Data-Gouv-ML/pcri-erc-participations-et-projets-laureats huggingface dataset:
Projet ERC : Natural BionicS (Horizon 2020, appel 2018, Synergy grants)
Entité participante : Italian Institute of Technology — Pays : Italie — Rôle : PI
Type d'entité : Recherche
Financement ERC de l'entité : 3281875.0 €

Missing a limb leads to dramatic impairments in the capacity to move and interact with the environment and to a substantial worsening in quality of life. This deficiency is also associated with a large portion of the sensory-motor cortex facing neural deafness. Missing or damaged limbs can in principle be substituted by robotic limbs, connected to humans with neural interfacing. Despite massive research efforts, however, the bionic reconstruction of limbs currently faces important translational challenges. We aim at filling this gap between academic research and clinical impact with a patient-centric approach that synergistically combines breakthroughs in surgery (Aszmann), neural interfacing (Farina), and robotics (Bicchi). We propose to surgically create bio-connectors (compacted in a bio-hub) to access the spinal cord circuitries by using biological pathways of encoding and decoding neural information. Neural interfacing with the bio-hub will determine an input/output information flow with the spinal cord by decoding the activity of spinal neural cells (output) and stimulating transplanted biological afferent organs (input). The sensory-motor image of the missing limb emerging from this interfacing will be projected in soft robotic arms/legs that will embed kinematic synergies and tactile-proprioceptive functions, intimately matched with the neural sensory-motor synergies extracted from the bio-hub. In this way, Natural BionicS aims at creating a fully integrated, symbiotic replacement of human limbs with robotic parts that the user will feel and command as part of the body. This aim will be achieved with clinical translation aided by the establishment of a Bionic Clinical Board of the three PIs. Here the options of bionic reconstruction will be explored for each patient on a bi-monthly basis, the engineering solutions will be adapted to the clinical challenges, and patients will be identified who best profit from the radical new developments of Natural BionicS.

Mots-clés : prosthetics,neural interfacing,rehabilitation engineering,reconstructive surgery,bionic medicine,soft robotics,sensory motor integration
Projet ERC : CICURE (Horizon 2020, appel 2018, Proof of concept grants)
Domaine scientifique : Life Science
Panel : Physiology in Health, Disease and Ageing
Entité participante : University Hospital Cologne — Pays : Allemagne — Rôle : PI
Type d'entité : Enseignement supérieur ou secondaire
Financement ERC de l'entité : 150000.0 €

Mitochondria are found within every human cell and are responsible for the majority of energy production in the cell. When the mitochondria do not function properly, they cause devastating diseases affecting many and often multiple organs with the highest energy needs, such as skeletal muscle, brain, heart and liver. Over the years we have steadily increased our understanding of the genetic and molecular mechanisms leading to mitochondrial disease, developed different models and biomarkers. Unfortunately, development of effective therapeutic approaches able to improve the outcome of the diseases or at least to ameliorate or postpone the symptoms was much less effective. Today, therapeutic options for mitochondrial diseases still remain focused on supportive dietary interventions aimed at relieving complications. Therefore, it would be ideal if a single approach could be developed that would be equally effective with various mitochondrial diseases most often characterized by complex I deficiency. Our preliminary data show that by removing the major mitochondrial matrix protease CLPXP, and therefore stabilizing CI, we could ameliorate the symptoms of respiratory deficiency in different cellular models of mitochondrial dysfunction. The loss of CLPP in these models resulted not only in increased stability of CI, but also normalized NAD+/ NADH that collectively resulted in improved proliferation and survival rates. Remarkably, even partial loss of ClpXP activity in respiratory deficient cells led to mild increase in the CI levels, opening an exciting prospect for therapeutic interventions. Therefore, the overall goal of this project is to explore the possibility of targeting CLPP activity to ameliorate symptoms of mitochondrial diseases in in vivo models through genetic interventions and search for specific protease inhibitors.

