Data-Gouv-ML/pcri-erc-participations-et-projets-laureats huggingface dataset:
Projet ERC : DYNOME (Horizon 2020, appel 2019, Consolidator grants)
Domaine scientifique : Physical Sciences and Engineering
Panel : Physical and analytical chemical sciences
Entité participante : Weizmann Institute of Science — Pays : Israël — Rôle : PI
Type d'entité : Enseignement supérieur ou secondaire
Financement ERC de l'entité : 2368531.0 €

Gene expression is an inherently stochastic process. Random expression bursts cause tremendous cell-to-cell variations in mRNA and protein levels. The consequences are beneficial in some instances, e.g., in cell differentiation, and harmful in others, e.g., in bacterial drug tolerance. A key interest in biology is therefore to decipher the kinetics that characterise this noise. What is the distribution of transcription rates in a cell population? Are gene expression dynamics heritable? Do gene networks communicate via the ‘Morse code’ of expression burst? Detailed answers to these questions are pending due to insufficient methods to temporally resolve gene expression noise at single-molecule resolution. A ‘transparent cell’ is needed for which transcription and translation kinetics is accessible for many genes in parallel. DYNOME is my answer to this challenge. DYNOME combines (i) a super-resolution detect-and-bleach strategy, (ii) multi-colour barcoding to monitor up to six genes in parallel, (iii) a lineage tracking tool, and (iv), lab-on-a-chip bioreactors to steer growth conditions. Using this innovative bio-dynamics platform, I will monitor gene expression dynamics at the single-molecule level for many genes in single cells at the same time over many generations. My targets for DYNOME are stochastic decision-making events in bacteria and in eukaryotic cells that include (i) a stochastic phenotype switch (B. subtilis), (ii) the development of non-genetic drug resistance (E. coli), and (iii) cell cycle control (S. cerevisiae). The results will reach far beyond these organisms. Decrypting cell-individuality with kinetic models will be a breakthrough both in basic and in applied sciences with impacts on the development of drugs against bacterial invasions, the design of new and useful functionalities in cells, and on our understanding of how biological variability arises from the laws of statistical physics.

Mots-clés : single molecule tracking,gene expression dynamics,photon counting,kinetic models
Projet ERC : REGENETHER (Horizon 2020, appel 2014, Starting grants)
Domaine scientifique : Life Science
Panel : Prevention, Diagnosis and Treatment of Human Diseases
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 : 959485.0 €

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 : EPGR (Horizon 2020, appel 2016, Consolidator grants)
Domaine scientifique : Physical Sciences and Engineering
Panel : Mathematics
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 : 508750.0 €

General relativity has been introduced by A. Einstein in 1915. It is a major theory of modern physics and at the same time has led to fascinating mathematical problems. The present proposal focusses on two aspects of the evolution problem for the Einstein equations which has been initiated by the pioneering work of Y. Choquet-Bruhat in 1952. The Einstein equations form a nonlinear system of partial differential equations of hyperbolic type whose complexity raises significant challenges to its mathematical analysis. The goal of this project is to strengthen our understanding of two important themes concerning the evolution problem in general relativity. On the one hand, the control of low regularity solutions of the Einstein equations, a topic which is intimately linked with the celebrated cosmic censorship conjectures of R. Penrose, a major open problem in the field. On the other hand, the question of the stability of particular solutions of the Einstein equations in the wake of the groundbreaking proof of the stability of the Minkowski space-time due to D. Christodoulou and S. Klainerman. These directions are extremely active and have recently led to impressive results. More specifically, this project proposes to consider the following two work packages -Going beyond the bounded L2 curvature theorem. This result has been recently obtained by the PI in collaboration with S. Klainerman and I. Rodnianski and is the sharpest result in so far as low regularity solutions of the Einstein equations are concerned. Yet, the fundamental quest towards a scale invariant well-posedness criterion for the Einstein equations remains wide open. -The black hole stability problem. This problem concerns the stability of the Kerr metrics which form a 2-parameter family of solutions to the Einstein vacuum equations. Many results have been obtained concerning various versions of linear stability, but significant challenges remain in order to tackle the nonlinear stability result.

