Data-Gouv-ML/pcri-erc-participations-et-projets-laureats huggingface dataset:
Projet ERC : TREATCilia (Horizon 2020, appel 2016, Starting grants)
Domaine scientifique : Life Science
Panel : Integrative Biology: from Genes and Genomes to Systems
Entité participante : University of Freiburg — Pays : Allemagne — Rôle : PI
Type d'entité : Enseignement supérieur ou secondaire
Financement ERC de l'entité : 909667.5 €

Background: Cilia are hair-like, microtubule-based organelles protruding from most quiescent mammalian cells. They play essential roles in cell signalling (primary cilia) as well as movement of fluid (motile cilia). Although individually rare, cilia dysfunction affects up to 1 in 500 people in Europe, significantly reducing quality of life and lifespan due to dysfunction of multiple organs, including the kidneys, liver, heart, brain, retina, airways and the skeleton. To date, treatment is purely symptomatic. Aim and Approach: TREATCilia aims to decipher novel treatment avenues and improve clinical management for dynein-related ciliopathies. Next-generation sequencing based gene identification for dynein-related ciliopathies (ciliary chondrodysplasias and Primary Ciliary Dyskinesia, PCD) is employed to dissect the molecular basis and identify new therapeutic targets. Revealing genotype-phenotype mechanisms and their underlying cell signalling defects provides further insight into potential treatment options. Novel innovative curative approaches include high-throughput substance screening in model organisms such as the green algae Chlamydomonas and mammalian cells specially adapted for this purpose. Impact: Identification of novel ciliopathy genes will not only improve the biological understanding, but also reveal new treatment candidates. Furthermore, scrutinizing the molecular mechanisms of disease yields pharmacological entry points. TREATCilia develops a pre-clinical pipeline towards gene and mutation-specific treatments for hereditary conditions resulting from dynein-related ciliary dysfunction.

Mots-clés : pediatrics
Projet ERC : COSMIC (Horizon 2020, appel 2014, Starting grants)
Domaine scientifique : Life Science
Panel : Prevention, Diagnosis and Treatment of Human Diseases
Entité participante : University of Glasgow — Pays : Royaume-Uni — Rôle : Partner
Type d'entité : Enseignement supérieur ou secondaire
Financement ERC de l'entité : 155000.0 €

Background: One of the major challenges for malaria control and elimination is the phenomenally efficient spread of malaria through sexual stage malaria parasites (gametocytes). The epidemiology and dynamics of gametocytes are poorly understood: it is presently unknown when commitment to gametocytes first occurs during infections and what intrinsic or extrinsic factors influence gametocyte production and infectivity to mosquitoes. I hypothesize that continuous early commitment to gametocyte production and the preferential sequestration of mature gametocytes in the subdermal vasculature are key to explaining the high efficiency of malaria transmission. Aim: This proposal has three main aims: i) to determine when commitment to gametocyte production first occurs during experimental and natural infections; ii) to delineate environmental triggers that stimulate gametocyte production in the absence and presence of treatment; iii) to quantify the differential distribution of parasite developmental stages in different compartments of the human bloodstream. Approach: We will use novel parasite stage composition assays in combination with epidemiological methods to determine the dynamics of gametocyte commitment and maturation during controlled malaria infections in malaria-naive volunteers and during naturally acquired malaria infections in cohorts exposed to malaria in Burkina Faso. A stage-specific immunohistochemistry assay will, for the first time, directly quantify malaria stage composition in the subdermal vasculature and mosquito bloodmeals and allow comparison with other compartments of the circulation. Importance and Innovation: This is the first study to comprehensively characterize gametocyte commitment, maturation and infectivity in experimental and natural infections. This proposal will provide insight in one of the most important questions for malaria elimination: what processes are responsible for the phenomenally efficient transmission of malaria.

