Data-Gouv-ML/pcri-erc-participations-et-projets-laureats huggingface dataset:
Projet ERC : INCISED (Horizon 2020, appel 2019, Advanced grants)
Domaine scientifique : Physical Sciences and Engineering
Panel : Earth system science
Entité participante : UK Research and Innovation — Pays : Royaume-Uni — Rôle : Partner
Acronyme de l'entité : UKRI
Type d'entité : Recherche
Financement ERC de l'entité : 1328615.0 €

The West Antarctic Ice Sheet (WAIS) stores a substantial volume of freshwater on land. It is thought to be inherently unstable and so projections of future sea level rise require robust numerical ice sheet models, fully calibrated against geological data. The WAIS is widely believed to have collapsed in past warm interglacial periods, raising sea level by up to 3.3m, but perhaps surprisingly we do not yet have direct evidence of collapse from Antarctica that can be securely dated. Instead global sea level data have been used to infer that some combination of WAIS, Greenland and the East Antarctic Ice Sheet collapsed in one or more past interglacials, but with substantial uncertainty as to how this mass loss was partitioned between the ice sheets. This matters because it means that models projecting future sea level are calibrated against an assumption of how small the WAIS became during past warm periods. I argue that a fresh approach is needed, one that provides direct evidence of WAIS retreat that can be dated and quantified. INCISED will provide this by rapid drilling to the ice sheet bed to retrieve direct records of past collapse. New modelling of cosmogenic isotope concentrations shows that hypotheses of past WAIS collapses can be tested by analysis of subglacial bedrock from carefully selected sites. INCISED exploits recent engineering advances in ice coring and a new subglacial rock drill to take bedrock samples which will be used to determine past lowering of the ice surface to test for WAIS collapse. Numerical ice sheet modelling will link changes in past ice levels to quantify the range of possible sea level contribution. By determining and quantifying the configuration of WAIS during warm periods I will provide firm targets for ice sheet model calibration and thus more secure future sea level projections. INCISED will deliver a transformative change in modelling of WAIS sea level contributions as well as a significant equipment legacy.

Mots-clés : sea level,cosmogenic isotopes,subglacial engineering
Projet ERC : SegregActin (Horizon 2020, appel 2014, Starting grants)
Domaine scientifique : Life Science
Panel : Cellular, Developmental and Regenerative Biology
Entité participante : Commissariat à l’énergie atomique et aux énergies alternatives — Pays : France — Rôle : Partner
Acronyme de l'entité : CEA
Type d'entité : Recherche
Financement ERC de l'entité : 0.0 €

The ability of cells to use the actin cytoskeleton for a diversity of cellular processes is due to the fact that actin filaments, although assembled from identical subunits, are organized in a wide variety of structures of appropriate geometrical, dynamical and rheological properties. Key players in this regulation are specific sets of actin binding proteins (ABPs) interacting with each actin networks, to modulate spatially and temporally their properties. With this project, I want to understand 1/ how cells can generate the formation of actin structures of appropriate ABP composition from a common pool of cytoplasmic components and 2/ the relationship between the ABP composition of an actin network, its geometrical and dynamical properties, and its response to mechanical deformations. I will hypothesize that the generation of an actin network of appropriate ABP composition can be explained with an original model, taking into account the facts that 1/ actin filaments in cells are not all structurally identical, but adopt specific conformations that are favored and stabilized by certain families of ABPs; and 2/ the interaction of ABPs with actin depends of the geometrical organization of the filaments. Because this project imposes to study protein-protein interactions in the presence of multiple partners, I propose to develop an unprecedented strategy combining 1/ "bottom-up" reconstitutions, where limited sets of ABPs are added one-by-one in the system to understand their combined activities with actin; and 2/ "top-down" reconstitutions with protein extracts prepared from a genetically-tractable organism (the yeast S. cerevisiae), where proteins can be removed one-by-one, in order to study actin network properties in near-physiological conditions. This project will shed a new light on how cells organize their interior, and will represent a unique opportunity to understand how modifications in the expression of ABPs are associated with actin network defects.