Mots-clés : einstein equations,cauchy problem,low regularity solutions,black hole stability problem
Projet ERC : SM-Epigen (Horizon 2020, appel 2018, Starting 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 : 1500000.0 €

Genes and genomic elements are packaged by chromatin structures that regulate their activity. The fundamental unit of chromatin is the nucleosome, composed of an octamer of histones. The large numbers of histone modifications, chromatin remodelers and transcription factors (TFs) that interact with our genome has fuelled speculation that multiple elements act combinatorially to direct specific outcomes. However, the field lacks technologies for detection and analysis of such combinations, thus impeding our ability to test this hypothesis and shed light on human genome regulation. Our recent proof-of-principle for a single-molecule system for mapping combinatorial chromatin modifications holds the technological solution. This powerful method can identify directly unique combinations of epigenetic marks and reveal regulatory modules that can only be ascertained by single-molecule studies. The proposed project will scale-up and advance our technology to establish robust high-throughput systems for investigating combinatorial chromatin and TF interactions and identify their genomic locations, thus bridging the gap between single-molecule proteomics and genomics. We will apply it to address basic questions in epigenetic regulation during early development, and define the network of interactions between histone marks, DNA methylation and the core TFs in stem cells and differentiated cells. We will also harness our technology to reveal the tissue-of-origin of cell-free DNA circulating in our blood in the form of nucleosomes, and apply it to devise novel strategies for early detection of cancer and other diseases. Successful implementation and dissemination of these novel systems will yield a transformative new technology for functional genomics that will unravel the chromatin language during early development. This work will open new research directions at the interface of genomics and proteomics, and pave the way for the development of therapeutic and diagnostic tools.

Mots-clés : functional genomics
Projet ERC : MIGHTY_RNA (Horizon 2020, appel 2018, Consolidator grants)
Domaine scientifique : Life Science
Panel : Molecules of Life: Biological Mechanisms, Structures and Functions
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 : 1792850.0 €

Genome editing is an essential tool for life sciences. Recent ground-breaking discovery in microbiology drew our attention to the genome editing ability of bacteria (CRISPR). Since its discovery, CRISPR has revolutionized the way of editing a genome. Despite its wide use, CRISPR-genome editing has limitations, especially in the use for medical applications. Numerous studies have shown that it suffers from the off-target effect. Its use is also restricted by its particular sequence requirement and its poor accessibility to a structured genome. Furthermore, recent studies suggested that it might act as a virulence factor within human cells. These limitations demand new genome editing tools. This proposal sets out to understand the molecular mechanism of Tetrahymena DNA elimination. This naturally occuring genome editing is mediated by a eukaryotic RNA system (Twi1). This system uses an entirely different mechanism from CRISPR and has potential to perform more effectively. I will first investigate how small RNA-loaded Twi1 (“target searcher”) recognizes its target and whether its performance exceeds other target searchers including CRISPR/Cas9. I will use single-molecule fluorescence for high resolution observations and develop a high-throughput single-molecule method for transcriptome-wide understanding. Second, I aim to identify a Twi1-related DNA nuclease(s) that carries out DNA elimination. I will use cutting-edge tools of single-molecule pull-down and multi-color FRET together with mass spectrometry. The nanoscopic understanding of a searcher (Twi1) and the identification of a nuclease will help create a new genome editing tool (e.g. a fusion of Twi1 and the nuclease) that potentially perform better than Cas9. Thereby, this fundamental study on “mighty RNA” will make a long-term impact for applications in science and technology. To realize this ambitious project, I will utilize my experience of studying small RNAs (funded by ERC Starting Grant).

Mots-clés : single molecule fluorescence,fret,genome editing,small rna,argonaute,microrna,crispr,cas9,rna interference,protein nucleic acid interactions
Projet ERC : No Sex No Conflict (Horizon 2020, appel 2019, Consolidator grants)
Domaine scientifique : Life Science
Panel : Environmental Biology, Ecology and Evolution
Entité participante : University of Lausanne — Pays : Suisse — Rôle : PI
Acronyme de l'entité : UNIL
Type d'entité : Enseignement supérieur ou secondaire
Financement ERC de l'entité : 1989769.0 €

