Data-Gouv-ML/pcri-erc-participations-et-projets-laureats huggingface dataset:
Projet ERC : INTUMORX (Horizon 2020, appel 2016, Starting grants)
Domaine scientifique : Life Science
Panel : Physiology in Health, Disease and Ageing
Entité participante : University of Helsinki — Pays : Finlande — Rôle : PI
Acronyme de l'entité : UH
Type d'entité : Enseignement supérieur ou secondaire
Financement ERC de l'entité : 1972905.0 €

The considerable variability within tissue microenvironments as well as the multiclonality of cancers leads to intratumoral heterogeneity. This increases the probablility of cellular states that promote resistance to therapy and eventually lead to reconstitution of the tumor by treatment-resistant cancer cells, which in some cases have properties of normal tissue stem cells. Wnt signals are important in the maintenance of stem cells in various epithelial tissues, including in lung development and regeneration. We hypothesized that Wnt signals contribute to tumor heterogeneity in genetically engineered KrasG12D; Tp53Δ/Δ (”KP”) mouse lung adenocarcinomas (LUAD). We observed that a subpopulation of LUAD cells exhibited high Wnt reporter activity and had increased tumor forming ability, which could be suppressed by silencing of Wnt signaling pathway components or by small molecule Wnt inhibitors in vitro and in vivo. KP LUAD cells show hierarchical features with two distinct populations, one with increased Wnt reporter activity and another forming a niche that provides the Wnt signal. Lineage-tracing experiments in the autochthonous KP tumors demonstrated that Wnt responder cells have increased tumor propagation ability in vivo. Strikingly, selective ablation of the Wnt responder cells resulted in tumor stasis. CRISPR-based targeting or small molecules targeting Wnt signaling reduced tumor growth and prolonged survival in the autochthonous KP mouse lung cancer model. These results indicate that maintenance of heterogeneity within tumors may be advantageous for the tumor cell population collectively. We propose to elucidate the molecular and cellullar mechanisms that control stem-like and niche cell phenotypes using a combination of novel lentiviral vectors and genetically modified mice in the context of the KP LUAD model. These efforts may lead to novel therapeutic concepts in human lung cancer.

Mots-clés : lgr5,kras,lung cancer,cancer stem cell,cancer heterogeneity
Projet ERC : Browsec (Horizon 2020, appel 2017, Consolidator grants)
Domaine scientifique : Physical Sciences and Engineering
Panel : Computer science and informatics
Entité participante : Wolfgang Pauli Institute — Pays : Autriche — Rôle : Partner
Acronyme de l'entité : WPI
Type d'entité : Recherche
Financement ERC de l'entité : 205000.0 €

The constantly increasing number of attacks on web applications shows how their rapid development has not been accompanied by adequate security foundations and demonstrates the lack of solid security enforcement tools. Indeed, web applications expose a gigantic attack surface, which hinders a rigorous understanding and enforcement of security properties. Hence, despite the worthwhile efforts to design secure web applications, users for a while will be confronted with vulnerable, or maliciously crafted, code. Unfortunately, end users have no way at present to reliably protect themselves from malicious applications. BROWSEC will develop a holistic approach to client-side web security, laying its theoretical foundations and developing innovative security enforcement technologies. In particular, BROWSEC will deliver the first client-side tool to secure web applications that is practical, in that it is implemented as an extension and can thus be easily deployed at large, and also provably sound, i.e., backed up by machine-checked proofs that the tool provides end users with the required security guarantees. At the core of the proposal lies a novel monitoring technique, which treats the browser as a blackbox and intercepts its inputs and outputs in order to prevent dangerous information flows. With this lightweight monitoring approach, we aim at enforcing strong security properties without requiring any expensive and, given the dynamic nature of web applications, statically infeasible program analysis. BROWSEC is thus a multidisciplinary research effort, promising practical impact and delivering breakthrough advancements in various disciplines, such as web security, JavaScript semantics, software engineering, and program verification.

