Data-Gouv-ML/pcri-erc-participations-et-projets-laureats huggingface dataset:
Projet ERC : NO-ESKAPE (Horizon 2020, appel 2016, Consolidator grants)
Domaine scientifique : Physical Sciences and Engineering
Panel : Synthetic Chemistry and Materials
Entité participante : Leiden University — Pays : Pays-Bas — Rôle : PI
Type d'entité : Enseignement supérieur ou secondaire
Financement ERC de l'entité : 1784041.25 €

Antibiotic resistance poses an alarming threat to global health. Most worrisome are the so-called “ESKAPE” pathogens (E. faecium, S. aureus, K. pneumoniae, A. baumanii, P. aeruginosa, and Enterobacter species), a collection of organisms capable of escaping the effects of almost all conventional antibiotics. Key to combating drug-resistant bacteria is the identification of new antibacterial targets and the ability to exploit these targets with novel and unconventional antibiotics. The microbial world produces a wealth of antibacterial compounds that, while not suitable for therapeutic use, operate by diverse and unique modes of action. This proposal describes innovative approaches aimed at the discovery and development of such compounds as leads towards novel antibiotics with entirely new modes of action. Using a multidisciplinary approach, firmly grounded in synthetic organic chemistry, I will prepare and validate new antibiotics that target the ESKAPE pathogens by exploiting mechanisms critical to their survival and/or resistance. To tackle the Gram-positive ESKAPE pathogens a number of new approaches to interfering with bacterial cell wall biosynthesis will be examined. Specifically, novel (semi)synthetic compounds capable of binding to and sequestering various bacterial cell wall precursors will be prepared and their antibiotic activity assessed. To address the Gram-negative ESKAPE pathogens, inhibitors of the metallo-beta-lactamase enzymes responsible for much of their antibiotic resistance will be pursued. These inhibitors will be achieved via a combination of rational design strategies and innovative natural product screening approaches. The 21st century threat of a post-antibiotic era makes clear the need for innovation in antibacterial drug discovery. The strategies outlined in this proposal address this threat head-on with the aim of delivering valuable lead compounds in pursuit of novel antibiotics.

Mots-clés : antibiotics,semi synthesis,peptides,natural products,bacterial cell wall,metallo beta lactamase inhibitors,mechanism of action,antibacterial assays,resistance assays,enzyme assays
Projet ERC : HIV1ABTHERAPY (Horizon 2020, appel 2014, Starting grants)
Domaine scientifique : Life Science
Panel : Immunity, Infection and Immunotherapy
Entité participante : University Hospital Cologne — Pays : Allemagne — Rôle : PI
Type d'entité : Enseignement supérieur ou secondaire
Financement ERC de l'entité : 1500000.0 €

Antibodies are destined to neutralize pathogens and can prevent and fight infectious diseases. Over the last years, advances in single B cell cloning resulted in the isolation of highly potent and broad HIV-1 neutralizing antibodies (bNAbs) that have been shown to prevent SHIV infection in non-human primates (NHPs). Recently, we have demonstrated that a combination of bNAbs can suppress HIV-1 replication in humanized mice, reducing viremia to undetectable levels. Moreover, bNAb therapy of SHIV-infected NHPs induced a rapid decline in viremia, followed by a prolonged control due to the long half-life of the antibodies. While these results strongly encourage the clinical evaluation of bNAbs in HIV-1 therapy, it is of critical importance to understand how the therapeutic potential of antibodies can be harnessed in the most effective way. Therefore, we aim to: I.) Identify exceptionally potent HIV-1 neutralizing antibodies that will be a crucial component of immunotherapy. By establishing novel methods for single-cell sorting and high-throughput sequencing we want to identify bNAbs targeting novel epitopes. II.) Prevent HIV-1 escape applying rationally designed treatment strategies targeting conserved functional sites for HIV-1 entry. III.) Evaluate immune markers and function in relation to bNAb administration in humans. Being at the forefront of one of the first clinical trials studying an HIV-1-directed bNAb, we will have the unique opportunity to investigate the interplay of antibody therapy and the host immune system. This proposal aims to strongly advance the field of HIV-1 antibody therapy and therefore enable the introduction of a new therapeutic modality for HIV-1, and will gain insights for antibody-mediated therapy in other infectious diseases.

