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

Post-transcriptional control of human gene expression is conferred by >1000 mRNA-binding proteins (RNA-BPs), which determine the utilisation and fate of mRNAs, with the aetiology of a wide-range of disorders (e.g. neurological, inflammatory, and neoplastic) being due to their dysregulation. Multifunctionality is a feature of RNA-BPs and understanding how this is coordinated and regulated is pivotal to delineating the molecular circuitry of post-transcriptional gene regulatory networks, to understand why they go wrong and how they may be manipulated. Poly(A)-binding proteins (PABPs) are central multifunctional regulators of mRNA fate, controlling multiple aspects of mRNA translation, stability and quality via interacting with functionally diverse protein partners. Consequently, their deficiency impacts physiological processes such as gametogenesis, metabolism and learning/memory, although mechanistic bases of these phenotypes are unclear, highlighting the importance of understanding their functions and regulation. A key gap in our knowledge is how PABP protein interactions, and therefore functions, are coordinated since many of its partners bind the same “PABC domain” site, through a shared “PAM2” motif. However, our recent findings lead to a novel hypothesis, which I will address, namely that the post-translational modification (PTM) status (acetylation or dimethylation) of a functionally important PABC residue, K606, determines PAM2-partner binding specificity and PABP multifunctionality. Uncovering that “histone-code like” acetylation-methylation switches operate in RNA-BPs, to coordinate their functions and achieve post-transcriptional regulation of mRNA networks, would represent a step-change in the state-of-the-art. This is especially timely since acetylations/methylations are emerging from proteomic studies as common in RNA-BPs and thus, PABP may provide an important paradigm for understanding how these PTMs coordinate post-transcriptional control.

Mots clés : pabpc1, pabp1, pam2, rna binding protein, post transcriptional control, post translational modification, mrna translation, mrna stability, lysine acetylation, lysine methylation, micro rna

Participants :
- University of Edinburgh (Royaume-Uni) — Coordinator, beneficiary, Enseignement supérieur ou secondaire, subvention : 183454.8 €
Projet PTMCnano (Horizon 2020, appel à projets 2016)
Action : Postdoctoral Fellowships - European Fellowships
Panel : Physics
Statut du projet : CLOSED

Post-transition metal chalcogenides (PTMCs) such as InSe or GaSe are members of the rapidly expanding family of two-dimensional (2D) materials. Unlike graphene, they possess an electronic band gap, enabling electrostatic confinement of electrons by using local gate electrodes, and therefore the creation of quantum dots (QD). QDs can be employed as the bases for spin qubits, possible building blocks of solid state quantum computers. Recent results of the host suggest that PTMCs may surpass other gapped 2D crystals in electron mobility, making possible the fabrication of QDs of exceptional quality. Moreover, their near-direct band gap enables their use in photovoltaic, photodetection and LED applications, and opens the way for interfacing photons with spin qubits, essential in long-distance communication between quantum computers. The proposed objectives entail the realization of electrostatic confinement to study state of the art PTMC QDs, and testing their viability as spin qubits via magnetoconductance measurements, and also the investigation of the electro-optical response of 2D heterostructures to address single photon to electron conversion in QDs, and possibilities towards application in communication, sensing and solar power conversion. During the fellowship, the Researcher will have the unique opportunity to learn from pioneers of the research on 2D materials. He will master the cutting-edge stacking technique of the host, necessary to fabricate high-quality 2D heterostructures, and other crucial skills in this rapidly developing field. Furthermore, the Researcher will expand his knowledge on electro-optical characterization methods of nanophotonic devices, and on the physics of 2D crystals and light-matter interaction. The training and the research on QDs and photonic devices will be a significant boost to the Researcher’s career, and give him the necessary skills and experience for the foundation of a future quantum electro-optical research group.

