Data-Gouv-ML/pcri-erc-participations-et-projets-laureats huggingface dataset:
Projet ERC : AutoCAb (Horizon 2020, appel 2018, Consolidator grants)
Domaine scientifique : Life Science
Panel : Biotechnology and Biosystems Engineering
Entité participante : Weizmann Institute of Science — Pays : Israël — Rôle : PI
Type d'entité : Enseignement supérieur ou secondaire
Financement ERC de l'entité : 2337500.0 €

We propose to develop the first high-throughput strategy to design, synthesize, and screen repertoires comprising millions of single-domain camelid antibodies (VHH) that target desired protein surfaces. Each VHH will be individually designed for high stability and target-site affinity. We will leverage recent methods developed by our lab for designing stable, specific, and accurate backbones at interfaces, the advent of massive and affordable custom-DNA oligo synthesis, and machine learning methods to accomplish the following aims: Aim 1: Establish a completely automated computational pipeline that uses Rosetta to design millions of VHHs targeting desired protein surfaces. The variable regions in each design will be encoded in DNA oligo pools, which will be assembled to generate the entire site-targeted repertoire. We will then use high-throughput binding screens followed by deep sequencing to characterize the designs’ target-site affinity and isolate high-affinity binders. Aim 2: Develop an epitope-focusing strategy that designs several variants of a target antigen, each of which encodes dozens of radical surface mutations outside the target site to disrupt potential off-target site binding. The designs will be used to isolate site-targeting binders from repertoires of Aim 1. Each high-throughput screen will provide unprecedented experimental data on target-site affinity in millions of individually designed VHHs. Aim 3: Use machine learning methods to infer combinations of molecular features that distinguish high-affinity binders from non binders. These will be encoded in subsequent designed repertoires, leading to a continuous “learning loop” of methods for high-affinity, site-targeted binding. AutoCAb’s interdisciplinary strategy will thus lead to deeper understanding of and new general methods for designing stable, high-affinity, site-targeted antibodies, potentially revolutionizing binder and inhibitor discovery in basic and applied biomedical research.

Mots-clés : protein design,antibody design,camelid antibodies,repertoire design,deep sequencing,stability design,diagnostics,inhibitors,affinity design,specificity design,rosetta design
Projet ERC : VARMET (Horizon 2020, appel 2014, Advanced grants)
Domaine scientifique : Physical Sciences and Engineering
Panel : Physical and analytical chemical sciences
Entité participante : Università della Svizzera italiana — Pays : Suisse — Rôle : PI
Acronyme de l'entité : USI
Type d'entité : Enseignement supérieur ou secondaire
Financement ERC de l'entité : 2488827.0 €

We propose to extend the time scale accessible to atomistic-based simulation methods from the current range to millisecond and beyond without special-purpose machines. We shall do this by combining and extending two recent developments: a recent reformulation of the enhanced sampling problem into a powerful variational principle that opens a wealth of possibilities and provides a novel and fruitful standpoint for new developments; and a procedure for extracting rates from enhanced runs. We shall apply the methods thus developed to two major problems of great practical interest. One is the lifetime of a ligand-protein bound state. This quantity is not easily accessible experimentally and yet it is crucial in drug design to determine the potency of a drug. We plan to develop a viable and widely applicable way to compute it. The other is a study of crystallization from solution, for which we wish to determine the nucleation mechanism and nucleation rates and understand and control crystal growth. These are all issues of great relevance in engineering, pharmacology and nanotechnology. Besides being relevant on their own merits, these two applications present different challenges to the enhanced methods. We also believe that new methods should not be developed in an abstract way but in close interaction with real-life applications.
Projet ERC : IndiGene (Horizon 2020, appel 2018, Synergy grants)
Entité participante : Wellcome Trust — Pays : Royaume-Uni — Rôle : Partner
Acronyme de l'entité : WT
Type d'entité : Recherche
Financement ERC de l'entité : 831727.0 €

We propose to thoroughly investigate and characterise the sources of variation that results in varying phenotypes in a complex vertebrate. As well as characterising the genetic and environmental sources of variation, we will also investigate individual stochastic variation present even in fixed settings (both genetically and environmentally). To achieve this we will exploit the unique properties of Medaka fish, which can be fully inbred from the wild. We have already inbred and performed whole genome sequencing of a panel of 111 diverse Medaka fish from a single location; we propose to phenotype these fish in depth with high replication structure, ranging from organismal to molecular phenotypes. We will also phenotype entirely wild fish from the same source population as the panel with a subset of the phenotypes. We will analyse the data using state of the art methods to partition variation between genetic, environmental and stochastic components, and their interactions. We will integrate across both the different levels of phenotypic information across the cardiovascular system, and also across vertebrate phenotypes, in particular the extensive human phenotypes. By using genetic crosses and CRISPR-Cas9 techniques we will definitively prove specific interactions. We will host a “Research Hotel” for other phenotyping schemes to be applied to this panel, in particular from the Zebrafish community. This comprehensive and carefully replicated study will allow us to understand the opportunities and limitations of genetic stratification and personalised medicine in humans.
Projet ERC : PHOTOMASS (Horizon 2020, appel 2018, Consolidator grants)
Domaine scientifique : Physical Sciences and Engineering
Panel : Physical and analytical chemical sciences
Entité participante : University of Oxford — Pays : Royaume-Uni — Rôle : PI
Type d'entité : Enseignement supérieur ou secondaire
Financement ERC de l'entité : 1999574.0 €