Mots-clés : cytoskeleton,actin networks,cellular organization,actin binding protein segregation,reconstituted systems,single molecule imaging,mechanotransduction,lipid membranes
Projet ERC : SegregActin (Horizon 2020, appel 2014, Starting grants)
Domaine scientifique : Life Science
Panel : Cellular, Developmental and Regenerative Biology
Entité participante : Centre national de la recherche scientifique — Pays : France — Rôle : Partner
Acronyme de l'entité : CNRS
Type d'entité : Recherche
Financement ERC de l'entité : 0.0 €

The ability of cells to use the actin cytoskeleton for a diversity of cellular processes is due to the fact that actin filaments, although assembled from identical subunits, are organized in a wide variety of structures of appropriate geometrical, dynamical and rheological properties. Key players in this regulation are specific sets of actin binding proteins (ABPs) interacting with each actin networks, to modulate spatially and temporally their properties. With this project, I want to understand 1/ how cells can generate the formation of actin structures of appropriate ABP composition from a common pool of cytoplasmic components and 2/ the relationship between the ABP composition of an actin network, its geometrical and dynamical properties, and its response to mechanical deformations. I will hypothesize that the generation of an actin network of appropriate ABP composition can be explained with an original model, taking into account the facts that 1/ actin filaments in cells are not all structurally identical, but adopt specific conformations that are favored and stabilized by certain families of ABPs; and 2/ the interaction of ABPs with actin depends of the geometrical organization of the filaments. Because this project imposes to study protein-protein interactions in the presence of multiple partners, I propose to develop an unprecedented strategy combining 1/ "bottom-up" reconstitutions, where limited sets of ABPs are added one-by-one in the system to understand their combined activities with actin; and 2/ "top-down" reconstitutions with protein extracts prepared from a genetically-tractable organism (the yeast S. cerevisiae), where proteins can be removed one-by-one, in order to study actin network properties in near-physiological conditions. This project will shed a new light on how cells organize their interior, and will represent a unique opportunity to understand how modifications in the expression of ABPs are associated with actin network defects.

Mots-clés : cytoskeleton,actin networks,cellular organization,actin binding protein segregation,reconstituted systems,single molecule imaging,mechanotransduction,lipid membranes
Projet ERC : ANTI-ATOM (Horizon 2020, appel 2018, Starting grants)
Domaine scientifique : Physical Sciences and Engineering
Panel : Fundamental constituents of matter
Entité participante : Queen's University Belfast — Pays : Royaume-Uni — Rôle : PI
Acronyme de l'entité : QUB
Type d'entité : Enseignement supérieur ou secondaire
Financement ERC de l'entité : 1318419.0 €

The ability of positrons to annihilate with electrons, producing characteristic gamma rays, gives them important use in medicine via positron-emission tomography (PET), diagnostics of industrially-important materials, and in elucidating astrophysical phenomena. Moreover, the fundamental interactions of positrons and positronium (Ps) with atoms, molecules and condensed matter are currently under intensive study in numerous international laboratories, to illuminate collision phenomena and perform precision tests of fundamental laws. Proper interpretation and development of these costly and difficult experiments requires accurate calculations of low-energy positron and Ps interactions with normal matter. These systems, however, involve strong correlations, e.g., polarisation of the atom and virtual-Ps formation (where an atomic electron tunnels to the positron): they significantly effect positron- and Ps-atom/molecule interactions, e.g., enhancing annihilation rates by many orders of magnitude, and making the accurate description of these systems a challenging many-body problem. Current theoretical capability lags severely behind that of experiment. Major theoretical and computational developments are required to bridge the gap. One powerful method, which accounts for the correlations in a natural, transparent and systematic way, is many-body theory (MBT). Building on my expertise in the field, I propose to develop new MBT to deliver unique and unrivalled capability in theory and computation of low-energy positron and Ps interactions with atoms, molecules, and condensed matter. The ambitious programme will provide the basic understanding required to interpret and develop the fundamental experiments, antimatter-based materials science techniques, and wider technologies, e.g., (PET), and more broadly, potentially revolutionary and generally applicable computational methodologies that promise to define a new level of high-precision in atomic-MBT calculations.