Mots clés : 2d material, heterostructure, nanoconstriction, quantum point contact, quantum dot, spin qubit, photodetector, solar cell

Participants :
- University of Manchester (Royaume-Uni) — Coordinator, beneficiary, Enseignement supérieur ou secondaire, subvention : 183454.8 €
Projet HeartAtaK (Horizon 2020, appel à projets 2015)
Action : Postdoctoral Fellowships - European Fellowships
Panel : Life Sciences
Statut du projet : CLOSED

Potassium channels are widely distributed and have many important biological functions in the human body. Of special interest is the Kv11.1 channel, whose main function is the repolarization of the membrane after a cardiac action potential. Unfortunately, this channel can be blocked by a variety of structurally diverse drugs causing the long QT syndrome (LQTS), a cardiac repolarization disorder that can lead to arrhythmia and sudden heart death. Due to this very severe side effect, a variety of drugs with otherwise good therapeutic profiles have been withdrawn from the market. Nowadays, cardiac Kv11.1 is an important anti-target in drug development to exclude any potential side effects that could lead to LQTS. In contrast, tumour cells require the expression of specific isoforms of Kv11.1 for survival making these channels a potential anti-cancer drug target – as long as these drugs do not bind to the heart isoform. The major goal of this project is the elucidation of the structure of Kv11.1 via X-ray crystallography or cryo-EM. I have established large-scale protein production of a Kv11.1-chimera using the baculovirus/insect cell expression system, thus enabling biophysical and structural studies to provide structural information on a range of time- and spatial resolution scales. This will not only shed light on the structural motifs responsible for binding a variety of structurally diverse drugs but also improve the fundamental knowledge for the understanding of the special biophysical properties of this channel. By taking these techniques together I will be able to determine how known inhibitors bind, and so identify new isoform specific binding pockets to guide isoform-specific drug design. My career goal is to pursue fundamental and translational research in structural biology of human membrane protein, with a focus on medically important targets and further drug development. This project will bring me closer to that goal.

Mots clés : potassium channel, drug development, integral membrane protein

Participants :
- University of Leeds (Royaume-Uni) — Coordinator, beneficiary, Enseignement supérieur ou secondaire, subvention : 183454.8 €
Projet BluGram (Horizon 2020, appel à projets 2014)
Action : Postdoctoral Fellowships - Global Fellowships
Panel : Life Sciences
Statut du projet : TERMINATED

Powdery mildew caused by the fungus Blumeria graminis f.sp. tritici (Bgt) is a devastating disease of wheat with poorly understood plant-pathogen interactions. Sequencing of the Bgt genome indicated that hundreds of effector proteins are manipulating the plant cell and determining the virulence spectrum of a particular mildew strain. Bgt rapidly adapted to the introduction of the new host species bread wheat, which arose only 8,000-10,000 years ago. Bgt has since evolved into strains which are specialized on domesticated wheat and such which grow on wild wheat species. Genes responsible for the host specificity in an obliagte biotrophic fungus are unknown. To study the mechanisms of adaptive evolution in the highly repetitive Bgt genome, whole genome re-sequencing data of a mapping population derived from a cross between Bgt isolates that differ in their host specialization will be used to determine the frequency and distribution of recombination events and precise mapping of recombination breakpoints. Of particular interest is to study the impact of recombination on the clusters of effector genes. The factors that determine host specificity will be genetically mapped. This will allow conclusions on which and how many genes were responsible for the Bgt adaptation to the bread wheat host. The proposed research is taking a multi-disciplinary approach combining whole genome re-sequencing, classical genetics, molecular plant pathology and comparative genomics. This study will broaden our understanding of Bgt genome evolution and will help to design rational strategies for sustainable powdery mildew disease management.

