliminary data generated in my laboratory. I hypothesize that chromatin-bound enzymes of central metabolism and subnuclear metabolite gradients contribute to gene regulation and cellular identity. To address this hypothesis, we will first systematically profile chromatin-bound metabolic enzymes, chart nuclear metabolomes across representative leukemia cell lines, and develop tools to measure local metabolite concentrations at distinct genomic loci. In a second step, we will then develop and apply technology to perturb these nuclear metabolite patterns by forcing the export of metabolic enzymes for the nucleus, aberrantly recruiting these enzymes to selected genomic loci, and perturbing metabolite patterns by addition and depletion of metabolites. In all these conditions we will measure the impact of nuclear metabolism on chromatin structure and gene expression. Based on the data obtained, we will model for the effects of cellular metabolites on cancer cell identity and proliferation. In line with the recent discovery of oncometabolites and the clinical use of antimetabolites, we expect to predict chromatin-bound metabolic enzymes that can be exploited as druggable targets in oncology. In a final aim we will validate these targets in leukemia and develop chemical probes against them. Successful completion of this project has the potential to transform our understanding of nuclear metabolism in control of gene expression and cellular identity.

Mots-clés : folate metabolism,nuclear metabolomics,transcription,target discovery
Projet ERC : GALVANI (Horizon 2020, appel 2019, Synergy grants)
Entité participante : Hôpital de la Timone Adulte — Pays : France — Rôle : Partner
Type d'entité : Recherche
Financement ERC de l'entité : 1033501.0 €

Epilepsy is a neurological disorder affecting 65 million people worldwide. Pharmacological treatments or surgery are ineffective in one third of the cases – 19 million people. Recent findings indicate that non-invasive brain transcranial current stimulation (tCS) is safe and of therapeutic promise in epilepsy. However, it is not yet indicated as a standard treatment due to major scientific limitations: unknown mechanisms of action, insufficient account for patient-specific factors, poor understanding of short- and long-term effects. Our ambition is to transform the care of a large fraction of patients living with drug-resistant epilepsies by solving a fundamental problem: to efficiently target and control large-scale epileptic brain networks with tCS-induced neuromodulatory weak electric fields. To proceed, GALVANI’s synergetic research strategy addresses four interdisciplinary challenges: (1) Unravel the intricate relationship between weak electric fields and their neurophysiological effects at the level of neurons, neuronal assemblies and networks; (2) Maximize their therapeutic effects by altering the neurodynamics of patient-specific epileptogenic networks; (3) Develop optimal personalized neuromodulation protocols for novel multichannel tCS technologies; (4) Test optimized protocols in a cohort of patients and objectively define potential responders. The required competences and resources are met in GALVANI, uniting the passion and background of three experts and their teams in biomathematics (computational neuroscience), biophysics (bioelectromagnetism) and medicine (epileptology). The project vision is that critical features of pathological networks can be effectively captured in a new generation of hybrid computational models developed for tailored therapy. The inflection point is to prevent epileptic seizures from a bottom-up mechanistic understanding and control of tCS effects. This will entail a paradigm shift in epileptic disorders and beyond.

Mots-clés : epilepsy,therapeutic neuromodulation,electric fields,bioelectromagnetism,neurophysiological,models,biophysical models,personalized models,signal processing,optimization,transcranial stimulation,clinical trial
Projet ERC : Code4Memory (Horizon 2020, appel 2014, Consolidator grants)
Domaine scientifique : Social Sciences and Humanities
Panel : The Human Mind and Its Complexity
Entité participante : University of Glasgow — Pays : Royaume-Uni — Rôle : PI
Type d'entité : Enseignement supérieur ou secondaire
Financement ERC de l'entité : 371699.23 €