Mots-clés : mitochondrial diseases,ci deficiency,clpp protease,treatment
Projet ERC : MitoCRISTAE (Horizon 2020, appel 2018, Advanced grants)
Domaine scientifique : Life Science
Panel : Molecules of Life: Biological Mechanisms, Structures and Functions
Entité participante : Max Planck Society — Pays : Allemagne — Rôle : Partner
Acronyme de l'entité : MPG
Type d'entité : Recherche
Financement ERC de l'entité : 1115592.84 €

Mitochondrial cristae biogenesis is an enigma ever since the first imaging of mitochondria, the ‘powerhouses’ of eukaryotic cells, by electron microscopy in the 1950s. The mitochondrial cristae, dynamic and structurally conserved invaginations of the mitochondrial inner membrane, are essential for respiratory ATP generation. Thereby, the form and function of the mitochondrial inner membrane are deeply intertwined. Indeed, irregular or disturbed cristae morphologies are believed to cause numerous human diseases, including neurodegeneration, cardiomyopathies, metabolic disorders and cancer. Previous approaches to study cristae biogenesis have relied primarily on the use of 2D electron microscopy and biochemistry to analyse mutant cells defective in cristae formation. Based on striking pilot experiments, we propose to study cristae biogenesis by a radically different approach. We will induce synchronous cristae development in gene-edited cell lines initially defective in cristae formation. We will then follow de novo cristae biogenesis over time by combining a series of enabling approaches, including live cell and MINFLUX super-resolution microscopy, 3D (cryo) electron microscopy, label-free (SWATH) mass spectrometry, and single molecule counting. These technologies have just emerged in the last few years, and thus this proposal would not have been possible a few years ago. The primary aim of this proposal is to establish a deep, comprehensive and quantitative understanding of cristae biogenesis in human cells. Using theses insights, we will also investigate the effects of mutations in mitochondrial proteins associated with human diseases on cristae biogenesis. Altogether, if successful, the outcome will represent a paradigm shift in our knowledge of how mitochondrial ultrastructure in healthy and diseased cells is generated and maintained. Our findings might spark innovative and novel strategies for the treatment of devastating human mitopathies.

Mots-clés : mitochondrial ultrastructure,inner membrane architecture,super resolution microscopy
Projet ERC : mitoUPR (Horizon 2020, appel 2018, Starting grants)
Domaine scientifique : Life Science
Panel : Cellular, Developmental and Regenerative Biology
Entité participante : Goethe University Frankfurt — Pays : Allemagne — Rôle : PI
Type d'entité : Enseignement supérieur ou secondaire
Financement ERC de l'entité : 1437500.0 €

Mitochondrial function is central for cellular metabolism and energy balance. However, many diseases, including cancer and neurodegenerative diseases, affect mitochondrial function and proteostasis. Upon mitochondrial protein misfolding, mitochondria activate the mitochondrial unfolded protein response (UPRmt) to restore proteostasis, a poorly characterized pathway in mammalian cells. Notably, the effects of the UPRmt on its direct environment – mitochondria – and on cytosolic homeostasis remain unknown. Strikingly, non-cell autonomous signaling of metabolism and folding state has been described in recent years, particularly in worms. However, the possible role of UPRmt in such processes is undescribed. Using newly available tools to acutely induce the UPRmt in mammalian cells, combined with cutting-edge quantitative mass spectrometry, microscopy, next generation sequencing, and gene editing approaches, we propose to address these important open questions by studying the influence UPRmt exerts on the environments of i) mitochondria (including to study the composition and regulation of RNA granules), ii) cytosol (adjustments of translation, metabolism, and proliferation) and iii) neighboring cells (modification by non-cell autonomous signaling). Additionally, we aim to develop an iPSC-based UPRmt model. On cellular and organismal level, there ought to be mechanisms to signal changes in metabolism and proteostasis to increase robustness in neighboring environments. Studying these effects will be crucial for a better understanding of human disease and carries severe implications: i) the possibility of therapeutic treatment by modulating neighboring compartments or cells and ii) the possibility that diseases inducing the UPRmt could have unknown paracrine and endocrine effects on the organism. This proposal holds the potential to uncover a novel layer of regulation of cellular stress with an extensive influence on our understanding of the UPRmt and disease.