Mots clés : blumeria graminis tritici, wheat, recombination, effector gene, host specialization, plant pathogen interactions, adaptive evolution, powdery mildew

Participants :
- University of Haifa (Israël) — Coordinator, beneficiary, Enseignement supérieur ou secondaire, subvention : 260674.2 €
- University of Zurich (Suisse) — Partner, organization partner, Enseignement supérieur ou secondaire, subvention : 0.0 €
Projet SPLICEOSACT (Horizon 2020, appel à projets 2017)
Action : Postdoctoral Fellowships - European Fellowships
Panel : Life Sciences
Statut du projet : CLOSED

Pre-mRNA splicing is a fundamental maturation step of eukaryotic mRNAs that consists of the removal of introns and the concomitant ligation of exons by two successive transesterification reactions. This complex biological process is catalyzed by the spliceosome, a gigantic ribonucleoprotein particle that assembles de novo on each intron and uses a single RNA-based active site to perform both reactions. The spliceosome is composed of five snRNPs (U1, U2, U4, U5, U6) that are recruited to pre-mRNAs in a stepwise manner. When a pre-catalytic spliceosome, consisting of all five snRNPs, is formed on a pre-mRNA it has no pre-existing active site and undergoes extensive compositional and conformational changes to become “catalytically competent”. During this transition, two snRNPs (U1 and U4) are lost and several new factors are recruited, ensuring the formation and stabilization of the active site as well as the correct positioning of the pre-mRNA’s reactive groups in the catalytic centre. Thanks to recent technological advances in Electron Microscopy (EM), a series of cryoEM structures of fully assembled “active” spliceosomes at atomic resolution have been solved in the host group and elsewhere, in the past two years. These structures, which have created much excitement in the RNA community, visualize the spliceosome during each step of the catalytic cycle and allow a mechanistic understanding of catalysis. However, due to the scarcity of high-resolution information on earlier complexes, many questions remain regarding spliceosome activation. My project aims at filling a gap in our understanding of pre-mRNA splicing by unraveling the molecular details of spliceosome activation. To that end, I will use a combination of biochemical characterization and cryoEM to study yeast spliceosome captured at discrete early stages of activation.

Mots clés : cryoem, structural biology, rna metabolism, rna splicing, biochemistry

Participants :
- UK Research and Innovation (Royaume-Uni) — Coordinator, beneficiary, Recherche, subvention : 195454.8 €
Projet ROQ-WACh (Horizon 2020, appel à projets 2015)
Action : Postdoctoral Fellowships - European Fellowships
Panel : Life Sciences
Statut du projet : CLOSED

Precise regulation of gene expression is achieved through the coordinated action of genomic cis-regulatory modules (CRMs). The identification of CRMs has long been a goal of functional genomics as CRM dysregulation can have devastating consequences for health and development such as autism. For example, mutations in the MeCP2 gene, which encodes protein that binds methylated DNA and regulates gene expression in neurons, results an Autism Spectrum Disorder termed Rett Syndrome. While thought to modulate CRM activity as a repressor, MeCP2’s function remains ambiguous and would benefit from a functional genomics characterization. To identify CRMs I recently developed a novel approach called FIREWACh. Here, I propose to utilize FIREWACh first to identify active CRMs within a homogenous population of neurons, identifying genomic loci of CRMs whose function may be compromised by MeCP2 mutations. I will adapt FIREWACh to allow the quantification of CRM output in a new method I propose to call ROQ-WACh (regulatory output quantification within accessible chromatin) by addition of barcodes to reporter mRNAs. This will allow high-throughput readout of CRM activity globally in vivo and will be broadly applicable to many biological fields. Lastly, I aim to combine the above approaches to quantify the changes in CRM output in response to pathological mutations in MeCP2. This Marie Sklodowska-Curie Action will allow me (the Experienced Researcher, Matthew Murtha) mobility to Spain to join the laboratory of Dr. Manel Esteller (Host Supervisor), renowned epigeneticist and expert in DNA-methylation biology to perform the research. Together the approaches and data generated by this MSCA action will provide key insights into the relationship between methylated DNA, precise control of gene expression, and high-order phenotypes such as cognitive behaviors.