We propose to transform our understanding of biomolecular interactions and self-assembly by directly visualising the associated molecular mechanisms. To achieve this, we will capitalise on our recent development of interferometric scattering mass spectrometry (iSCAMS), which enables not only the detection and imaging of single biomolecules in solution, but also the accurate determination of their molecular mass at the single molecule level. These studies, and the development of the associated technology, will bridge the gap between high-resolution structural and low-resolution solution-based methods for studies of biomolecular interactions and assembly. We will achieve these ambitious goals by pursuing five interconnected objectives chosen according to their potential to maximise scientific and societal impact by addressing fundamental questions related to biological function and health: (1) Determine the physicochemical origins of mono- and polydispersity; (2) Visualise the mechanism of viral capsid assembly; (3) Reveal the molecular basis of cytoskeletal dynamics; (4) Capture the aggregation and inhibition of amyloid aggregation. These four system-oriented objectives will be accompanied by a technological objective, (5) aimed at implementing improvements in terms of dynamic range and resolution of iSCAMS required for studying self-assembly. As a consequence of the universal applicability of our approach for characterising molecular interactions, oligomeric distributions and dynamics in a facile fashion in solution, this ambitious project opens up a broad range of exciting applications beyond molecular biophysics in fields as drug-discovery, bioanalytical and biomedical science.

Mots-clés : biophysical chemistry,label free imaging and sensing
Projet ERC : Ph.D. (Horizon 2020, appel 2019, Starting grants)
Domaine scientifique : Physical Sciences and Engineering
Panel : Condensed matter physics
Entité participante : Ruhr University Bochum — Pays : Allemagne — Rôle : PI
Acronyme de l'entité : RUB
Type d'entité : Enseignement supérieur ou secondaire
Financement ERC de l'entité : 918353.75 €

We recently reported the first observation of dynamic adaptive colloidal crystals exhibiting characteristics similar to those commonly associated with living organisms: self-replication, self-healing, adaptation, competition, motility. Here, I propose to do the first experiments to clarify precisely how dynamic adaptive behavior arises far from equilibrium and how to control it. The key to both is a fundamental question at the heart of condensed matter, statistical and nonlinear physics: When far from equilibrium, in the presence of fluctuations and faced with multiple steady states with small energy differences, how does a system evolve? Specifically, my objectives are (1) to form crystals with periodic and aperiodic patterns, e.g. 2D Bravais lattices, quasicrystals, using passive identical particles, (2) to quantify their formation energies through the effective temperature of Brownian particles, (3) to identify the conditions for emergence and control of adaptive behavior. Then, I will draw a complete phase map of these dynamic adaptive colloidal crystals using fitness landscapes to characterize each pattern. I will further ask to what extent this control is extendable down to the few-nm scale, where fluctuations are even stronger and if and how these findings change when using nonidentical, in size or shape, but still passive particles. My system comprises quasi-2D-confined pure-polystyrene 500-nm spheres suspended in water. An energy flux to drive the system far from equilibrium and sustain it there is supplied by an ultrafast laser. My method exploits only three physical tenets, nonlinearity, fluctuations and positive/negative feedback mechanisms acting on identical passive particles, yet generates extremely rich emergent dynamics. A full understanding of how such dynamics arise from so few basic ingredients will advance our understanding of complex systems in addition to numerous practical applications to self-assembly, microfluidics, nanoscience and biology.
Projet ERC : Ph.D. (Horizon 2020, appel 2019, Starting grants)
Domaine scientifique : Physical Sciences and Engineering
Panel : Condensed matter physics
Entité participante : Bilkent University — Pays : Turquie — Rôle : Partner
Type d'entité : Recherche
Financement ERC de l'entité : 581646.25 €