Mots-clés : web security,formal methods,program verification
Projet ERC : NATCOOP (Horizon 2020, appel 2015, Starting grants)
Domaine scientifique : Social Sciences and Humanities
Panel : The Social World and Its Diversity
Entité participante : University of Oslo — Pays : Norvège — Rôle : Partner
Acronyme de l'entité : UiO
Type d'entité : Enseignement supérieur ou secondaire
Financement ERC de l'entité : 136805.0 €

The constraints and dynamics set by nature have a deep and significant impact on economic fundamentals and the ability to successfully manage renewable resources. This can be taken into account to formulate effective policies. However, the causal pathway from the natural to the social environment and its feedback for sustainable resource use is often overlooked, not the least because preferences and incentives are traditionally viewed as being stable and fixed. Yet, it is high time to take this new perspective: Social-ecological systems around the globe are under mounting stress and common pool resources are vital, in particular in developing countries. This project aims to establish how nature shapes preferences and incentives of economic agents and how this in turn affects common-pool resource management. To this end, I investigate three mechanisms: (A) how tipping points and thresholds in the natural system may encourage cooperation; (B) how the volatility of resource abundance influences risk preferences and how this in turn affects community-based management; and (C) how leadership, which is closely linked to risk preferences, interacts with the natural environment to foster cooperation that overcomes common-pool dilemmas. NATCOOP's bold agenda pushes the frontier of economics and sustainability science. Not only the investigation of the feedbacks between nature and cooperation from a new angle, also the scale and scope of the project -- combining cases from different socio-economic and ecological setting at three continents with theoretical and statistical work -- will generate new knowledge and be highly rewarding. Though challenging, I am confident that my background in economics and ecology puts me in an ideal position to achieve this important task. My ultimate goal is to identify circumstances in which natural preconditions and the social setting may go hand in hand to promote the sustainable use of renewable resources.

Mots-clés : natural resources,endogenous preferences,thresholds,leadership,common pool resources,game theory
Projet ERC : NORVAS (Horizon 2020, appel 2015, Starting grants)
Domaine scientifique : Life Science
Panel : Prevention, Diagnosis and Treatment of Human Diseases
Entité participante : Karolinska Institutet — Pays : Suède — Rôle : PI
Acronyme de l'entité : KI
Type d'entité : Enseignement supérieur ou secondaire
Financement ERC de l'entité : 1493125.0 €

The contribution of cardiovascular disease to human morbidity and mortality continues to steadily increase in our aging European society. In response, extraordinary efforts have been launched to determine the molecular and pathophysiological characteristics of its etiology. The collective work of multiple research groups has uncovered a complex transcriptional and post-transcriptional regulatory milieu, which is believed to be essential for maintaining cardiovascular homeostasis. Recently, non-coding RNAs, especially the ones with antisense capabilities such as microRNAs or ‘natural antisense transcripts’ (NATs) have received much attention. They have been identified as important transcriptional and post-transcriptional inhibitors of gene expression. This current proposal describes the development of novel diagnostic and therapeutic strategies to limit the burden of cardiovascular disease in general, and abdominal aortic aneurysms as well as carotid stenosis and subsequent stroke in particular. Using transcriptomic profiling techniques on human diseased tissue samples, we have identified two NATs (SLFNL-AS1 and NUDT6) as novel crucial regulators of smooth muscle cell survival via targeting CTPS1 and the fibroblast growth factor 2 (FGF2) in the vascular system. We are using disease-relevant experimental in vivo models (rodents and LDLR-/- mini-pigs) to functionally assess how inhibition of these two NATs influences aneurysm progression and atherosclerotic plaque vulnerability. One focus of our studies is to utilize local delivery mechanisms for non-coding RNA modulators, such as drug eluting balloons and stents, to enhance the translational feasibility of our findings. Furthermore, we have access to unique human plasma material from patients with early and advanced forms of aneurysm disease, enabling us to investigate the biomarker value of non-coding RNAs in recognizing patients with acutely ruptured aneurysms, as well as predicting the future risk of rupture.

