Data-Gouv-ML/pcri-erc-participations-et-projets-laureats huggingface dataset:
Projet ERC : HISTONEMEMORY (Horizon 2020, appel 2016, Consolidator grants)
Domaine scientifique : Life Science
Panel : Molecules of Life: Biological Mechanisms, Structures and Functions
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 : 1999750.0 €

Cell type specific organization of DNA into chromatin is an important determinant of gene expression and cell identity. During cell division, epigenetic information in chromatin must be transmitted to daughter cells in order to maintain cell identity or commit to a developmental program. However, it remains unknown how epigenetic states are inherited during cell division. Elucidating molecular mechanisms underlying epigenetic cell memory thus represents a major challenge in biology critical to understand development and disease. Chromatin undergoes genome-wide disruption during DNA replication and histone marks are diluted 2-fold due to new histone deposition. Yet, how this impacts on establishment and maintenance of gene expression programs is not known. I hypothesize that chromatin replication represents a critical window for epigenetic cell memory and cell fate decisions, and predict that three histone-based processes play critical roles in guarding cell identity: 1) new histone deposition to regulate nucleosome occupancy and transcription factor (TF) binding, 2) accurate transmission of old modified histones by dedicated recycling machinery, and 3) recruitment of regulatory proteins to new and old histones to direct epigenome maintenance. To dissect these events mechanistically and test causal roles in cell fate decisions, I propose a research program integrating explorative proteomics and histone chaperone structure-function analysis with stem cell biology and new cutting-edge genomic tools developed by my research group. The proposed research will 1) identify novel mechanisms of histone chaperoning and deposition specific to new and old histones, 2) reveal how nucleosome assembly govern TF binding during DNA replication, and 3) address the significance of old histone recycling and new histone deposition for pluripotency and commitment. This will provide a major advance in understanding the molecular mechanisms that govern epigenetic cell memory.

Mots-clés : histone chaperones,histone readers,epigenetics
Projet ERC : cis-CONTROL (Horizon 2020, appel 2016, Consolidator grants)
Domaine scientifique : Life Science
Panel : Integrative Biology: from Genes and Genomes to Systems
Entité participante : Vlaams Instituut voor Biotechnologie — Pays : Belgique — Rôle : PI
Acronyme de l'entité : VIB
Type d'entité : Recherche
Financement ERC de l'entité : 1999660.0 €

Cell-state switching in cancer allows cells to transition from a proliferative to an invasive and drug-resistant phenotype. This plasticity plays an important role in cancer progression and tumour heterogeneity. We have made a striking observation that cancer cells of different origin can switch to a common survival state. During this epigenomic reprogramming, cancer cells re-activate genomic enhancers from specific regulatory programs, such as wound repair and epithelial-to-mesenchymal transition. The goal of my project is to decipher the enhancer logic underlying this canalization effect towards a common survival state. We will then employ this new understanding of enhancer logic to engineer synthetic enhancers that are able to monitor and manipulate cell-state switching in real time. Furthermore, we will use enhancer models to identify cis-regulatory mutations that have an impact on cell-state switching and drug resistance. Such applications are currently hampered because there is a significant gap in our understanding of how enhancers work. To tackle this problem we will use a combination of in vivo massively parallel enhancer-reporter assays, single-cell genomics on microfluidic devices, computational modelling, and synthetic enhancer design. Using these approaches we will pursue the following aims: (1) to identify functional enhancers regulating cell-state switching by performing in vivo genetic screens in mice; (2) to elucidate the dynamic trajectories whereby cells of different cancer types switch to a common survival cell-state, at single-cell resolution; (3) to create synthetic enhancer circuits that specifically kill cancer cells undergoing cell-state switching. Our findings will have an impact on genome research, characterizing how cellular decision making is implemented by the cis-regulatory code; and on cancer research, employing enhancer logic in the context of cancer therapy.