Mots-clés : malaria,gametocytes,transmission,infectivity,anopheles,mosquito,sequestration,elimination
Projet ERC : EVOIMMECH (Horizon 2020, appel 2016, Starting grants)
Domaine scientifique : Life Science
Panel : Environmental Biology, Ecology and Evolution
Entité participante : University of Exeter — Pays : Royaume-Uni — Rôle : PI
Type d'entité : Enseignement supérieur ou secondaire
Financement ERC de l'entité : 1420837.0 €

Bacteria have a range of immune mechanisms, but it is unclear why this diverse armamentarium evolved. The most important immune mechanisms are (1) Surface Modification (SM) (2) Abortive infection (Abi) (3) Restriction Modification (R-M) (4) CRISPR-Cas and (5) prokaryotic Argonaute (pAgo), all of which can occur as stand-alone mechanisms or in combination. The individual mechanisms differ in key aspects, such as their fitness costs (constitutive versus inducible), specificity (indiscriminate versus specific), the recipient of the benefits (individual versus group), the speed of de novo resistance evolution (rapid versus slow), and heritability of immunity. Here I will take a combined in vitro and in vivo approach to tease apart the variables that drive the evolution of these diverse stand-alone and integrated bacterial immune strategies in nature, and examine their associated co-evolutionary dynamics. I focus on three ecological variables that are consistently important in host-symbiont co-evolution: (1) force of infection (2) spatial structure (3) presence of mutualists (plasmids). First, I will perform in vitro manipulations using Pseudomonas aeruginosa PA14 variants that carry either single or multiple immune mechanisms. Next, I will sequence metagenomes, transcriptomes and viromes of microbial communities from environments that differ in ecological variables that are important in vitro, to examine their importance in vivo. Key ecological mechanisms identified in the first two parts of the project will be used to guide mesocosm experiments to experimentally confirm that these mechanisms are the drivers of the observed patterns of resistance and co-evolution in nature. Finally, I will share my data with mathematical biologists to generate theoretical models to predict and manipulate the evolution of bacterial immune mechanisms, which will facilitate tailored species protection in agriculture and industry.

Mots-clés : bacteria,phage,plasmid,surface modification,restriction modification,crispr cas,prokaryotic argonaute,abortive infection
Projet ERC : EVOIMMECH (Horizon 2020, appel 2016, Starting grants)
Domaine scientifique : Life Science
Panel : Environmental Biology, Ecology and Evolution
Entité participante : University of Liverpool — Pays : Royaume-Uni — Rôle : Partner
Type d'entité : Enseignement supérieur ou secondaire
Financement ERC de l'entité : 15000.0 €

Bacteria have a range of immune mechanisms, but it is unclear why this diverse armamentarium evolved. The most important immune mechanisms are (1) Surface Modification (SM) (2) Abortive infection (Abi) (3) Restriction Modification (R-M) (4) CRISPR-Cas and (5) prokaryotic Argonaute (pAgo), all of which can occur as stand-alone mechanisms or in combination. The individual mechanisms differ in key aspects, such as their fitness costs (constitutive versus inducible), specificity (indiscriminate versus specific), the recipient of the benefits (individual versus group), the speed of de novo resistance evolution (rapid versus slow), and heritability of immunity. Here I will take a combined in vitro and in vivo approach to tease apart the variables that drive the evolution of these diverse stand-alone and integrated bacterial immune strategies in nature, and examine their associated co-evolutionary dynamics. I focus on three ecological variables that are consistently important in host-symbiont co-evolution: (1) force of infection (2) spatial structure (3) presence of mutualists (plasmids). First, I will perform in vitro manipulations using Pseudomonas aeruginosa PA14 variants that carry either single or multiple immune mechanisms. Next, I will sequence metagenomes, transcriptomes and viromes of microbial communities from environments that differ in ecological variables that are important in vitro, to examine their importance in vivo. Key ecological mechanisms identified in the first two parts of the project will be used to guide mesocosm experiments to experimentally confirm that these mechanisms are the drivers of the observed patterns of resistance and co-evolution in nature. Finally, I will share my data with mathematical biologists to generate theoretical models to predict and manipulate the evolution of bacterial immune mechanisms, which will facilitate tailored species protection in agriculture and industry.

