Data-Gouv-ML/pcri-erc-participations-et-projets-laureats huggingface dataset:
Projet ERC : RegEvolve (Horizon 2020, appel 2014, Consolidator grants)
Domaine scientifique : Life Science
Panel : Cellular, Developmental and Regenerative Biology
Entité participante : Max Planck Society — Pays : Allemagne — Rôle : PI
Acronyme de l'entité : MPG
Type d'entité : Recherche
Financement ERC de l'entité : 2000000.0 €

The ability to regenerate lost body parts is widespread amongst animals, yet humans, for example, can only regenerate specific organs. Why some animals regenerate while others hardly do remains a fascinating conundrum, especially so in face of “survival of the fittest”. Even amongst planarian flatworms, famous for their ability to regenerate from random tissue fragments, species exist that have completely lost the ability to regenerate. This proposal will exploit the unique diversity of planarian regenerative abilities amongst to ask why some worms regenerate while others do not. We and others have established that planarian Wnt signalling acts as critical node in the evolution of regeneration defects. Using this finding as strategic focus for comparisons between regenerating and non-regenerating species, we will investigate i) the cell biological mechanisms that shape Wnt pathway activity; ii) the genomic mechanisms that differentially deploy critical pathway regulators; and iii) evolutionary mechanisms in form of life history trait trade-offs as possible driving force behind the drift of regenerative abilities. Key to the project is a diverse collection of regenerating and regeneration-deficient species that my lab has established. Focused comparisons between our two primary model species D. lacteum and S. mediterranea, employing pan-planarian antibodies and functional genomics, will allow us to understand the detailed causes of altered pathway activity. Comparisons amongst the entire collection of 50 species will provide the necessary breadth for identifying and studying the evolutionary principles that “naturally select” regeneration-deficient planarians. The comparative approach of RegEvolve will thus uniquely bridge the proximate (molecular)- with the ultimate (evolutionary) causes of regeneration defects and such interdisciplinary endeavour between molecular and evolutionary regeneration research will lead to new and profound insights into both fields.

Mots-clés : planaria,evolution,regeneration
Projet ERC : PP-MAGIC (Horizon 2020, appel 2019, Consolidator grants)
Domaine scientifique : Physical Sciences and Engineering
Panel : Physical and analytical chemical sciences
Entité participante : University of Freiburg — Pays : Allemagne — Rôle : PI
Type d'entité : Enseignement supérieur ou secondaire
Financement ERC de l'entité : 2000000.0 €

The abusive use of antibiotics has led to multidrug-resistant bacteria and the acute threat of a post-antibiotic era. However, apart from resisters, there is a subgroup of bacteria called persisters that surviveby recalcitrance to antibiotic treatment. Persisters are not resistant to antibiotics but simply survive by metabolic shutdown. Upon withdrawal of antibiotics, these persisters resuscitate and regenerate the colony. They are heavily involved in failure of antibiotic treatment and the development of chronic infections. Bacterial persistence is controlled by the stringent response, which itself is mediated by hyperphosphorylated nucleotides, known as the magic spot (MS) nucleotides or (p)ppGpp. The importance of the stringent response, its omnipresence in the domain of bacteria, its connection to persister formation and tolerance to (antibiotic) stress, and its absence in mammals has led to significant research in microbiology. However, until recently these activities have not been paralleled by the development of chemical biology approaches. The current proposal aims to fill this gap by research into (1) synthetic methodology targeting the magic spot nucleotides and their analogs, (2) tools to identify target proteins of (p)ppGpp, and more generally (p)ppNpp (3) analytical approaches to extract, resolve, and quantify (p)ppGpp, (4) strategies to control the stringent response and persister formation with light (5) inhibitors of the stringent response. These new tools will enable a detailed understanding of the stringent response and thus ultimately help in the design of new antibiotics effective against persisters. The goal is to develop methods to force bacteria into the persistent state or inversely wake them up by using light and small molecules. Forcing bacteria out of persistence and blocking their entry into this state in combination with antibiotic treatment is a highly promising strategy to avoid the development of chronic bacterial infections.

