Data-Gouv-ML/pcri-erc-participations-et-projets-laureats huggingface dataset:
Projet ERC : SpectrO (Horizon Europe, appel 2024, Consolidator grants)
Domaine scientifique : Social Sciences and Humanities
Panel : The Human Mind and Its Compl exity
Entité participante : Centre Hospitalier Universitaire Vaudois — Pays : Suisse — Rôle : Partner
Acronyme de l'entité : CHUV
Type d'entité : Organismes publics (hors enseignement & recherche)
Financement ERC de l'entité : 176641.5 €

Opioids are irreplaceable and effective analgesics– at the group level. However, clinicians still cannot predict how much pain relief each patient will achieve, nor who will develop addiction. By treating the variability of opioid effects as noise, the group-based efficacy studies fail to explain why opioids relieve pain in some people, but not in others. Here, I will turn the current approach on its head. By harnessing the valuable information inherent in opioids’ variable and diverse effects, I aim to achieve a breakthrough in our ability to predict individual patient responses to opioids and enable effective personalised pain treatment. SpectrO has three main objectives:  1) First, I will employ large-scale data to generate robust and reproducible evidence on the full spectrum of opioid effects and resolve key controversies in the opioid literature (WP1: comprehensive samples).  Next, I will hone in on each extreme of the opioid effects spectrum to:  2) Answer why opioid effects are so variable and diverse. A newly discovered human genetic knockout model affords unprecedented insights into human endogenous opioid function, far beyond the current state-of-the-art (WP2: opioid-insensitive sample).  3) Produce randomised controlled evidence at the individual level through a N-of-1 case series with double-blind dose titration for individual dose efficacy determination. WP3 represents a leap forward in opioid research, promising to close the gap between the group-based trials (which show no benefit of long-term opioids) and the clinical experience that some patients do benefit (opioid-sensitive sample).  My unique track record in leading large interdisciplinary opioid trials and conducting innovative literature syntheses lends feasibility to this ambitious project. SpectrO will set a new direction for opioid research, offering powerful new resources and methods to resolve key mechanistic questions and urgent public health issues on pain and addiction.

Mots-clés : pain,reward,addiction,experience,mood,affect,well being
Projet ERC : EXPLOAD (Horizon Europe, appel 2021, Consolidator grants)
Domaine scientifique : Life Science
Panel : Environmental B iology, Ecology  and E volution
Entité participante : Université d'Oslo — Pays : Norvège — Rôle : PI
Acronyme de l'entité : UiO
Type d'entité : Enseignement supérieur ou secondaire
Financement ERC de l'entité : 597349.0 €

DNA can survive millennia post-mortem, spanning ecological and evolutionary transitions and providing a unique window into the processes underlying biodiversity. As such sequencing ancient DNA from temporally spaced samples can allow the testing of hypotheses related to evolutionary responses to ecological change and novel selection pressures through direct quantification of ecological and genetic parameters collected before, during and after genetic changes in selection pressures. Here, I propose to do just this, taking advantage of a natural experiment of an emblematic study system in evolutionary biology: parallel independent adaptation to freshwater by marine-adapted threespine sticklebacks through the rise in frequency of freshwater-associated alleles. Utilising palaeogenomics to sample genomes along this evolutionary continuum and the project will address a key and long-standing question: is there a mutational cost to natural selection? This is a timely question, as ongoing rapid global climatic change is a major source of novel selection pressures, therefore, understanding the dynamics of natural selection will provide key insights into potential outcomes for biodiversity. The methods developed in this project will not only benefit the growing field of paleogenomics but also other fields where data is collected in a temporal manner, such as experimental evolution and epidemiology. Ultimately, achievement of these goals requires the formation of a dedicated, closely knit team, focusing on both the methodological challenges as well as their bigger picture application to high-risk high-gain ventures. With ERC funding this can become a reality, enabling the interface of palaeogenomics and evolutionary biology to be pushed to the new limits of the modern sequencing era.