Mots-clés : antibodies,hiv 1
Projet ERC : ENGRAB (Horizon 2020, appel 2019, Advanced grants)
Domaine scientifique : Life Science
Panel : Immunity, Infection and Immunotherapy
Entité participante : Istituto Nazionale Genetica Molecolare — Pays : Italie — Rôle : PI
Acronyme de l'entité : INGM
Type d'entité : Recherche
Financement ERC de l'entité : 2478125.0 €

Antibodies represent a powerful defense mechanism due to their capacity to link specific antigen recognition with effector functions and are currently developed as drugs for prophylaxis and therapy of infectious diseases. The generation of antibody diversity represents a remarkable example of protein engineering that is coupled to a stringent mechanism of clonal selection. In the ENGRAB project we propose first to develop an integrated bioinformatics platform to unravel the clonal dynamics of antibody responses and use it to formulate and test hypotheses on the factors that drive antibody selection in primary and recall responses, thus providing a rational basis for vaccination strategies. Second, we will establish the general relevance and impact of receptor-based antibodies, a new type of naturally engineered antibodies generated by templated DNA insertions into immunoglobulin genes. Third, we will use different bispecific antibody formats, including those produced by templated insertions, to engineer, in the same molecule, two binding sites for the HIV spike in order to increase neutralization potency and breadth. Fourth, we will engineer the Fc portion of antibodies to HSV, S. aureus and M. tuberculosis to increase their effector function through loss-of-binding to pathogen Fc receptors or gain-of-binding to human activatory Fc receptors. The program is strongly supported by preliminary findings and will deliver an innovative platform to interrogate natural antibody repertoires and new strategies to engineer antibodies to improve their therapeutic efficacy. The ENGRAB project deals with mechanisms of antibody diversification and engineering with implications for vaccination and immunotherapy. It is therefore submitted to LS6. Given its translational potential it also falls within the scope of LS7.

Mots-clés : antibody engineering,neutralizing antibodies,bispecific antibodies,memory b cells,plasma cells,somatic mutations,affinity maturation,vaccines,templated insertions
Projet ERC : 3D_Tryps (Horizon 2020, appel 2016, Starting grants)
Domaine scientifique : Life Science
Panel : Immunity, Infection and Immunotherapy
Entité participante : Ludwig-Maximilians-Universität München — Pays : Allemagne — Rôle : PI
Acronyme de l'entité : LMU
Type d'entité : Enseignement supérieur ou secondaire
Financement ERC de l'entité : 1498175.0 €

Antigenic variation is a widely employed strategy to evade the host immune response. It has similar functional requirements even in evolutionarily divergent pathogens. These include the mutually exclusive expression of antigens and the periodic, nonrandom switching in the expression of different antigens during the course of an infection. Despite decades of research the mechanisms of antigenic variation are not fully understood in any organism. The recent development of high-throughput sequencing-based assays to probe the 3D genome architecture (Hi-C) has revealed the importance of the spatial organization of DNA inside the nucleus. 3D genome architecture plays a critical role in the regulation of mutually exclusive gene expression and the frequency of translocation between different genomic loci in many eukaryotes. Thus, genome architecture may also be a key regulator of antigenic variation, yet the causal links between genome architecture and the expression of antigens have not been studied systematically. In addition, the development of CRISPR-Cas9-based approaches to perform nucleotide-specific genome editing has opened unprecedented opportunities to study the influence of DNA sequence elements on the spatial organization of DNA and how this impacts antigen expression. I have adapted both Hi-C and CRISPR-Cas9 technology to the protozoan parasite Trypanosoma brucei, one of the most important model organisms to study antigenic variation. These techniques will enable me to bridge the field of antigenic variation research with that of genome architecture. I will perform the first systematic analysis of the role of genome architecture in the mutually exclusive and hierarchical expression of antigens in any pathogen. The experiments outlined in this proposal will provide new insight, facilitating a new view of antigenic variation and may eventually help medical intervention in T. brucei and in other pathogens relying on antigenic variation for their survival.