Mots-clés : magic spot nucleotides,alarmones,antibiotics
Projet ERC : ArpComplexity (Horizon 2020, appel 2018, Synergy grants)
Entité participante : The Francis Crick Institute — Pays : Royaume-Uni — Rôle : CO-PI
Type d'entité : Recherche
Financement ERC de l'entité : 4148087.0 €

The actin cytoskeleton of the cell is critical for the complex, integrated processes associated with development, operation and sustainability of the human body. The Arp2/3 complex consisting of seven protein subunits is essential to stimulate dynamic branched actin networks needed for multiple cellular processes. The Arp2/3 complex has always been considered as a single entity, but in humans and other mammals, three of the Arp2/3 complex subunits are encoded by two isoforms, thus allowing the formation of eight distinct Arp2/3 complexes. The Way lab has shown that Arp2/3 subunit composition dramatically affects the formation and stability of branched actin networks. The Way and Gomes labs have shown how specific Arp2/3 isoforms are essential for muscle development. Our synergistic, high-risk, high-gain goal is to define the role of Arp2/3 complex diversity at three hierarchies of biology: 1. Molecular basis of Arp2/3 diversification With purified isoform-specific complexes we will perform cryo-electron microscopy and single molecule fluorescence microscopy to reveal the structural variations and influence of Arp2/3 diversity on actin networks in vitro. 2. Cellular function of different Arp2/3 complexes With cells expressing specific Arp2/3 isoforms, we will use quantitative live cell imaging and cryoelectron tomography to reveal the dependence of cellular actin networks on Arp2/3 diversity and its functional consequences. 3. Developmental and physiological role of individual Arp2/3 complexes. With genetically modified cultured myofibers and transgenic mice, we will use an array of imaging approaches to reveal the contribution of different Arp2/3 family members to muscle development, structure and physiology. Our interdisciplinary plan builds on the strengths of our three labs, takes advantage of unique reagents and powerful model systems, and will allow us to determine how Arp2/3 diversity contributes to biological complexity at multiple scales.

Mots-clés : actin,arp2,3 complex,skeletal muscle,cryo em
Projet ERC : ArpComplexity (Horizon 2020, appel 2018, Synergy grants)
Entité participante : University of Lisbon — Pays : Portugal — Rôle : PI
Type d'entité : Recherche
Financement ERC de l'entité : 3207935.0 €

The actin cytoskeleton of the cell is critical for the complex, integrated processes associated with development, operation and sustainability of the human body. The Arp2/3 complex consisting of seven protein subunits is essential to stimulate dynamic branched actin networks needed for multiple cellular processes. The Arp2/3 complex has always been considered as a single entity, but in humans and other mammals, three of the Arp2/3 complex subunits are encoded by two isoforms, thus allowing the formation of eight distinct Arp2/3 complexes. The Way lab has shown that Arp2/3 subunit composition dramatically affects the formation and stability of branched actin networks. The Way and Gomes labs have shown how specific Arp2/3 isoforms are essential for muscle development. Our synergistic, high-risk, high-gain goal is to define the role of Arp2/3 complex diversity at three hierarchies of biology: 1. Molecular basis of Arp2/3 diversification With purified isoform-specific complexes we will perform cryo-electron microscopy and single molecule fluorescence microscopy to reveal the structural variations and influence of Arp2/3 diversity on actin networks in vitro. 2. Cellular function of different Arp2/3 complexes With cells expressing specific Arp2/3 isoforms, we will use quantitative live cell imaging and cryoelectron tomography to reveal the dependence of cellular actin networks on Arp2/3 diversity and its functional consequences. 3. Developmental and physiological role of individual Arp2/3 complexes. With genetically modified cultured myofibers and transgenic mice, we will use an array of imaging approaches to reveal the contribution of different Arp2/3 family members to muscle development, structure and physiology. Our interdisciplinary plan builds on the strengths of our three labs, takes advantage of unique reagents and powerful model systems, and will allow us to determine how Arp2/3 diversity contributes to biological complexity at multiple scales.