Episodic memory refers to the fascinating human ability to remember past events in a highly associative and information rich way. But how are these memories coded in human brains? Any mechanism accounting for episodic memory must accomplish at least two functions: to build novel associations, and to represent the information constituting the memory. Neural oscillations, regulating the synchrony of neural assemblies, are ideally suited to accomplish these two functions, but in opposing ways. On the one hand, neurophysiological work suggests that increased synchrony strengthens synaptic connections and thus forms the basis for associative memory. Neurocomputational work, on the other hand, suggests that decreased synchrony is necessary to flexibly express information rich patterns in a neural assembly. Therefore, a conundrum exists as to how oscillations code episodic memory. The aim of this project is to propose and test a new framework that has the potential to reconcile this conflict. The central idea is that synchronization and desynchronization cooperatively code episodic memories, with synchronized activity in the hippocampus in the theta (~4 Hz) and gamma (~ 40-60 Hz) frequency range mediating the building of associations, and neocortical desynchronization in the alpha (~10 Hz) and beta (~15 Hz) frequency range mediating the representation of mnemonic information. Importantly the two modules, with their respective synchronous/asynchronous behaviours, must interact during the formation and retrieval of episodic memories, but how and whether this is the case remains untested to date. I will test these fundamental questions using a multidisciplinary and multi-method approach, including human single cell recordings, neuroimaging, brain stimulation, and computational modelling. The results from these experiments have the potential to reveal the neural code that human episodic memory is based on, which is still one of the biggest mysteries of the human mind.

Mots-clés : brain oscillations,episodic memory,desynchronization,synchronization,information coding
Projet ERC : EMODI (Horizon 2020, appel 2015, Proof of concept grants)
Entité participante : Universidade Nova de Lisboa — Pays : Portugal — Rôle : PI
Acronyme de l'entité : NOVA
Type d'entité : Enseignement supérieur ou secondaire
Financement ERC de l'entité : 147500.0 €

Epithelial barriers are essential for organism’s homeostasis and survival. Defects in resistance of body barrier epithelial tissues and their repair are thought to underlie a range of diseases, which affect millions. Antonio Jacinto’s group has discovered that Septate/Tight Junctions are essential for epithelial repair. These cell-cell junctions can be potentially targeted by candidate compounds that have been identified by Thelial, a Start-Up that will collaborate in this project. In EMODI we will complete preclinical proof of concept of the potential therapeutic activity of two selected compounds, relying on scientific results and technologies developed under ERC starting grant awarded to Dr. Antonio Jacinto. Regarding clinical application, we will focus on rare (orphan) diseases which have been associated to impaired epithelial repair in the gastro-intestinal track for which there are very limited treatment options: Sjoergen Syndrome (SjS) and Eosinophilic Esophagitis (EoE). The plan of activities involves the following steps: 1) Biological efficacy testing of the-1 and the-2 in a zebrafish Tight Junction model and in mouse models of the diseases under focus; 2) Development of IPR based on the biological testing; 3) Consolidate outcomes of steps 1 and 2 into a business plan; 4) Present the business plan to VC funds to seek for extra round of funding. The long-term aim is clinical development of our candidates not only in the context of SjS and EoE but also towards a range of o diseases where impaired epithelial barrier function is impaired and a cause of morbidity.
Projet ERC : COMIET (Horizon 2020, appel 2014, Consolidator grants)
Domaine scientifique : Physical Sciences and Engineering
Panel : Products and processes engineering
Entité participante : Institute for Bioengineering of Catalonia — Pays : Espagne — Rôle : PI
Acronyme de l'entité : IBEC;IBEC-CERCA
Type d'entité : Recherche
Financement ERC de l'entité : 1997190.0 €

Epithelial barriers protect the body against physical, chemical, and microbial insults. Intestinal epithelium is one of the most actively renewing tissues in the body and a major site of carcinogenesis. Functional in vitro models of intestinal epithelium have been pursued for a long time. They are key elements in basic research, disease modelling, drug discovery, and tissue replacing and have become prime models for adult stem cell research. By taking advantage of the self-organizing properties of intestinal stem cells, intestinal organoids have been recently established, showing cell renewal’s kinetics resembling to the one found in vivo. However, the development of in vitro 3D tissue equivalents accounting for the dimensions, architecture and access to the luminal contents of the in vivo human intestinal tissue together with its self-renewal properties and cell complexity, remains a challenge. The goal of this project is to engineer intestinal epithelial tissue models that mimic physiological characteristics found in in vivo human intestinal tissue, to open up new areas of research on human intestinal diseases. The proposed models will address the in vivo intestinal epithelial cell renewal and migration, the multicell-type differentiation and the epithelial cell interactions with the underlying basement membrane while providing access to the luminal content to go beyond the state-of-the-art organoid models. To do this, we propose to develop an experimental setup that combines microfabrication techniques, tissue engineering components and recent advances in intestinal stem cell research, exploiting stem cell self-organizing characteristics. We anticipate this setup to recapitulate the 3D morphology, the spatio-chemical gradients and the dynamic microenvironment of the living tissue. We expect the new device to prove useful in understanding cell physiology, adult stem cell behaviour, and organ development as well as in modelling human intestinal diseases.

