Data-Gouv-ML/pcri-actions-marie-curie-participations-et-projets-laureats huggingface dataset:
Projet MDRZYMES (Horizon 2020, appel à projets 2016)
Action : Postdoctoral Fellowships - European Fellowships
Panel : Chemistry
Statut du projet : CLOSED

Enzymes are remarkable catalysts. The unmatched rate accelerations and exacting selectivities that these protein molecules achieve have whetted the appetite of chemists to harness the prowess of enzyme catalysis for industrial applications. However, natural enzymes can only catalyze a small fraction of the reactions routinely employed by synthetic chemists. As a result, creating designer biocatalysts with the ability to efficiently catalyze transformations not found in nature’s repertoire is a long-standing goal in chemical biology. To meet this challenge, this proposal describes our plans to generate proficient enzymes for palladium-catalyzed cross-coupling reactions. Specifically, we will create hybrid catalysts by recruiting active palladium complexes to the promiscuous binding sites of multidrug resistance gene regulators. We will validate productive assemblies by a rigorous biophysical characterization and evaluate the resulting artificial metalloenzymes for their ability to catalyze model Suzuki-Miyaura cross-coupling reactions. To refine the activities and selectivities of these primitive catalysts we will explore directed evolution protocols to identify mutations in the protein scaffolds that are beneficial for catalysis. In one strategy, we will establish a fluorescence-based screening approach that allows for testing libraries of hybrid catalysts in multi-well format. Another strategy will evaluate the possibility of performing cross-coupling reaction in vivo. Toward this end, artificial metalloenzymes will be assembled in the periplasm and utilized for the synthesis of a non-standard amino acid, which subsequently can be incorporated into a selection marker. As a result, bacteria producing improved variants will outgrow those with less efficient catalysts under selection conditions. Overall, our efforts will generate proficient designer enzymes that could prove valuable for applications in sustainable chemical processes.

Mots clés : artificial metalloenzymes, enzyme design, protein engineering, directed evolution of biocatalysts, transition metal catalysis

Participants :
- University of Groningen (Pays-Bas) — Coordinator, beneficiary, Enseignement supérieur ou secondaire, subvention : 165598.8 €
Projet EPIMAC (Horizon 2020, appel à projets 2014)
Action : Doctoral Networks - Industrial Doctorates
Panel : Life Sciences
Statut du projet : CLOSED

Epigenetic mechanisms allow cells to adjust gene expression in response to environmental cues. Increased understanding of this area has led to excitement about the potential of applying epigenetic regulation to drug discovery. EPIMAC aims to pursue the potential of epigenetics as a novel and innovative therapeutic modality for immuno-inflammatory diseases, in particular Inflammatory Bowel Disease (IBD). IBD is a severe and disabling chronic inflammation of the gastrointestinal tract affecting millions of people worldwide. Current treatment strategies are not successful because the precise etiology unclear. It is increasingly clear that deregulated epigenetic processes are associated with the aberrant inflammatory response seen in IBD. Recent reports suggest that inhibitors of epigenetic modifications developed by GlaxoSmithKline (GSK), such as histone deacetylase (HDAC) inhibitors, bear potential in treating inflammatory states (Nicodeme et al, Nature 2010; Kruidenier et al, Nature 2012). The EPIMAC consortium has the ambition to educate a group of next-generation scientists that master genetics, epigenetics, target discovery, pharmacology, preclinical validation and regulatory issues, and at the same time have a good understanding of clinical implementations of the drug pipeline of our pharmaceutical partner GSK. GSK is one of the world's leading research-based pharmaceutical and healthcare companies that aims to team up with academic partners in EPIMAC through its dedicated discovery performance unit named EpiNova in conjunction with 2 immuno-pharmacology units. An SME specializing in epigenetic compound targeting to inflammatory cells, Chroma Therapeutics, will contribute technology to EPIMAC. EPIMAC will educate and train these scientists by providing them with a versatile and multidisciplinary doctoral program, allowing them to become excellent scientists skilled to overcome the current challenges in IBD.