Mots clés : rett syndrome, mecp2, firewach, neurobiology, disease, mutations

Participants :
- Institut d'Investigació Biomédica de Bellvitge (Espagne) — Coordinator, beneficiary, Recherche, subvention : 158121.6 €
Projet METAREPAIR (Horizon 2020, appel à projets 2020)
Action : Postdoctoral Fellowships - European Fellowships
Panel : Life Sciences
Statut du projet : SIGNED

Preclinical and epidemiological studies indicate that some dietary patterns, such as high-fat diet (HFD), are associated with increased risk for many cancers, including prostate cancer (PCa). However, our mechanistic understanding of the link between diet and cancer remains limited. To help deconvolute the connection between nutrition and tumorigenesis, METAREPAIR will investigate the role of genomic instability in mediating the effect of nutritional metabolism on PCa aggressiveness. I hypothesize that the oncogenicity of ‘HFD-like’ diets is in part due to a diet-induced erosion of DNA repair capacity caused by altered epigenetic and epitranscriptomic landscapes. Based on enticing preliminary data indicating that diet-dependent alterations of one carbon metabolites can impact DNA damage repair efficacy and DNA repair-pathway choice, I present a model whereby changes in nutritional metabolism affect the activity of writers and erasers of histone and RNA methylation marks and consequently impair their role in orchestrating DNA damage repair. I will test this model by manipulating in vitro the levels of key metabolites and then use an innovative experimental toolkit to assess the dynamics of DNA repair in PCa cells. The effect of metabolic manipulation onto DNA repair will be studied through the mechanistic lens of RNA and histone methylation. This diet-DNA damage link will be tested in vivo as a tool for precision nutrition intervention to sensitize PCa tumours to DNA-damaging therapies. The findings of METAREPAIR could unveil a yet-unexplored link between metabolic perturbations and genomic stability, with far reaching implications at fundamental as well as translational level. By allowing me to deliver innovative science in both the applied and basic aspects of DNA repair and RNA role in it, METAREPAIR represents a career-changing opportunity that will place me in a strong position to pursue my next career step of becoming an independent researcher.

Mots clés : cancer metabolism, high fat diet, dna damage response, dna repair, epigenetics, epitranscriptomics

Participants :
- FIRC Institute of Molecular Oncology (Italie) — Coordinator, beneficiary, Recherche, subvention : 171473.28 €
Projet PredOpt (Horizon 2020, appel à projets 2017)
Action : Postdoctoral Fellowships - European Fellowships
Panel : Life Sciences
Statut du projet : CLOSED

Predicting the timing of events is not only crucial to our survival but seamlessly contributes to everyday activities like riding bicycles, dancing or playing sports. Human and animal prediction of timing is statistically optimal, however, how such behavior arises from neural circuitry is poorly understood. Here I outline a theoretical framework, testable hypotheses and a set of experiments that will help uncover the neural circuits that integrate previous experience to make optimal estimates about the timing of events. In this proposal, the systematic investigation of optimality in complex forms of timing behavior is based on exploiting known neural circuits belonging to simple timing behavior. The anatomical origins of simple timing tasks like eyeblink conditioning are extremely well-characterized in the cerebellum of different species. Using this, I propose a framework for extending this circuit to understand optimal timing in a series of targeted physiology, behavior and optogenetics experiments. This research, if successful, will reveal the neural basis for how the nervous system combines previously encountered stimuli and recent observations to generate statistically optimal estimates and will generate valuable insights into the underpinnings of biological intelligence.