Mots-clés : in vitro epithelial barriers,intestinal tissue models,intestinal stem cells
Projet ERC : PolarizeMe (Horizon 2020, appel 2017, Consolidator grants)
Domaine scientifique : Life Science
Panel : Cellular, Developmental and Regenerative Biology
Entité participante : University of Münster — Pays : Allemagne — Rôle : Partner
Acronyme de l'entité : WWU
Type d'entité : Enseignement supérieur ou secondaire
Financement ERC de l'entité : 740148.86 €

Epithelial polarity is one of the most fundamental types of cellular organization, and correct cellular polarization is vital for all epithelial tissue. Failure to establish polarity leads to severe phenotypes, from catastrophic developmental deficiencies to life-threatening diseases such as cancer. Despite knowing much about the signalling and trafficking machinery vital for polarity, we lack quantitative knowledge about the intracellular mechanical processes which organize and stabilize epithelial polarity. This presents a critical knowledge gap, as any elaborated understanding of intracellular organization needs to include the forces and viscoelastic mechanical properties that position organelles and proteins. As such, the main aim of POLARIZEME is to determine the intracellular mechanical processes relevant for epithelial polarization, thus providing a mechanical understanding of polarity. We will combine advanced optical tweezers technology with cutting-edge molecular biology tools to rigorously test new intracellular transport concepts such as the active, diffusion-like forces that can position organelles or the recently introduced cortical actin flows that can drag polarity-defining proteins around the cell. Thus we propose (i) to quantify active forces and intracellular mechanics and their relation to organelle positioning, (ii) to quantify polarized cortical and cytoplasmic flows, and (iii) to measure the forces and mechanical obstacles relevant for direct vesicle trafficking. These quantitative biophysics experiments will be supported by mathematical modelling and the development of two new instruments which (a) allow for automated intracellular mechanics measurements over extended time periods and (b) combine multi-view light-sheet microscopy with optical tweezers and UV ablation. Overall, we will provide a new access to understand and describe polarity by merging the physical and biological aspects of its initiation, maintenance and stability.

Mots-clés : cell mechanics,polarity,viscoelastic properties,active fluctuations,cortical flows,optogenetics
Projet ERC : EspLORE (Horizon 2020, appel 2016, Consolidator grants)
Domaine scientifique : Physical Sciences and Engineering
Panel : Products and processes engineering
Entité participante : Politecnico di Milano — Pays : Italie — Rôle : PI
Acronyme de l'entité : POLIMI
Type d'entité : Enseignement supérieur ou secondaire
Financement ERC de l'entité : 1981875.0 €

EspLORE aims at addressing the potential of carbon-atom wires for developing novel functional coatings in an application-oriented approach. Carbon-atom wires, based on sp-hybridization, are the ultimate 1-dimensional carbon nanostructure (1-atom diameter) with functional properties strongly dependent on the wire length and termination. The design and control of the wire structure opens the way to build materials with tunable properties, which is at present a largely unexplored topic. The core concept of EspLORE is to exploit the present fundamental knowledge of carbon-atom wires as isolated molecules/nanostructures to explore the applied science and engineering of new materials in the form of thin film assemblies and nanocomposites, so to fill the large existing gap between basic science and engineering. To this aim the main challenging goals are: 1) the controlled synthesis of wires; 2) the development of strategies to assemble wires in thin films and nanocomposites; 3) the exploration of potential use of wire-based materials in direct energy conversion devices (e.g. photovoltaics, water splitting, fuel cells). The proposed methodology includes fabrication of wires by physical methods, their deposition/assembling on surfaces, and the experimental study of structural, electronic and optical properties. Structure-property relationship is investigated at a multiscale level, moving from the single wire level (atomic scale) to multi-wire interactions (nanoscale) and up to extended systems (macroscale). The outcomes of the project will put the foundations for the materials engineering of wire-based systems and their realistic implementation in advanced technological applications. These materials, able to provide complementary properties to graphene, will synergistically contribute to open new perspectives for an innovative ‘all-carbon’ approach to present and future challenges in many fields of engineering and technology.