Mots-clés : enhancer,cell state transition,epigenomic reprogramming,gene therapy,drug resistance,wound repair,bioinformatics,cis regulatory modules,single cell,microfluidics,non coding snps
Projet ERC : INTERCELLAR (Horizon 2020, appel 2016, Consolidator grants)
Domaine scientifique : Life Science
Panel : Biotechnology and Biosystems Engineering
Entité participante : UK Research and Innovation — Pays : Royaume-Uni — Rôle : PI
Acronyme de l'entité : UKRI
Type d'entité : Recherche
Financement ERC de l'entité : 2162500.0 €

Cell-to-cell communication is fundamental to multicellular organisms. The exchange of information and resources between cells and tissues enables co-ordination of responses to environmental and developmental signals. In plants, the cytoplasm of adjacent cells is connected by plasma membrane-line pores called plasmodesmata (PD) that cross the cell wall, generating cytoplasmic continuity between cells and tissues. This interconnected cytoplasm is termed the symplast and is unique to plants. In plants, growing evidence suggests that innate immune responses rely on regulation of symplastic connectivity. My group previously discovered that regulation of PD (whether they are open or closed) is critical for immune responses. Further, we have shown that pathogens suppress host regulation of PD in an effort to maintain symplastic continuity between cells. We don’t know why the host regulates the symplast during defence: while data suggests that different defence responses might differently exploit the symplast, we don’t understand how the symplast defines the success of a response. Similarly, we don’t know how a pathogen benefits from maintaining connectivity with surrounding host cells – is this to allow the movement of molecules to suppress defence, or is it to optimise access to host resources? This programme will investigate the question of how the symplast contributes to defence and infection strategies. We aim to understand how these strategies play out in an infection context. We will use experimental and computational approaches to generate models that allow us to predict the outcome of infection upon the basis of symplastic processes and PD regulation. Ultimately, this will create a framework for novel strategies to enhance pathogen resistance.

Mots-clés : innate immunity,cell to cell communication,plasmodesmata,symplast,mamp triggered immunity
Projet ERC : SmartCells (Horizon 2020, appel 2016, Consolidator grants)
Domaine scientifique : Physical Sciences and Engineering
Panel : Condensed matter physics
Entité participante : Université Paris Cité — Pays : France — Rôle : Partner
Acronyme de l'entité : UP Cité
Type d'entité : Enseignement supérieur ou secondaire
Financement ERC de l'entité : 953990.03 €

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 : Cytokine Signalosome (Horizon 2020, appel 2016, Starting grants)
Domaine scientifique : Life Science
Panel : Immunity, Infection and Immunotherapy
Entité participante : University of Dundee — Pays : Royaume-Uni — Rôle : PI
Type d'entité : Enseignement supérieur ou secondaire
Financement ERC de l'entité : 1687500.0 €

Cells use an intricate network of intracellular signalling molecules to translate environmental changes, sensed via surface receptors, into cellular responses. Despite their prominent role in regulating every aspect of life, we lack a comprehensive understanding of how signalling networks convey extracellular information into specific bioactivities and fate decisions. To rationally manipulate cell fate, which could fundamentally change the way that we treat human diseases, first we need a systematic understanding of how signalling is initiated and propagated inside the cell. I discovered that specificity of cytokine receptor signalling not only depends on cellular determinants such as receptor density and endocytic trafficking, but can be systematically altered by modulating ligand binding parameters and receptor binding geometries. A fundamentally novel approach combining high-throughput flow cytometry and QMS with engineered cytokine surrogate ligands able to fine-tune signalling responses will generate detailed maps of the signalling networks engaged by cytokines in time and space to unveil the mechanistic basis that allow a receptor to trigger different signal activation programs and bioactivities in response to different ligands. By quantitatively characterizing the signalling programs activated by ligands, using state-of-the-art biochemical, biophysical, structural, genetic and fluorescence imaging techniques, I plan to identify events critical for cellular decisions. By fully characterizing the intracellular signalling network hard-wired inside a cell and understanding its dynamic in response to environmental changes will we be able to comprehend and manipulate the enormous functional plasticity exhibited by cells. TInsights generated will open new fields of investigation where engineered ligands prove indispensable to understand complex biological responses and greatly advance our understanding of cytokine biology and human immunology in health and disease.

Mots-clés : protein engineering,surrogate ligands,cytokines,signallosome
Projet ERC : KARMA (Horizon 2020, appel 2020, Consolidator grants)
Domaine scientifique : Life Science
Panel : Physiology in Health, Disease and Ageing
Entité participante : University of Turin — Pays : Italie — Rôle : PI
Acronyme de l'entité : UNITO
Type d'entité : Enseignement supérieur ou secondaire
Financement ERC de l'entité : 1996853.0 €

