Data-Gouv-ML/pcri-erc-participations-et-projets-laureats huggingface dataset:
Projet ERC : RNAREG (Horizon 2020, appel 2015, Starting grants)
Domaine scientifique : Life Science
Panel : Cellular, Developmental and Regenerative Biology
Entité participante : Royal Netherlands Academy of Arts and Sciences — Pays : Pays-Bas — Rôle : PI
Acronyme de l'entité : KNAW
Type d'entité : Recherche
Financement ERC de l'entité : 1500000.0 €

Gene expression is a highly dynamic and inherently variable process. Yet, it needs to be tightly regulated, especially during the cell cycle, when continuous large-scale changes occur to the proteome. Even small deviations in the expression levels of a single protein in individual cells can de-regulate cell cycle entry and promote tumorigenesis. Here, I will develop new technology to study gene expression dynamics in single cells to uncover how active regulation and stochastic variability shape the expression of key cell cycle genes and ensure reliable cell cycle-entry decisions. I recently developed a protein multimerization system, called SunTag, which allows very bright fluorescence imaging, as well as manipulation of transcription. To understand how accurate expression levels of a core set of cell cycle proteins are achieved, I will combine single-cell RNA sequencing with SunTag fluorescence imaging technology to visualize, with single molecule sensitivity, the rates of transcription, translation and mRNA degradation. These analyses will identify the contribution of each type of regulation to accurate gene expression, and will reveal how active regulation ensures correct cell cycle decisions in the presence of stochastic expression variability. Furthermore, I will develop new methodology to specifically perturb the different types of gene expression control during defined cell cycle stages. This will enable an unprecedented ability to interrogate the function of gene expression control for cell cycle entry, and will identify the genes for which tight control of expression is critical for correct cell cycle decisions. Together, this approach will: 1) Uncover how individual regulatory mechanisms (e.g. regulation of transcription, translation or mRNA degradation) contribute to accurate cell cycle entry through gene expression control of key cell cycle proteins 2) Examine how stochastic variability in gene expression influences the decision to enter the cell cycle
Projet ERC : REGENETHER (Horizon 2020, appel 2014, Starting grants)
Domaine scientifique : Life Science
Panel : Prevention, Diagnosis and Treatment of Human Diseases
Entité participante : Institut national de la santé et de la recherche médicale — Pays : France — Rôle : Partner
Acronyme de l'entité : Inserm
Type d'entité : Recherche
Financement ERC de l'entité : 340515.0 €

Gene therapy using adeno-associated viral (AAV) vectors has shown early promise in clinical trials. The therapeutic transgene cassette can be packaged in different AAV capsid pseudotypes, each having a unique transduction profile. At present, AAV capsid serotype selection for a specific clinical trial is based on effectiveness in small animal models. We (and others) have shown substantial progress in improving gene therapy for eye diseases in rodents. However, small animal studies are not often predictive of human outcome when it comes to the efficacy of viral delivery. Moreover, non-human primates used as pre-clinical animal models do not display any pathology making them unsuitable for testing efficacy. Here, I propose to overcome these bottlenecks in translational gene therapy by generating non-human primate models of retinal degeneration where effects of therapies and prosthesis on sight restoration can be tested. Generating transgenic primates using germline transgenesis would be very costly and ethically problematic. I thus propose to induce retinal disease locally, following delivery of pathogenic genes within specific subsets of cells in the non-human primate retina (Aim A). In Aim B, I propose to develop novel AAVs for use in human gene therapy using directed evolution. This bioengineering approach has yielded AAVs with enhanced delivery properties in the murine retina and applying it to post-mortem human retinas will generate AAVs responding to a clinical need in gene therapy. All together, the creation of models of disease in primates combined with novel AAVs tested in human post-mortem retinas will enable us to validate therapies aiming at vision restoration and neuroprotection in retinas with a macula and high central visual acuity, removing a major roadblock in the development of ocular therapeutics for humans.
Projet ERC : GRAMS (Horizon 2020, appel 2018, Consolidator grants)
Domaine scientifique : Physical Sciences and Engineering
Panel : Universe sciences
Entité participante : Scuola Internazionale Superiore di Studi Avanzati — Pays : Italie — Rôle : PI
Acronyme de l'entité : SISSA
Type d'entité : Enseignement supérieur ou secondaire
Financement ERC de l'entité : 1993920.0 €

