Data-Gouv-ML/pcri-erc-participations-et-projets-laureats huggingface dataset:
Projet ERC : CELLNAIVETY (Horizon 2020, appel 2016, Consolidator grants)
Domaine scientifique : Life Science
Panel : Prevention, Diagnosis and Treatment of Human Diseases
Entité participante : Weizmann Institute of Science — Pays : Israël — Rôle : PI
Type d'entité : Enseignement supérieur ou secondaire
Financement ERC de l'entité : 2000000.0 €

An important goal of stem cell therapy is to create “customized” cells that are genetically identical to the patient, which upon transplantation can restore damaged tissues. Such cells can be obtained by in vitro direct reprogramming of somatic cells into embryonic stem (ES)-like cells, termed induced pluripotent stem cells (iPSC). This approach also opens possibilities for modelling human diseases in vitro. However, major hurdles remain that restrain fulfilling conventional human iPSC/ESC potential, as they reside in an advanced primed pluripotent state. Such hurdles include limited differentiation capacity and functional variability. Further, in vitro iPSC based research platforms are simplistic and iPSC based “humanized” chimeric mouse models may be of great benefit. The recent isolation of distinct and new “mouse-like” naive pluripotent states in humans that correspond to earlier embryonic developmental state(s), constitutes a paradigm shift and may alleviate limitations of conventional primed iPSCs/ESCs. Thus, our proposal aims at dissecting the human naïve pluripotent state(s) and to unveil pathways that facilitate their unique identity and flexible programming. Specific goals: 1) Transcriptional and Epigenetic Design Principles of Human Naïve Pluripotency 2) Signalling Principles Governing Human Naïve Pluripotency Maintenance and Differentiation 3) Defining Functional Competence and Safety of Human Naïve Pluripotent Stem Cells in vitro 4) Novel human naïve iPSC based cross-species chimeric mice for studying human differentiation and disease modelling in vivo. These aims will be conducted by utilizing engineered human iPSC/ESC models, CRISPR/Cas9 genome-wide screening, advanced microscopy and ex-vivo whole embryo culture methods. Our goals will synergistically lead to the design of strategies that will accelerate the safe medical application of human naive pluripotent stem cells and their use in disease specific modelling and applied stem cell research.

Mots-clés : cell therapy,ipsc,pluripotency,embryonic stem cells  escs,stem cell differentiation,epigenetics,reprogramming,trophoblast stem cells,germ cells,pgcs,dna methylation
Projet ERC : INVADIS (Horizon 2020, appel 2015, Consolidator grants)
Domaine scientifique : Life Science
Panel : Immunity, Infection and Immunotherapy
Entité participante : Institut Pasteur — Pays : France — Rôle : PI
Type d'entité : Recherche
Financement ERC de l'entité : 2750000.0 €

An infection is defined by the deleterious consequences of the interactions between a pathogen and a host. Thus, studying the biology of infection reveals critical properties of hosts and pathogens, and is a way forward to address basic biological questions and improve health. We study listeriosis, a systemic infection caused by Listeria monocytogenes (Lm). Lm is a human foodborne pathogen that crosses the intestinal barrier, disseminates systemically, replicates in liver and spleen and reaches the central nervous system (CNS) and fetoplacental unit. Given the remarkable journey Lm makes in its host, studying listeriosis offers unprecedented opportunities to understand host cell biology, physiology and immune responses, guided by Lm. The mucosal, CNS and fetoplacental tropisms of Lm are shared by other microbes which pathogenesis is far less understood. Lm therefore stands as a unique model microorganism of general biological and medical significance. The major challenge of this project is to go beyond reductionist approaches and embrace the complexity of actual infections. We will use stem cell-derived organoids, live imaging, genetically engineered mouse models, the clinical and biological data from a unique cohort of 900 patients and the corresponding causative Lm strains, to investigate the molecular mechanisms of Lm tissue invasion, dissemination and host responses. Specifically, we will (i) decipher the cell biology of microbial translocation across the intestinal epithelium; (ii) study the impact of microbial portal of entry on microbial fate, dissemination and host responses; (iii) harness Lm biodiversity to identify novel virulence factors and (iv) discover new host factors predisposing to invasive infections. Building on the unique combination of advanced experimental systems and exclusive clinical data, this integrative and innovative project will reveal novel, physiologically relevant mechanisms of infection, with scientific and biomedical implications.