Mots-clés : positron and positronium interactions with atoms and molecules,atomic many body theory,low energy antimatter,high precision atomic many body calculations
Projet ERC : NeuroRibo (Horizon 2020, appel 2016, Advanced grants)
Domaine scientifique : Life Science
Panel : Neuroscience and Disorders of the Nervous System
Entité participante : Max Planck Society — Pays : Allemagne — Rôle : PI
Acronyme de l'entité : MPG
Type d'entité : Recherche
Financement ERC de l'entité : 2348483.0 €

The ability of the nervous system to respond adaptively relies on modifications to existing proteins as well as changes in gene transcription and mRNA translation. It is now clear that synapses possess the capacity for local protein synthesis, owing to the localization of ribosomes and mRNAs within dendrites. There is emerging interest in the possibility that ribosomes, as cellular machines, are not as static as typically assumed- and may be heterogeneous in composition and specialized for particular functions and cellular compartments. Intriguingly, several studies have noted the presence of ribosomal protein mRNAs in the dendrites and axons, raising the possibility that locally synthesized ribosomal proteins might serve to modify the local ribosome population. Amongst the players in protein synthesis, many signaling proteins, RNA-binding proteins, and most translation factors have been considered as potential regulatory hubs. The ribosomes, thus far, have not been considered. Here we propose to discover the nature and diversity of ribosomes present in neurons, their dendrites and their synapses in the rodent brain. Using a combination of RNA-sequencing, Mass Spectrometry, Fluorescence In situ Hybridization, and new labelling approaches to visualize nascent proteins, we will determine whether neuronal ribosomes are heterogeneous and specialized in different subcellular compartments. The proposed experiments will determine the relationship between the ribosome composition and the neuronal mRNAs that undergo translation. We will also examine how plasticity sculpts the ribosome population to regulate the changes in the proteome that are dynamically regulated by ongoing synaptic events and plasticity.

Mots-clés : 1  dendritic protein synthesis,2  dendrite,3  synaptic plasticity
Projet ERC : HapticCell (Horizon 2020, appel 2016, Proof of concept grants)
Entité participante : University of London — Pays : Royaume-Uni — Rôle : PI
Acronyme de l'entité : U. London
Type d'entité : Enseignement supérieur ou secondaire
Financement ERC de l'entité : 128016.0 €

The ability to handle and operate on cells is an emerging technology that will accelerate the development of novel cell-based therapies. By being able to modify donor cells in-vitro to fight disease more effectively and in volume will have paradigm shifting advances in a wide range of fields such as biotechnology, pharmacology, agriculture, oncology, genetics and embryology. As highlighted by the Innovate UK Cell Therapy Catapult, by 2017 the cell-based therapy manufacturing industry will be worth more than €4.5billion. To realise this opportunity, it is vital clinicians and manufacturers have access to efficient tools that are also repeatable. Several methods exist that enable the manual manipulation of cells, amongst which microinjection tasks is the most common. However, current techniques are labour intensive, vary in quality, and lack the measurement of force between the tools used and the cell needed to reduce damage during contact. Moreover, as these processes are not automated and can only be performed one cell at a time, it is prohibitively expensive to produce new cell-based therapies at the volumes needed for clinical trials. To address these unmet needs, we present ‘HapticCell’, a robotic micromanipulation platform for low cost autonomous microinjection tasks. In this ERC-PoC project, we will extend our ERC research in telehaptic micromanipulation to support schemes for automation and establish its technical feasibility in performing repeatable microinjection tasks in volume appropriate for clinical needs. Further, in collaboration with spin out company Yantric, UCL Business and identified first customers, we will conduct the necessary commercial activities to translate HapticCell into the real world. To start, we envisage HapticCell to be an indispensable tool for achieving higher throughput in the in-vitro fertilisation (IVF) market, which will then act as a stepping stone into the broader single cell manipulation domain and cell-therapy production.