We recently reported the first observation of dynamic adaptive colloidal crystals exhibiting characteristics similar to those commonly associated with living organisms: self-replication, self-healing, adaptation, competition, motility. Here, I propose to do the first experiments to clarify precisely how dynamic adaptive behavior arises far from equilibrium and how to control it. The key to both is a fundamental question at the heart of condensed matter, statistical and nonlinear physics: When far from equilibrium, in the presence of fluctuations and faced with multiple steady states with small energy differences, how does a system evolve? Specifically, my objectives are (1) to form crystals with periodic and aperiodic patterns, e.g. 2D Bravais lattices, quasicrystals, using passive identical particles, (2) to quantify their formation energies through the effective temperature of Brownian particles, (3) to identify the conditions for emergence and control of adaptive behavior. Then, I will draw a complete phase map of these dynamic adaptive colloidal crystals using fitness landscapes to characterize each pattern. I will further ask to what extent this control is extendable down to the few-nm scale, where fluctuations are even stronger and if and how these findings change when using nonidentical, in size or shape, but still passive particles. My system comprises quasi-2D-confined pure-polystyrene 500-nm spheres suspended in water. An energy flux to drive the system far from equilibrium and sustain it there is supplied by an ultrafast laser. My method exploits only three physical tenets, nonlinearity, fluctuations and positive/negative feedback mechanisms acting on identical passive particles, yet generates extremely rich emergent dynamics. A full understanding of how such dynamics arise from so few basic ingredients will advance our understanding of complex systems in addition to numerous practical applications to self-assembly, microfluidics, nanoscience and biology.
Projet ERC : DIM-CrIC (Horizon 2020, appel 2019, Proof of concept grants)
Domaine scientifique : Life Science
Panel : Immunity, Infection and Immunotherapy
Entité participante : CNRS Innovation — Pays : France — Rôle : Partner
Type d'entité : Organismes privés (hors enseignement)
Financement ERC de l'entité : 9800.0 €

We will develop and test a treatment for pancreatic ductal adenocarcinoma (PDAC). To this aim, we will synthesize and evaluate the efficacy of novel inhibitors of nucleic acid-induced inflammation that we have identified. Indeed, nucleic acid-induced chronic inflammation is a major driver of tumorigenesis. Because the canonical pathway that triggers nucleic acid-induced chronic inflammation relies on the STING protein, identifying ways to activate or inhibit STING is a major goal of current research. We have identified a novel endogenous pathway that antagonizes STING though the production of a second messenger molecule. This pathway prevents spurious STING activation and regulates nucleic acid-associated inflammation. We have developed a set of analogues of this small molecules for wich we demonstrate the ability to prevent STING activation in vitro and now wish to ameliorate the intracellular delivery of these molecules to assess their in vivo efficacy on PDAC-associated inflammation. PDAC is a suitable model for establishing the proof of concept of efficacy of the treatment we propose, because we show that knocking-out STING impairs PDAC growth. Therefore, DIM-CriC will provide novel means to tackle STING-dependent inflammation in PDAC. Ultimately, this work should pave the way to assessment in additional tumorigenesis models that present a STING-dependent inflammatory profile, unraveling a novel route to block cancer-related inflammation to the benefit of patients.

Mots-clés : sting,inhibitors,pancreatic adenocarcinoma,inflammation,cancer
Projet ERC : WallCrossAG (Horizon 2020, appel 2018, Consolidator grants)
Domaine scientifique : Physical Sciences and Engineering
Panel : Mathematics
Entité participante : University of Edinburgh — Pays : Royaume-Uni — Rôle : PI
Type d'entité : Enseignement supérieur ou secondaire
Financement ERC de l'entité : 1999840.0 €

We will establish stability conditions and wall-crossing in derived categories as a standard methodology for a wide range of fundamental problems in algebraic geometry. Previous work based on wall-crossing, in particular my joint work with Macri, has led to breakthroughs on the birational geometry of moduli spaces and related varieties. Recent advances have made clear that the power of stability conditions extends far beyond this setting, allowing us to study vanishing theorems or bounds on global sections, Brill-Noether problems, or moduli spaces of varieties. The Brill-Noether problem is one of the oldest and most fundamental questions of algebraic geometry, aiming to classify possible degrees and embedding dimensions of embeddings of a given variety into projective spaces. Recent work by myself, a post-doc (Chunyi Li) and a PhD student (Feyzbakhsh) of mine has established wall-crossing as a powerful new method for such questions. We will push this method further, all the way towards a proof of Green's conjecture, and the Green-Lazarsfeld conjecture, for all smooth curves. We will use similar methods to prove new Bogomolov-Gieseker type inequalities for Chern classes of stable sheaves and complexes on higher-dimensional varieties. In addition to constructing stability conditions on projective threefolds---the biggest open problem within the theory of stability conditions, we will apply them to study moduli spaces of sheaves on higher-dimensional varieties, and to characterise special abelian varieties. We will use the construction of stability conditions for families of varieties in my current joint work to systematically study the geometry of Fano threefolds and fourfolds, in particular their moduli spaces, by establishing relations between different moduli spaces, and describing their Torelli maps. Finally, we will study rationality questions, with a particular view towards a wall-crossing proof of the irrationality of the very general cubic fourfold.