General Relativity (GR) describes gravity on a huge range of scales, field strengths and velocities. However, despite its successes, GR has been showing its age. Cosmological data support the existence of a Dark Sector, but may also be interpreted as a breakdown of our understanding of gravity. Also, GR is intrinsically incompatible with quantum field theory, and should be replaced, at high energies, by a (still unknown) quantum theory of gravity. This deadlock may prelude to a paradigm change in our understanding of gravity, possibly triggered by the direct observations of neutron stars and black holes by gravitational-wave interferometers. The recent LIGO/Virgo observations, and in particular the coincident detection of electromagnetic and gravitational signals from neutron-star binaries, have already made a huge impact on our theoretical understanding of gravity, by severely constraining several extensions of GR. GRAMS is a high-risk/high-gain project seeking to push the implications of these observations even further, by exploring whether the existing LIGO/Virgo data, and in particular their absence of non-perturbative deviations from GR, are consistent with gravitational theories built to reproduce the large-scale behaviour of the Universe (i.e. the existence of Dark Energy and/or Dark Matter), while at the same time passing local tests of gravity thanks to non-perturbative screening mechanisms. I will prove that the very fact of screening local scales makes gravitational emission in these theories much more involved than in GR, and also intrinsically unlikely to yield results in agreement with existing (and future) gravitational-wave observations. This would be a huge step forward for our understanding of cosmology, as it would rule out a modified gravity origin for the Dark Sector. Even if this conjecture is incorrect, GRAMS will provide the first numerical-relativity simulations of compact binaries ever in gravitational theories of interest for cosmology.

Mots-clés : modified gravitational theories
Projet ERC : MOLBEC (Horizon 2020, appel 2019, Advanced grants)
Domaine scientifique : Physical Sciences and Engineering
Panel : Physical and analytical chemical sciences
Entité participante : TU Dortmund University — Pays : Allemagne — Rôle : PI
Type d'entité : Enseignement supérieur ou secondaire
Financement ERC de l'entité : 2069909.71 €

Generating a Bose Einstein Condensate (BEC) or Fermi gas of molecules is a long-standing goal of modern molecular science. Molecular BEC is a macroscopic millimeter-size quantum object with a large number of molecules occupying the lowest center-of-mass quantum state. In stark contrast to atoms, molecules possess internal degrees of freedom and stronger interactions that lead to the emergence of new phenomena. Strong dipole-dipole interactions give rise to new ordered states of matter, quantum crystals. Many-body effects start dominating collision dynamics where even molecular rotational excitations are dissipated as angular-momenta-carrying quasiparticles within the condensate. Despite intense experimental efforts, these fascinating ideas remain in the realm of theory. The main difficulty in turning theory into reality has been the absence of general molecular cooling methods. Recently, we have demonstrated the first experiment where collisions between cold molecules trapped in a 1 K deep superconducting magnetic trap are achieved without laser cooling [Segev et al. Nature, 572 (2019)], opening a clear path to molecular evaporation. We here propose to cool molecules by removing the fastest ones from the trap and letting the rest thermalize to lower temperatures via collisions. This method has been used to produce atomic BECs and we are the first group reaching identical initial conditions that are necessary for the successful application of the evaporative cooling. Generality of our approach is the key to successful search for a suitable molecular candidate. As an alternative to evaporation we suggest applying direct laser cooling on magnetically stopped NH radicals. We are confident that one of our approaches will lead to the long-sought generation of molecular quantum degenerate gas. Our proposal opens new fields and will find applications in areas ranging from quantum chemistry to quantum information science.

