Data-Gouv-ML/pcri-erc-participations-et-projets-laureats huggingface dataset:
Projet ERC : RIBOFOLD (Horizon 2020, appel 2017, Advanced grants)
Domaine scientifique : Life Science
Panel : Molecules of Life: Biological Mechanisms, Structures and Functions
Entité participante : Max Planck Society — Pays : Allemagne — Rôle : PI
Acronyme de l'entité : MPG
Type d'entité : Recherche
Financement ERC de l'entité : 2482600.0 €

Protein domains start to fold co-translationally while they are being synthesized on the ribosome. Co-translational folding starts in the confined space of the ribosomal polypeptide exit tunnel and is modulated by the speed of translation. Although defects in protein folding cause many human diseases, the mechanisms of co-translational folding and the link between the speed of translation and the quality of protein folding is poorly understood. Here I propose to study when, where and how proteins emerging from the ribosome start to fold, how the ribosome and auxiliary proteins bound at the polypeptide exit affect nascent peptide folding, what causes ribosome pausing during translation, and how pausing affects nascent peptide folding. Our recent results (Holtkamp et al., Science 2015; Buhr et al., Mol Cell 2016) provide the proof of principle for monitoring translation and protein folding simultaneously at high temporal resolution. First, we will follow translation processivity and folding trajectories for proteins of different domain structure types using time-resolved ensemble kinetics and single-molecule setups. The structures of complexes with stalled folding intermediates will be solved by cryo-electron microscopy. Second, we will investigate the effects of the chaperone trigger factor, the signal recognition particle, and other protein biogenesis factors on the folding landscape. Third, we will analyze transient ribosome pauses in vivo (based on ribosome profiling data) and in vitro (based on time-resolved translation assays and mathematical modeling) and identify the events that cause pausing. Finally, we will probe how changes in translational processivity affect the conformational landscape of a protein. We expect that these results will open new horizons in understanding co-translational protein folding and will help to understand the molecular basis of many diseases.

Mots-clés : co translational protein folding
Projet ERC : PDPcardio (Horizon 2020, appel 2019, Consolidator grants)
Domaine scientifique : Life Science
Panel : Biotechnology and Biosystems Engineering
Entité participante : University of Freiburg — Pays : Allemagne — Rôle : PI
Type d'entité : Enseignement supérieur ou secondaire
Financement ERC de l'entité : 1998750.0 €

Protein phosphatase-1 (PP1) is a ubiquitously expressed enzyme known to dephosphorylate a large number of the phosphorylated serines and threonines. The catalytic subunit PP1c is bound to regulatory proteins in holoenzymes. These play specific and fundamental roles in physiological processes and pathologies. One key role lies in the regulation of important cardiac signaling pathways and calcium homoeostasis. Accordingly, deregulation of PP1 has been implicated in cardiac dysfunctions. Powerful tools to study PP1 biology are our own developed PP1-disrupting peptides (PDPs) that selectively release PP1c (bound to PDP: PDP–PP1c) activity in cells. Recently, we showed that PDP treatment counteracts kinase hyperactivity and seals the arrhythmogenic sarcoplasmic reticulum (SR)-calcium-leak in human heart failure tissue. Mechanistic data indicated that PDP–PP1c-mediated dephosphorylation of the ryanodine receptor type 2 (RyR2) is involved in this effect. Nevertheless, given the large amount of potential PP1 substrates, so far the scope of PDP action is unknown, and therefore the mechanisms underlying this beneficial and potentially therapeutic effect of the PDPs in heart failure are unclear and currently hard to investigate. PDPcardio will address these challenges by providing new chemical biology methodologies combined with proteomics approaches using PDPs to guide PP1c to its substrates and to identify PDP-mediated interactions of PP1. These strategies will enable identifying the scope of PDP action in general, and in particular they will be applied here in cardiomyocytes to study the effects of PDP–PP1c. The results will provide the basis to fine-tune targeting PP1 for the treatment of heart insufficiency. Furthermore, the principles and methods developed here will be applicable more generally for defining the interaction scope of target-bound ligands (drugs) as well as for using PP1 as tool in synthetic biology.