Mots-clés : infection,barrier,pathophysiology,bacteria,epithelial,cell,tissue,in vivo,animal models,imaging,human host
Projet ERC : NeoTs (Horizon 2020, appel 2019, Advanced grants)
Domaine scientifique : Life Science
Panel : Immunity, Infection and Immunotherapy
Entité participante : Max Delbrück Center for Molecular Medicine — Pays : Allemagne — Rôle : PI
Acronyme de l'entité : MDC
Type d'entité : Recherche
Financement ERC de l'entité : 2499573.75 €

An old question in tumor immunology is whether cancer cells can spontaneously activate T cells that in turn destroy them, termed immunosurveillance. While firmly established for virus-associated tumors, immunosurveillance of spontaneous tumors is still controversial. Intuitively, autochthonous cancer models may be better suited than transplantation model to address this question, yet current models bear pitfalls and do not resemble the sporadic nature of human cancer. Importantly, they are not conclusive. Cancer cell transplantation is artificial and induces acute inflammation, facilitating T cell activation. It may be suited, however, if tumor antigen expression and cell proliferation can be regulated and induced when resting conditions have been re-established. We will investigate, in two novel cancer models, the fate of T cells specific for naturally occurring mouse and human neoantigens under resting conditions, resembling pathophysiologic conditions. We hypothesize that induction of a large foreign antigen harboring several epitopes, but not a mouse point-mutant neoantigen, activate functional T cells under resting conditions, while both will do under acute inflammatory conditions. We further conditionally express human mutations, either proven or predicted neoantigens, in cancer cells syngeneic to mice with a diverse human T cell receptor repertoire restricted to HLA-A2. Our studies will answer the questions, whether the initial antigen encounter induces functional or dysfunctional T cells, what distinguishes antigens that can or cannot induce functional T cells, what is the long-term fate of the T cells, why are spontaneous T cell responses rare relative to mutation load and how precisely can neoantigens be predicted. This project will clarify the role of immunosurveillance and addresses the question whether the best target antigens are retained or lost before cancer becomes clinically apparent, which is of high clinical relevance.

Mots-clés : cancer,neoantigen,t cell receptor,humanized mouse model
Projet ERC : NanoGlia (Horizon 2020, appel 2019, Starting grants)
Domaine scientifique : Life Science
Panel : Neuroscience and Disorders of the Nervous System
Entité participante : University of Bonn — Pays : Allemagne — Rôle : PI
Type d'entité : Enseignement supérieur ou secondaire
Financement ERC de l'entité : 1497193.0 €

An omnipresent but understudied environmental risk for our immune system is pollution by nano-sized plastics. Plastic particles have been detected in a wide variety of ecosystems and are speculated to enter and spread in the food web all the way to humans. Ingested nanoplastics can translocate from the gut to the lymph and circulatory systems and have the capacity to cross the blood-brain barrier in mammals. It has been recently shown that nanoplastics cause behavioural disorders in fish, and thus may also represent a risk for human health, in particular for brain function. However, the long-term bioavailability and toxicity of nanoplastics in the brain are unknown. Microglia as the main neuroimmune cells have not only a defence function required during inflammatory conditions, but constantly sense and response to environmental changes as part of their housekeeping functions that are essential for neuronal homeostasis. This places microglia at the interface between normal and abnormal brain development and function. In line with this, we have recently discovered that chronic microglial activation causes neurodegeneration. As highly phagocytic cells, microglia internalize nanoplastics reaching the brain. This process might in turn lead to their acute or chronic activation, thereby triggering neurological disorders. In NanoGlia, we will use rodent animal models to investigate behavioural as well as cellular and molecular changes in the brain that occur upon ingestion of nanoplastics. We will further determine nanoplastics-induced developmental reprogramming events in fetal microglia that may influence brain organogenesis and function. Understanding how nanoplastics triggers microglial activation during embryogenesis and postnatal stages and whether this immune activation leads to permanent changes in brain development and function will reveal ground-breaking mechanistic insights into the environmentally triggered pathogenesis of neurological disorders.