Genomic conflicts are major drivers of evolutionary innovation and play an increasingly recognized role in human disease. Intra-genomic conflicts arise because self-promoting elements such as driving centromeres or transposable elements (TEs) can spread in a population without increasing the fitness of their carriers. Inter-genomic conflicts arise when genes have opposite fitness effects in different carriers, as is the case for genes underlying traits with distinct optimal values in males and females. Here I propose to use asexual species as a novel system to studying intra- and inter-genomic conflicts. Because there is no recombination or segregation under asexual reproduction, intra-genomic conflict disappears as the interests of all genetic elements become aligned with those of their host. This allows us to test the predictions that intra-genomic conflict drives the evolution of TE virulence, centromeres, and centromere-binding proteins. Furthermore, because asexual species are comprised of only females, male phenotypes are no longer under selection and sexual conflict over optimal trait values therefore disappears. This proposal leverages the replicated loss of conflicts in independently evolved asexual lineages of Timema stick insects to identify conflict driven aspects of genomic and phenotypic evolution in sexual species. Because Timema have an XX:XO sex determination system, males can be recovered from asexual lineages via X-chromosome losses. This allows for the study of male reproductive traits, sexual dimorphism and sex-biased gene expression in species where selection has been acting solely on females for prolonged time periods, and for the identification of traits and biological processes subject to sexual conflict. By combining phenotypic, experimental and next-generation sequencing approaches, we will generate a cohesive understanding of how intra- and inter-genomic conflict shape phenotype and genome evolution.
Projet ERC : The BoS (Horizon 2020, appel 2020, Starting grants)
Domaine scientifique : Social Sciences and Humanities
Panel : The Social World and Its Diversity
Entité participante : University of Liège — Pays : Belgique — Rôle : PI
Type d'entité : Enseignement supérieur ou secondaire
Financement ERC de l'entité : 1497000.0 €

Genomics technologies promise to shape the ideal animal of the future. Social sciences so far mostly took interest in the medical domain with the Human Genome Project and its aftermath. However, a great deal of fast-pace developments are occurring in livestock genomics. This has become a mundane genomics infrastructure, routinely used in late capitalist societies. This infrastructure offers to solve pressing societal issues, such as improving the health of animals, lowering their environmental impact or enhancing the biodiversity. Focusing on the case of cattle livestock, The BoS project aims to describe and analyze how societal values are being translated in bovine bodies. It asks the following guiding research questions: how are such values as health, environment or biodiversity incorporated in cattle selection and reproduction? Conversely, how are bodies transformed by these values, and through which techniques and practices? To answer those questions, The BoS project will provide a political anthropology of the genomics infrastructure, contributing to sociology of scientific knowledge, science & technology studies and environmental humanities. Phase 1 carries out three laboratory ethnographies in centres of scientific excellence that contribute to global livestock genomics, so as to provide context-sensitive accounts of how values of health, the environment and biodiversity are turned into knowledge. Phase 2 follows the knowledge in the wider world of social actors, carrying out participant observations and semi-structured interviews, to question the transformation of cattle bodies by genomics. The project is very innovative as livestock genomics offers an unprecedented case study of actual applications of genomics knowledge. Three PhD students will be respectively in charge of one of the fieldworks (one centre / one value). A postdoc researcher will investigate the historical contexts for each fieldwork and provide conceptual insight to the PhDs students.

Mots-clés : animal genomics,infrastructure,values,societal dimensions
Projet ERC : OPREP (Horizon 2020, appel 2016, Starting grants)
Domaine scientifique : Physical Sciences and Engineering
Panel : Computer science and informatics
Entité participante : Technion – Israel Institute of Technology — Pays : Israël — Rôle : PI
Type d'entité : Enseignement supérieur ou secondaire
Financement ERC de l'entité : 1500000.0 €

Geometric data is prevalent in many areas of science and technology. From the surface of the brain to the intricate shapes of free-form architecture, complex geometric structures arise in many fields, and problems such as analysis, processing and synthesis of geometric data are of great importance. One major challenge in tackling such problems is choosing an adequate discrete representation of the geometric data. Traditionally, surface geometric data is treated as an irregularly sampled signal in three-dimensional space, yielding a representation as either a point cloud, or a polygonal mesh. Further analysis and manipulation are done directly on this discrete representation, resulting in algorithms which are often combinatorial, leading to difficult numerical optimization problems. The goal of this research is to explore a fundamentally different approach of representing geometric data through the space of scalar functions defined on it, and representing geometric operations as algebraic manipulations of linear operators acting on such functions. We will investigate the basic theory behind such a representation, addressing questions such as: what are the best function spaces to work with? Which operators can be consistently discretized, leading to discrete theorems analogous to continuous ones? How should multi-scale processing of geometric data be treated in this novel representation? To validate our approach, we will explore how this representation can be leveraged for devising efficient solutions to difficult real-world geometry processing problems, such as numerical simulation of intricate phenomena on curved surfaces, surface correspondence and quadrangular remeshing. By shifting the focus from geometry-centric representations and considering instead shapes through the lens of functional operators, we could potentially lay the ground for a fundamental change in the way that geometric data is treated and understood.