Mots clés : gastroenterology, inflammatory bowel diseases, drug development

Participants :
- Eureka (Pays-Bas) — Partner, organization partner, Organismes privés (hors enseignement), subvention : 0.0 €
- Amsterdam University Medical Centers (Pays-Bas) — Partner, beneficiary, Enseignement supérieur ou secondaire, subvention : 0.0 €
- GlaxoSmithKline (United Kingdom) (Royaume-Uni) — Partner, beneficiary, Organismes privés (hors enseignement), subvention : 273287.88 €
- Amsterdam University Medical Centers (Pays-Bas) — Coordinator, beneficiary, Organismes privés (hors enseignement), subvention : 1021497.12 €
- University Medical Center Utrecht (Pays-Bas) — Partner, organization partner, Enseignement supérieur ou secondaire, subvention : 0.0 €
Projet NEUROTILES (Horizon 2020, appel à projets 2017)
Action : Postdoctoral Fellowships - European Fellowships
Panel : Life Sciences
Statut du projet : CLOSED

Epilepsy is a life-threatening progressive disorder causing uncontrolled activity of the brain (seizure); it carries among the highest burden of disease and significant social stigma. Temporal lobe epilepsy (TLE) is the most frequent syndrome, the least responsive to medications and the most linked to severe psychiatric and cognitive co-morbidities. When drug resistance ensues, neurosurgery and deep-brain stimulation are invasive options to carefully consider. Thus, TLE treatment demands urgent innovative interventions. Is it possible to generate ‘replacement parts’ to heal the diseased brain? The idea of repairing the brain using engineered transplants is nowadays more appealing than ever thanks to the ground-breaking advent of ‘mini-brains in a dish’ (brain organoids). Remarkably, brain organoids can be derived from human stem cells, thus carrying unique potential for targeted studies. However, their application in regenerative medicine has yet to thrive. Therefore, the interaction of brain organoids with mammalian brain tissue remains unexplored. In this project, I engage in the challenge of generating surrogate brain areas as transplants for epilepsy treatment. Specifically, I will focus on the hippocampus, a central structure in learning and memory which is crucially involved in TLE. I will push an unprecedented biohybrid design based on the synergetic exploitation of organoid technology and innovative neural engineering tools to pursue, for the first time ever, the establishment of a dialogue between engineered and mammalian brain tissue. The foundation of NEUROTILES stems in the emerging concept that brain repair strategies from regenerative medicine and neural engineering are distinct yet complementary. In the era of artificial intelligence and nanotechnology, NEUROTILES will promote a revolutionary framework for brain repair strategies and ultimately ignite the establishment of the novel field of ‘enhanced’ regenerative medicine.

Mots clés : epilepsy, brain organoid, hippocampus, functional brain repair, biohybrid system, closed loop control, electrophysiology, brain slice

Participants :
- Eindhoven University of Technology (Pays-Bas) — Coordinator, beneficiary, Enseignement supérieur ou secondaire, subvention : 177598.8 €
Projet GrapheneBiosensor (Horizon 2020, appel à projets 2016)
Action : Postdoctoral Fellowships - European Fellowships
Panel : Information Science and Engineering
Statut du projet : CLOSED

Episodes of harmful blue algae blooms and the associated algal toxin microcystin-LR (MC-LR) occur frequently in bodies of water worldwide as consequences of eutrophication resulting from anthropogenic activities such as agricultural run-off, urban waste, and manufacturing of detergents and global warming. It had been confirmed that microcystins were responsible for some poisonings of animals and humans where water sources contained toxic cyanobacteria blooms. Microcystins were potent and specific in inhibiting protein phosphatases 1 and 2A (PPl, PP2A). Acute or prolonged exposure to microcystins would cause liver damage, followed by a massive intrahepatic hemorrhage and probably leading to death. In 1998, the provisional guideline concentration limit of 1 μg/L MC-LR in drinking water was assigned by the World Health Organization (WHO). The development of reliable methods for monitoring MC-LR in water resources is of great interest to determine the occurrence and to prevent exposure to the toxin. Several methods have been developed to detect MC-LR, such as high-performance liquid chromatography/mass spectrometry (HPLC/MS) , bio-, biochemical- and immune-assays, which require long processing times, sophisticated instruments, complex procedures, or high processing cost and are in general used in the laboratory, not in situ. A sensitive, specific, simple, and rapid method for monitoring MC-LR could help to prevent exposure to the toxin. The unique physical and electrochemical properties (e.g., high electrical conductivity, ease of functionalization, high electrochemically active surface area, and broad range of working potentials in aqueous solutions) of graphene make them a candidate material for developing novel and fit-for-purpose electrochemical biosensors/immunosensors as alternatives to the time-consuming, expensive, non-portable and often skills-demanding conventional methods of analysis involved in water quality assessment.