Mots-clés : phosphatases,drug discovery,molecular mechanism of cell signalling,heart insufficiency and failure
Projet ERC : UBIQUITON (Horizon 2020, appel 2017, Proof of concept grants)
Entité participante : Institute of Molecular Biology — Pays : Allemagne — Rôle : PI
Acronyme de l'entité : IMB
Type d'entité : Recherche
Financement ERC de l'entité : 149900.0 €

Protein ubiquitylation plays a key role in determining the function and fate of proteins in virtually every biological pathway. The deregulation of such fundamental processes causes various diseases, such as cancer, neurodegeneration and inflammation. Understanding the impact of ubiquitylation is therefore critical for improving human health and welfare. Ubiquitin signalling is predominantly mediated by polyubiquitin chains of distinct linkages. Yet, this process is still poorly understood, largely due to a complete lack of methods for the manipulation of ubiquitin linkage. Here we propose to overcome this problem by establishing an inducible system for substrate- and linkage-selective polyubiquitylation of any target protein in vitro or in living cells. This innovative research tool, which we have named the “Ubiquiton” system, is based on a set of recombinant, tailor-made ubiquitylation enzymes in combination with appropriate tags appended to the desired substrate proteins. Having demonstrated feasibility of the method in principle, we now aim at developing the system for general use as a research and discovery tool kit for molecular biology and biotechnology. To this end, we will design expression constructs for a range of experimental systems and subcellular compartments and demonstrate the versatility of the method in different cell types, verifying its applicability in compartment-specific processes in the nucleus, the cytoplasm and at internal membranes. The Ubiquiton system will enable researchers to induce linkage-specific polyubiquitylation of desired targets in vivo and in vitro, prepare polyubiquitylated proteins for biochemical analysis, identify linkage-specific interaction partners and control protein fate in living cells. It will therefore serve as an innovative research tool for any molecular or cell biologist wishing to investigate the physiology of polyubiquitylation in health and disease.

Mots-clés : biotechnology,research tools,posttranslational protein modifications,protein engineering,ubiquitin
Projet ERC : MMA (Horizon 2020, appel 2016, Starting grants)
Domaine scientifique : Physical Sciences and Engineering
Panel : Synthetic Chemistry and Materials
Entité participante : University of Basel — Pays : Suisse — Rôle : PI
Type d'entité : Enseignement supérieur ou secondaire
Financement ERC de l'entité : 1466916.0 €

Protein-based hydrogels are commonly used as adhesives and sealants in surgical settings. Fibrin gels, for example, are biocompatible, however their use is hampered by poor mechanical properties. Previous attempts to improve fibrin gel mechanics relied on interpenetrating networks in combination with PEO, collagen and other polymers, however, only modest improvements were observed. The important challenge lies in understanding how molecular design principles can influence gel mechanics on the macroscale. The goal of this research is to develop mechanically tunable protein hydrogels. Upon mixture of two liquid components, the systems I propose would spontaneously form a gel matrix consisting of oligomerized proteins that mimic the extracellular matrix and possess controllable mechanical responses. By understanding protein nanomechanics at the single-molecule level, and designing modes of energy dissipation into hydrogel networks, my project will have an impact by bridging the knowledge gap between single-molecule and macroscopic mechanical responses. My approach is ground-breaking because I am leveraging the discoveries I made on a family of super-stable receptor-ligand proteins (Cohesins & Dockerin (Coh-Doc)). These reversible receptor-ligands can be broken and reformed thousands of times, yet still maintain high stability (1/2 covalent bond strength). After having pioneered the application of these mechano-stable domains as molecular handles in single-molecule experiments, I propose the following frontier research: A) I will use molecular engineering of Coh-Doc complexes to test the hypothesis that mechanical properties of bulk materials can be rationally designed based on single-molecule mechanical behavior of receptor-ligands. B) I will adapt the system to seamlessly merge with the native fibrin clotting pathway, providing a self-healing mechano-stable fibrin-based gel that could be applied as a liquid or spray and strongly adhere to cells and tissues.

Mots-clés : single molecule biophysics
Projet ERC : MaCChines (Horizon 2020, appel 2017, Advanced grants)
Domaine scientifique : Life Science
Panel : Biotechnology and Biosystems Engineering
Entité participante : National Institute of Chemistry — Pays : Slovénie — Rôle : PI
Acronyme de l'entité : NIC;KI
Type d'entité : Recherche
Financement ERC de l'entité : 2362838.75 €

Proteins are the most versatile and complex smart nanomaterials, forming molecular machines and performing numerous functions from structure building, recognition, catalysis to locomotion. Nature however explored only a tiny fraction of possible protein sequences and structures. Design of proteins with new, in nature unseen shapes and features, offers high rewards for medicine, technology and science. In 2013 my group pioneered the design of a new type of modular coiled-coil protein origami (CCPO) folds. This type of de novo designed proteins are defined by the sequence of coiled-coil (CC) dimer-forming modules that are concatenated by flexible linkers into a single polypeptide chain that self-assembles into a polyhedral cage based on pairwise CC interactions. This is in contrast to naturally evolved proteins where their fold is defined by a compact hydrophobic core. We recently demonstrated the robustness of this strategy by the largest de novo designed single chain protein, construction of tetrahedral, pyramid, trigonal prism and bipyramid cages that self-assemble in vivo. This proposal builds on unique advantages of CCPOs and represents a new frontier of this branch of protein design science. I propose to introduce functional domains into selected positions of CCPO cages, implement new types of building modules that will enable regulated CCPO assembly and disassembly, test new strategies of caging and release of cargo molecules for targeted delivery, design knotted and crosslinked protein cages and introduce toehold displacement for the regulated structural rearrangement of CCPOs required for designed molecular machines, which will be demonstrated on protein nanotweezers. Technology for the positional combinatorial library-based single pot assembly of CCPO genes will provide high throughput of CCPO variants. Project will result in new methodology, understanding of potentials of CCPOs for designed molecular machines and in demonstration of different applications.