Mots-clés : genome architecture,antigenic variation
Projet ERC : ResisTEST (Horizon 2020, appel 2018, Proof of concept grants)
Entité participante : Autonomous University of Barcelona — Pays : Espagne — Rôle : PI
Acronyme de l'entité : UAB
Type d'entité : Enseignement supérieur ou secondaire
Financement ERC de l'entité : 150000.0 €

Antimicrobial resistance (AMR) has become a worldwide epidemic, causing more than for 700.000 deaths per year globally, expected to rise to 10 million deaths annually, by 2050. AMR is associated with an increase in morbidity, longer hospitalization time and a marked increase in the associated medical costs. While several attempts are being enforced to reduce the misuse and abuse of antibiotics, we are in dire needs of methods to rationalize the use of antibiotics. Currently, bacterial cultures are the staple diagnostic method of AMR. However, this method presents important drawbacks, such as a long turnaround time, which can be up to two weeks for some bacterial strains, low sensitivity, and the requirement to have, at least to a certain degree, prior information on the putative causative bacteria. All in all, these factors lead to the administration of wide-spectrum antibiotics in the meantime, leading to inefficient treatments, antibiotic changes and AMR occurrences. Hence, it is critical developing novel diagnostic methods offering a faster, high-sensitive alternative to bacterial cultures, the staple in AMR diagnostics. While several systems, such as DNA sequencing, are currently being developed, they require costly equipment and specialized training, limiting its use. In this regard, in ResisTEST we take advantage of our expertise in molecular biology and the knowledge and technology developed in an ERC StG to propose a fast, high-sensitive AMR detection approach that, once further developed into a diagnostic kit, will allow the isolation and real-time monitoring of the expression of different resistance gene without the need of prior knowledge on the pathogen. Therefore, this disruptive approach could represent a significant breakthrough in the fight against AMR, allowing to define, with unprecedented precision, the antibiotic of choice for the treatment of infections where AMR is suspected.

Mots-clés : ribosome,immunoprecipitation,transcriptome,antibiotic resistance
Projet ERC : APOSITE (Horizon 2020, appel 2018, Consolidator grants)
Domaine scientifique : Life Science
Panel : Cellular, Developmental and Regenerative Biology
Entité participante : University of Tübingen — Pays : Allemagne — Rôle : Partner
Type d'entité : Enseignement supérieur ou secondaire
Financement ERC de l'entité : 89578.08 €

Apoptotic cell death is essential for development, immune function or tissue homeostasis, and it is often deregulated in disease. Mitochondrial outer membrane permeabilization (MOMP) is central for apoptosis execution and plays a key role in its inflammatory outcome. Knowing the architecture of the macromolecular machineries mediating MOMP is crucial for understanding their function and for the clinical use of apoptosis. Our recent work reveals that Bax and Bak dimers form distinct line, arc and ring assemblies at specific apoptotic foci to mediate MOMP. However, the molecular structure and mechanisms controlling the spatiotemporal formation and range of action of the apoptotic foci are missing. To address this fundamental gap in our knowledge, we aim to unravel the composition, dynamics and structure of apoptotic foci and to understand how they are integrated to orchestrate function. We will reach this goal by building on our expertise in cell death and cutting-edge imaging and by developing a new analytical pipeline to: 1) Identify the composition of apoptotic foci using in situ proximity-dependent labeling and extraction of near-native Bax/Bak membrane complexes coupled to mass spectrometry. 2) Define their contribution to apoptosis and its immunogenicity and establish their assembly dynamics to correlate it with apoptosis progression by live cell imaging. 3) Determine the stoichiometry and structural organization of the apoptotic foci by combining single molecule fluorescence and advanced electron microscopies. This multidisciplinary approach offers high chances to solve the long-standing question of how Bax and Bak mediate MOMP. APOSITE will provide textbook knowledge of the mitochondrial contribution to cell death and inflammation. The implementation of this new analytical framework will open novel research avenues in membrane and organelle biology. Ultimately, understanding of Bax and Bak structure/function will help develop apoptosis modulators for medicine.
Projet ERC : AMPERE (Horizon 2020, appel 2017, Consolidator grants)
Domaine scientifique : Physical Sciences and Engineering
Panel : Physical and analytical chemical sciences
Entité participante : Sorbonne Université — Pays : France — Rôle : PI
Acronyme de l'entité : Sorbonne U
Type d'entité : Enseignement supérieur ou secondaire
Financement ERC de l'entité : 1508718.75 €

