Data-Gouv-ML/pcri-erc-participations-et-projets-laureats huggingface dataset:
Projet ERC : ChromoSOMe (Horizon 2020, appel 2018, Consolidator grants)
Domaine scientifique : Life Science
Panel : Cellular, Developmental and Regenerative Biology
Entité participante : Centre national de la recherche scientifique — Pays : France — Rôle : PI
Acronyme de l'entité : CNRS
Type d'entité : Recherche
Financement ERC de l'entité : 1561563.0 €

Cell division is crucial for the development of complex organisms, for the homeostasis of tissues, and for the reproductive capacity of individuals. While most somatic cells are diploid and proliferate through mitosis, multiplication of sexually reproducing species relies on haploid gametes that are generated through a specialized cell division process called meiosis. To achieve this reduction in ploidy, two rounds of chromosome segregation follow a single phase of genome replication. Inaccuracy in this process leads to gametes that carry an incorrect number of chromosomes and to aneuploid embryos after fertilization. In their vast majority, these are non-viable and lead to spontaneous abortion: defective meiotic division is therefore a major obstacle in achieving reproduction. However, the key principles that drive this process are still poorly understood, one main reason being the diversity of the molecular scenarios that have been adopted across evolution to regulate oocyte chromosome segregation. To dissect the key components of oocyte meiotic chromosome segregation, we propose to carry out a multi-disciplinary approach, combining several nematode species with the use of high-resolution live and electron microscopy, cutting edge genomic and proteomic technologies, and biochemistry coupled to in silico modeling. In Work Package 1 (WP1), we will analyze the molecular mechanisms controlling the self-assembly of the chromosome segregation machinery -the meiotic spindle- in the oocyte. WP2 will focus on defining how chromosome segregation is achieved in oocytes with non-canonical kinetochore geometry. WP3 aims at analyzing meiotic divisions in parthenogenetic nematodes with specific meiotic constraints, such as centrosomal oogenesis and unichromosomal genomes. By considering the wealth of mechanisms that can drive chromosome segregation in oocytes, this project will provide decisive steps towards understanding the essential and universal features of female meiosis.

Mots-clés : oocyte meiosis,kinetochore,microtubule,chromosome segregation
Projet ERC : TOPOCELL (Horizon 2020, appel 2019, Proof of concept grants)
Domaine scientifique : Physical Sciences and Engineering
Panel : Condensed matter physics
Entité participante : CNRS Innovation — Pays : France — Rôle : Partner
Type d'entité : Organismes privés (hors enseignement)
Financement ERC de l'entité : 7900.0 €

Cell migration is essential for tissue development, homeostasis, tumor progression, including the responses to wounds and inflammation. Cell interactions with their microenvironment affect many cellular functions such as spreading, migration and even differentiation. These interactions can be studied by incorporating micro- and nanotechnology-related tools. The design of substrates based on these technologies offers new possibilities to probe the cellular responses to changes in their physical environment. The investigations of the physical interactions of cells and their surrounding matrix can be carried out in well-defined and near physiological conditions. In tissues, cells encounter confined environments and narrow spaces that could favor or prevent migration. In the DURACELL ERC project, we are studying the impact of substrate stiffness on cell migration. We propose to develop and use microfabricated substrates to control substrate confinement and topography and thus analyze cellular responses. Such elastomeric substrates are designed that contain ordered micron-sized pillars allowing cells to transmigrate through versatile confined spaces. The development of accurate methods to study cellular transmigration is important to answer fundamental biological processes and for cell-based therapy and drug screening. The well-accepted methods for transmigration assays including Boyden chambers, microfluidic devices present important limitations including spatial and temporal resolutions, limited variability and control of porosity composition and geometry. To overcome these limitations, the goal of TRANSCELL is to develop in-plane micropillar substrates whose geometry can be easily tuned to control and analyze cell transmigration, cell sorting and ultimately genetic expression profiles. We anticipate that the versatility of this method will offer new opportunities for fundamental research in cell biology, but also in cell therapies and drug screening.