Mots clés : graphene, mc lr, biosensor, electrochemical detection, nanomaterials

Participants :
- Swansea University (Royaume-Uni) — Coordinator, beneficiary, Enseignement supérieur ou secondaire, subvention : 195454.8 €
Projet INDITOL (Horizon 2020, appel à projets 2018)
Action : Postdoctoral Fellowships - European Fellowships
Panel : Environment and Geosciences
Statut du projet : CLOSED

Episodes of hypoxia and acute warming can be major environmental stressors for coastal marine fishes, that will increase in frequency and severity with global change. Hypoxia and warming share a common physiological mode of action in fishes, both challenge the animal's capacity to provide sufficient O2 to respiring tissues. Within fish populations, individuals may vary in tolerance of these stressors; the existence of such variation can define the ability of populations to persist in a more stressful world. Moreover, when individuals vary in tolerance, underlying physiological mechanisms for variation can be explored. Understanding of mechanisms is very valuable because the persistence of variation in tolerance, within populations, may indicate that there are functional trade-offs, whereby being tolerant is not systematically advantageous but has costs. Using controlled experiments on European sea bass, an emblematic coastal species, my aims are to: 1) document variation in sub-lethal tolerance of hypoxia and acute warming in a population of 200 juveniles, and reveal cross-tolerance; 2) demonstrate that relative tolerance depends upon each individual’s intrinsic respiratory physiology; 3) investigate how tolerance relates to underlying mitochondrial efficiency, and 4) evaluate whether tolerance trades-off against important individual traits, as growth rate and tendency to suffer from oxidative stress. The experiments comprise innovative state-of-the-art techniques of sea bass husbandry; in-vivo respirometry and exercise performance; sub-lethal tolerance endpoints based upon cardiorespiratory performance, and assays of mitochondrial function in fresh tissues. Data will be analyzed to reveal trait correlations and dependencies, and existence of functional trade-offs. These multiple level studies, to reveal functional trade-offs of tolerance to hypoxia and warming, will provide novel and important insights into the nature of fish populations in a more stressful world.

Mots clés : acute warming, environmental physiology, fish, hypoxia, global change, individual variation, respiratory metabolism, tolerance

Participants :
- Centre national de la recherche scientifique (France) — Coordinator, beneficiary, Recherche, subvention : 184707.84 €
Projet UNREP (Horizon 2020, appel à projets 2016)
Action : Postdoctoral Fellowships - European Fellowships
Panel : Social Sciences and Humanities
Statut du projet : CLOSED

Equal representation is at the core of representative democracy, but are citizens actually in favour of it? There are good reasons to think that citizens may take a variety of stances toward unequal representation (i.e. differential group influence over policy) particularly when it comes to groups that elicit strong emotional reactions (e.g. racialised minorities). Citizens may think that policy-affected groups deserve extra input (due to affectedness), less input (due to bias), or the same amount of input as everyone else. However, it is impossible to say anything meaningful about these attitudes since we know almost nothing about them. This lack of knowledge is a serious shortcoming with real-world implications: these preferences shape politics and, by extension, the functioning of representative democracies. My proposed study is thus relevant not only for recent debates in political science over both the extent and origins of unequal representation, but also for contemporary politics – with its surging populist claims that certain groups have excessive influence over policy. This project looks beyond an abstract commitment to equal democratic representation, investigating how citizens feel about the influence of specific groups on concrete issues. It does so by employing large-scale, representative panel surveys and innovative survey experiments in the US and the Netherlands, whose key similarities and differences allow us to maximise the insights derived from a two-country comparison. Through methodological triangulation, this project will lead to novel insights, revealing the nature and determinants of preferences around unequal representation. The findings from this research will produce important results both for those seeking to better understand the connections between inequality and democracy and for anyone interested in the representation of marginalised groups and the growing appeal of populism.

Mots clés : public opinion, representation

Participants :
- Vrije Universiteit Amsterdam (Pays-Bas) — Partner, beneficiary, Enseignement supérieur ou secondaire, subvention : 0.0 €
- Utrecht University (Pays-Bas) — Coordinator, beneficiary, Enseignement supérieur ou secondaire, subvention : 165598.8 €
Projet Rep. Fork Restart (Horizon 2020, appel à projets 2016)
Action : Postdoctoral Fellowships - European Fellowships
Panel : Life Sciences
Statut du projet : CLOSED

Errors in replication of DNA lead to serious diseases like cancer, inherited neurological and muscular diseases. Replication is constantly challenged by various obstacles that can result in error-prone replication. Replication fork barriers (RFBs) include proteins bound to DNA, structure forming sequences and DNA/RNA hybrids. Replication forks (RFs) stalled or blocked at these barriers can be rescued by a converging fork. But if this fails blocked RF must be restarted to complete replication. Restart using homologous recombination (HR) can lead to gross chromosomal rearrangements and copy number variations. The newly restarted replication fork is also prone to slippage leading to mutation and rearrangements. The research questions I will address are how this RF is restarted and why it is error prone. I will focus on restart at a site-specific RFB in fission yeast, RTS1. Restart at RTS1 has been well characterised in the host laboratory. My project will identify DNA structures formed during the RF restart and characterise recruitment of factors involved in the restart of the collapsed RF. The acquired data will enable us to further understand the mechanism of RF restart and to unravel the cause of the error prone nature of newly restarted RF. I consider this fellowship a key step in my career as it allows me to transit from the analysis of site-specific lesions in prokaryotes (previous doctoral fellowship) to eukaryotic cells, gain experience in a wide range of techniques (2D gels, Electron microscopy, ChIP) and build contacts with experts in the field of eukaryotic replication restart. This is necessary for my future independent research and will enable me to set up my lab to study molecular actors and DNA structures during bypass of single lesions in bacteria and eukaryotic cells. The mentoring during the fellowship will provide me with the necessary training to successfully establish myself as an independent investigator.