Mots clés : cerebellum, time perception, eyeblink conditioning, optimal prediction

Participants :
- Erasmus MC (Pays-Bas) — Coordinator, beneficiary, Enseignement supérieur ou secondaire, subvention : 177598.8 €
Projet INDECOSTAB (Horizon 2020, appel à projets 2019)
Action : Postdoctoral Fellowships - Global Fellowships
Panel : Environment and Geosciences
Statut du projet : SIGNED

Predicting upcoming changes in ecosystems has become one of the priorities of current ecological research and conservation. This is especially crucial for ecosystems where large, durable ecological shifts – hereafter regime shifts – may occur following an increase in stressors (e.g. ocean temperature) or after perturbation events (e.g. hurricanes, fisheries). Because experimentally investigating regime shifts in ecosystems often requires large, impractical disturbance experiments, mathematical models have been used to investigate the factors underpinning such shifts, and predict where and when they might occur in a given ecosystem. This research effort has led to the development of indicators (metrics) based on the observed spatial structure of an ecosystem, which can inform on the proximity of a regime shift. While this approach has been explored for terrestrial ecosystems, virtually no work has been done to apply it to marine ecosystems, and in particular sub-tidal systems (e.g. coral reefs, algal beds). Yet, at least 500 million people depend on these ecosystems at global scale, and their potential for regime shifts in the current context of global changes has been extensively reported by the scientific and global policy literature. This project aims at opening a new research avenue by extending the previous approaches designed for terrestrial ecosystems to develop novel indicators of upcoming regime shifts for sub-tidal systems. We will do so by successively (1) develop a realistic, spatially-explicit model of ecological dynamics, using the coastal ecosystems of Easter Island as model systems; (2) derive indicators of upcoming shifts in coral reefs and algal beds and validate them on empirical data, and; (3) implement our results in widely-available software. Achieving these goals will advance our ability to predict regime shifts and ultimately provide globally-applicable indicators of ecosystem fragility for sub-tidal systems.

Mots clés : ecosystem modelling, regime shifts, coral reefs, marine ecosystems, ecosystem stability

Participants :
- Pontificia Universidad Católica de Chile (Chili) — Partner, organization partner, Enseignement supérieur ou secondaire, subvention : 0.0 €
- Utrecht University (Pays-Bas) — Coordinator, beneficiary, Enseignement supérieur ou secondaire, subvention : 205969.92 €
Projet SPITFIRE (Horizon 2020, appel à projets 2017)
Action : Postdoctoral Fellowships - European Fellowships
Panel : Environment and Geosciences
Statut du projet : CLOSED

Prediction of fish production is hindered by the lack of high-resolved data, and the complexity of the bio-physical systems affecting fish survival. A key factor determining the survival of larval fish is the relationship between predator recruitment and prey-predator overlap (match-mismatch hypothesis, MMH). MMH thus offers a mechanistic explanation for the fluctuations in fish recruitment, i.e. the number of fish entering the fishery. However, little is known about how MMH mechanistically explains population and ecosystem dynamics across species and regions. Therefore, the main goal of SPITFIRE is to quantify the ability of an improved MMH to globally explain fish dynamics, by acknowledging the roles of zooplankton (animal-like drifters, not just phytoplankton, plant-like drifters), space and mismatch. The data needed to achieve SPITFIRE objectives include long-term phytoplankton, zooplankton, fish distributions and their annual mean timings from a specific location (work package 1), and the Atlantic and the Pacific basins (work packages 1 and 2). All components necessary for project success are in-hand both through the collaborative network of experts already established and data resources via participants providing insight into MMH dynamics, fish life-history dynamics, oceanography, and both the Atlantic and the Pacific ecosystems. By comparing predator-prey relationships, SPITFIRE will help answer the major question in fish ecology and management – what determines fish recruitment? – and thus lead to better management of marine resources. The training-through-research, unique set of transferable skills and intellectual, methodological and interdisciplinary training that I will gain from this project are the essential skills I need to become a leading marine scientist. By building a robust research profile, I can ensure that professional independence to build my own lab will be a sound foundation when pursuing research positions and grants, such as ERC Grants.

Mots clés : match mismatch, overlap, fish survival, phenology, satellite ocean colour, fish recruitment, plankton dynamics, fisheries

Participants :
- University of Oslo (Norvège) — Coordinator, beneficiary, Enseignement supérieur ou secondaire, subvention : 208400.4 €