Mots-clés : mechanobiology,cell invasion,microfabrication,cell sorting,cancer
Projet ERC : REMIND (Horizon 2020, appel 2018, Consolidator grants)
Domaine scientifique : Life Science
Panel : Molecules of Life: Biological Mechanisms, Structures and Functions
Entité participante : Centre national de la recherche scientifique — Pays : France — Rôle : PI
Acronyme de l'entité : CNRS
Type d'entité : Recherche
Financement ERC de l'entité : 1446250.0 €

Cell viability and homeostasis rely on the stable maintenance of the epigenetic information conveyed by chromatin, which associates DNA and histone proteins in the cell nucleus and governs gene expression programs. Yet, epigenome integrity is challenged during all DNA transactions, including DNA damage repair. While much effort has been devoted to characterizing chromatin alterations in response to DNA damage and how they contribute to the repair response, our knowledge of this fundamental process is largely incomplete, and whether and how epigenetic features are re-established following a genotoxic stress challenge is still unexplored. Thus, a comprehensive framework of the mechanisms underlying the maintenance of epigenome integrity in response to DNA damage is lacking. The present project aims to fill this important gap by profiling the epigenome of repair patches following UVC damage in human cells and by characterizing the molecular players contributing to chromatin restoration/plasticity. I propose an integrated approach that tackles this question at different levels of chromatin organization, from histone and DNA modifications up to higher-order chromatin folding. Building on our unique expertise and through the development of powerful novel methodologies, combining cutting-edge imaging, proteomics and epigenomic technologies, we will elucidate mechanisms for (1) histone modification re-establishment and maintenance and (2) DNA methylation inheritance at repair sites. We will also investigate how repair-associated changes in DNA and histone modifications reflect at the level of (3) higher-order chromatin organization in the tridimensional nuclear space, and dissect (4) functional crosstalks between the epigenetic changes that arise in damaged chromatin. This ambitious research project represents an unprecedented effort towards a comprehensive and integrated understanding of epigenome maintenance mechanisms in response to genotoxic stress.

Mots-clés : dna damage repair,epigenome integrity,histone modifications,dna methylation,higher order chromatin organization
Projet ERC : RibiTool (Horizon 2020, appel 2019, Starting grants)
Domaine scientifique : Physical Sciences and Engineering
Panel : Synthetic Chemistry and Materials
Entité participante : University of York — Pays : Royaume-Uni — Rôle : PI
Type d'entité : Enseignement supérieur ou secondaire
Financement ERC de l'entité : 1494411.0 €

Cell-surface proteins are decorated with a variety of different carbohydrate structures that play central roles in mammalian biology. The complex nature of glycan structures and the pathways by which they are assembled make it a challenging task to decipher their exact function in cells, knowledge that is essential if we are to understand how malfunctioning leads to disease. This proposal aims to deliver innovative approaches to probe a distinct pathway of glycosylation essential to mammalian biology and to use these strategies to provide novel insights into the mechanisms underlying normal cellular functioning and disease pathology. The work programme is built around a specific type of O-linked cell-surface glycan that carries two critical ribitol-phosphate (RboP) residues, unique carbohydrates that so far have not been identified in other mammalian glycoconjugates. Failure to correctly assemble this glycan causes a range of congenital muscular dystrophies known as α-dystroglycanopathies. Despite its importance in disease pathology, many aspects of RboP utilisation and functioning in mammalian cells are poorly understood. The proposed programme offers a powerful and original approach to address these key issues in cell biology by creating a set of novel chemical tools. These tools will enable the probing and manipulation of both RboP-carrying glycoconjugates as well as the enzymes responsible for installing RboP onto the glycans in a cellular context. Integration of these tools with fundamental 3-D structural information and studies in cellular models of α-dystroglycanopathy will offer the unprecedented opportunity to directly link genetic defects to molecular and cellular aspects of enzyme function and through to observed changes in glycosylation status. These pioneering strategies will impact our fundamental understanding of key processes in mammalian cells and will also enable the exploitation of this unique pathway for the design of therapeutic strategies.