Mots-clés : mitochondrial unfolded protein response,protein misfolding,proteostasis,non cell autonomous signaling,ageing,mitochondrial rna processing,rna granules,metabolism,quantitative proteomics
Projet ERC : RiboLife (Horizon 2020, appel 2018, Starting grants)
Domaine scientifique : Life Science
Panel : Biotechnology and Biosystems Engineering
Entité participante : Max Planck Society — Pays : Allemagne — Rôle : Partner
Acronyme de l'entité : MPG
Type d'entité : Recherche
Financement ERC de l'entité : 265772.39 €

Modern cellular life strictly depends on DNA as genetic material. However, a large body of evidence infers the existence of a previous, more primitive biology in which RNA also stored information in cellular entities. Recreating a living cellular fossil representing this transition from an ancient RNA world to modern DNA-based life would fundamentally advance our understanding of our biology’s history, and enable us to explore its biological properties experimentally. However, the reengineering of existing molecular systems into a viable doppelganger of the Last Universal Common Ancestor (LUCA) or one of its precursors is extremely challenging. I propose to use a novel, combined top-down and bottom-up approach to create a modern-day doppelganger of LUCA by engineering bacterial hybrids with core cellular functions encoded on RNA. Using Darwinian Evolution as driver, my team and I will prototype and refine synthetic RNA-replicons through alternating replication in both cell-free and intracellular environments. This “dual evolution” approach will shape increasingly complex RNA networks capable of encoding complex genetic information. Following this, we will use these networks to create information-rich RNA chromosomes, enabling the transfer of essential genomic information from DNA to RNA. Finally, we will address this intergenomic transplantation by combining a novel RNA-delivery strategy with iterative rounds of genome deletion and complementation using state-of-the art CRISPR-Cas9 assisted genome editing. The proposed research will fundamentally advance synthetic biology, and could positively answer the transformative questions: Can we create, program and evolve life-like systems that can survive in both cell-free and intracellular environments? Can we use these entities to construct an alternative biology in which central cellular activities are encoded on genomes not made of DNA?

Mots-clés : synthetic cells,in vitro self replication,rna replication,directed evolution,genome transplantation,rna phages,origin of life
Projet ERC : InSpIRe (Horizon 2020, appel 2020, Consolidator grants)
Domaine scientifique : Life Science
Panel : Neuroscience and Disorders of the Nervous System
Entité participante : KTH Royal Institute of Technology — Pays : Suède — Rôle : PI
Acronyme de l'entité : KTH
Type d'entité : Enseignement supérieur ou secondaire
Financement ERC de l'entité : 2380000.0 €

Modern fluorescence microscopy can provide rapid, real-time functional imaging of brain activities (light sheet) or to visualize with high definition and specificity the synaptic organization (super resolution, expansion). However, rapidity and precision are still too far apart to allow studies of fast dynamics with intra-synaptic precision mainly due to incompatible optical and probes requirements in current technologies. My aim is to fill this gap with the development of an optical platform, named InSpIRe, which allows real-time volumetric imaging of brain tissues with intra-synaptic level of details thanks to a new optical scheme coupled to the photo-switching properties of recently engineered red-shifted probes. InSpIRe will take advantage of rsFusionRed, a new palette of reversibly switching fluorescent proteins, which we recently introduced. The contrast and photo-resistance of rsFusionRed imaging will be increased with an optical strategy that uncouple the geometry of the illumination for switching and fluorescence excitation, which we demonstrated in our MoNaLISA microscope. In InSpIRe these concepts are brought to a new level to record volumetric dynamics in brain tissues without compromising resolution and speed. We will craft a new interference pattern, which optically imprint small-sub-resolved- volumes of rsFusionRed in the 3D tissues architecture. These volumes will be read-out with an oblique sheet of light to increase speed and minimize photo-bleaching. Unlike lattice light sheet we use one objective lens, which increases the slice accessibility and unlike STED/STORM the acquisition is faster. InSpIRe will record movies with molecular resolution without losing the larger neuronal architecture, which can shine light to open question in the field of organelles trafficking. As a proof of principle, we will study the dynamics of the endoplasmic reticulum, which are little known in synapses, and which we could, for the first time, show with precision.