Mots-clés : microglia,developmental neuroimmunology,neuroimmunology
Projet ERC : AncientAdhesives (Horizon 2020, appel 2018, Starting grants)
Domaine scientifique : Social Sciences and Humanities
Panel : The study of the human past
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 : 1499926.0 €

AncientAdhesives addresses the most crucial problem in Palaeolithic archaeology: How to reliably infer cognitively complex behaviour in the deep past. To study the evolution of Neandertal and modern human cognitive capacities, certain find categories are taken to reflect behavioural and thus cognitive complexitye.g. Among these are art objects, personal ornaments and complex technology. Of these technology is best-suited to trace changing behavioural complexity, because 1) it is the least vulnerable to differential preservation, and 2) technological behaviours are present throughout the history of our genus. Adhesives are the oldest examples of highly complex technology. They are also known earlier from Neandertal than from modern human contexts. Understanding their technological complexity is thus essential to resolve debates on differences in cognitive complexity of both species. However, currently, there is no agreed-upon method to measure technological complexity. The aim of AncientAdhesives is to create the first reliable method to compare the complexity of Neandertal and modern human technologies. This is achieved through three main objectives: 1. Collate the first comprehensive body of knowledge on adhesives, including ethnography, archaeology and (experimental) material properties (e.g. preservation, production). 2. Develop a new archaeological methodology by modifying industrial process modelling for archaeological applications. 3. Evaluate the development of adhesive technological complexity through time and across species using a range of explicit complexity measures. By analysing adhesives, it is possible to measure technological complexity, to identify idiosyncratic behaviours and to track adoption and loss of complex technological know-how. This represents a step-change in debates about the development of behavioural complexity and differences/similarities between Neanderthals and modern humans.

Mots-clés : behavioural complexity,technological complexity,process modelling
Projet ERC : CancerAneuploidy (Horizon 2020, appel 2020, Starting grants)
Domaine scientifique : Life Science
Panel : Physiology in Health, Disease and Ageing
Entité participante : Tel Aviv University — Pays : Israël — Rôle : PI
Acronyme de l'entité : TAU
Type d'entité : Enseignement supérieur ou secondaire
Financement ERC de l'entité : 1612500.0 €

Aneuploidy, an imbalanced number of chromosomes or chromosome arms, is a distinct feature of cancer. Recent years have seen conceptual, methodological and technical advances in the field of cancer aneuploidy research, but we are just beginning to scratch the surface of the underlying biology, and the potential vulnerabilities of aneuploid cancer cells remain under-explored. Cancer aneuploidy is therefore a biological enigma and a missed opportunity for cancer therapy. Identifying the “Achilles heels” of aneuploidy remains a holy grail of cancer research. However, current models of aneuploidy fail to fully recapitulate the cellular consequences of aneuploidy in cancer, thus compromising the identification of aneuploidy-induced cellular vulnerabilities. The time is ripe to tackle cancer aneuploidy with state-of-the-art genomic and functional approaches. In this project, I propose to address the following key questions: 1) What forces shape the evolution of aneuploidy in tumors? We will integrate in silico analyses of clinical data, in vitro modeling in isogenic human cell lines, and in vivo experiments in mice, to elucidate how various cellular contexts shape the tumor aneuploidy landscape. 2) What cellular vulnerabilities are induced by aneuploidy? We will combine isogenic cell lines with large-scale genetic and chemical perturbation screens, in order to identify, validate, and mechanistically dissect vulnerabilities induced by aneuploidy in human cancer cells. These research aims fall well within my unique expertise. I mapped various aneuploidy landscapes and developed innovative experimental and computational tools for studying cancer aneuploidy. A successful completion of the project will shed light on the context-dependent cellular consequences of aneuploidy in cancer and provide proof-of-concept for its potential targeting. Ultimately, identifying aneuploidy-specific vulnerabilities will pave the way for the therapeutic exploitation of this hallmark of cancer.

