Data-Gouv-ML/pcri-erc-participations-et-projets-laureats huggingface dataset:
Projet ERC : BCM-UPS (Horizon 2020, appel 2015, Consolidator grants)
Domaine scientifique : Life Science
Panel : Physiology in Health, Disease and Ageing
Entité participante : Technical University of Munich — Pays : Allemagne — Rôle : PI
Acronyme de l'entité : TUM
Type d'entité : Enseignement supérieur ou secondaire
Financement ERC de l'entité : 1973255.0 €

B-cell malignancies are characterized by high levels of genomic instability, which critically contribute to their pathogenesis and evolution. Recently, the fundamental role of the ubiquitin proteasome system (UPS) in maintaining genome integrity has been appreciated. Two major new therapeutic modalities in B-cell malignancies, proteasome inhibitors and imunomodulatory drugs (IMiDs), target the UPS and demonstrate particular efficacy in multiple myeloma (MM) and mantle cell lymphoma (MCL), two incurable entities with poor prognosis. This suggests the presence of aberrant ubiquitylation events, whose identities have however remained mostly elusive. Our recent studies identify fundamental roles of orphan ubiquitin ligases of the Cullin Ring ligase family (CRLs) and their counterparts, the deubiquitylating enzymes (DUBs) in the cellular DNA damage response machinery, and characterize these candidates as novel oncogenes or tumour suppressors in MM and MCL. These findings provide the foundation for our hypothesis that deregulated ubiquitylation events involving CRLs and DUBs have a far reaching impact on the pathogenesis of B-cell malignancies and can serve as new therapeutic targets and biomarkers. We therefore propose a multistep strategy in which we will (1) characterize previously orphan CRLs and DUBs, which we have distinguished as candidate oncogenes and tumour suppressors in MM (FBXO3, USP24), MCL (FBXO25), or MM and MCL (CRBN), respectively; (2) decipher the global role of CRLs and DUBs in MM and MCL using defined genetic screens; (3) identify relevant substrates of CRLs/DUBs discovered in (2) using mass spectrometry; and (4) validate CRL/DUB candidates in preclinical mouse models and defined patient cohorts as to their disease relevance. We expect that our interdisciplinary approach will unravel the overall role of the UPS in the pathophysiology, evolution and treatment of B-cell malignancies.

Mots-clés : b cell malignancies,ubiquitin proteasome system
Projet ERC : BeyondMoore (Horizon 2020, appel 2020, Starting grants)
Domaine scientifique : Physical Sciences and Engineering
Panel : Computer science and informatics
Entité participante : Koç University — Pays : Turquie — Rôle : PI
Type d'entité : Enseignement supérieur ou secondaire
Financement ERC de l'entité : 1500000.0 €

BEYONDMOORE addresses the timely research challenge of solving the software side of the Post Moore crisis. The techno-economical model in computing, known as the Moore’s Law, has led to an exceptionally productive era for humanity and numerous scientific discoveries over the past 50+ years. However, due to the fundamental limits in chip manufacturing we are about to mark the end of Moore’s Law and enter a new era of computing where continued performance improvement will likely emerge from extreme heterogeneity. The new systems are expected to bring a diverse set of hardware accelerators and memory technologies. Current solutions to program such systems are host-centric, where the host processor orchestrates the entire execution. This poses major scalability issues and severely limits the types of parallelism that can be exploited. Unless there is a fundamental change in our approach to heterogeneous parallel programming, we risk substantially underutilizing upcoming systems. BEYONDMOORE offers a way out of this programming crisis and proposes an autonomous execution model that is more scalable, flexible, and accelerator-centric by design. In this model, accelerators have autonomy; they compute, collaborate, and communicate with each other without the involvement of the host. The execution model is powered with a rich set of programming abstractions that enable a program to be modeled as a task graph. To efficiently execute this task graph, BEYONDMOORE will develop a software framework that performs static and dynamic optimizations, issues accelerator-initiated data transfers, and reasons about parallel execution strategies that exploit both processor and memory heterogeneity. To aid the optimizations, a comprehensive cost model that characterizes both target applications and emerging architectures will be devised. Complete success of BEYONDMOORE will enable continued progress in computing which in turn will power science and technology in the life after Moore’s Law.
Projet ERC : BINGO (Horizon 2020, appel 2019, Consolidator grants)
Domaine scientifique : Physical Sciences and Engineering
Panel : Fundamental constituents of matter
Entité participante : Commissariat à l’énergie atomique et aux énergies alternatives — Pays : France — Rôle : PI
Acronyme de l'entité : CEA
Type d'entité : Recherche
Financement ERC de l'entité : 2420370.0 €