Mots-clés : mutation load,ancient dna,adaptation,threespine stickleback
Projet ERC : AssemblingLife (Horizon Europe, appel 2022, Consolidator grants)
Domaine scientifique : Social Sciences and Humanities
Panel : The Human Mind and Its Compl exity
Entité participante : Université d'Oslo — Pays : Norvège — Rôle : PI
Acronyme de l'entité : UiO
Type d'entité : Enseignement supérieur ou secondaire
Financement ERC de l'entité : 1974940.0 €

Biology invites us to understand life as “hard work”. Living beings are mainly viewed as systems requiring the constant input of energy and the detailed regulation by genetic material. These ideas of life very much influence the general understanding of living systems, and, particularly interesting for this project, it influences current philosophy of science accounts of the understanding and explanation of living processes. But what if life is much less “hard work” than often presented? And what if genes should be understood as “nudgers” rather than as “directing” living processes? Self-assembly is the spontaneous formation of complex patterns and structure. It can be visualized as a pile of lego bricks turning into a Ninjago fortress on its own. There are no lego-builders. The parts “self-assemble”, possibly as a result of chemical and physical processes working between and on the parts. Recent nanoscience research efforts at the intersection of chemistry, biology, and material science, increasingly utilize self-assembly processes in the development of new materials, technologies and understanding of living systems.  AssemblingLife will, on an interdisciplinary basis, build a new theoretical framework withing the philosophy of science for understanding and explaining life, building on the increasing focus and knowledge about self-assembly processes that carry the potential to shift our view of life. The project will provide a new understanding of genetic causation starting from the idea of genes as “nudging” self-assembly processes rather than as providing detailed regulation, and it will develop new theory of scientific explanation that will account for the observation that self-assembly processes do not behave like classical mechanisms or interventions targets. AssemblingLife plan for contributing novel and needed theory and conceptual tools both to the philosophy of science and to the empirical life sciences.

Mots-clés : philosophy of biology,philosophy of life science,philosophy of nanoscience
Projet ERC : AB-AG-INTERACT (Horizon Europe, appel 2023, Consolidator grants)
Domaine scientifique : Life Science
Panel : Biotechnology and Biosystems E ngineering
Entité participante : Université d'Oslo — Pays : Norvège — Rôle : PI
Acronyme de l'entité : UiO
Type d'entité : Enseignement supérieur ou secondaire
Financement ERC de l'entité : 2000000.0 €

Antibody-antigen binding is the basis of two fundamental biotherapeutic pillars: monoclonal antibodies (1) and vaccines (2). To accelerate therapeutics discovery, we need to perform antibody (Ab) and antigen (Ag) design in silico. Specifically, we need to address a fundamental immuno-biotechnological challenge: understanding the interaction rules that predict Ab-Ag binding. Solving this challenge demands the convergence of biotechnology, computational structural biology, and machine learning (ML). My lab is one of the few worldwide to have this transdisciplinary expertise.  Research problem: Currently, the predictive performance of Ab-Ag binding is poor, and an understanding of the underlying rules of Ab-Ag binding is mostly absent. We previously showed that both unprecedentedly large datasets (>10^5 Ab-Ag sequence pairs) and extensive structural information on the Ab-Ag binding interface (paratope, epitope) are needed to increase prediction accuracy and recover binding rules. Targeted breakthrough: To address the lack of large-scale Ab-Ag sequence and structural data, we will develop a method for high-throughput screening of >10^3 Ab paratope-mutated variants binding to >10^3 of Ag epitope-mutated variants, generating sequence data of Ab-Ag binding pairs at an unprecedented scale (>10^6 sequence Ab-Ag pairs). Structural information of the entirety of the sequence-based Ab-Ag binding data will be generated by building and innovating on recent breakthroughs in computational structural biology. To derive Ab-Ag interaction rules from the generated data, we will develop ML techniques for Ab-Ag binding prediction and rule recovery. We will demonstrate experimentally that we have begun to understand Ab-Ag interaction rules. Impact: The proposed research generates the exact data necessary to recover the rules of Ab-Ag binding and provides a first groundbreaking insight into those rules, moving us closer to in silico on-demand antibody and vaccine design.
Projet ERC : KINTSUGI (Horizon Europe, appel 2024, Consolidator grants)
Domaine scientifique : Life Science
Panel : Physiology in Health, Disease and Ageing
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 : 21430.0 €