Applied electrochemistry plays a key role in many technologies, such as batteries, fuel cells, supercapacitors or solar cells. It is therefore at the core of many research programs all over the world. Yet, fundamental electrochemical investigations remain scarce. In particular, electrochemistry is among the fields for which the gap between theory and experiment is the largest. From the computational point of view, there is no molecular dynamics (MD) software devoted to the simulation of electrochemical systems while other fields such as biochemistry (GROMACS) or material science (LAMMPS) have dedicated tools. This is due to the difficulty of accounting for complex effects arising from (i) the degree of metallicity of the electrode (i.e. from semimetals to perfect conductors), (ii) the mutual polarization occurring at the electrode/electrolyte interface and (iii) the redox reactivity through explicit electron transfers. Current understanding therefore relies on standard theories that derive from an inaccurate molecular-scale picture. My objective is to fill this gap by introducing a whole set of new methods for simulating electrochemical systems. They will be provided to the computational electrochemistry community as a cutting-edge MD software adapted to supercomputers. First applications will aim at the discovery of new electrolytes for energy storage. Here I will focus on (1) ‘‘water-in-salts’’ to understand why these revolutionary liquids enable much higher voltage than conventional solutions (2) redox reactions inside a nanoporous electrode to support the development of future capacitive energy storage devices. These selected applications are timely and rely on collaborations with leading experimental partners. The results are expected to shed an unprecedented light on the importance of polarization effects on the structure and the reactivity of electrode/electrolyte interfaces, establishing MD as a prominent tool for solving complex electrochemistry problems.

Mots-clés : supercapacitors,electrolytes,molecular dynamics
Projet ERC : RECEIVE (Horizon 2020, appel 2017, Starting grants)
Domaine scientifique : Life Science
Panel : Cellular, Developmental and Regenerative Biology
Entité participante : Max Planck Society — Pays : Allemagne — Rôle : PI
Acronyme de l'entité : MPG
Type d'entité : Recherche
Financement ERC de l'entité : 506553.95 €

Arbuscular mycorrhiza (AM) is an ancient plant-fungus symbiosis that is wide-spread in the plant kingdom. AM improves plant nutrition, stress resistance and general plant performance and thus represents a promising addition to sustainable agricultural practices. Mineral nutrients are released from the fungus to the plant at highly branched hyphal structures, the arbuscules, which form inside root cortex cells. Like the cells of other multicellular eukaryotes, plant cells show a remarkable developmental plasticity. Single cell re-differentiation is a fascinating process during arbuscule development, which can be conceptually separated into distinct stages controlled by the plant cell which precisely guide the step-wise formation of different parts of the arbuscule. It involves cell autonomous transcriptional reprogramming and subcellular remodelling, leading to repositioning of subcellular structures, cell polarization and multiplication of organelles. It is currently unknown how cell-autonomous reprogramming during arbuscule development is regulated. RECEIVE utilizes an integrated strategy combining transcriptional profiling, transcription factor identification, interaction network analysis with reverse genetics and cell biological techniques to understand the coordinated step-wise progression of arbuscule development. RECEIVE builds on the hypothesis that each stage of arbuscule development is accompanied by a stage-specific wave of gene expression and that transcriptional regulation is a key determinant of the developmental progress from stage to stage. The characterisation of these waves and the identification of the underlying transcriptional regulatory nodes is the focus of this project. RECEIVE aims to bridge a major knowledge gap about the molecular basis of one of the most important symbioses on earth.