BINGO will set the grounds for a large-scale bolometric experiment searching for neutrinoless double beta decay with a background index of about 10-5 counts/(keV kg y) and with very high energy resolution – of the order of 1.5‰ – in the region of interest. These features will enable a search for lepton number violation with unprecedented sensitivity. The BINGO approach can lead to the demonstration of the Majorana nature of neutrino even in the unfavourable case of direct ordering of neutrino masses. BINGO is based on luminescent bolometers for the rejection of the dominant alpha surface background. It will focus on two extremely promising isotopes – 100Mo and 130Te – that have complementary merits and deserve to be both considered for future large-scale searches. The project will bring three original ingredients to the well-established technology of hybrid heat-light bolometers: i) the light-detector sensitivity will be increased by an order of magnitude thanks to Neganov-Luke amplification; (ii) a revolutionary detector assembly will reduce the total surface radioactivity contribution by at least one order of magnitude; (iii) for the first time in an array of macrobolometers, an internal active shield, based on ultrapure ZnWO4 scintillators with bolometric light readout, will suppress the external gamma background. These challenging technologies will be extensively tested in a two-isotope demonstrator, dubbed MINI‑BINGO, which will be located in an underground laboratory in a dedicated cryogenic infrastructure built with ERC funds. The BINGO approach can be implemented in the next-generation search CUPID, a proposed follow up of the CUORE experiment. BINGO can improve dramatically the sensitivity of CUPID, using two isotopes at the same time and providing the demonstration of its background goal. Subsequently, the intrinsic modularity of the bolometric technique would make sensible to proceed to further expansions, capable of penetrating the direct-ordering band.

Mots-clés : neutrinoless double beta decay,low temperature detectors
Projet ERC : BRCA INSIGHTS (Horizon 2020, appel 2020, Advanced grants)
Domaine scientifique : Life Science
Panel : Molecules of Life: Biological Mechanisms, Structures and Functions
Entité participante : Università della Svizzera italiana — Pays : Suisse — Rôle : PI
Acronyme de l'entité : USI
Type d'entité : Recherche
Financement ERC de l'entité : 1868152.5 €

BRCA1, BRCA2 and associated factors are frequently mutated in familial and sporadic cancers of the breast and ovary. The BRCA proteins have canonical functions together with the RAD51 recombinase in DNA double-strand break repair by homologous recombination. More recently, it was discovered that the same proteins have separate, recombination-independent roles in the metabolism of challenged replication forks. It is currently debated whether defects in the canonical and/or non-canonical functions of BRCA contribute to tumorigenesis. As BRCA1 and BRCA2 function in various processes, interact with numbers of co-factors, and can be extensively post-translationally modified, phenotypes associated with their defects are often very pleiotropic. Here I propose to use a biochemical approach, which will allow us to study the precise functions of these proteins with defined substrates and co-factors in controlled systems. BRCA1 and BRCA2 represent some of the largest factors in human proteome. Using state-of-the-art protein expression strategies, we are now able to produce sufficient quantities of the respective complexes in their native or post-translationally modified states to make biochemistry feasible. We aim to define how the BRCA proteins help couple the initial steps in DNA break repair including nucleolytic processing of DNA breaks, RAD51 loading on ssDNA and subsequent invasion of homologous DNA template. We will also determine the precise non-canonical functions of RAD51, RAD52 and BRCA1/2 complexes in fork remodeling, fork protection and fork restart, which prevents pathological degradation of nascent DNA under replication stress. We anticipate that these diverse functions of BRCA proteins are governed by their co-factors, post-translational modifications and specific substrates. A biochemical approach is uniquely suited to understand the mechanisms how BRCA proteins regulate DNA metabolic pathways to promote genome stability and prevent tumorigenesis.