Mots-clés : algebraic geometry,derived categories,stability conditions,wall crossing,moduli spaces,brill noether,fano varieties,bogomolov gieseker inequality
Projet ERC : QuantGeomLangTFT (Horizon 2020, appel 2014, Starting grants)
Domaine scientifique : Physical Sciences and Engineering
Panel : Mathematics
Entité participante : University of Edinburgh — Pays : Royaume-Uni — Rôle : PI
Type d'entité : Enseignement supérieur ou secondaire
Financement ERC de l'entité : 1100947.5 €

We will use modern techniques in derived algebraic geometry, topological field theory and quantum groups to construct quantizations of character varieties, moduli spaces parameterizing G-bundles with flat connection on a surface. We will leverage our construction to shine new light on the geometric representation theory of quantum groups and double affine Hecke algebras (DAHA's), and to produce new invariants of knots and 3-manifolds. Our previous research has uncovered strong evidence for the existence of a novel construction of quantum differential operators -- and their extension to higher genus surfaces -- in terms of a four-dimensional topological field theory, which we have dubbed the Quantum Geometric Langlands (QGL) theory. By construction, the QGL theory of a surface yields a quantization of its character variety; quantum differential operators form just the first interesting example. We thus propose the following long-term projects: 1. Build higher genus analogs of DAHA's, equipped with mapping class group actions -- thereby solving a long open problem -- by computing QGL theory of arbitrary surfaces; recover quantum differential operators and the (non-degenerate, spherical) DAHA of G, respectively, from the once-punctured and closed two-torus. 2. Obtain a unified construction of both the quantized A-polynomial and the Oblomkov-Rasmussen-Shende invariants, two celebrated -- and previously unrelated -- conjectural knot invariants which have received a great deal of attention. 3. By studying special features of our construction when the quantization parameter is a root of unity, realize the Verlinde algebra as a module over the DAHA, shedding new light on fundamental results of Cherednik and Witten. 4. Develop genus one, and higher, quantum Springer theory -- a geometric approach to constructing representations of quantum algebras -- with deep connections to rational and elliptic Springer theory, and geometric Langlands program.

Mots-clés : topological field theory,geometric langlands,quantum groups,character varieties,a polynomial,double affine hecke algebras,mapping class groups,braid groups,knot invariants
Projet ERC : Strained2DMaterials (Horizon 2020, appel 2014, Starting grants)
Domaine scientifique : Physical Sciences and Engineering
Panel : Condensed matter physics
Entité participante : Freie Universität Berlin — Pays : Allemagne — Rôle : PI
Acronyme de l'entité : FU
Type d'entité : Enseignement supérieur ou secondaire
Financement ERC de l'entité : 1997452.0 €

We will use strain engineering as an enabling tool to study previously inaccessible or hard-to-study phenomena in two-dimensional atomic crystals (2DACs: graphene, bilayer graphene, and monolayer transition metal dichalcogenides). In our first objective, we develop unique experimental tools to control and characterize mechanical strain in 2DACs. These are the distinguishing features of our approach: (i) The use of very low disorder suspended devices; (ii) Both uniform and controlled non-uniform strain will be induced; (iii) The level of strain will be precisely adjusted and determined in-situ during measurements. We will then use controllably-strained samples to study electrical, mechanical, thermal, and optical properties of 2DACs: Application of strain in suspended graphene will be shown to control amplitudes and dispersion relation of flexural out-of-plane phonons (FPs), a mode unique to 2D and quasi-2D materials. We will demonstrate, for the first time, that FPs dominate electrical, thermal, and mechanical of suspended graphene. Moreover, we will show dramatic mechanical softening of graphene in the regime of weak strain, similar to "entropic spring" behaviour seen in polymers. We will engineer strain distributions in high-mobility suspended graphene devices that translate into near-constant "pseudomagnetic field" and observe Quantum Hall-like quantization at zero external magnetic field. Strain-induced changes in topology of the band structure of bilayer graphene will be shown to affect Quantum Hall states and the Berry phase. Through strain engineering, we will controllably adjust - and even make spatially dependent - the band gap energy and binding energies of excitons in monolayer transition metal dichalcogenides (TMDCs). We will study complex interplay between and direct and indirect excitons and look for emergence of a new phase of matter, an excitonic insulator, in strained narrow-bandgap TMDC.

Mots-clés : graphene,two dimensional materials,quantum hall effect