Air pollution, exacerbated by heatwaves and wildfires, affects primarily the lungs, leading to potentially life-threatening effects eluding conventional treatments. In response, KINTSUGI adopts a new perspective by exploring lung resilience mechanisms, to understand how respiratory health is maintained in most individuals: drawing on evidence from both a broad evolutionary standpoint, where humans have evolved in environments exposed to particles and proofs of lung resilience observed particularly in smokers, it seeks to redefine the paradigm of investigating lung response to particulate pollution. For that, KINTSUGI focuses on the airway submucosal gland (SMG), an ectodermal appendage lining the airways, renowned for its unique properties in mucus secretion, antimicrobial activity and a potential niche for proximal airway stem cells. The hypothesis posits the airway SMG as a crucial signalling hub, orchestrating responses to external perturbations to ensure proximal lung resilience. Using dissected clinical samples of SMG, it aims to unravel cell interactions intricacies within this niche, ultimately generating a "SMG-related resilience signature". Additionally, 3D in vitro models replicating the in vivo architecture and function of airway SMGs will be established for the study of mucociliary clearance, antimicrobial activity, and regeneration studies under both homeostatic conditions and particles exposure. KINTSUGI further integrates probabilistic mathematical modelling, considering microscopic interaction rules within the SMG, to elucidate macroscopic behaviours underlying lung resilience at different time scales. KINTSUGI anticipates impacting broader scientific communities, as such health, biology, and evolution, by uncovering fundamental insights into the mechanisms governing resilience. The impact on health and its potential to resonate across diverse scientific disciplines positions KINTSUGI as a ground-breaking initiative with far-reaching implications.

Mots-clés : lung resilience,particulate pollution,airway submucosal gland,lung organoid
Projet ERC : CELL-FIT (Horizon Europe, appel 2024, Consolidator grants)
Domaine scientifique : Life Science
Panel : Cell Biology, Development, Stem Cells and R egeneration
Entité participante : Université d'Utrecht — Pays : Pays-Bas — Rôle : PI
Type d'entité : Enseignement supérieur ou secondaire
Financement ERC de l'entité : 1999993.0 €

Every tissue in our body is a mosaic formed by individual cells that have different levels of cellular fitness. Competitive interactions, where the relative differences in fitness determine cell survival, therefore have a major impact on the physiology of a wide variety of tissues. Cell competition is versatile and abundant, and it impacts a broad spectrum of processes, ranging from early embryonic development to aging. Yet, due to the heterogeneity of competitive interactions, both in space and time, the dynamics of this process are difficult to unravel. For instance, it is unclear which long-term adaptations of cellular behavior cell competition induces. Furthermore, the consequences of a locally activated response on overall tissue fitness are unknown. The overall objective of this project is to unravel spatial and temporal regulation of cell competition. Specifically, I aim to understand the: 1) Cell competition-driven adaptations of cellular behavior 2) Mechanistic regulation of competitive cellular interactions 3) Contribution of cell competition to tumor growth in different tissues  The foundation of this project is formed by our innovative 3D co-culture system which my team developed to dissect competitive behavior at molecular, cellular, and population scales. We will combine this system with a newly generated toolbox to recognize and manipulate interacting and competing cells. By leveraging our leading expertise in long-term quantitative imaging and single cell multi-omics, we will mechanistically untangle cell competition in primary intestinal cancer in space and time. To understand how competition affects different types of tumor growth and find shared regulators of this process, we will expand our co-culture systems to different tissues. Together, this provides the unique opportunity to tackle a fundamental question in cell biology: How is cell competition regulated in space and time and how does this impact tissue composition and tumor growth?