Mots-clés : cold molecules,many body effects in chemistry
Projet ERC : INCOVID (Horizon 2020, appel 2016, Advanced grants)
Domaine scientifique : Physical Sciences and Engineering
Panel : Computer science and informatics
Entité participante : Saarland University — Pays : Allemagne — Rôle : PI
Type d'entité : Enseignement supérieur ou secondaire
Financement ERC de l'entité : 2460000.0 €

Generating huge amounts of visual data, be it images or videos, has never been easier than today. This creates a growing demand for lossy codecs (coders and decoders) that produce visually convincing results also for very high compression rates. Popular transform-based codecs such as JPEG and JPEG 2000 have reached a state where one cannot expect significant improvements anymore. To go beyond their limitations, fundamentally different ideas are needed. Inpainting-based codecs can change this situation. They store only a small, carefully optimised part of the data. In the decoding step, the missing information is filled in with a suitable inpainting mechanism. A successful realisation of inpainting-based codecs can offer decisive advantages over transform-based codecs: The stored information is more intuitive and closer to the mechanisms of human perception. Moreover, the concept is very flexible: It allows to integrate a number of different features and can be tailored towards dedicated applications. Most importantly, the higher the compression rate, the larger are the qualitative advantages over transform-based codecs. However, the potential of these codecs is widely unexplored so far, since difficult fundamental problems must be solved first. This includes optimisation of the data and the inpainting process, sophisticated data coding, and the design of real-time capable sequential and parallel numerical algorithms. We are committed to addressing all these challenges in an integrated approach: We cover the entire spectrum from its theoretical foundations over benchmarking and highly efficient numerical algorithms to codecs for specific applications, and a real-time 4K video player as demonstrator. This will lift inpainting methods from a visually pleasant image editing tool to a fundamental paradigm in coding. Research results that enter forthcoming coding standards will also have an impact on everybody's daily life.

Mots-clés : inpainting,image compression,partial differential equations  pdes,variational methods,exemplar based inpainting,video coding,optical flow,numerical algorithms,optimisation
Projet ERC : ConflictResolution (Horizon 2020, appel 2019, Starting grants)
Domaine scientifique : Life Science
Panel : Molecules of Life: Biological Mechanisms, Structures and Functions
Entité participante : Helmholtz Zentrum München — Pays : Allemagne — Rôle : PI
Acronyme de l'entité : HMGU
Type d'entité : Recherche
Financement ERC de l'entité : 1497530.0 €

Genetic and epigenetic instability contribute to cancers, aging, developmental disorders, and neurological diseases, so in-depth understanding how this instability arises is an important question affecting millions in Europe. Physical conflicts between the transcription and DNA replication machineries are a potent endogenous source of this instability. My preliminary data indicate that a single collision can trigger long-term epigenetic changes and affect the normal expression state of genes. I hypothesize that collisions can rewire gene expression networks and lead to cellular transformations relevant to disease and development. Unfortunately, this mechanism is largely understudied owing to the lack of suitable cellular systems to characterize collisions in molecular detail. My proposal will address this key gap in knowledge. I recently pioneered a unique human cell-based episomal system to analyse collisions in an inducible and localized fashion. Using this highly tractable system, we will molecularly characterize the (epi)genetic consequences and identify novel factors that prevent or resolve collisions (Aim 1). To address the relevance of collisions in disease, we will establish a novel proximity-labelling system (Split-APEX2) to map collision sites and identify their associated genetic and chromatin changes in a breast cancer cell model. This cutting-edge technology will decipher their role in pathological transformations observed in breast cancer genomes (Aim 2). To link collisions to developmental transformations, we will determine their potential to induce local epigenetic changes during zygotic genome activation in mouse embryonic cells. This approach can shift the paradigm how cells in development first start to differ from each other and reprogram their genome into different cell types (Aim 3). Uncovering the key principles of collisions may implement highly innovative approaches to avoid or establish cellular transformations in disease and development.