Mots-clés : bacteria,phage,plasmid,surface modification,restriction modification,crispr cas,prokaryotic argonaute,abortive infection
Projet ERC : PhyMeBa (Horizon 2020, appel 2015, Consolidator grants)
Domaine scientifique : Physical Sciences and Engineering
Panel : Condensed matter physics
Entité participante : University of Cambridge — Pays : Royaume-Uni — Rôle : PI
Acronyme de l'entité : U. Cambridge
Type d'entité : Enseignement supérieur ou secondaire
Financement ERC de l'entité : 1999229.0 €

Bacteria play a critical role in the life of higher organisms. Their behavior is constrained by the physical properties of their habitat: first and foremost, the presence of a surrounding fluid. Most bacteria are motile, and most motile bacteria swim in fluids using slender helical appendages called flagella rotated by specialized motors. While many bacteria have only one flagellum, most well-studied pathogenic bacteria possess multiple flagella. Why have some bacteria evolved to use many flagella when others survive with one? In order to answer this question, one needs to understand quantitatively how multiple flagella provide a fitness advantage to a cell exploring its environment. The principal difficulty in deriving rigorous models for swimming bacteria lies in the {nonlinear} nature of the underlying external physics, which involves nonlocal hydrodynamic interactions between flagella, short-range steric and electrostatic interactions, and elastic deformations of the flagella, which not only bend and twist but also undergo conformational changes. In this project, we will develop novel experimentally-testable theoretical modeling of the configurations and regimes relevant to swimming bacteria with multiple flagella with a focus on the mechanical forces at play. As a fundamental departure with past work, we will seek to exploit the slenderness and relative proximity of the flagella to incorporate all nonlocal hydrodynamic interactions between flagella analytically and to simplify the determination of elastic stresses. This will allow us, in turn, to determine precisely the distribution of flagellar forces and derive a predictive framework for the stochastic behavior of swimming cells. The project will provide first-principle understanding of the external forces at play in one of the most important processes in biology and will help answer a number of outstanding physical questions on the behavior of swimming bacteria and the interactions with their environment.

Mots-clés : mechanics of biological systems,soft matter in biology,locomotion of microorganisms
Projet ERC : Tolerome (Horizon 2020, appel 2015, Consolidator grants)
Domaine scientifique : Life Science
Panel : Environmental Biology, Ecology and Evolution
Entité participante : Hebrew University of Jerusalem — Pays : Israël — Rôle : PI
Acronyme de l'entité : HUJI
Type d'entité : Enseignement supérieur ou secondaire
Financement ERC de l'entité : 1978750.0 €

Bacterial ability to evolve strategies for evading antibiotic treatment is a fascinating example of an evolutionary process, as well as a major health threat. Despite efforts to understand treatment failure, we lack the means to prevent evolution of resistance when a new drug is released to the market. Most efforts are directed towards understanding the mechanisms of antibiotic resistance. Whereas ‘resistance’ is due to mutations that enable microorganisms to grow even at high concentrations of the drug, ‘tolerance’ is the ability to sustain a transient treatment, for example by entering a mode of transient dormancy. The importance of tolerance in the clinic has not been investigated as thoroughly as resistance. The presence of tolerant bacteria is not detected in the clinic because of the inherent difficulty of tracking dormant bacteria that often constitute only a minute fraction of the bacterial population. I hypothesize that bacterial dormancy may evolve quickly in the host under antibiotic treatment. This hypothesis is strengthened by our recent results demonstrating the rapid evolution of dormancy leading to tolerance in vitro, and by the increasing number of cases of treatment failure in the clinic not explained by resistance. My goal is to develop a multidisciplinary approach to detect, quantify and characterize tolerant bacteria in the clinic. Using my background in quantitative single-cell analyses, I will develop microfluidic devices for the rapid detection of tolerant bacteria in the clinic, systems biology tools to isolate and analyze dormant sub-populations directly from clinical isolates. I will search for the genetic mutations leading to tolerance, namely build what I term here the ‘tolerome’. The results will be analyzed in a mathematical framework of tolerance evolution. This approach should reveal the role of tolerance in the clinic and may lead to a paradigm shift in the way bacterial infections are characterized and treated.