Mots-clés : homologous recombination,replication stress,brca1,brca2,rad51
Projet ERC : CHIPS (Horizon 2020, appel 2017, Starting grants)
Domaine scientifique : Life Science
Panel : Prevention, Diagnosis and Treatment of Human Diseases
Entité participante : Stockholm University — Pays : Suède — Rôle : Partner
Type d'entité : Enseignement supérieur ou secondaire
Financement ERC de l'entité : 576850.0 €

Background: Acrylamide is a chemical formed in many commonly consumed foods and beverages. It is neurotoxic, crosses the placenta and has been associated with restriction of fetal growth in humans. In animals, acrylamide causes heritable mutations, tumors, developmental toxicity, reduced fertility and impaired growth. Therefore, the discovery of acrylamide in food in 2002 raised concern about human health effects worldwide. Still, epidemiological studies are limited and effects on health of prenatal exposure have never been evaluated. Research gaps: Epidemiological studies have mostly addressed exposure during adulthood, focused on cancer risk in adults, and relied on questionnaires entailing a high degree of exposure misclassification. Biomarker studies on prenatal exposure to acrylamide from diet are critically needed to improve exposure assessment and to determine whether acrylamide leads to major diseases later in life. Own results: I have first authored a prospective European study showing that prenatal exposure to acrylamide, estimated by measuring hemoglobin adducts in cord blood, was associated with fetal growth restriction, for the first time. Objectives: To determine the effects of prenatal exposure to acrylamide alone and in combination with other potentially toxic adduct-forming exposures on the health of children and young adults. Methods: Both well-established and innovative biomarker methods will be used for characterization of prenatal exposure to acrylamide and related toxicants in blood from pregnant women and their offspring in prospective cohort studies with long-term follow-up. Risk of neurological disorders, impaired cognition, disturbed reproductive function and metabolic outcomes such as obesity and diabetes will be evaluated. Perspectives: CHIPS project will provide a better understanding of the impact of prenatal exposure to acrylamide from diet on human health urgently needed for targeted strategies for the protection of the health.

Mots-clés : epidemiology,diet,prenatal exposure,biomarkers
Projet ERC : onCOMBINE (Horizon 2020, appel 2016, Advanced 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 : 2488306.0 €

Background: Molecular targeted therapy (TT; e.g., monoclonal antibodies, mAbs, and protein kinase inhibitors, PKIs) intercepts oncogene and other addictions of tumours. However, unlike chemotherapy, which employs cocktails of drugs, only rarely does TT harness poly-pharmacology. Because lung cancer is the major cause of oncology related fatalities and many driver mutations are known, this disease offers opportunities for establishing and generalizing novel TT combinations and their interface with the immune system. Working hypothesis: High granularity maps of compensatory loops evoked by TT, along with deeper understanding of mechanisms underlying drug action, resistance and interactions with lymphoid/myeloid cells, will conceptualize drug combinations able to persistently inhibit tumours, while inducing only limited toxicities. Goal and specific aims: Addressing resistance to TT, potential synergies and the immune system, we will employ lung cancer models driven by mutant EGFR, HER2, MET or AXL. Phosphoproteomics, transcriptomics and RNA interference, will enable mapping adaptations evoked by specific drugs. Once identified, we will test combinations of interceptors able to inhibit the primary target as well as the emerging, resistance-conferring route(s). Next, we will determine the mechanisms of action of selected interceptors (e.g., apoptosis, immunological cytotoxicity and senescence) as bases for optimising effective combinations. Homo-combinations of antibodies (i.e., antibodies recognising distinct epitopes of a receptor), hetero-combinations targeting distinct signalling and immune receptors, and combinations with PKIs will be examined in animal models. Significance: More than 30 PKIs and >25 mAbs are approved in oncology, but most are used as monotherapies. Detailed knowledge of adaptation-driven resistance, mechanisms of drug action and immune effectors, will guide the long awaited application of TT combinations in oncology, including lung cancer.