Mots-clés : actin,arp2,3 complex,skeletal muscle,cryo em
Projet ERC : CARsen (Horizon 2020, appel 2020, Starting grants)
Domaine scientifique : Life Science
Panel : Prevention, Diagnosis and Treatment of Human Diseases
Entité participante : University of Tübingen — Pays : Allemagne — Rôle : PI
Type d'entité : Enseignement supérieur ou secondaire
Financement ERC de l'entité : 1818637.0 €

The adoptive transfer of T cells expressing CD19-directed chimeric antigen receptors (CARs) has yielded remarkable efficacy in patients with hematological B-cell malignancies. CARs are a class of synthetic receptors that reprogram T cell specificity, function and metabolism. Engineered T cells are applicable in principle to other cancers and diseases, but clinical success will critically depend on further progress to overcome current limitations such as antigenic heterogeneity or impaired T cell trafficking and function. We propose to develop CAR T cells targeting senescent cells as a novel therapeutic concept for cancer and senescence-associated diseases. Cellular senescence is a stress-response program characterized by stable cell cycle arrest that serves as a potent tumor-suppressive mechanism. Conversely, accumulation of senescent cells generates a chronic inflammatory milieu, which contributes to a plethora of pathologies, such as liver or lung fibrosis and can even promote tumor progression. Our preliminary data demonstrate that CAR T cells can efficiently clear senescent cells, providing therapeutic benefit in a murine model of liver fibrosis. We thus firmly believe that senolytic CAR T cells have broad therapeutic potential. To this end, we will apply innovative engineering strategies to develop modular CAR designs tailored to senescence-specific requirements. We will determine safety and efficacy of senolytic CAR T cells in murine models of cellular senescence and solid tumors. Importantly, we will evaluate combined treatment approaches of senescence-inducing therapies with CAR T cells targeting senescent and proliferating tumor cells. Finally, we will investigate engineering tools to optimally direct senolytic CAR activity to mediate durable tumor regression. This project combines two emerging concepts of anticancer therapies and goes beyond current applications of CAR therapies. The efforts may lead to promising new therapeutic avenues.

Mots-clés : adoptive t cell transfer,gene engineering,car t cells,car designs,solid tumors,anticancer therapies,cellular senescence,sasp,senolytics,senescence associated diseases,immunotherapy,translational research
Projet ERC : Troy Stem Cells (Horizon 2020, appel 2014, Starting grants)
Domaine scientifique : Life Science
Panel : Physiology in Health, Disease and Ageing
Entité participante : TU Dresden — Pays : Allemagne — Rôle : Partner
Acronyme de l'entité : TUD
Type d'entité : Enseignement supérieur ou secondaire
Financement ERC de l'entité : 284522.5 €

The adult mammalian stomach can be divided into three distinct parts: From the proximal fore-stomach over the corpus to the distal pylorus. Due to constant exposure to mechanical stress and to hostile contents of the lumen, highly specialized cell types have to be constantly reproduced in order to maintain the function of the gastrointestinal tract. Recently, the applicant identified Troy+ chief cells as a novel stem cell population in the corpus epithelium. Troy+ chief cells displayed a very low proliferation rate indicating their quiescent nature compared to other known gastro-intestinal tract stem cells. Interestingly, these stem cells can actively divide upon tissue damage, suggesting distinctive statuses under conditions of homeostasis and injury. As Troy+ stomach stem cells exhibit interconvertible characteristics i.e. quiescent and proliferative, they represent a unique model of adult stem cells with which we can study 1) the dynamics of stem cell propagation in homeostasis and regeneration and the underlying mechanism of this switch by analysing molecular and epigenetic profiles. Subsequently, by analysing mRNA expression profiles and epigenetic changes in Troy+ stem cells between homeostasis and injury repair, we will generate a list of genes with potentially interesting functions in cell fate decisions. We will therefore investigate 2) the stomach stem cell programme in homeostasis and regeneration using in vitro and in vivo functional genetics. Lastly, we will characterise 3) human stomach stem cells in normal and pathological conditions. Here we pursue three main aims: - Investigating Troy+ stem cell dynamics during homeostasis and injury repair - Unmasking the stomach stem cell programme using in vitro and in vivo functional genetics - Characterising human stomach stem cells