Mots-clés : ribitol,glycosylation,chemical tools,organic synthesis,metabolic labelling,enzyme probes,inhibitors,bioorthogonal chemistry,structural biology,cellular disease models
Projet ERC : SmartCells (Horizon 2020, appel 2016, Consolidator grants)
Domaine scientifique : Physical Sciences and Engineering
Panel : Condensed matter physics
Entité participante : Centre national de la recherche scientifique — Pays : France — Rôle : PI
Acronyme de l'entité : CNRS
Type d'entité : Recherche
Financement ERC de l'entité : 1093724.15 €

Cells are complex, autonomous genetic machines with rich information processing capabilities. Synthetic Biology builds on these properties to design novel, synthetic genetic programs in cells with the aim of benefiting humans. Yet, safety and efficiency issues require creation of synthetic circuits that are reliable over a large range of operating conditions and stable to all sorts of perturbations. This is a tremendous challenge for synthetic biologists, as the robustness of any circuit is limited by their high dependence on the cellular host machinery and the fundamental stochastic nature of gene expression. Taking inspiration from physics and engineering we have imagined a computer-based feedback loop that can remotely, in real-time, control the state of a synthetic genetic program running in cells. Here, we will combine microfluidics, optogenetics, structured illumination, inference methods and control algorithm into such a real time control device of gene expression for yeast cells. We will then study how cells can be controlled at different scales and with increasing levels of complexity from a simple circuit to a simple multicellular ecosystem. Specifically, we aim at: (1) Understanding the potential and limits of such a control method. We will ask to what extent robust control can be achieved at the single cell level over a broad range of operating conditions. (2) Taking control of complex circuits. In particular, we will take control of key genes of the large regulatory network in charge of yeast adaptation to osmotic stress and dissect their roles in setting the mechano-biology properties of yeast. (3) Taking control of multicellular systems. We will control the collective dynamics of a population of cells via single cell control at selected locations. This framework will establish solid scientific and technological foundations of a novel research area combining physics, engineering and synthetic biology to take control of living systems.

Mots-clés : systems biology,micro  and nano  systems engineering
Projet ERC : T-Rex (Horizon 2020, appel 2015, Consolidator grants)
Domaine scientifique : Life Science
Panel : Cellular, Developmental and Regenerative Biology
Entité participante : Vlaams Instituut voor Biotechnologie — Pays : Belgique — Rôle : PI
Acronyme de l'entité : VIB
Type d'entité : Recherche
Financement ERC de l'entité : 1998813.0 €

Cells communicate with the outside world through proteins anchored in their plasma membrane and hereto constantly adjust their plasma membrane (PM) proteome. In this adjustment process, removing proteins from the PM mainly occurs through clathrin-mediated endocytosis (CME). Mechanistically however, this process remains poorly understood in plants. A recent study from my group has shown that, in contrast to other model systems, plant CME involves two early endocytic adaptor protein complexes: the evolutionary conserved Adaptor Protein 2 complex (AP-2) and the newly identified TPLATE complex (TPC). In the same study, we also show that both complexes have overlapping but also independent functions in driving CME in plants, implying that plants use additional ways to recognize membrane proteins (cargo) for internalization. In this project I will use an integrative approach to unravel the early steps of CME in plants. Specifically, I will address the following biological questions: - Is the evolutionary retention of the TPC in plants causal to specific cargo recognition? (WP1) - What are the spatio-temporal dynamics of TPC and CME effectors at the plasma membrane? (WP2) - How does acute removal of TPC subunits affect complex recruitment and CME? (WP3) - How is the TPC organized at the structural level? (WP4) - Which interactions occur and can we couple subunit/domain structures to functionality? (WP5) To answer these questions, I will combine state-of-the art proteomics with highly dynamic multi-color live cell imaging and structural biology. The overall objective is to gain a deep mechanistic insight into the developmentally essential process of CME in plants. This will enable me to specifically specifically modulate the abundance of plasma membrane proteins involved in nutrient uptake, toxin avoidance, cell wall formation and hormone and defence responses. Understanding TPC-dependent CME will also provide insight into evolutionary aspects of endocytosis.