Mots-clés : cancer genetics,aneuploidy,chromosomal instability
Projet ERC : PFKFBLOCK (Horizon 2020, appel 2015, Proof of concept grants)
Entité participante : Vlaams Instituut voor Biotechnologie — Pays : Belgique — Rôle : PI
Acronyme de l'entité : VIB
Type d'entité : Recherche
Financement ERC de l'entité : 150000.0 €

Angiogenesis, the growth of new blood vessels, contributes to major pathologies such as blinding ocular disease, inflammation and cancer. Blocking angiogenesis has therefore become a major field of research and an attractive therapeutic strategy. Current anti-angiogenic therapies focus on blockade of pro-angiogenic factors, such as VEGF. However, in cancer, insufficient efficacy, resistance and toxicity restrict the success of anti-VEGF agents. There is thus an urgent unmet need for novel anti-angiogenic strategies. In our ERC Advanced research grant (ECMetabolism), we developed an entirely novel anti-angiogenic concept and strategy, based on targeting key metabolic pathways in endothelial cells (ECs), cells lining blood vessels. More in particular, we identified - for the first time - that PFKFB3, a key glycolytic regulator, as a novel and promising target for anti-angiogenic therapy. Our findings show that glucose metabolism determines vessel sprouting and that lowering glycolysis only partially and transiently (by blocking PFKFB3) sufficed to inhibit pathological angiogenesis without causing systemic effects. In this ERC proof of concept project, PFKFBLOCK, we aim to develop lead small molecule compounds, blocking PFKFB3, and evaluate their potential to block pathological angiogenesis. Currently, no specific and orally available PFKFB3 blocker exists underscoring the value of our proposal and the necessity to develop such blocker for therapeutic applications. Through collaboration with a drug discovery unit we will identify lead molecules with novel intellectual property potential. Those lead compounds will be validated in relevant in vivo models and considered to be patented. The ultimate goal of this project is to get the best PFKFB3 inhibitor in clinical trials.

Mots-clés : angiogenesis,endothelial cell metabolism,drug discovery,small molecule compounds,anti angiogenic therapy
Projet ERC : HighMemory (Horizon 2020, appel 2020, Starting grants)
Domaine scientifique : Life Science
Panel : Neuroscience and Disorders of the Nervous System
Entité participante : CERCA Institution — Pays : Espagne — Rôle : PI
Acronyme de l'entité : CERCA;I-CERCA
Type d'entité : Recherche
Financement ERC de l'entité : 1499826.0 €

Animals and humans adapt to changes in the environment through the encoding and storage of previous experiences. Although associative learning involving a reinforcer has been the major focus in the field of cognition, other forms of learning are gaining popularity as they are likely more relevant and frequent in human daily choices. Indeed, associations between non-reinforcing stimuli represent the most evolutionarily advanced way to increase the chances of predicting future events and adapting individuals’ behavior. Animals are also able to form these higher-order conditioning processes, but more research is needed to understand how the brain encode and store these complex cognitive processes. In this project, I propose to study the role of hippocampo-cortical circuits in higher-order conditioning processes. These processes explain why subjects are often repulsed or attracted by stimuli, which do not have intrinsic repellent or appealing value and they were never explicitly paired with negative or positive outcomes. A proposed explanation of these “ungrounded” aversion or attraction is that these stimuli were incidentally associated with other cues directly reinforced, through a process called mediated learning (ML). However, with increased incidental associations, the subjects acquire more information, allowing them to separate the real saliences of the different stimuli. Therefore, ML evolves into “reality testing”(RT), a behavioral process that has been even less studied. These processes involve multiple brain regions and are characterized by accessible phases, making them perfect models to study the circuit-level regulation of complex behavior. By using genetic, pharmacological, imaging and mouse behavioral approaches (sensory preconditioning), HighMemory proposes to characterize at macro- (brain regions), meso- (cell-types) and micro-scale (activity changes), the causal involvement of hippocampo-cortical projections in higher-order conditioning processes.