Mots-clés : stomach,stem cells,lineage tracing,wnt signalling,organoid culture
Projet ERC : Troy Stem Cells (Horizon 2020, appel 2014, Starting grants)
Domaine scientifique : Life Science
Panel : Physiology in Health, Disease and Ageing
Entité participante : Austrian Academy of Sciences — Pays : Autriche — Rôle : PI
Acronyme de l'entité : OAW
Type d'entité : Organismes privés (hors enseignement)
Financement ERC de l'entité : 570478.12 €

The adult mammalian stomach can be divided into three distinct parts: From the proximal fore-stomach over the corpus to the distal pylorus. Due to constant exposure to mechanical stress and to hostile contents of the lumen, highly specialized cell types have to be constantly reproduced in order to maintain the function of the gastrointestinal tract. Recently, the applicant identified Troy+ chief cells as a novel stem cell population in the corpus epithelium. Troy+ chief cells displayed a very low proliferation rate indicating their quiescent nature compared to other known gastro-intestinal tract stem cells. Interestingly, these stem cells can actively divide upon tissue damage, suggesting distinctive statuses under conditions of homeostasis and injury. As Troy+ stomach stem cells exhibit interconvertible characteristics i.e. quiescent and proliferative, they represent a unique model of adult stem cells with which we can study 1) the dynamics of stem cell propagation in homeostasis and regeneration and the underlying mechanism of this switch by analysing molecular and epigenetic profiles. Subsequently, by analysing mRNA expression profiles and epigenetic changes in Troy+ stem cells between homeostasis and injury repair, we will generate a list of genes with potentially interesting functions in cell fate decisions. We will therefore investigate 2) the stomach stem cell programme in homeostasis and regeneration using in vitro and in vivo functional genetics. Lastly, we will characterise 3) human stomach stem cells in normal and pathological conditions. Here we pursue three main aims: - Investigating Troy+ stem cell dynamics during homeostasis and injury repair - Unmasking the stomach stem cell programme using in vitro and in vivo functional genetics - Characterising human stomach stem cells

Mots-clés : stomach,stem cells,lineage tracing,wnt signalling,organoid culture
Projet ERC : Troy Stem Cells (Horizon 2020, appel 2014, Starting grants)
Domaine scientifique : Life Science
Panel : Physiology in Health, Disease and Ageing
Entité participante : University of Cambridge — Pays : Royaume-Uni — Rôle : Partner
Acronyme de l'entité : U. Cambridge
Type d'entité : Enseignement supérieur ou secondaire
Financement ERC de l'entité : 715398.37 €

The adult mammalian stomach can be divided into three distinct parts: From the proximal fore-stomach over the corpus to the distal pylorus. Due to constant exposure to mechanical stress and to hostile contents of the lumen, highly specialized cell types have to be constantly reproduced in order to maintain the function of the gastrointestinal tract. Recently, the applicant identified Troy+ chief cells as a novel stem cell population in the corpus epithelium. Troy+ chief cells displayed a very low proliferation rate indicating their quiescent nature compared to other known gastro-intestinal tract stem cells. Interestingly, these stem cells can actively divide upon tissue damage, suggesting distinctive statuses under conditions of homeostasis and injury. As Troy+ stomach stem cells exhibit interconvertible characteristics i.e. quiescent and proliferative, they represent a unique model of adult stem cells with which we can study 1) the dynamics of stem cell propagation in homeostasis and regeneration and the underlying mechanism of this switch by analysing molecular and epigenetic profiles. Subsequently, by analysing mRNA expression profiles and epigenetic changes in Troy+ stem cells between homeostasis and injury repair, we will generate a list of genes with potentially interesting functions in cell fate decisions. We will therefore investigate 2) the stomach stem cell programme in homeostasis and regeneration using in vitro and in vivo functional genetics. Lastly, we will characterise 3) human stomach stem cells in normal and pathological conditions. Here we pursue three main aims: - Investigating Troy+ stem cell dynamics during homeostasis and injury repair - Unmasking the stomach stem cell programme using in vitro and in vivo functional genetics - Characterising human stomach stem cells