Mots-clés : non coding rna,microrna,abdominal aortic aneurysm,stroke
Projet ERC : StroMaP (Horizon 2020, appel 2017, Starting grants)
Domaine scientifique : Life Science
Panel : Physiology in Health, Disease and Ageing
Entité participante : Weizmann Institute of Science — Pays : Israël — Rôle : PI
Type d'entité : Enseignement supérieur ou secondaire
Financement ERC de l'entité : 1499990.0 €

The contribution of genetic and epigenetic changes to rewiring of cancer cells into their malignant state has been much studied. But tumors are more than cancer cells and the tumor microenvironment (TME) is a key player in tumor progression. We lack an overarching view of how, despite being genomically stable, the TME is heterogeneously reprogrammed across time and space to promote evolution of aggressive disease. Recently I discovered that Heat-Shock Factor 1 (HSF1), a cytoprotective transcription factor (TF), is vital to this reprogramming, promoting malignancy in patients and mice upon activation in the stroma. Other stress TFs have also been implicated. This leads me to hypothesize that stress responses help tumors adapt and evolve into aggressive malignancies, by enabling heterogeneity and phenotypic diversity in the TME. This plasticity is achieved through cycles of massive transcriptional rewiring orchestrated by a network of stress TFs. To test this hypothesis in a global way we will proceed in three aims. First we will define patterns of stress response activation in the TME by multiplexed immunofluorescence of patient tumors. Then, we will map the associated transcriptional landscape in patients by RNA-sequencing down to single cell resolution and interrogate it in the context of a novel theory of evolutionary tradeoffs so as to discover signatures that promote tumor aggressiveness. Next, we will identify actionable nodes for intervention and test them in cell co-cultures and mouse models. The expected outcome of the proposed research is a detailed network of stress responses that can explain how the TME is rewired in tumors and how variable this rewiring is. This knowledge will provide new ways to target the TME in order to complement treatments focused on cancer cells. More generally, we address key aspects of stress responses, tissue plasticity, hoemostasis and evolution that are expected to be valuable across diverse fields of biology.

Mots-clés : tumor microenvironment,tumor heterogeneity,stress responses,transcription regulation,cancer evolution,evolutionary medicine
Projet ERC : TRANSREG (Horizon 2020, appel 2017, Starting grants)
Domaine scientifique : Life Science
Panel : Physiology in Health, Disease and Ageing
Entité participante : University of Zurich — Pays : Suisse — Rôle : PI
Acronyme de l'entité : UZH
Type d'entité : Enseignement supérieur ou secondaire
Financement ERC de l'entité : 1977148.0 €

The control of translation is a key determinant of protein abundance, which in turn defines cellular states. The impact of translational regulation may be even greater during the transition from homeostasis to malignancy, as revealed by the surprisingly low correlations between mRNA and protein levels in human cancer databases. This raises the intriguing possibility that through an ability to generate aberrant downstream networks of translational regulators, oncogenic drivers might impose altered protein synthesis programs that become the driving force for tumor formation and malignant progression. We recently unveiled a hitherto unappreciated role for upstream open reading frame (uORF) translation in tumorigenesis and unearthed a novel switch from conventional EIF2 initiation factor-mediated to alternative EIF2A-mediated uORF translation. These observations suggest that uORFs constitute an exciting new frontier in the field of translational regulation with the potential to fundamentally impact cellular fate. Here, I propose to systematically analyze the function of uORFs during tumorigenesis. First, we will conduct an in vivo CRISPR/CAS9-based screen in mice to elucidate the role of thousands of uORFs in development, differentiation and upon oncogenic transformation. Second, focusing on select uORFs surfacing in the screen, we will document their role during tumor initiation and progression. Third, we will develop novel tools to detect uORF translation in vivo, exploit them to monitor uORF translation during different stages of tumorigenesis, gain mechanistic insight into their function and finally test the relevance of these findings in human cancer. Collectively, these approaches will provide unprecedented and comprehensive insight into the function of uORFs, unravel new paradigms in the control of gene expression and expose novel strategies for cancer diagnostics and treatment.