Mots-clés : cell competition,quantitative microscopy
Projet ERC : CANPLAST (Horizon Europe, appel 2021, Consolidator grants)
Domaine scientifique : Life Science
Panel : Prevention,  Diagnosis and T reatment of Human Diseases
Entité participante : Institut national de la santé et de la recherche médicale — Pays : France — Rôle : PI
Acronyme de l'entité : Inserm
Type d'entité : Recherche
Financement ERC de l'entité : 1492500.0 €

Novel cancer molecular-targeted therapies allow to significantly prolong the survival of cancer patients. However, the inevitable acquisition of resistance mechanisms limits the clinical benefit of these treatments. To fully understand how resistance develops, it is crucial to better integrate tumor heterogeneity, cancer cell plasticity and microenvironment changes by applying cutting-edge single cell technologies directly on sequentially sampled biopsies from cancer patients. Additionally, to achieve deeper and longer-lasting clinical responses for cancer patients, we will need to target the rare drug-tolerant persister cancer cells. Samples collected before, during and after treatment will be used to fully describe the characteristics of the cells that are the source of genetic resistant variants that ultimately give rise to tumor relapses. By combining the establishment of patient-derived models, drug-screening of epigenetic inhibitors, transcriptomic and epigenetic characterization of persister cells we will aim to highlight their vulnerabilities. Finally, identify the driver mechanisms of genomic evolution by elucidating the link between oncogenic kinases and DNA repair pathways activity will be our innovative strategy to exploit putative susceptibilities to impeach the survival of resistant cells. The use of DNA repair substrate combined with CRISPR gene knockout will aim at confirming the value of targeting DNA repair pathways to profoundly transform the outcome of patients with metastatic cancer. Overall, by applying new technological breakthrough at the single cell level on patient biopsies, digging into the intrinsic nature of persister cells and taking advantages of DNA repair defects we will identify innovative treatment strategies to avoid the emergence of resistance in patients.

Mots-clés : persister cancer cells,targeted therapy,resistance
Projet ERC : immSC-AgingFate (Horizon Europe, appel 2023, Consolidator grants)
Domaine scientifique : Life Science
Panel : Physiology in Health, Disease and Ageing
Entité participante : Gulbenkian Institute for Molecular Medicine — Pays : Portugal — Rôle : PI
Acronyme de l'entité : GIMM
Type d'entité : Recherche
Financement ERC de l'entité : 1998843.0 €

Adult stem cells (SCs) sustain tissue renewal and repair throughout life. The SC niche is fundamental in the regulation of SC function and an important contributor to SC decline in aging. While alterations in the tissue’s immune environment are emerging as important contributors to impairments found in aged organs, their contribution to SC dysfunction in aging is unknown. The skeletal muscle (SkM) is a paradigmatic model to study age-related loss of repair capacity. Muscle stem cell (MuSC) function during regeneration requires plasticity in transit between states of quiescence, activation and differentiation. MuSC functional impairments in aging result from changes in the extrinsic cues that govern their behavior, but also cell intrinsic alterations, including senescence and defects in lineage commitment. However, we still have a limited understanding of how changes in the environment manifest as SC intrinsic defects. Our previous work indicates that changes in immune signaling are important drivers of MuSC dysfunction and regenerative decline in aging. Here, we propose to identify the contribution of specific immune populations and signals to changes in regenerative capacity and MuSC activity in aging (Aim 1). We hypothesize that the immune environment is an essential regulator of MuSC plasticity and lineage commitment under regenerative pressure, and immune alterations underlie defects in MuSC lineage fidelity in aging. We propose to map the trajectories of MuSCs diverging from the myogenic lineage and uncover the changes in epigenetic landscape that underlie the loss of lineage fidelity associated with immune aging, identifying transcriptional regulators of MuSC fate (Aim 2). The knowledge generated on the mechanisms linking immune aging and MuSC dysfunction will be tested for the conservation in human SkM and will be applied to improve the success of MuSC-based therapies in aging (Aim 3).
Projet ERC : VirulenceControl (Horizon Europe, appel 2021, Consolidator grants)
Domaine scientifique : Life Science
Panel : Immunity, Infection and I mmunotherapy
Entité participante : Gulbenkian Institute for Molecular Medicine — Pays : Portugal — Rôle : PI
Acronyme de l'entité : GIMM
Type d'entité : Recherche
Financement ERC de l'entité : 1796073.0 €