Mots-clés : transcriptional regulation,root symbiosis,plant biology,arbuscular mycorrhiza,transient cell differentiation
Projet ERC : SONCITIES (Horizon 2020, appel 2019, Consolidator grants)
Domaine scientifique : Social Sciences and Humanities
Panel : Cultures and cultural production
Entité participante : University of Oxford — Pays : Royaume-Uni — Rôle : PI
Type d'entité : Enseignement supérieur ou secondaire
Financement ERC de l'entité : 1999825.0 €

Architecture and urban design, disciplines heavily rooted in visual epistemologies, have long neglected sound, or else treated it in very limited ways: as a physical quantity that can be modelled and controlled; or else as noise, something to be reduced or eliminated. The neglect of sound on the part of the built environment professions has been damaging for cities, which suffer from poor acoustic design. As cities come under increasing scrutiny in a rapidly urbanising world, it is time to turn attention to one of the most pervasive—yet most neglected—aspects of urban life: how cities sound; how the experience of urban soundscapes is differentiated along social and cultural lines; and how to harness the creative potential of sound to build healthier, more inclusive, more sustainable cities. SONCITIES will bring together sound theorists, urban sociologists, architects, urban designers and sound artists to develop the conceptual framework of sonic urbanism: a new acoustic paradigm for cities. First, we will conduct unprecedented ethnographic research with urban residents and communities, aiming to discover how people experience and shape urban soundscapes in their everyday lives. On this basis we will form a mobile urban sound laboratory to generate new sonic modes of urban analysis in dialogue with built environment practitioners internationally. Finally, we will develop new sonic modes of urban design in the context of Design Weeks, public exhibitions, and creative sonic interventions in cities: projects that will serve as prototypes for sonic urbanism. SONCITIES is led by a sound theorist and sound art practitioner at Oxford University with a proven record of collaboration with architects and urbanists. Through SONCITIES, sound will be placed at the forefront of creative practice in architecture and urban design, and sonic urbanism will emerge as an innovative theoretical paradigm that fundamentally transforms how cities are understood, designed and experienced.

Mots-clés : sound studies,sound in architecture and urban design,urban sound,sound art,sound and environment,urban sociology
Projet ERC : ARiAT (Horizon 2020, appel 2019, Starting grants)
Domaine scientifique : Physical Sciences and Engineering
Panel : Computer science and informatics
Entité participante : University of London — Pays : Royaume-Uni — Rôle : Partner
Acronyme de l'entité : U. London
Type d'entité : Enseignement supérieur ou secondaire
Financement ERC de l'entité : 60385.0 €

Arithmetic theories are logical theories for reasoning about number systems, such as the integers and reals. Such theories find a plethora of applications across computer science, including in algorithmic verification, artificial intelligence, and compiler optimisation. The appeal of arithmetic theories is their generality: once a problem has been formalised in a decidable such theory, a dedicated solver can in principle be used in a push-button fashion to obtain a solution. Arithmetic theories are also of great importance for showing decidability and complexity results in a variety of domains. Decision procedures for quantifier-free and linear fragments of arithmetic theories have been among the most intensively studied and impactful topics in theoretical computer science. However, emerging applications require more expressive theories, including support for quantifiers, counting, and non-linear functions. Unfortunately, the lack of understanding of the computational properties of such extensions means that existing decision procedures are not applicable or do not scale. The overall goal of this proposal is to advance the state-of-the-art in decision procedures for expressive arithmetic theories. To this end, starting with a recent breakthrough made by the PI, we will develop novel and optimal quantifier-elimination procedures for linear arithmetic theories, which we plan to eventually integrate into mainstream SMT solvers. Furthermore, we aim to improve complexity bounds and push the decidability frontier of extensions of arithmetic theories with counting and non-linear operations. The proposed research requires to tackle long-standing open problems---some of them being decades old. In short, the project will lay algorithmic foundations on which next-generation decision procedures and reasoners for arithmetic theories will be built.

Mots-clés : logic in computer science,arithmetic theories,decision procedures,algorithmic verification,quantifier elimination,counter machines