Mots-clés : translational regulation,upstream open reading frames,crispr screening
Projet ERC : smMIET (Horizon 2020, appel 2019, Advanced grants)
Domaine scientifique : Physical Sciences and Engineering
Panel : Physical and analytical chemical sciences
Entité participante : University of Göttingen — Pays : Allemagne — Rôle : PI
Acronyme de l'entité : GAU
Type d'entité : Enseignement supérieur ou secondaire
Financement ERC de l'entité : 2740188.0 €

The core aim of the project is to develop the technology of Single-Molecule Metal-Induced Energy Transfer (smMIET) for resolving macromolecular structure and dynamics with sub-nanometre spatial resolution and nanosecond temporal resolution. Metal-Induced Energy Transfer or MIET was first developed in our group in 2012 for mapping cellular membranes with nanometre axial resolution. It exploits the effect that a fluorescent molecule, when brought close to a metal surface, can transfer its excited state energy to surface plasmons in the metal, which leads to a strong distance-dependence of its fluorescence lifetime and intensity. This strong lifetime-distance dependence allows for converting a measured fluorescence lifetime into a distance from the metal surface. Combining this concept with single-molecule localization super-resolution microscopy and with fluorescence correlation spectroscopy will resolve three-dimensional structures with nanometre isotropic resolution, and structural dynamics on the nanometre length scale with nanosecond temporal resolution. Among its many applications, the project will develop and apply smMIET for resolving the global structure of macromolecular complexes and its dynamics, the conformational fluctuations of intrinsically disordered proteins, the dynamics of lipid membranes in a leaflet-resolved manner, or the transport of proteins across lipid bilayers. We will establish smMIET as a toolbox for structural and molecular biology that is comparable and complementary in its usefulness and versatility to conventional Förster Resonance Energy Transfer (FRET) or Fluorescence Correlation Spectroscopy (FCS).

Mots-clés : single molecule localization super resolution microscopy,single molecule fluorescence spectroscopy,nano optics and plasmonics
Projet ERC : Mari.Time (Horizon 2020, appel 2018, Consolidator grants)
Domaine scientifique : Life Science
Panel : Environmental Biology, Ecology and Evolution
Entité participante : University of Vienna — Pays : Autriche — Rôle : PI
Acronyme de l'entité : Univie
Type d'entité : Enseignement supérieur ou secondaire
Financement ERC de l'entité : 1975000.0 €

The correct timing of biological processes is crucial for organisms. The moon is an important timing cue for numerous marine species, ranging from brown and green algae to corals, worms and fishes. It acts either directly or via the synchronization of monthly (circalunar) inner clocks. Such lunar timing mechanisms typically control the gonadal maturation and behavioral changes associated with reproductive rhythms, including spectacular mass-spawning events. Despite their biological importance, the mechanisms underlying circalunar clocks, as well as their responses to naturalistic stimuli are unknown. My lab has spearheaded research into the mechanisms underlying circalunar timing systems, establishing tools and resources for two well-suited, complementary animal models: Platynereis dumerilii and Clunio marinus. We unraveled first principles of the circalunar clock, e.g. its continuous function in the absence of oscillation of the daily (circadian) clock. Recent unpublished work revealed the first gene that functionally impacts on circalunar rhythms. By capitalizing on these powerful tools and key findings, my lab is in a leading position to dissect the mechanisms of circalunar clocks and their interaction with other rhythms and the environment via three objectives: (1) A reverse genetic approach to unravel how nocturnal light sets the phase of the monthly clock. (2) A forward genetic screen to identify molecules involved in the circalunar clock, an experimental strategy that was the key to unravel the principles of animal circadian clocks. (3) By growing animals in outside tanks and subjecting them to established analyses, we will test our lab-based results in more naturalistic conditions. This project will substantially deepen our mechanistic insight into marine rhythms – ecologically important phenomena – and provide a first basis to predict how environmental changes might impact on timing systems of crucial importance to many marine species and likely beyond.