Mots-clés : single cell manipulation
Projet ERC : PROT-STRUCT-DISEASE (Horizon 2020, appel 2020, Consolidator grants)
Domaine scientifique : Life Science
Panel : Integrative Biology: from Genes and Genomes to Systems
Entité participante : University of Edinburgh — Pays : Royaume-Uni — Rôle : PI
Type d'entité : Enseignement supérieur ou secondaire
Financement ERC de l'entité : 2000000.0 €

The ability to identify damaging genetic variants is central to the diagnosis, treatment and prevention of human disease. Computational phenotype predictors are widely used for prioritising likely pathogenic mutations, but their utility is limited by their accuracy. Conversely, experimental characterisation of variants is powerful but time consuming and difficult to perform on a large scale, limiting applicability in routine variant prioritisation. In this project, we will improve our ability to identify pathogenic variants through a combination of computational and experimental approaches. Fundamental to our strategy will be our consideration of alternate molecular mechanisms by which mutations can cause disease, in contrast to the current overwhelming focus on loss-of-function. First, we will use structural bioinformatics to investigate the different molecular mechanisms underlying pathogenic mutations, and learn how they are related to protein structure and phenotype. Next, we will perform deep mutational scanning (DMS) on at least 10 human disease genes, enabling us to measure fitness and elucidate molecular mechanisms for all possible single amino-acid substitutions. This will facilitate the direct identification of novel pathogenic variants, and allow us to evaluate the performance existing computational phenotype predictors. Finally, we will implement our own computational variant prioritisation pipeline and meta-predictor, using our new understanding of molecular mechanisms to integrate computational phenotype and stability predictors and DMS data with structural and other protein-level features. Crucially, we will demonstrate the utility of our approach in application to sequencing data from clinical and population cohort studies. Together, the knowledge we learn, the experimental data we measure, and the tools we develop will improve our ability to identify novel pathogenic variants, and thus diagnose human genetic disorders.

Mots-clés : structural bioinformatics,deep mutational scanning,computational phenotype prediction,mutations,dominant negative effect,gain of function
Projet ERC : CellTrainer (Horizon 2020, appel 2017, Proof of concept grants)
Entité participante : Yantric inc for profit corporation — Pays : Etats-Unis — Rôle : Partner
Acronyme de l'entité : Yantric inc for profit corporation
Type d'entité : Organismes privés (hors enseignement)
Financement ERC de l'entité : 21966.0 €

The ability to operate on cells is a fundamental capability when developing novel cell based therapies. In this context, the skills needed to manually inspect, prepare and modify cells in-vitro with repeatable micro-nano precision are essential; enabling the creation of new biomedical solutions to fight disease more effectively. Highlighted by the Innovate UK Cell Therapy Catapult, the market opportunity for improved micromanipulation techniques is valued to be >€4.5billion in 2017 and applicable to a wide range of fields from biotechnology, pharmacology to embryology. To realise this opportunity, it is vital to have a well-trained workforce capable of performing repeatable high precision manipulations at a cellular level. However, current training techniques are laborious, vary in quality, and do not take advantage of the inexpensive technologies available today that can improve the expertise of the clinical operators without the need for expensive learning facilities. To address these unmet needs, we present CellTrainer, a virtual reality simulation based training system. Based on the empirical data and biomechanical models gained through our novel micro/nano telehaptic systems that were developed as part of our ERC-AdG grant, in this ERC-PoC project we propose to develop a real-time Virtual Reality (VR) physics engine to simulate different micro/nano training environments and objectively monitor user performance whilst providing clinical learning feedback. In collaboration with spin out company Yantric, UCL Business and identified first customers, we will conduct the necessary commercial activities to translate CellTrainer into the real world. At first, we envisage CellTrainer to be an indispensable tool in reducing the time needed to train up expert clinical users for the in-vitro fertilisation (IVF) market. Lessons learnt here will then be used to access the broader cell based therapy domain and overcoming challenges related workforce productivity.