Mots-clés : stomach,stem cells,lineage tracing,wnt signalling,organoid culture
Projet ERC : SENTIENT (Horizon 2020, appel 2017, Starting grants)
Domaine scientifique : Physical Sciences and Engineering
Panel : Systems and communication engineering
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 : 1499941.0 €

The advances in electronic communication and computation have enabled the ubiquity of Cyber-Physical Systems (CPS): digital systems that regulate and control all sorts of physical processes, such as chemical reactors, water distribution and power networks. These systems require the timely communication of sensor measurements and control actions to provide their prescribed functionalities. Event-triggered control (ETC) techniques, which communicate only when needed to enforce performance, have attracted attention as a mean to reduce the communication traffic and save energy on (wireless) networked control systems (NCS). However, despite ETC’s great communication reductions, the scheduling of the aperiodic and largely unpredictable traffic that ETC generates remains widely unaddressed – hindering its true potential for energy and bandwidth savings. To address this problem, I will take up the following scientific challenges: (1) the construction of models for ETC’s communication traffic; (2) the design of schedulers based on such models guaranteeing prescribed performance levels. To reach these goals, I will employ scientific methods at the cross-roads between theoretical computer science, control systems and communications engineering. I propose to follow a two step approach that I have recently demonstrated: (i) modeling as timed-priced-game-automata (TPGA) the timing of communications of event-triggered control systems; and (ii) solving games over TPGAs to prevent data communication collisions and ensure prescribed performances for the control tasks. I will produce algorithms facilitating the efficient implementation of control loops over shared communication resources and increasing the energy efficiency of wireless NCS by orders of magnitude. The advances will be demonstrated on automotive and wireless water-distribution control applications, showcasing the potential economic impact from the reduction of implementation and maintenance costs on CPSs.

Mots-clés : event triggered control,symbolic,formal methods for control
Projet ERC : RegSign (Horizon 2020, appel 2020, Starting grants)
Domaine scientifique : Life Science
Panel : Prevention, Diagnosis and Treatment of Human Diseases
Entité participante : Biomedical Research Foundation of the Academy of Athens — Pays : Grèce — Rôle : PI
Acronyme de l'entité : BRFAA
Type d'entité : Recherche
Financement ERC de l'entité : 1500000.0 €

The advent of immune checkpoint inhibitors (ICI), that target regulatory pathways in T cells to unleash antitumor immune responses, has revolutionized cancer immunotherapy. However, despite the enormous success of ICI in the treatment of cancer, a significant proportion of patients do not respond, while responses are frequently accompanied by life-threatening autoimmune related adverse events (irAEs). Predictive biomarkers of clinical responses and new therapeutic strategies to harness anti-tumor immunity, while keeping autoimmunity in check represent a currently unmet need. Tregs, are an ideal candidate, since they are physiologically engaged in maintenance of self-tolerance, are the dominant suppressive population in the tumor microenvironment (TME), promote tumor growth, correlate with poor prognosis and importantly, represent a fundamental impediment of cancer immunotherapy success. Building upon my extensive expertise on Tregs in autoimmunity and cancer, the abundance of circulating Tregs in cancer patients, and preliminary data demonstrating a robust transcriptomic and metabolic reprogramming of circulating Tregs in advanced melanoma patients experiencing irAEs, RegSign proposes: 1) to integrate single cell mass-cytometric, transcriptomic, metabolic and stability analysis of circulating Tregs to create a “liquid biopsy” for prediction of ICI efficacy and irAEs development, 2) to identify novel Treg-based therapeutic targets via innovative humanized patient derived xenograft models and 3) to modulate Treg metabolic checkpoints for the management of irAEs. Decoding Tregs signatures in cancer will empower the discovery of personalized predictive biomarkers and novel targets for cancer immunotherapy.

Mots-clés : biomarkers,cancer immunotherapy,therapeutic targets,regulatory t cells