The most severe form of malaria in humans is caused by Plasmodium falciparum. Cytoadhesion of infected red blood cells (iRBCs) to host endothelium and iRBC rigidification are the major contributors to pathology. Cytoadhesion is mediated by transport of a protein called PfEMP1 onto the surface of the iRBC. It prevents clearance of iRBCs in the spleen and promotes parasite survival, but can cause the obstruction of blood vessels leading to pathology. Thus, the parasite has to strike a fine balance between preventing its own clearance through sufficiently strong cytoadhesion and control of rigidity, and killing the host. The paradigm in the field is that the strength of cytoadhesion is dominated by expression of PfEMP1 variants with different affinities for host cell receptors. We now have strong evidence that the parasite can rapidly regulate its cytoadhesive properties using a family of atypical kinases (the FIKK kinases) it exports into the host cell. This gives the parasite a yet unrecognized ability to respond to conditions encountered in the host, such as fever or hypoxia in areas of high parasite sequestration, and influence disease outcome. This is important: Of the 6 human infecting Plasmodium species only P. falciparum exports FIKK kinases into the host cell. As this species is responsible for ~95% of all fatal human malaria cases, it is paramount to understand FIKK- function in pathogenesis. We will use cutting edge approaches to: (1) identify the function of FIKK kinases in controlling cytoadhesion and rigidity in conditions frequently encountered in the human host and determine RBC remodelling in samples from patients. (2) Identify the molecular underpinnings of FIKK function in controlling cytoadhesion and (3) perform a thorough biochemical characterisation of the atypical FIKK kinase family. In summary we aim to answer the paramount question about the functional role and the evolution of the FIKK kinases and the pathogenesis of P. falciparum malaria.

Mots-clés : host pathogen interaction,parasitology,malaria,plasmodium falciparum,kinases,virulence,phosphoproteomics
Projet ERC : MITOSIZE (Horizon Europe, appel 2024, Consolidator grants)
Domaine scientifique : Life Science
Panel : Cell Biology, Development, Stem Cells and R egeneration
Entité participante : Helmholtz Zentrum München — Pays : Allemagne — Rôle : PI
Acronyme de l'entité : HMGU
Type d'entité : Recherche
Financement ERC de l'entité : 1999933.0 €

Mitochondrial DNA (mtDNA) constitutes a substantial proportion of DNA in eukaryotes, and its regulation is critical not only for mitochondrial function but also for cell survival. However, it is still unclear how mtDNA copy number is maintained during cell proliferation and how mtDNA copy number impacts on cell function. Recently, my group showed that in budding yeast, mtDNA copy number is tightly linked to cell volume to maintain constant concentrations, providing an elegant and potentially conserved strategy for mtDNA homeostasis. But how is mtDNA coupled to cell volume? Based on my group’s work, we proposed that nuclear-encoded mtDNA maintenance factors produced in proportion to cell volume limit mtDNA replication and stability. This provides a conceptual mechanism for how cells link mtDNA copy number to total cellular protein content, and opens the door to a quantitative and molecular understanding of mtDNA homeostasis.  With MITOSIZE, I will reveal the molecular basis of this ‘limiting machinery’ mechanism. To test whether the mechanism is conserved across species and to chloroplast DNA, I will use two evolutionary distant eukaryotes: S. cerevisiae, whose size I can control genetically, and C. reinhardtii, whose size I can control with light. I will use an interdisciplinary approach combining molecular biology, quantitative live-cell imaging, and modelling to develop a quantitative understanding based on measurements of mtDNA replication and degradation. I will then unravel the contribution of the ‘limiting machinery’ regulation to the dynamic adaptation of mtDNA to changing environments. Moreover, by breaking the coupling of mtDNA copy number to cell volume, I will dissect how cell volume and mtDNA copy number determine cell function and aging. By identifying the molecular regulation underlying organellar DNA homeostasis, I will address a fundamental question in cell biology and open the door to new intervention strategies for mtDNA misregulation in diseases.

Mots-clés : mitochondrial dna,cell size,single cell imaging,chloroplast dna