Mots-clés : synthetic biology,bionanostructures,geneticaly encoded molecular machines,recombinant protein,protein cages,golden gate gene assembly
Projet ERC : AxScale (Horizon 2020, appel 2018, Starting grants)
Domaine scientifique : Physical Sciences and Engineering
Panel : Fundamental constituents of matter
Entité participante : Max Planck Society — Pays : Allemagne — Rôle : PI
Acronyme de l'entité : MPG
Type d'entité : Recherche
Financement ERC de l'entité : 517267.5 €

Pseudoscalar QCD axions and axion-like Particles (ALPs) are an excellent candidate for Dark Matter or can act as a mediator particle for Dark Matter. Since the discovery of the Higgs boson, we know that fundamental scalars exist and it is timely to explore the Axion/ALP parameter space more intensively. A look at the allowed axion/ALP parameter space makes it clear that these might exist at low mass (below few eV), as (part of) Dark Matter. Alternatively they might exist at higher mass, above roughly the MeV scale, potentially as a Dark Matter mediator particle. AxScale explores parts of these different mass regions, with complementary techniques but with one research team. Firstly, with RADES, it develops a novel concept for a filter-like cavity for the search of QCD axion Dark matter at a few tens of a micro-eV. Dark Matter Axions can be discovered by their resonant conversion in that cavity embedded in a strong magnetic field. The `classical axion window' has recently received much interest from cosmological model-building and I will implement a novel cavity concept that will allow to explore this Dark Matter parameter region. Secondly, AxScale searches for axions and ALPs using the NA62 detector at CERN's SPS. Especially the mass region above a few MeV can be efficiently searched by the use of a proton fixed-target facility. During nominal data taking NA62 investigates a Kaon beam. NA62 can also run in a mode in which its primary proton beam is fully dumped. With the resulting high interaction rate, the existence of weakly coupled particles can be efficiently probed. Thus, searches for ALPs from Kaon decays as well as from production in dumped protons with NA62 are foreseen in AxScale. More generally, NA62 can look for a plethora of `Dark Sector' particles with recorded and future data. With the AxScale program I aim at maximizing the reach of NA62 for these new physics models.

Mots-clés : dark matter,axion,proton fixed target
Projet ERC : QuCIP (Horizon 2020, appel 2017, 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 : 1740135.75 €

QuCIP will deliver the first historical-critical commentary on a sizable portion of the Qur’an in English, covering the three longest and most complex compositions in the Islamic scripture, surahs 2–4, as well as the short opening surah 1. The project will thereby put forward a pioneering proof of concept for an integrative exegetical approach capable of addressing three core dimensions of the Qur’an: the compositional structure of Qur’anic texts, the intricate processes of literary growth and redactional expansion by which many of them have been shaped, and the theological concerns governing the Qur’an’s appropriation of antecedent (especially Jewish and Christian) ideas, traditions, and literary forms. Pre-modern Islamic exegesis will be critically scrutinised as a valuable repository of close scriptural reading, even if its premises and conclusions are not always persuasive to a modern historian. The result will be a paradigmatic benchmark transforming the methodological toolkit of the discipline. In realising this ambitious project, the PI will be supported by three postdoctoral scholars. Two of them will undertake foundational research into the Qur'an's compositional grammar and into Qur’anic law. The third postdoctoral researcher will support the PI’s engagement with the voluminous Islamic exegetical literature and write a reception history of surah 4. The project team will furthermore produce an edited volume or special journal issue.

Mots-clés : qur an,islam,scripture
Projet ERC : COOLER (Horizon 2020, appel 2018, Advanced grants)
Domaine scientifique : Physical Sciences and Engineering
Panel : Earth system science
Entité participante : Université Grenoble Alpes — Pays : France — Rôle : Partner
Acronyme de l'entité : UGA
Type d'entité : Enseignement supérieur ou secondaire
Financement ERC de l'entité : 0.0 €