Mots-clés : persistence,antibiotics,infections
Projet ERC : PorCSperM (Horizon 2020, appel 2016, Proof of concept grants)
Entité participante : University of Edinburgh — Pays : Royaume-Uni — Rôle : PI
Type d'entité : Enseignement supérieur ou secondaire
Financement ERC de l'entité : 139986.0 €

Based on an ongoing ERC project on characterising and studying the motility of highly-idealised, model micro-swimmers, we have built and validated a first-generation portable prototype device for assaying accurately bull sperm motility. To move to a more advanced prototype requires integrated software and hardware development and the setting up of standard protocols to render the measurement procedure robust for non-expert operators. Such a device, with integrated hardware and software, for Portable Characterisation of Sperm Motility (PorCSperM) will assembled and applied to bull semen in this project, but is in principle applicable to other animals, and perhaps also to human fertility.

Mots-clés : sperm motility,microorganism motility,bull fertility,differential dynamic microscopy,active matter physics
Projet ERC : APMPAL-HET (Horizon 2020, appel 2017, Advanced grants)
Domaine scientifique : Social Sciences and Humanities
Panel : Individuals, Markets and Organisations
Entité participante : CERCA Institution — Pays : Espagne — Rôle : PI
Acronyme de l'entité : CERCA;I-CERCA
Type d'entité : Recherche
Financement ERC de l'entité : 889978.01 €

Based on the APMPAL (ERC) project we continue to develop the frameworks of internal rationality (IR) and optimal signal extraction (OSE). Under IR investors/consumers behave rationally given their subjective beliefs about prices, these beliefs are compatible with data. Under OSE the government has partial information, it knows how policy influences observed variables and signal extraction. We develop further the foundations of IR and OSE with an emphasis on heterogeneous agents. We study sovereign bond crisis and heterogeneity of beliefs in asset pricing models under IR, using survey data on expectations. Under IR the assets’ stochastic discount factor depends on the agents’ decision function and beliefs; this modifies some key asset pricing results. We extend OSE to models with state variables, forward-looking constraints and heterogeneity. Under IR agents’ prior beliefs determine the effects of a policy reform. If the government does not observe prior beliefs it has partial information, thus OSE should be used to analyse policy reforms under IR. If IR heterogeneous workers forecast their productivity either from their own wage or their neighbours’ in a network, low current wages discourage search and human capital accumulation, leading to low productivity. This can explain low development of a country or social exclusion of a group. Worker subsidies redistribute wealth and can increase productivity if they “teach” agents to exit a low-wage state. We build DSGE models under IR for prediction and policy analysis. We develop time-series tools for predicting macro and asset market variables, using information available to the analyst, and we introduce non-linearities and survey expectations using insights from models under IR. We study how IR and OSE change the view on macro policy issues such as tax smoothing, debt management, Taylor rule, level of inflation, fiscal/monetary policy coordination, factor taxation or redistribution.

Mots-clés : heterogeneous agents,asset pricing,fiscal policy,monetary policy,subjective investor expectations,inequality
Projet ERC : WEAR (Horizon 2020, appel 2018, Proof of concept grants)
Entité participante : Champalimaud Foundation — Pays : Portugal — Rôle : PI
Type d'entité : Recherche
Financement ERC de l'entité : 149820.0 €