Cellular homeostasis is controlled by the RAS-MAPK pathway. This pathway is dysregulated in human diseases, especially cancer, in which more than 50% of cases carry aberrations that hyperactivate RAS-MAPK signaling. In this context, KRAS mutations are the most frequent oncogenic drivers. Therapeutic suppression of pathogenic KRAS-RAF-MAPK signaling to achieve disease control in cancer patients still represents a challenging target. KRAS dimers and multimers at the membrane (collectively referred, together with adaptors and effectors, as to “KRAS signalosome”) influence the activation of KRAS signaling. I provided the first biological evidence that dimerization is required for the function of oncogenic KRAS (Ambrogio et al, Cell, 2018). Indeed, one fascinating and still largely unexplored aspect of KRAS biology is the functional impact of KRAS complexes at the membrane for signaling and drug sensitivity. No inhibitors of oncogenic KRAS clustering have been identified so far. Interestingly, wild-type KRAS antagonizes oncogenic KRAS, resulting in reduced oncogenic signaling. The overarching goal of this proposal is the characterization in vitro and in vivo of the “KRAS signalosome” in terms of functional dynamics and related actionable vulnerabilities. My strong background in KRAS biology provides me with the expertise to propose an ambitious, yet feasible plan to understand the tumor suppressor effect of wild-type KRAS protomers in mutant KRAS-driven complexes by identifying and validating membrane interactors differentially recruited by wild-type and mutant KRAS (Work package 1). In parallel, I will study the relevance of RAF kinases localization at the membrane as key feature to sustain oncogenic MAPK activity in vivo (Work package 2). Finally, I will screen new compounds to interfere with RAFs function at the cell membrane and will determine the therapeutic impact of disrupting mutant KRAS signalosome using mouse models in vivo (Work package 3).

Mots-clés : kras oncogene,mapk signaling pathway,genetically engineered mouse models,kras dimerization,raf kinases,novel therapeutic approaches
Projet ERC : DUB-DECODE (Horizon 2020, appel 2014, 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 : 1972570.0 €

Cellular processes are largely governed by sophisticated protein posttranslational modification (PTM)-dependent signaling networks, and a systematic understanding of regulatory PTM-based networks is a key goal in modern biology. Ubiquitin is a small, evolutionarily conserved signaling protein that acts as a PTM after being covalently conjugated to other proteins. Reversible ubiquitylation forms the most versatile and largest eukaryote-exclusive signaling system, and regulates the stability and function of almost all proteins in cells. Deubiquitylases (DUBs) are ubiquitin-specific proteases that remove substrate-conjugated ubiquitin, and thereby regulate virtually all ubiquitylation-dependent signaling. Because of their central role in ubiquitin signaling, DUBs have essential functions in mammalian physiology and development, and the dysregulated expression and mutation of DUBs is frequently associated with human diseases. Despite their vital functions, very little is known about the proteins and ubiquitylation sites that are regulated by DUBs and this knowledge gap is hampering our understanding of the molecular mechanisms by which DUBs control diverse biological processes. Recently, we developed a mass spectrometry-based proteomics approach that allowed unbiased and site-specific quantification of ubiquitylation on a systems-wide scale. Here we propose to comprehensively investigate DUB-regulated ubiquitin signaling in human cells. We will integrate interdisciplinary approaches to develop next-generation cell models and innovative proteomic technologies to systematically decode DUB function in human cells. This will enable a novel and detailed understanding of DUB-regulated signaling networks, and open up new avenues for further research into the mechanisms and biological functions of ubiquitylation and of ubiquitin-like modifiers.

Mots-clés : ubiquitin signaling,deubiquitylases,mass spectrometry,quantitative proteomics
Projet ERC : TREAT-PD (Horizon 2020, appel 2017, Consolidator grants)
Domaine scientifique : Life Science
Panel : Prevention, Diagnosis and Treatment of Human Diseases
Entité participante : Lund University — Pays : Suède — Rôle : PI
Type d'entité : Enseignement supérieur ou secondaire
Financement ERC de l'entité : 2000000.0 €

Cellular reprogramming is a new and rapidly emerging field where somatic cells can be turned into pluripotent stem cells or other somatic cell types simply by overexpression of specific combinations of genes. This remarkable discovery allows for the generation of patient specific cell lines that will serve as major tools for understanding how diseases arise and develop, and they may also prove useful for drug screens, diagnostics and other biomedical applications. We have developed a reprogramming technique that directly converts human fibroblasts to functional dopamine (DA) neurons, which is the subtype that is affected in Parkinson’s Disease (PD). This opens up for possibilities to generate therapeutic neurons, including patient specific neurons on demand. These neurons, and the techniques for producing them, will become valuable tools for understanding and treating neurodegenerative diseases such as PD. Direct cell conversion is of particular interest for cell replacement therapy as the reprogramming does not involve a proliferating cell intermediate, and thus the risk of uncontrolled proliferation and tumor formation after transplantation is minimized. This project integrates mechanistic studies based on single cell sequencing to improve the technology and control of cell fate such that a large number of authentic DA neurons are obtained. Induced DA neurons will be generated from individuals with PD and age matched healthy donors and subjected to comparative assessments in vitro and in vivo in order to investigate whether any potential PD-associated pathology emerges in the patient derived cells. This will then guide future decisions regarding autologous vs. allogeneic donors. The cells will be extensively validated using pre-clinical animal models of PD. The studies will include direct comparison with primary fetal and hESC-derived DA neurons on criteria important for clinical use such as midbrain subtype identity and in vivo potency and efficacy.