Mots-clés : super resolution light microscopy,optical nanoscopy,fluorescence imaging,live cell imaging,neuronal imaging techniques,sted,resolft,synaptic protein trafficking,fluorescent proteins
Projet ERC : HETEROPOLIS (Horizon 2020, appel 2016, Starting grants)
Domaine scientifique : Social Sciences and Humanities
Panel : Individuals, Markets and Organisations
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 : 1497505.0 €

Modern societies are characterized by tremendous heterogeneity in economic outcomes: from heterogeneity in wages and employment, to heterogeneity in capital income, wealth and health outcomes. It is unclear, however, how to map heterogeneity in these outcomes to heterogeneity in welfare. This mapping is crucial for the design of tax and benefit systems, providing insurance against individual risk and redistributing income between individuals, while maintaining proper incentives. The main objectives of HETEROPOLIS are: 1) to provide new insights on the relation between inequality in earnings, wealth and consumption, 2) to develop a new consumption-based method to measure welfare inequality and heterogeneity in the marginal value of social transfers, 3) to provide and implement a simple, but general evidence-based framework to evaluate the differential design of social insurance based on observable heterogeneity, 4) to analyse selection effects due to unobservable heterogeneity and how they affect social insurance design, 5) to analyse heterogeneity in behavioural “biases” and their consequences for policy design. The first part of HETEROPOLIS analyses the use of registry-based consumption measures to evaluate heterogeneity in welfare and exploits a newly developed data set based on administrative registers for the universe of Swedish households providing comprehensive and detailed information on income, wealth, labour market outcomes and other variables. The second part develops and implements a general evidence-based framework to evaluate the design of multi-faceted social insurance programs in a heterogeneous world. The final part of HETEROPOLIS analyses and estimates different sources of heterogeneity that affect market efficiency and justify further government interventions.
Projet ERC : ScalableControl (Horizon 2020, appel 2018, Advanced grants)
Domaine scientifique : Physical Sciences and Engineering
Panel : Systems and communication engineering
Entité participante : Lund University — Pays : Suède — Rôle : PI
Type d'entité : Enseignement supérieur ou secondaire
Financement ERC de l'entité : 2500000.0 €

Modern society is critically dependent on large-scale networks for services such as energy supply, transportation and communications. The design and control of such networks is becoming increasingly complex, due to their growing size, heterogeneity and autonomy. A systematic theory and methodology for control of large-scale interconnected systems is therefore needed. In an ambitious effort towards this goal, this project will develop rigorous tools for control synthesis, adaptation and verification. Many large-scale systems exhibit properties that have not yet been systematically exploited by the control community. One such property is positive (or monotone) system dynamics. This correspond to the property that all states of a network respond in the same direction when the demand or supply is perturbed in some node. Scalable methods for control of positive systems are starting to be developed, but several fundamental questions remain: How can existing results be extended to scalable synthesis of dynamic controllers? Can results for linear positive systems be extended to nonlinear monotone ones? How about systems with resonances? The second focus area, adaptation, takes advantage of recent progress in machine learning, such as statistical concentration bounds and approximate dynamic programming. Adaptation is of fundamental importance for scalability, since high-fidelity models are very expensive to generate manually and hard to maintain. Thirdly, since systematic procedures for control synthesis generally rely on simplified models and idealized assumptions, we will also develop scalable methods to bound the effect of imperfections, such as nonlinearities, time-variations and parameter uncertainty that are not taken into account in the original design. The research will be carried out in interaction with industry studying a new concept for district heating networks. This collaboration will give access to experimental data from a full scale demonstration plant.