Mots clés : replication fork barrier, stalled, blocked replication fork, replication stress, dna structures, mechanism of replication fork restart, structure of restarted replication fork

Participants :
- University of Sussex (Royaume-Uni) — Coordinator, beneficiary, Enseignement supérieur ou secondaire, subvention : 183454.8 €
Projet DEKANT (Horizon 2020, appel à projets 2020)
Action : Postdoctoral Fellowships - European Fellowships
Panel : Social Sciences and Humanities
Statut du projet : SIGNED

Ethics and political philosophy are integral to human individual activities and social interactions, and yet modern philosophy since Immanuel Kant has reinforced the separation of these two domains. DEKANT aims to resolve the confusion in the intellectual foundation of ethics and show how it can reclaim its interrelation with political philosophy. It will achieve this aim by analysing the long-neglected, yet significant, influence of Alexander Gottlieb Baumgarten on Kant’s division of ethics from political philosophy, or what Kant calls the ‘doctrine of virtue’ from the ‘doctrine of right’. Although, over the past 20 years, philosophers have struggled to understand why Kant separated so clearly between the two domains, we still do not have a complete grasp of this separation. The key to understanding this separation is the conceptual apprehension of Baumgarten’s legacy in Kant’s philosophy. By filling the knowledge gap and gathering fresh insights into an important but neglected figure in the history of philosophy, we can gain an improved understanding of a crucial distinction in Kant’s philosophy. DEKANT’s hypothesis is that this new understanding proves the advantage of a unified model of ethics for resolving concrete contemporary problems. By contrast to Kant’s dualist model of ethics/political philosophy in which the concept of justice is employed in the domain of the ‘doctrine of right’ alone, Baumgarten’s unified model of ethics, which includes both ethical and political theory, centrally incorporates the concept of justice. Analysing the influence of Baumgarten on Kant will thus show that developing a refined concept of justice is important for answering the questions arising from the tension between ethics and political philosophy. Working closely with Professor Reidar Maliks, a world-renowned expert in Kant and contextual methods, DEKANT will establish me as a leading scholar and enable me to obtain a tenured position in philosophy.

Mots clés : immanuel kant, ethics, moral philosophy, political philosophy, right, virtue, justice, alexander gottlieb baumgarten, value theory, philosophy of law, early modern philosophy, politics

Participants :
- University of Oslo (Norvège) — Coordinator, beneficiary, Enseignement supérieur ou secondaire, subvention : 214158.72 €
Projet Human Repl Mech (Horizon 2020, appel à projets 2018)
Action : Postdoctoral Fellowships - European Fellowships
Panel : Life Sciences
Statut du projet : CLOSED

Eukaryotic DNA replication is mediated by a complex machinery consisting of several dozen proteins that ensures precise duplication of chromosomes in S phase of the cell cycle. The Diffley laboratory recently reconstituted the core Saccharomyces cerevisiae replication machinery in vitro from 19 replication factors containing about 50 individual protein subunits. This system allowed to study mechanisms of yeast MCM loading onto DNA and of yeast CMG replicative helicase activation. In human cells however, the process of replication initiation and its regulation are less well understood. In particular, the firing factors that activate the CMG helicase differ in domain composition and phospho-regulation from the yeast orthologs. Mechanistic studies are required to understand how human DNA replication is initiated and regulated at the molecular level. I will first reconstitute human DNA replication in vitro from completely recombinant components using methodology that I developed during my PhD. I will then use this system to study how the human replicative helicase is activated on the molecular level and how activation is regulated by phosphorylation using biochemistry. I will use cryo-electron microscopy (cryo-EM) to study the architecture of complexes involved in replication initiation. The reconstituted human system could in future enable studies on disease mechanisms and could allow screening for antiproliferative small molecule inhibitors.

Mots clés : dna replication, in vitro reconstitution, human proteins, cmg helicase activation, regulation, phosphorylation, biochemistry, cryo em, protein complexes, baculovirus insect cell expression, bigbac

Participants :
- The Francis Crick Institute (Royaume-Uni) — Coordinator, beneficiary, Recherche, subvention : 212933.76 €