Mots-clés : microinjection,virtual reality training,simulation for cellular therapies
Projet ERC : CellTrainer (Horizon 2020, appel 2017, Proof of concept grants)
Entité participante : University of London — Pays : Royaume-Uni — Rôle : PI
Acronyme de l'entité : U. London
Type d'entité : Enseignement supérieur ou secondaire
Financement ERC de l'entité : 128029.0 €

The ability to operate on cells is a fundamental capability when developing novel cell based therapies. In this context, the skills needed to manually inspect, prepare and modify cells in-vitro with repeatable micro-nano precision are essential; enabling the creation of new biomedical solutions to fight disease more effectively. Highlighted by the Innovate UK Cell Therapy Catapult, the market opportunity for improved micromanipulation techniques is valued to be >€4.5billion in 2017 and applicable to a wide range of fields from biotechnology, pharmacology to embryology. To realise this opportunity, it is vital to have a well-trained workforce capable of performing repeatable high precision manipulations at a cellular level. However, current training techniques are laborious, vary in quality, and do not take advantage of the inexpensive technologies available today that can improve the expertise of the clinical operators without the need for expensive learning facilities. To address these unmet needs, we present CellTrainer, a virtual reality simulation based training system. Based on the empirical data and biomechanical models gained through our novel micro/nano telehaptic systems that were developed as part of our ERC-AdG grant, in this ERC-PoC project we propose to develop a real-time Virtual Reality (VR) physics engine to simulate different micro/nano training environments and objectively monitor user performance whilst providing clinical learning feedback. In collaboration with spin out company Yantric, UCL Business and identified first customers, we will conduct the necessary commercial activities to translate CellTrainer into the real world. At first, we envisage CellTrainer to be an indispensable tool in reducing the time needed to train up expert clinical users for the in-vitro fertilisation (IVF) market. Lessons learnt here will then be used to access the broader cell based therapy domain and overcoming challenges related workforce productivity.

Mots-clés : microinjection,virtual reality training,simulation for cellular therapies
Projet ERC : TagIt (Horizon 2020, appel 2015, Starting grants)
Domaine scientifique : Physical Sciences and Engineering
Panel : Synthetic Chemistry and Materials
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 : 1499106.0 €

The ability to probe dynamic cellular events that involve disease-associated proteins is limited, to a large extent, by the lack of development of a strategy that can use small coupling partners to react in chemoselective fashion with rapid kinetics that does not interfere with biological function(s) and localisation. In this application, I describe a conceptually new bioorthogonal-labelling approach that combines the introduction of a minimal non-canonical amino acid with chemoselective reactions, which display rapid kinetics, to label proteins in live cells. The small size of the new alkene-tagged amino acids, which will be genetically encoded, should not interfere with the protein’s innate structure, function(s) or localisation. Site-selective bioorthogonal labelling will be achieved through the use of a new photo-triggered [2+2] cycloaddition reaction with an alkene-bearing fluorophore and the known inverse-electron-demand Diels-Alder reaction with a fluorogenic tetrazine. Although the former offers potentially improved spatial and temporal resolution, the latter allows for turn-on fluorescence. The proposed new methodology will be applied in the context of a key cytokine involved in cancer progression. The ability to label this cytokine with minimal perturbation of its structure, function(s) and localisation will enable monitoring of its internalisation and intracellular trafficking pathways in cells that overexpress its receptor. In doing so, new insight into cancer biology will be generated that will inform the construction of safer, selective and more efficient protein-drug conjugates for targeted cancer treatment. The concept proposed here is designed to be generally applicable to label and study disease-associated proteins that are difficult to access by means of conventional protein-labelling methods and constitute the first integrated, interdisciplinary approach for the development of protein drug-conjugates.

Mots-clés : bioorthogonal chemistry,ligand drug conjugates,photocycloadditions,inverse electron demand diels alder,cysteine,genetic encoding,protein labelling,cancer therapy