Mots-clés : transcription replication conflicts,genetic and epigenetic instability,proximity labelling,dna replication,transcription,breast cancer,development
Projet ERC : CholangioConcept (Horizon 2020, appel 2014, Consolidator grants)
Domaine scientifique : Life Science
Panel : Physiology in Health, Disease and Ageing
Entité participante : University of Tübingen — Pays : Allemagne — Rôle : PI
Type d'entité : Enseignement supérieur ou secondaire
Financement ERC de l'entité : 1998898.0 €

Genetic heterogeneity and complexity are hallmarks of metastatic solid tumors and therapy resistance inevitably develops upon treatment with cytotoxic drugs or molecular targeted therapies. Cholangiocarcinoma (CCC, or bile duct cancer) represents the second most frequent primary liver tumor and has emerged as a health problem with sharply increasing incidence rates, in particular of intrahepatic CCC (ICC). The reason for increased CCC incidence remains unclear, but influences of western lifestyle and a resulting altered hepatic metabolism have been discussed. Surgical resection represents the only curative option for the treatment of CCC, however, many tumors are irresectable at the time of diagnosis. CCC represents a highly aggressive and metastatic tumor type and currently no effective systemic therapy regimen exists. The overall molecular mechanisms driving CCC formation and progression remain poorly characterized and it thus becomes clear that a detailed molecular characterization of cholangiocarcinogenesis and the identification of robust therapeutic targets for CCC treatment are urgently needed. Taking advantage of our strong expertises in chimaeric (mosaic) liver cancer mouse models and stable in vivo shRNA technology, we here propose a comprehensive and innovative approach to i) dissect molecular mechanisms of cholangiocarcinogenesis, with a particular emphasis on Kras driven ICC development from adult hepatocytes and oncogenomic profiling of ICC metastasis, ii) to employ direct in vivo shRNA screening to functionally identify new therapeutic targets for CCC treatment and iii) to characterize the role of the gut microbiome for CCC progression and metastasis. We envision this ERC-funded project will yield important new insights into the molecular mechanisms of CCC development, progression and metastasis. As our work comprises direct and functional strategies to identify new vulnerabilities in CCC, the obtained data harbor a very high translational potential.
Projet ERC : ReCAP (Horizon 2020, appel 2016, Consolidator grants)
Domaine scientifique : Life Science
Panel : Integrative Biology: from Genes and Genomes to Systems
Entité participante : University of Copenhagen — Pays : Danemark — Rôle : PI
Acronyme de l'entité : UCPH
Type d'entité : Enseignement supérieur ou secondaire
Financement ERC de l'entité : 1997592.92 €

Genome evolution is driven by the generation of diversity. In mammals, genome diversification occurs in germline during the specialised division (meiosis) in gametes, when chromosomes recombine and assort into new haploid sets as they are passed from parent to offspring. Recently, the traditional view that genome diversification occurs exclusively in the germline has been challenged by findings that mutations in early embryos may cause predisposition to childhood cancers. We are uniquely placed to explore genome diversification in the germline and early embryos due to our breakthroughs in developing single-cell genomics and reproductive technologies. Our strategic aim is to uncover the capacity for genetic diversity in the human genome and investigate how DNA repair capacity in adult oocytes and early embryos facilitates genome stability. This will allow us to identify the selective forces that shape the genomic landscape in humans. Based on preliminary data, we hypothesize that repair capacity determines reproductive fitness of mammalian females, and that impaired repair capacity may underlie infertility, miscarriage, and congenital disorders. In Objective 1 we focus on adult oocytes, their survival in the adult ovary and the maintenance of genetic quality as women age. Objective 2 investigates genome diversification and stability in early embryos and putative ‘self-corrective’ mechanisms that restore the genetic quality of embryos. This proposal will shed light on a poorly understood area of enormous socioeconomic and medical importance.