Mots-clés : chronobiology,photobiology
Projet ERC : TechEvo (Horizon 2020, appel 2016, Starting grants)
Domaine scientifique : Social Sciences and Humanities
Panel : Institutions, Governance and Legal Systems
Entité participante : National University of Ireland — Pays : Irlande — Rôle : PI
Acronyme de l'entité : NUI
Type d'entité : Enseignement supérieur ou secondaire
Financement ERC de l'entité : 1496599.0 €

The creation and accumulation of knowledge are processes at the heart of technological change and economic growth. Attention has been directed at aggregate measures of knowledge production in regional and national contexts, but little consideration has been given to the properties of knowledge produced in specific places. How does the nature of knowledge that is produced vary over space, what conditions the scope of technologies generated in different locations, and how do these knowledge sets impact the performance of local firms and industries? To date, the way in which specific regional knowledge capabilities influence the evolution of local technology trajectories and thus shape geographies of economic prosperity have not yet been considered systematically. The objective of the “Technology Evolution in Regional Economies” (TechEvo) project is to address these significant shortcomings. Focusing on the evolution of scientific and technical knowledge, as indicated by patent, trademark and scientific literature records, the point of departure is the pan-European knowledge space for all 28 European Union member countries, plus Norway and Switzerland, over the time period 1981-2015. The knowledge space, based on the co-occurrence matrix of particular knowledge domains (629), maps the proximity of patent technology classes and enables the development of regional measures of knowledge specialization for all 1,369 (NUTS3) regions. Set in an evolutionary framework the investigation provides ground breaking insights into how innovative entities and individual inventors are embedded in social and cognitive local and non-local networks, and how regional technology trajectories are shaped through entry, exit, and selection processes. TechEvo will provide a wealth of indicators, models and tools that will assist firms and policy makers in place-based investment decisions, and deliver a science and technology policy evaluation tool capable of assessing impact.

Mots-clés : evolutionary economic geography,technological change,knowledge space,invention and innovation,science and technology policy,research and development,patent and citation analysis,related variety
Projet ERC : FRESCO (Horizon 2020, appel 2014, Advanced grants)
Domaine scientifique : Physical Sciences and Engineering
Panel : Synthetic Chemistry and Materials
Entité participante : University of Bristol — Pays : Royaume-Uni — Rôle : PI
Type d'entité : Enseignement supérieur ou secondaire
Financement ERC de l'entité : 2436379.0 €

The creation of new molecular entities and subsequent exploitation of their properties is central to a broad spectrum of research disciplines from medicine to materials but progress has been limited by the difficulties associated with chemical synthesis. We are now proposing a fundamentally new strategy, which has the potential to revolutionise how we conduct complex organic synthesis. The basic C–C bond-forming step involves the reaction of a lithiated carbamate with a boronic ester to give a homologated boronic ester with complete stereocontrol. Furthermore, the reaction shows >98% efficiency in most cases and can be conducted iteratively and in one pot (up to 9 iterations has been demonstrated with full stereocontrol). We will now extend this methodology to more functionalised carbamates as this will enable the rapid synthesis of polypropionates, which are amongst the most important classes of biologically active molecules. The robust methodology is now ripe for transfer to the solid phase as this will enable the preparation of libraries of these molecules. Through applying our assembly-line-synthesis methodology to complex molecules with diverse structures, we will demonstrate its scope, robustness, and full potential. The methodology enables stereochemistry to be ‘dialled in’ to a carbon chain, which in turn controls the conformation and we will exploit this feature in the shape-selective synthesis of molecules. We will explore how the sense of helical chirality of these molecules can be switched (M to P) just with light. We will target helical molecules with specific groups at specific places for optimum binding to disrupt protein–protein interactions involved in cancer. Finally, our methodology provides ready access to a family of building blocks that represent common repeat units found in polyketides. By combining these building blocks iteratively using lithiation-borylation, we should be able to rapidly and reliably prepare complex natural products.

Mots-clés : asymmetric synthesis,synthetic methodology,natural products