Mots-clés : systems theory,network dynamics,formal methods
Projet ERC : MechaniChiral (Horizon 2020, appel 2016, Consolidator grants)
Domaine scientifique : Physical Sciences and Engineering
Panel : Synthetic Chemistry and Materials
Entité participante : University of Southampton — Pays : Royaume-Uni — Rôle : PI
Type d'entité : Enseignement supérieur ou secondaire
Financement ERC de l'entité : 1998927.5 €

Molecular chirality is a central theme in chemistry; in 2015 approximately 13% of publications in J. Am. Chem. Soc. and 12% in Angew. Chem. concerned chirality. All previously studied forms of molecular asymmetry (central, axial, planar and helical chirality) have found applications throughout the sub-disciplines of chemistry including as catalysts, materials and sensors. Mechanically chiral rotaxanes are molecules in which the mechanical bond between a macrocycle and dumbbell-shaped component is the source of asymmetry rather than the covalent structure of the components themselves. These unusual molecules represent a novel and unexplored chiral supramolecular environment as the lack of a scalable synthetic approach for their isolation in enantiopure form has prevented all but the most cursory investigation of their properties. Thus, mechanical chirality remains an unexplored frontier of molecular asymmetry with the potential to deliver novel functions and impact across a range of chemical disciplines from materials chemistry to the synthesis of pharmaceutically active compounds. The Goldup Group has recently demonstrated the first practical method for the synthesis of enantiopure mechanically chiral rotaxanes using a flexible active template methodology and thus the stage is finally set for the study and exploitation of this novel form of supramolecular asymmetry. Within the period of this ERC Consolidator Grant the PI will lead a team to investigate the synthesis, properties and applications of these intriguing mechanically chiral molecules.

Mots-clés : rotaxane,molecular machines,mechanically interlocked
Projet ERC : NDI (Horizon 2020, appel 2014, Proof of concept grants)
Entité participante : University of Ulm — Pays : Allemagne — Rôle : PI
Type d'entité : Enseignement supérieur ou secondaire
Financement ERC de l'entité : 147500.0 €

Molecular imaging is the current standard of care for the diagnosis (staging) of cancer, the evaluation of cancer treatment effectiveness, and is generating evidence as the best predictor for earlier diagnosis of Alzheimer’s disease. Molecular imaging differs from traditional imaging in that probes known as biomarkers are used to help image particular pathways. The goal is to image injected bio-active molecules (biomarkers) in vivo, allowing targeted imaging of the processes these molecules participate in. Currently, the most common clinical modality for molecular imaging is Positron Emission Tomography (PET), a nuclear imaging method with high costs that exposes patients to potentially harmful radiation. It is currently impossible to perform molecular imaging with magnetic resonance imaging (MRI) scanners due to low molecular sensitivity. Our primary goal is the development and commercialization of a novel technology for molecular imaging using existing MRI scanners, which could dramatically improve the early diagnosis of cancer and Alzheimer's disease, and serve as a platform for future medical research. We will develop a new "tracer" agent for MRI, using nano-diamonds. Using a novel polarization scheme, as well as 13C enriched diamonds, we increase the nano-diamond MRI signal more than a 10,000,000-fold at room temperature. This will provide a solution for molecular imaging which is cheaper, does not expose patients to ionized radiation, and allows earlier diagnosis of cancer metastasis due to the superior spatial resolution of MRI. The proposed project aims to bring this idea to the proof-of-concept level by demonstrating the imaging of cancerous tumors in a biological model, using an industrial MRI scanner and nano-diamond tracers. In parallel, we will also develop our future regulatory strategy, explore the market potential and secure potential customers. Ultimately, we intend to launch a company to bring this product to market.

Mots-clés : cancer diagnostic,alzheimer s disease diagnostic,molecular imaging,nano diamond applications,quantum medical applications,hyperpolarization,quantum spin control