Mots-clés : geometry processing,discrete differential geometry,tangent vector fields
Projet ERC : GENE FOR CURE (Horizon 2020, appel 2015, Advanced grants)
Domaine scientifique : Life Science
Panel : Prevention, Diagnosis and Treatment of Human Diseases
Entité participante : Assistance publique - Hôpitaux de Paris — Pays : France — Rôle : Partner
Acronyme de l'entité : AP-HP
Type d'entité : Recherche
Financement ERC de l'entité : 307440.0 €

Given that (i) not all patients with a monogenic disease affecting the lymphohaematopoietic system have an HLA-genoidentical sibling donor and (ii) severe immunological complications worsen the outcome in HLA-partially-matched hematopoietic stem cell transplantation (HSCT), the genetic modification of autologous hematopoietic stem cells (HSCs) has become a powerful curative treatment option for these individuals. The present project seeks to further consolidate the rationale for replacing HLA-partially-matched HSCT with a gene therapy approach. Wiskott-Aldrich syndrome is a primary immunodeficiency whose severity is due to impairment of both lymphoid and myeloid cell function. We have reported robust evidence showing that the infusion of gene-corrected autologous HSCs enables the restoration of the T cell function. However, we are still cautious with regard to claiming the stable correction of autoimmunity and thrombocytopenia. Accordingly, we plan to thoroughly monitor long-term B cell functional outcomes and the platelet count in our treated patients. Moreover, we wish to extend the gene therapy approach to the SCID caused by mutations in the DLREIC gene, since the long-term post-HSCT outcomes are particularly poor. The preclinical work has been completed; initiation of a clinical protocol is the next step. Immune-dysregulation polyendocrinopathy enteropathy X-linked (IPEX) and sickle cell anaemia (SCA) are the last two target diseases. IPEX is a devastating disease caused by mutation of FOXP3 transcription factor; it may be possible to correct it by infusing gene-modified CD4+Tcells. We intend to accumulate the data required to prove our working hypothesis. SCA is a worldwide public health issue. We are seeking to improve the conventional gene therapy procedure and to evaluate the efficacy of CrisP/Cas9-mediated disruption of the CIS-regulatory elements required for HbF silencing. This disruption may provide a cure for SCA.

Mots-clés : genetic diseases of the hematopoietic stem cells,blood cells
Projet ERC : IceCommunities (Horizon 2020, appel 2017, Consolidator grants)
Domaine scientifique : Life Science
Panel : Environmental Biology, Ecology and Evolution
Entité participante : University of Milan — Pays : Italie — Rôle : PI
Acronyme de l'entité : UNIMI
Type d'entité : Enseignement supérieur ou secondaire
Financement ERC de l'entité : 1720738.0 €

Glaciers show a pattern of retreat at the global scale. Increasing areas are exposed and colonized by multiple organisms, but lack of global studies hampers a complete understanding of the future of recently deglaciated terrains. What will be the fate of these areas? How do animals, plants and microorganisms colonize them? How do they interact to perform successful colonization? Which are the climatic, geological and biogeographical processes determining colonization patterns? How does ecosystem functioning evolves through time? Until now, the complete reconstruction of soil communities was hampered by the complexity of identification of organisms, thus analyses at broad geographical and taxonomic scale have been so far impossible. IceCommunities will combine innovative methods and a global approach to boost our understanding of the evolution of ecosystems in recently deglaciated areas. I will investigate chronosequences ranging from recently deglaciated terrains to late successional stages of soil pedogenesis. Through environmental DNA metabarcoding I will identify species from multiple taxonomic groups (bacteria, fungi, protists, soil invertebrates, plants), to obtain a complete reconstruction of biotic communities along glacier forelands over multiple mountain areas across the globe. This will allow measuring the rate of colonization at an unprecedented detail. Information on assemblages will be combined with analyses of soil, landscape and climate to identify the drivers of community changes. I will also identify the impact of eco-geographical factors (climate, regional pool of potential colonizers) on colonization. Analysis of functional traits will allow reconstructing how functional diversity emerges during community formation, and how it scales to the functioning of food webs. IceCommunities will help to predict the future development of these increasingly important ecosystems, providing a supported rationale for the appropriate management of these areas

Mots-clés : environmental dna,dna metabarcoding,global change biology,functional traits