Behavior is ultimately the observable output of the nervous system. Thus, to properly diagnose and monitor nervous system disorders it is crucial that we assess behavior comprehensively. However, every day clinical practice still relies mostly on subjective methods to evaluate behavior. The ability to adequately analyse behaviour is also critical during drug development, from the preclinical (animal models) to the clinical stages. Results from our ERC-funded work revealed that the combination of inertial sensor data with an unsupervised algorithm provides an optimal method for an easy to implement unbiased behavior classification that adequately captured the outcome of neural circuit’s computations. In this PoC we proposed to develop this technology into a product that provides a continuous, quantitative and comprehensive behavior assessment that is also versatile, covering the diverse spectrum from the pre-clinical to the clinical context. In this POC we will 1) refinement and validate of inertial sensors in animal models, 2) enable their integration into a Body Area Network, 3) Evolve our unsupervised algorithm into a stand-alone software that is versatile and easy to use. In addition to these technical aims, we propose to explore commercial opportunities and societal benefits, in particular in the medical and drug development sector. We will conduct market analysis and develop a business case for this product, while expanding industry contacts for production and commercialization. Our proposal will lead to a ground-breaking technical solution for quantitative, automated behavioral assessment in animal models of disease and humans that will have an important societal impact through innovation in diagnosis, disease monitoring, and drug development.

Mots-clés : inertial sensors,wearable,wireless,behaviour,unsupervised classification
Projet ERC : DITSB (Horizon 2020, appel 2019, Consolidator grants)
Domaine scientifique : Life Science
Panel : Prevention, Diagnosis and Treatment of Human Diseases
Entité participante : Institut national de la santé et de la recherche médicale — Pays : France — Rôle : PI
Acronyme de l'entité : Inserm
Type d'entité : Recherche
Financement ERC de l'entité : 2000000.0 €

Beta-thalassemia and sickle cell disease (SCD) are caused by mutations affecting the synthesis or the structure of the adult hemoglobin (Hb) beta-chain. The only definitive cure is transplantation of allogeneic hematopoietic stem cells (HSCs) from an HLA-matched donor, an option available to <30% of the patients. The clinical severity of beta-hemoglobinopathies is alleviated by the co-inheritance of mutations causing expression of fetal gamma-globin in adult life - a condition termed hereditary persistence of fetal hemoglobin (HPFH). Transplantation of autologous, genetically modified HSCs is an attractive therapeutic option for patients lacking a suitable donor. To this aim, genome editing approaches based on the use of site-specific nucleases have been explored by many groups, including ours. These approaches may either revert the single point mutation causing SCD or reactivate fetal globin expression, by mimicking HPFH mutations or by decreasing the level of BCL11A, a master repressor of fetal Hb synthesis. Site-specific nucleases, however, generate double-strand breaks (DSBs) in the genome and raise safety concerns for clinical applications, particularly when used in DSB-sensitive HSCs. In this proposal, we aim at exploiting targeted base-editing to develop novel, efficacious and safe strategies for beta-hemoglobinopathies without generating DSBs. This will be attempted by (i) correcting the SCD-causing mutation, (ii) mimicking HPFH mutations in the gamma-globin promoters, or (iii) modulating the activity of a BCL11A erythroid-specific enhancer. These approaches will be tested in human adult erythroid cell lines and patient HSCs, differentiated in vitro and in vivo into mature red cells to evaluate editing efficiency, fetal Hb expression, phenotypic cell correction and biosafety. The ultimate goal of the project is to provide sufficient proof of efficacy and safety to enable the clinical development of base-edited HSCs for the therapy of beta-hemoglobinopathies.

Mots-clés : editing,crispr,cas9,beta hemoglobinopathies
Projet ERC : BioCHANGE (Horizon 2020, appel 2016, Proof of concept grants)
Entité participante : University of St Andrews — Pays : Royaume-Uni — Rôle : PI
Type d'entité : Enseignement supérieur ou secondaire
Financement ERC de l'entité : 149428.0 €

Biodiversity CHANGE is a major, but still underappreciated, threat to humanity. It arises when there is unprecedented turnover in the identities of species that comprise ecological assemblages. To understand, monitor and ameliorate this CHANGE, and to enable appropriate societal responses, policy makers and conservation managers urgently need access to the best possible data. At present the ability of practitioners to elucidate ecosystem responses to anthropogenic impacts is hampered by data availability. Building on ERC AdvG BioTIME, BioCHANGE will provide a proof of concept that existing fragmented data can be assembled into an open access, authoritative database to form a crucial resource for addressing societal challenges arising from the biodiversity crisis.

Mots-clés : biological diversity,data,open access,society,conservation,people and nature