Quantifying the feedbacks between tectonic processes in the lithosphere and climatic processes in the atmosphere is an overarching goal in Earth-Systems research, as it underpins our ability to differentiate natural from anthropogenic climate forcing. Long-term cooling during the Cenozoic has been linked to the growth of mountain belts, which enhanced erosion, chemical weathering, organic-carbon burial and drawdown of atmospheric CO2. Conversely, it has been proposed that the cooler and more variable climate of the late Cenozoic led to increased topographic relief and erosion. This latter coupling, however, has not been decisively demonstrated and remains highly controversial. Advancing our understanding of these couplings requires the development of tools that record erosion rates and relief changes with higher spatial and temporal resolution than the current state-of-the-art, and integrating the newly obtained data into next-generation numerical models that link observed erosion-rate and relief histories to potential driving mechanisms. The project COOLER shoulders this task. We will: (1) develop new high-resolution thermochronology by setting up a world-leading 4He/3He laboratory; (2) develop numerical modelling tools that incorporate the latest insights in kinetics of thermochronological systems and make sample-specific predictions; (3) couple these tools to glacial landscape-evolution models, enabling modelling of real landscapes with real thermochronology data as constraints; and (4) study potential feedbacks between glacial erosion and tectonic deformation in carefully selected field areas. The new high-resolution data will be integrated and extrapolated to quantitatively assess the impact of late Cenozoic climate change on erosion rates. Integration and analysis of the data will lead to novel insights into the two-way coupling of glacial erosion and tectonics, as well as latitudinal trends in glacial erosion patterns.

Mots-clés : thermochronology,cenozoic climate change,erosion,numerical modelling
Projet ERC : QCDHighDensityCMS (Horizon 2020, appel 2020, Consolidator grants)
Domaine scientifique : Physical Sciences and Engineering
Panel : Fundamental constituents of matter
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 : 112660.0 €

Quantum Chromodynamics (QCD) is the theory of the strong force. Its high-temperature phase can be accessed experimentally via high energy heavy-ion collisions, allowing us to investigate how the macroscopic properties of nuclear matter arise from QCD interactions between quarks and gluons. With this proposal I aim to solve several fundamental and long-standing questions concerning the strong force and the evolution of the high density phase of QCD, the Quark Gluon plasma (QGP), that are related to the evolution of the early universe: a) Characterize the transport coefficient, qhat, of the Quark Gluon Plasma, which is related to its density b) Perform the equivalent of the Rutherford experiment in the QGP, to resolve the point-like quark and gluon scatterers within the QGP. c) Provide first experimental evidence of two important interference mechanisms that are expected to play a main role in the evolution of jets in a QGP, such as the Landau Pomeranchuk Migdal effect in QCD and the color coherence effect d) Study the phenomenology of the Lund plane, in particular selections on the branching time obtained from the splitting kinematics. Can it be used to draw a time-dependent picture of the jet shower? e)Perform the first attempt to time-scan the QGP with a yoctosecond chronometer using hadronic decays of W and Z bosons. As a world leader in the field of jet physics, also with a strong phenomenological background, I am in a unique position to to solve some of the most interesting problems concerning QCD at high densities by applying new ideas and techniques and exploring the jet substructure. The CMS detector capabilities for jet and electroweak boson reconstruction and the synergy between the pp and heavy ion communities within, make of CMS the ideal experimental detector to capitalize on my ideas and existing expertise. This grant will also provide the opportunity to reinforce the european contribution to the CMS heavy ion program and lead it.

Mots-clés : jet physics,jet quenching
Projet ERC : IQCC (Horizon 2020, appel 2014, Proof of concept grants)
Entité participante : Delft University of Technology — Pays : Pays-Bas — Rôle : PI
Acronyme de l'entité : TU Delft
Type d'entité : Enseignement supérieur ou secondaire
Financement ERC de l'entité : 150000.0 €

Quantum correlation measurements are essential to study and analyze the statistics of light fields, to observe quantum entanglement and are central in several emerging applications of quantum optics such as quantum cryptography, ballistic imaging, logic gates, quantum repeaters, fluorescence correlation spectroscopy and optical tomography. The measurement techniques have not evolved much since the report of the first quantum correlation measurement in 1956: macroscopic optical elements are used to divide a light beam and single photon detectors are placed in each arm, correlations among the detectors signals are then analyzed to yield correlation histograms. This implementation is bulky and prone to misalignment, when measuring higher-order correlations, the number of required components scales up exponentially. My ERC consolidator grant involves performing numerous quantum correlation measurements on light fields generated by single quantum dots coupled to atomic vapours. Here, a new architecture for a quantum correlation counter is proposed where the detectors are all integrated on a chip to offer the user a compact and robust device to measure quantum correlations up to orders as high as 4 and also able to resolve photon numbers with high fidelity. Eight contiguous superconducting single photon detectors coupled to an optical fiber will be used to achieve high detection efficiencies and unprecedented time resolution. Two prototypes of increasing complexity will be built and tested. The final system will form the starting point for a commercialization effort to be led by Single Quantum BV, a spin-off from my research group that produces single photon detectors. I expect an initial sales volume of 10 units/year to grow to 50 units/year after 5 years.

Mots-clés : quantum optics,nanoscience,nanotechnoloy,quantum information