Mots-clés : higher order conditioning,sensory preconditioning,mediated learning,reality testing,psychotic states,hippocampus,cortical regions
Projet ERC : ECO (Horizon 2020, appel 2020, Consolidator grants)
Domaine scientifique : Social Sciences and Humanities
Panel : Cultures and cultural production
Entité participante : University of Coimbra — Pays : Portugal — Rôle : PI
Type d'entité : Recherche
Financement ERC de l'entité : 1999291.0 €

Animals and plants feature prominently in cultural productions about the Amazon, testifying to the centrality of the region’s natural environment both for local populations and for the earth’s biosphere. The key hypothesis of ECO is that texts (broadly understood to include mythology, folk tales, the lyrics of songs, essays, literature, travel writings, etc.), cinema and art about this area highlight the ways in which non-human beings dynamically shape human cultural life. The project’s main challenge is to resort both to Amazonian thought and to the academic field of ecocriticism to assess how human cultural productions about Amazonia lend a voice to animals and plants. ECO develops the concept of zoophytography to describe the inscription of non-humans in texts, films and artworks, thus decentering humanity as the sole source of meaning-making. Research stream I. “Amazonian Zoophytography” formulates a definition of this notion and traces its roots to Indigenous and riverine epistemologies and to Western philosophy. Through archival research, ECO will then gather and analyze sources that portray Amazonian animals and plants from the beginning of the twentieth century onwards in two other research streams: II. “Animal Talk: Zoography Spelled Out” focuses on the articulation of animals in cultural productions about the Amazon; III. “Flora’s Voice: Phytographic Conversations” analyzes plant inscription in texts, cinema and artworks that question the role of vegetal life as a passive form of existence. ECO will make a significant contribution to the environmental humanities, offering an Amazonian perspective on ecocriticism, environmental philosophy and post-colonial studies. By creating a deeper understanding of conceptions of Amazonian fauna and flora, the project will reveal the interdependence of humans and non-humans, draw attention to environmental degradation in Amazonia and uncover more equitable views on animals and plants from the region.

Mots-clés : ecocriticism,environmental humanities,latin american studies,amazonian writings,cinema and art
Projet ERC : mARs (Horizon 2020, appel 2019, Consolidator grants)
Domaine scientifique : Life Science
Panel : Molecules of Life: Biological Mechanisms, Structures and Functions
Entité participante : European Molecular Biology Laboratory — Pays : Allemagne — Rôle : Partner
Acronyme de l'entité : EMBL
Type d'entité : Recherche
Financement ERC de l'entité : 0.0 €

Antibiotic resistance (AR) is spreading rapidly, leading to the development of highly virulent pathogens and multidrug-resistant ‘superbugs’, a major health concern of our era. Mobile DNA elements, transposons and integrons, effectively drive the spread of AR genes in microbial interaction hotspots, such as bacterial communities in humans and natural environments. Yet, our knowledge of their mechanisms remains very sparse. It is unclear how DNA movement occurs on the molecular level and how it is controlled in cells and communities; biochemical and structural data are rare and our view on their diversity and evolution is limited. Here I propose an integrated approach combining bioinformatics, genetics, microbiology, biochemistry, and structural biology to elucidate the mechanisms and diversity of mobile DNA driven resistance spreading. I want to (a) investigate the molecular mechanisms and regulation of AR gene movement in vitro, in model bacteria and in gut bacterial communities; (b) dissect the structure of the underlying molecular machineries to reveal how protein-DNA interplay promotes gene transfer; and (c) characterize the diversity, evolution and functional success of distinct molecular pathways. Mechanistic work will focus on selected mobile elements that confer resistance to last resort drugs and promiscuous gene carriers with high prevalence in health care. Bioinformatic quests will draw on recent (meta)genomic data to chart the clinical significance of molecular insights in situ. By bridging disciplines, I want to provide functionally annotated molecular movies of gene movement and explain how specific molecular strategies evolved to enable broad dissemination of resistance determinants. The insights gained in this research will provide in-depth knowledge on major AR transfer pathways and will have key implications for the development of novel intervention strategies and preventive measures aimed at reducing dissemination of drug resistance in bacteria.

Mots-clés : mobile genetic elements,multi drug resistant bacteria,antibiotic resistance transmission,gene transfer,molecular mechanism,microbiome