Mots-clés : plant clathrin mediated endocytosis,adaptor proteins,ap 2,tplate complex
Projet ERC : INPHORS (Horizon 2020, appel 2017, Advanced grants)
Domaine scientifique : Life Science
Panel : Cellular, Developmental and Regenerative Biology
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 : 2499998.0 €

Cells face a phosphate challenge. Growth requires a minimal concentration of this limiting resource because intracellular phosphate (Pi) is a compound of nucleic acids and modifies most cellular proteins. At the same time, cytosolic Pi may not rise much, because elevated cytosolic Pi can stall metabolism. It reduces the free energy that nucleotide triphosphate hydrolysis can provide to drive energetically unfavorable reactions. I will undertake a pioneering study to elucidate how cells strike this critical balance. We will identify a novel pathway for intracellular phosphate reception and signaling (INPHORS) and explore the role of acidocalcisomes in it. These studies may identify a key function of these very poorly understood organelles, provide one reason for their evolutionary conservation and elucidate a novel homeostatic system of critical importance for cellular metabolism. We recently provided first hints that a dedicated pathway for sensing and signaling intracellular Pi might exist, which regulates multiple systems for import, export and acidocalcisomal storage of Pi, such that cytosolic Pi homeostasis is guaranteed 1. Yeast cells will serve as an powerful model system for exploring this pathway and its physiological relevance. Yeast Pi transport and storage proteins are known. Furthermore, we can establish cell-free in vitro systems that reconstitute Pi-regulated transport and storage processes, providing an excellent basis for identifying signaling complexes and studying their dynamics. We will (A) generate novel tools to uncouple, individually manipulate and measure key parameters for the INPHORS pathway; (B) identify its components, study their interactions and regulation; (C) elucidate how acidocalcisomes are targeted by INPHORS and how they contribute to Pi homeostasis; (D) study the crosstalk between INPHORS and Pi-regulated transcriptional responses; (E) test the relevance of INPHORS for Pi homeostasis in mammalian cells.

Mots-clés : phosphate homeostasis,vacuole,yeast
Projet ERC : tRNAtoGO (Horizon 2020, appel 2020, Starting grants)
Domaine scientifique : Life Science
Panel : Physiology in Health, Disease and Ageing
Entité participante : University of Liège — Pays : Belgique — Rôle : PI
Type d'entité : Enseignement supérieur ou secondaire
Financement ERC de l'entité : 1499988.0 €

Cells integrate internal and external stimuli by continuously adapting their transcription and translation. tRNAs are heterogeneous and highly modified molecules necessary to correctly translate mRNAs into proteins. Even though their discovery goes back to the late 50s, it is only in the last years that their active role in regulating translation has started to be highlighted both in health and disease. Cancer stem cells (CSC) are a small population of transformed cells able to sustain tumor growth and responsible for metastasis and drug resistance. The incredible plasticity and genetic heterogeneity of CSC make it extremely difficult to find global markers and/or molecular footprints uniquely expressed by these cells. In the tRNAtoGO project, I postulate that the expression of a specific signature of tRNA molecules permits the establishment of onco-proteomes therefore sustaining cancer stem cells transformation. Therefore, the identification of a tRNA permissive signature might be predictive of the population of origin of CSC. To prove this hypothesis, I will use a combination of unbiased sequencing approaches, a genetic CRISPR-Cas9 based screen, mouse models and functional assays that will identify, in the intestine, the Wnt-driven transformation permissive tRNAs and associated modification enzymes signature and their biological role. In conclusion, this project aims to tackle the CSC concept from a new and extremely innovative prospective: I want to describe the cellular origin of CSC as a population harboring a permissive-tRNA signature for driving mutations.