Mots-clés : cell therapy,personalized treatment  cell reprogramming
Projet ERC : NeuroNanoChip (Horizon 2020, appel 2014, Proof of concept grants)
Entité participante : Amsterdam University Medical Centers — Pays : Pays-Bas — Rôle : PI
Type d'entité : Recherche
Financement ERC de l'entité : 135617.12 €

Cellular studies in neuroscience are hampered by the fact that in vitro cultures of primary neurons are complex, variable and heterogeneous, making studies on cultured neurons time consuming, labour intensive and not scalable. Especially for single cell studies on synaptic transmission and cellular trafficking, this is a major limitation. Both in academia and industry, mitotic cells are commonly used as a proxy for neurons (e.g. PC12 cells). However, while being less variable and better scalable, such cells model neurons only to a limited extent. These cells make no functional contacts (synapses) and do not have the same polarized organization that neurons have, which limits the validity for studies on synaptic transmission and cellular trafficking. Most commonly prescribed drugs for brain disorders target synapses. Yet, drug screening, lead finding/optimization and safety studies build either on cells that make no synapses or on labor-intensive low-throughput assays. Hence, new, standardized, scalable assays using real (synaptic) neurons, will provide a substantial step forward both for academia and industry. This application aims to develop a nano-electrode chip with an electrode array to stimulate, record and image many single neurons with high-resolution, for a period up to several weeks. This approach provides imaging data at single synapse and single organelle resolution and synaptic transmission data at high-throughput. Together, this will not only facilitate and standardize cellular assays using real neurons, but also upscale throughput 100 fold. In addition to the chip itself, we also see market potential for the method (growing/recording neurons on chips) and for a fee-for-service company that offers high throughput compound screening on synaptic neurons.

Mots-clés : neuroscience,synaptic transmission,nano electrode,exocytosis,cultured neurons,patch clamp,cellular trafficking,life cell imaging
Projet ERC : CentrioleBirthDeath (Horizon 2020, appel 2015, Consolidator grants)
Domaine scientifique : Life Science
Panel : Cellular, Developmental and Regenerative Biology
Entité participante : Calouste Gulbenkian Foundation — Pays : Portugal — Rôle : PI
Type d'entité : Recherche
Financement ERC de l'entité : 2000000.0 €

Centrioles assemble centrosomes and cilia/flagella, critical structures for cell division, polarity, motility and signalling, which are often deregulated in human disease. Centriole inheritance, in particular the preservation of their copy number and position in the cell is critical in many eukaryotes. I propose to investigate, in an integrative and quantitative way, how centrioles are formed in the right numbers at the right time and place, and how they are maintained to ensure their function and inheritance. We first ask how centrioles guide their own assembly position and centriole copy number. Our recent work highlighted several properties of the system, including positive and negative feedbacks and spatial cues. We explore critical hypotheses through a combination of biochemistry, quantitative live cell microscopy and computational modelling. We then ask how the centrosome and the cell cycle are both coordinated. We recently identified the triggering event in centriole biogenesis and how its regulation is akin to cell cycle control of DNA replication and centromere assembly. We will explore new hypotheses to understand how assembly time is coupled to the cell cycle. Lastly, we ask how centriole maintenance is regulated. By studying centriole disappearance in the female germline we uncovered that centrioles need to be actively maintained by their surrounding matrix. We propose to investigate how that matrix provides stability to the centrioles, whether this is differently regulated in different cell types and the possible consequences of its misregulation for the organism (infertility and ciliopathy-like symptoms). We will take advantage of several experimental systems (in silico, ex-vivo, flies and human cells), tailoring the assay to the question and allowing for comparisons across experimental systems to provide a deeper understanding of the process and its regulation.

Mots-clés : centrosome,centriole,drosophila