Mots-clés : cancer therapy,drug resistance,lung cancer,kinase inhibitors,monoclonal antibodies,tumour heterogeneity
Projet ERC : RNACoenzyme (Horizon 2020, appel 2019, Advanced grants)
Domaine scientifique : Life Science
Panel : Biotechnology and Biosystems Engineering
Entité participante : Heidelberg University — Pays : Allemagne — Rôle : PI
Type d'entité : Enseignement supérieur ou secondaire
Financement ERC de l'entité : 2500000.0 €

Background: RNA is an important regulator in biology. Recently we discovered the ubiquitous redox coenzyme nicotinamide adenine dinucleotide (NAD) to be attached to bacterial RNAs in a cap-like manner, and to modulate the functions of these RNAs, and others identified NAD-RNAs in eukaryotes. Enzymes were discovered that synthesize or break down NAD-RNAs. Scientific problems: NAD is just one of many coenzymes and metabolic intermediates that carry a nucleotide moiety which is not involved in the catalyzed reaction. Yet, it has been conserved through evolution, a fact that suggests high functional relevance. Hypothesis: The nucleotide moiety in coenzymes and metabolites is there for a reason: It enables cells to incorporate these compounds into specific RNAs. Linking reactive organic moieties to RNA may provide a biological strategy to localize these RNAs to enzymes, receptors, membranes or compartments, to sense environmental parameters, or to modulate the turnover or function of the RNAs or their targets. Objectives & research program: The aim of this project is to establish the scope and biological significance of coenzyme-linked RNAs in biology. We will expand the NAD captureSeq protocol to include reduced, phosphorylated, deamidated, and depyridinated NAD-RNAs. We will develop new CoenzymeSeq methods to identify cellular RNAs modified with coenzyme A, flavin, thiamine, and N-acetylglucosamine. We will apply these protocols to RNAs isolated from different organisms to explore the occurrence, abundance, and structural variety of such RNAs. For selected modified RNAs, we will unravel the biological significance and biosynthesis. Impact: This research challenges established textbook wisdom. It will provide fundamentally new links between gene regulation and metabolism in present-day biology and uncover a new layer of epitrancriptomic information. In addition, this project will impact our basic views on the evolution of metabolism and enzymatic catalysis.

Mots-clés : rna modification,metabolism,biocatalysis,evolution
Projet ERC : PlasmoSilencing (Horizon 2020, appel 2014, Advanced grants)
Domaine scientifique : Life Science
Panel : Immunity, Infection and Immunotherapy
Entité participante : Institut Pasteur — Pays : France — Rôle : Partner
Type d'entité : Recherche
Financement ERC de l'entité : 86250.95 €

Background: The human protozoan malaria parasite P. falciparum causes approximately 200 million infections and 0.7 million deaths (mainly children) per year. In the well-studied asexual blood stages, cyclic monocistronic gene activation occurs at the transcriptional level; however, relatively few transcription factors have been identified, thus other types of regulatory processes that contribute to this coordinated gene expression are believed to exist. Through the study of molecular process of monoallelic expression of immune evasion genes in P. falciparum (project funded by a previous ERC grant to A. Scherf), we discovered an entirely new mechanism of gene silencing. We demonstrated that an exoribonuclease silences genes linked to severe malaria. A non-canonical 3’-5’exoribonuclease termed PfRNase II destroys nascent RNA made from promoter regions, leading to cryptic unstable mRNA. Parasites carrying a deficient PfRNase II produce full-length mRNA and long noncoding RNA. The molecular events and the number of genes directly controlled by this novel type of posttranscriptional gene silencing remain elusive. Aim: This proposal aims to investigate the molecular mechanisms controlling PfRNase II-dependent gene silencing using innovative strategies such as the new genome editing technique (Cas9/CRISPR) developed in my laboratory for use in P. falciparum. We will study i) the recruitment of PfRNase II to promoter regions of severe malaria related genes using protein pull-down assays and ii) the genome occupancy of PfRNase II and two other 3’-5’ exoribonucleases to determine the total number of genes controlled by this mechanism. Impact: This project represents a major change in mainstream malaria parasite gene regulation paradigms with repercussions for other organisms. The proposed research will both open new avenues in molecular process that control severe malaria and appeal to young researchers to join this rather ‘untouched’ topic.