Mots-clés : trna,mrna translation
Projet ERC : FORCASTER (Horizon 2020, appel 2014, Consolidator grants)
Domaine scientifique : Physical Sciences and Engineering
Panel : Condensed matter physics
Entité participante : Centre national de la recherche scientifique — Pays : France — Rôle : PI
Acronyme de l'entité : CNRS
Type d'entité : Recherche
Financement ERC de l'entité : 2199310.0 €

Cells must move and position internal components to perform their function. We here focus on the physical designs which allow microtubule (MT) asters to exert forces in order to move and position themselves in vivo. These are arrays of MTs radiating from the centrosome, which fill up large portions of cells. They orchestrate nuclear positioning and spindle orientation for polarity, division and development. Forces that move asters are generated at nanometer and second scales by MT-associated motors from sites in the cytoplasm or at the cell surface. How MTs and force-generators self-organize to control aster motion and position at millimeter and hour scales is not known. We will use a suit of biophysical experiments and models to address how aster micro-mechanics contribute to aster migration, centration, de-centration and orientation in a single in vivo system, using the early stages of Sea urchin development as a quantitative model. We aim to: 1) Elucidate mechanisms that drive aster large-scale motion, using sperm aster migration after fertilization during which asters grow and move rapidly and persistently to the large-egg center. We will investigate how speeds and trajectories depend on boundary conditions and on the dynamic spatial organization of force-generators. 2) Implement magnetic-based subcellular force measurements of MT asters. We will use this to understand how single force-events are integrated at the scale of asters, how global forces may evolve will aster size, shape, in centration and de-centration processes, using various stages of development, and cell manipulation; and to compute aster friction. 3) Couple computational models and 3D imaging to understand and predict stereotyped division patterns driven by subsequent aster positioning and aster-pairs orientation in the early divisions of Sea urchin embryos and in other tissues. This framework bridging multiple scales will bring unprecedented insights on the physics of living active matter.

Mots-clés : cytoskeleton,microtubules,cell shape,cell mechanics,microfabrication,modelling
Projet ERC : CHANNELMAT (Horizon 2020, appel 2017, Proof of concept grants)
Entité participante : Kiel University — Pays : Allemagne — Rôle : PI
Acronyme de l'entité : CAU
Type d'entité : Enseignement supérieur ou secondaire
Financement ERC de l'entité : 150000.0 €

Cells respond to external mechanical stimuli through an activation of a cellular mechanism called mechanotransduction. The cellular responses in this mechanism are expressed by a modification in cellular proliferation, migration and differentiation, as well as in a strengthening of their adhesion. Likewise, diseases such as cancer and cardiac dysfunctions are also related to cellular mechanotransduction. Here we propose to take a novel 3D material porous material towards commercial applications. The material serves as a platform for controlling mechanotransduction (e.g. in implant materials) and enables a control of mechanotransduction by mimicking natural 3D cellular environments. Our material contains a novel form of microporous structures represented by micron-sized channels embedded in a polymer matrix of a well-defined stiffness that has been developed within the ERC project CELLINSPIRED. The material guarantees pore interconnectivity independently of pore density and size, a unique feature offered by our fabrication procedure, for which we have applied for a patent (EP 15166793.8, PCT/EP2016/060160). Furthermore, it also provides a large, three-dimensionally controlled cell-surface contact area, such that the mechanical properties of the environment will have large impact on the cells. Our goal in this project is to validate our novel material for cellular applications where mechanotransduction is targeted. The expected outcome of our project is to receive a demonstrator material that (1) has well-defined mechanical properties, porosities and pore dimensions, (2) is biocompatible and can be sterilized, (3) can be fabricated in different levels of complexity, (4) can activate mechanotransduction in cells, and (5) can be fabricated using high-throughput processes. As for commercialization, we aim to license the patent to biomaterials companies involved in applications that range from 3D cell cultures to implant materials.

Mots-clés : biomaterials,mechanotransduction,biophysics,cell adhesion