Mots-clés : meiosis,dna damage response,chromosome segregation,genomics,human oocytes,genome stability,recombination,evolutionary genetics
Projet ERC : DeFiNER (Horizon 2020, appel 2014, Consolidator grants)
Domaine scientifique : Life Science
Panel : Physiology in Health, Disease and Ageing
Entité participante : Foundation for Research and Technology Hellas — Pays : Grèce — Rôle : PI
Acronyme de l'entité : FORTH;ΙΤΕ
Type d'entité : Recherche
Financement ERC de l'entité : 1995000.0 €

Genome maintenance, chromatin remodelling and transcription are tightly linked biological processes that are currently poorly understood and vastly unexplored. Nucleotide excision repair (NER) is a major DNA repair pathway that mammalian cells employ to maintain their genome intact and faithfully transmit it into their progeny. Besides cancer and aging, however, defects in NER give rise to developmental disorders whose clinical heterogeneity and varying severity can only insufficiently be explained by the DNA repair defect. Recent work reveals that NER factors play a role, in addition to DNA repair, in transcription and the three-dimensional organization of our genome. Indeed, NER factors are now known to function in the regulation of gene expression, the transcriptional reprogramming of pluripotent stem cells and the fine-tuning of growth hormones during mammalian development. In this regard, the non-random organization of our genome, chromatin and the process of transcription itself are expected to play paramount roles in how NER factors coordinate, prioritize and execute their distinct tasks during development and disease progression. At present, however, no solid evidence exists as to how NER is functionally involved in such complex processes, what are the NER-associated protein complexes and underlying gene networks or how NER factors operate within the complex chromatin architecture. This is primarily due to our difficulties in dissecting the diverse functional contributions of NER proteins in an intact organism. Here, we propose to use a unique series of knock-in, transgenic and NER progeroid mice to decode the functional role of NER in mammals, thus paving the way for understanding how genome maintenance pathways are connected to developmental defects and disease mechanisms in vivo.

Mots-clés : dna damage,mouse models
Projet ERC : TARGET (Horizon 2020, appel 2020, Advanced grants)
Domaine scientifique : Life Science
Panel : Biotechnology and Biosystems Engineering
Entité participante : Board of the Swiss Federal Institutes of Technology — Pays : Suisse — Rôle : PI
Acronyme de l'entité : ETH Zurich
Type d'entité : Enseignement supérieur ou secondaire
Financement ERC de l'entité : 2239500.0 €

Genome sequencing combined with powerful new research technologies has greatly expanded the number of potential drug targets, offering enormous opportunities to address unmet medical needs. However, for proteins with flat, featureless surfaces or for protein-protein interactions, it has been difficult to impossible to generate ligands based on classical small molecules, hindering their evaluation as targets and the development of drugs. Herein, we propose a new method and its application for targeting the so-called "undruggable" proteins by tapping into a new chemical space, generated by "merging" biological and chemical compound libraries. In brief, millions of short cyclic peptides (4–6 amino acids) genetically encoded by phage display (generated with methods we established previously) will be expanded by combinatorially attaching via lateral groups > 1000 different chemical fragments in separate wells of microwell plates. We will develop a strategy that combines the elements of i) automation, ii) liquid transfer by acoustic dispensing, iii) single-round phage display panning, iv) "phage PCR" and a primer coding strategy, v) next-generation sequencing (NGS) and vi) computational sequence analysis to perform phage display selections with a library comprising > 1000 non-natural building blocks. We expect that this technology will deliver ligands to challenging proteins and facilitate their evaluation as drug targets. The ligands are kept small on purpose, below one kDa, and the polarity is limited so that they are more likely to be cell permeable and so they may directly serve as leads for the generation of oral drugs.

Mots-clés : drug development,undruggable targets,combinatorial libraries,cyclic peptides,phage display,high throughput screening,macrocycle drugs