Mots-clés : plasmodium,cryptic unstable rna,gene silencing,rnase degradation
Projet ERC : BacForce (Horizon 2020, appel 2019, Starting grants)
Domaine scientifique : Life Science
Panel : Cellular, Developmental and Regenerative Biology
Entité participante : Ludwig-Maximilians-Universität München — Pays : Allemagne — Rôle : PI
Acronyme de l'entité : LMU
Type d'entité : Enseignement supérieur ou secondaire
Financement ERC de l'entité : 1498864.0 €

Bacteria can generate mechanical forces that are important for the colonization of surfaces, formation of biofilms, and infection of host cells. This proposal addresses the fundamental question of how bacteria can control their force generation to robustly respond to chemo-mechanical cues on complex surfaces. Currently, a knowledge gap exists between the molecular regulation pathways on the one hand and the mechanical behavior on the other hand. One major impediment for understanding of how behavior is connected to control is, to date, the impossibility of studying bacterial force directly in unconstrained situations. Based on an initial study, I propose employing new methods for the unperturbed, high-resolution measurement of bacterial traction forces on wide spatiotemporal scales. Thus, the force-generation linking behavior to control can be investigated directly. The objectives are to (A) gain access to nanoscopic mechanical phenomena through the development of cutting-edge super-resolution traction force microscopy, (B) employ the methods to characterize how Pseudomonas aeruginosa controls pilus-generated forces while responding to chemical cues, and (C) establish how surface rigidity affects force generation by P. aeruginosa during biofilm formation. In an interdisciplinary approach, I will combine traction measurements with genetic perturbations, molecule labeling, and computer simulations to produce functional models of the mechanocontrol strategies. Altogether, I will establish a novel technique, opening up the possibility of studying nanoscopic force generation in many types of cells. Through these advances, I will characterize a set of mechanoregulation strategies in P. aeruginosa that are paradigmatic for diverse Gram-negative pathogens employing the same type of pili. Broadly, I expect that the studied bacterial control strategies have a generic, minimal nature and can appear as basic motives throughout development, homeostasis, and disease.

Mots-clés : traction force microscopy,mechanoregulation
Projet ERC : Piko (Horizon 2020, appel 2018, Consolidator grants)
Domaine scientifique : Physical Sciences and Engineering
Panel : Condensed matter physics
Entité participante : Board of the Swiss Federal Institutes of Technology — Pays : Suisse — Rôle : PI
Acronyme de l'entité : ETH Zurich
Type d'entité : Enseignement supérieur ou secondaire
Financement ERC de l'entité : 2366835.0 €

Bacteria cells appear to be less complex than our own cells -- yet they are better able to survive harsh conditions. Typically ~1 micron in size, they lack motor proteins; thus, they rely on fluctuations for intracellular transport. Bacteria in the environment often face starvation and exist in a non-proliferating quiescent state, which promotes antibiotic resistance and virulence. Entering quiescence, the bacterial cytoplasm displays signatures of the colloidal glass transition, with increasingly slow and heterogeneous diffusion. Also important for fitness during starvation is the formation of storage granules up to hundreds of nanometers in size. The complex state behavior of the bacterial cytoplasm is therefore important for their survival, but the physical nature of each of these processes is poorly understood. Our own cells are typically tens of microns in size and contain organelles including mitochondria, which originated from ancient bacterial endosymbionts. But little is known about the transport properties of the mitochondrial matrix, or how it responds to changes in mitochondrial membrane potential or energy production. The goal of this project is to elucidate the organization and dynamics of the bacterial cytoplasm and the mitochondrial matrix. A major obstacle to studying the interior of bacteria and mitochondria is the relevant length scales, which lie below the diffraction limit. Furthermore, to observe and quantify their adaptive response, many cells must be measured. Our strategy to overcome both of these technical challenges is to use high-throughput super-resolution fluorescence microscopy. We have developed new microscopes, capable of capturing thousands of super-resolved cells in each experiment. We propose to translate these developments to dynamic structured illumination and long-term molecular tracking. Broadly applicable, this will also enable the quantitative study of the subcellular properties of single bacteria cells or mitochondria.