Mots-clés : carbon nanostructures,polyynes and cumulenes,thin film deposition,pulsed laser ablation,in situ raman and sers,in situ scanning tunneling microscopy stm,electrical and optical properties
Projet ERC : ER_disease (Horizon 2020, appel 2014, Consolidator grants)
Domaine scientifique : Life Science
Panel : Physiology in Health, Disease and Ageing
Entité participante : University of Cambridge — Pays : Royaume-Uni — Rôle : PI
Acronyme de l'entité : U. Cambridge
Type d'entité : Enseignement supérieur ou secondaire
Financement ERC de l'entité : 1987273.75 €

Estrogen Receptor (ER) is the driving transcription factor in ~75% of all breast cancers. ER antagonists are routinely used for treatment, but significant variability exists in clinical response. We are interested in explaining this heterogeneity and exploiting the mechanistic insight. We have recently identified important, but previously uncharacterised cross-talk between ER and the progesterone receptor (PR) and androgen receptor (AR) pathways, both of which are commonly expressed in ER+ tumours. Recently, ER has been shown to be mutated in ~18-55% of metastatic breast cancers. In addition, two key ER-chromatin regulatory proteins, FoxA1 and GATA3, are mutated in primary ER+ disease. Finally we have discovered three previously unknown phosphorylation events on FoxA1. Aim 1: We will comprehensively explore the cross-talk that exists between ER and PR and AR pathways to determine the physiological effects on ER function. Aim 2: We will recapitulate the key mutations observed in ER, FoxA1 and GATA3, to assess the impact on ER-DNA interactions, ER transcriptional activity and cell growth and drug response. This will be explored under different hormonal contexts to identify how the mutational spectrum influences the cross-talk between ER and the parallel PR and AR pathways. Aim 3: We will identify upstream kinase pathways that influence FoxA1 and GATA3 function. Aim 4: We will establish a novel single locus chromatin purification method for isolation of specific chromatin loci, followed by Mass Spectrometry to characterise the potential role of PR and AR variants and to identify unknown regulatory factors. Given recent biological discoveries and technological advances, we are perfectly positioned to apply cutting-edge tools to glean mechanistic insight into the factors that determine variability within ER+ disease. This proposal aims to advance our understanding of ER+ tumour heterogeneity, revealing ways of exploiting this in a clinically meaningful manner.

Mots-clés : biochemistry and molecular mechanisms of signal transduction,proteomics,epigenetics and gene regulation
Projet ERC : MODELAGE (Horizon 2020, appel 2014, Starting grants)
Domaine scientifique : Physical Sciences and Engineering
Panel : Products and processes engineering
Entité participante : Universidad de Zaragoza — Pays : Espagne — Rôle : PI
Acronyme de l'entité : UNIZAR
Type d'entité : Enseignement supérieur ou secondaire
Financement ERC de l'entité : 1498636.0 €

Europe is facing a striking change in its demographics with an increasingly larger proportion of citizens aged 65 years and over. Aging is characterized by a progressive decline in the physiological functions of the body, with very notable effects on the heart. These effects are associated with a higher prevalence of arrhythmias, which, on top of deteriorating quality of life, increase the risk of other cardiovascular diseases like stroke, heart failure and neurological sequelae. Investigations targeting cardiac aging have often focused on assessing the effects of a specific contributing factor, at a single evaluation scale (molecular, cell, tissue, organ) and in many cases using animal species not relevant to humans in terms of aging mechanisms. MODELAGE proposes a multi-scale, multi-factorial research that is expected to make an important step in the characterization of human heart aging at both the population and individual levels. MODELAGE will work on an integrative methodological framework in which in silico modeling will be combined with in vitro cell and tissue analysis and in vivo electrocardiographic evaluation to investigate how cardiac aging manifests at a range of scales, from cell to body surface, and how electrical, structural and autonomic alterations contribute to such manifestations in humans. Indices describing spatio-temporal dynamics of cardiac electrophysiology will be evaluated in a population of young to senescent individuals using a novel feedback control approach. Inter-individual age-related variations in those indices will be assessed and correlated with markers of biological age (as opposed to chronological age). By investigating the mechanisms underlying inter-individual differences in cardiac dynamics, MODELAGE will set links to arrhythmia susceptibility and will propose novel non-invasive markers to identify high-risk senescent individuals for which preventive anti-arrhythmic treatment should be considered.

Mots-clés : in silico modeling,cardiac aging,signal processing,electrocardiogram,ventricular electrophysiology,arrhythmic risk markers,inter  and intra individual variability