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

Cell fate decisions is governed by the fine-tuned regulation of gene expression in all living organism. It is mostly realized by the cell-type specific assembly of regulatory networks consisting of Transcription Factors (TFs) and cofactors proteins. Thus, a multitude of combination between TF and cofactors will be set up to regulate the transcription in a precise spatiotemporal manner. The evolutionary conserved class of Hox TFs perfectly illustrates how a restricted number of TFs is able to promote diverse transcriptional programs. Hox proteins are involved in the specification of body forms and organs in animals. Despite this notorious architectural role, their operating mode remains controversial: they recognize similar DNA-binding sites in vitro, in sharp contrast with their specific functions in vivo. Thus, Hox proteins are likely acting with cofactors in vivo, and their identification was the core of my post-doctoral work. Notably, it revealed that mRNA-processing related proteins could constitute an important class of Hox cofactors. Thus, Hox specificity could also rely on mRNA-processing regulation, providing insightful molecular entry points to understand Hox function in development and disease. My research project aims at elucidating this novel facet of Hox activity. I propose two complementary aims developed in two model systems in order to decipher the molecular and functional impact of Hox-dependent mRNA processing regulation. I will decipher how interactions with splicing factors impact on the Hox functions in vivo in Drosophila embryos. Moreover, I will enlarge the cooperative role of HOX and splicing factors by performing large-scale interaction-screens of several human HOX and 2000 RNA-regulatory proteins in various normal and pathological cell contexts. Overall, my research program has the ambition to open novel perspectives on the role of TFs at the mRNA-regulatory level.

Mots clés : protein protein interaction, splicing, system biology, drosophila, human cell line

Participants :
- Centre national de la recherche scientifique (France) — Coordinator, beneficiary, Recherche, subvention : 116953.92 €
Projet SAMNets (Horizon 2020, appel à projets 2016)
Action : Postdoctoral Fellowships - European Fellowships
Panel : Life Sciences
Statut du projet : CLOSED

Cell life is not the property of any single protein or gene; rather it emerges from concerted actions of multiple molecules in cellular networks. Current proposal is focused on Signal Transduction Networks (STN) connecting the environment to cell responses. A major challenge is to understand how STN integrate and process environmental signals in a robust and reliable way and how they “compute” cell fate decisions depending on genetic background. To answer this question, the study will be focused on three interconnecting STNs: the Survival (PI3K/PTEN/AKT), Apoptotic (RASSF1/MST/LATS) and Mitogenic (EGFR/RAS/RAF/MEK/ERK) pathways, the SAM network. In the scope of current proposal the methods of signalling network reconstruction will be improved and the SAM network topology will be reconstructed in the panel of cell lines. Based on available data and reconstructed network topology the mechanistic site-specific dynamic model of SAM network will be developed and validated. Model predictions of dependence of signalling outputs behaviour on different perturbations (like small molecule inhibitors and their combinations) and background (mutations and protein expression levels) will be validated. The signalling outputs will be experimentally correlated to the cell fate decisions. The developed models will relate mutational information to treatment responses in the context of different expression landscapes and they will explain and predict mechanisms of intrinsic and acquired drug resistances, which often cannot be picked up by only intuitive reasoning. During the project the applicant will get training in a range of modern computational modelling, biochemical and molecular biology techniques used to study intracellular signalling networks. As a result, he will acquire skills of efficient integration of wet and dry parts of systems biology which will uniquely qualify him in the field significantly enhancing his career prospects.

Mots clés : systems biology, map kinases, signalling transduction networks, cell fate, apoptosis, mathematical modelling, network reconstruction, nonlinear dynamics

Participants :
- National University of Ireland (Irlande) — Coordinator, beneficiary, Enseignement supérieur ou secondaire, subvention : 187866.0 €
Projet SugarOsmoSignalling (Horizon 2020, appel à projets 2014)
Action : Postdoctoral Fellowships - European Fellowships
Panel : Life Sciences
Statut du projet : CLOSED

Cell walls provide plant cells with structural support during growth and differentiation as well as with protection against environmental stress. Cell wall composition and structure is adapted to these functional requirements by a dedicated mechanism to maintain cell wall integrity (CWI). The available evidence suggests that the CWI mechanism is an important regulator of cell wall and carbohydrate metabolism and that signalling of sugar levels and osmotic conditions is vital for its function. Furthermore, interdependencies between pathogen defence and the CWI mechanism are becoming apparent. By performing a forward genetic screen in Arabidopsis, I will identify novel components involved in sugar-signalling in the context of CWI maintenance and pathogen defence. Using a combination of genetic mapping and next-generation sequencing, I will determine the identity of the components, whose specific activities will be identified through targeted functional analyses. In the second part of my project I will determine functions of the signalling metabolites trehalose-6-phosphate and glycerol-3-phophate in CWI maintenance and analyse the osmo-sensitive regulation of these functions. After characterizing time-dependent quantitative changes in metabolite levels and related enzyme activities upon impaired CWI and in combination with osmotic support, I will examine specific functions of metabolites / enzymes by analysing developmental, hormonal and structural responses in Arabidopsis overexpression and knockout lines. This project takes advantage of CWI maintenance involvement in a variety of biological processes to identify signalling components and osmo-sensitive mechanisms for the coordination of carbohydrate metabolism with cell wall metabolism and pathogen defence. The knowledge generated in this project will provide novel functional insights into metabolic processes relevant for facilitating bioenergy production and increasing the yield of food crops.

Mots clés : plants, cell wall, carbohydrate metabolism, signalling, plant pathogen interaction

Participants :
- Norwegian University of Science and Technology (Norvège) — Coordinator, beneficiary, Enseignement supérieur ou secondaire, subvention : 208400.4 €
Projet INTERSPREC (Horizon 2020, appel à projets 2017)
Action : Postdoctoral Fellowships - European Fellowships
Panel : Life Sciences
Statut du projet : CLOSED

Cell-cell interaction mechanisms play a role in many fundamental biological processes from symbiotic interactions of fungi and bacteria with their host plants to fertilization both in animals and plants. In plant reproduction, pollen tube (PT) reception is a cell-cell communication process allowing the recognition of the male gametophyte (the PT) by the female gametophyte necessary for fertilization. To investigate this process, the host lab used interspecific crosses between certain Arabidopsis thaliana accessions and A.lyrata pollen, where most PTs are not recognized, causing a failure in sperm release and thus fertilization. In contrast, several other A.thaliana accessions almost perfectly recognize interspecific PTs. Preliminary results identified the gene At5g62150 as a key player for species-specific PT recognition. At5g62150 codes for a LysM-domain containing glycan-binding peptide, pointing at glycosylation patterns for the distinction of intra- and interspecific PTs, a mechanism already known to be important in symbiosis and immunity. It was found that differences in the regulation of At5g62150 in distinct species is responsible for recognition, as the amino acid sequence does not differ between A. thaliana other accessions. With this proposal, we will first attest and manipulate the expression profile of At5g62150 in different accessions to correlate its regulation with its function. Then, we propose to dissect the regulation of At5g62150 in different ways: identification and study of the essential cis-regulatory element for regulation and Y1H screening and Reverse ChIP to find trans-acting regulators. The output will not only pave the way for the understanding and manipulating crosses barriers in plants, which is highly relevant for plant breeding, and shed light on cell-cell communication processes in general, but also will establish a novel, powerful instrument (Reverse ChIP) to investigate DNA-protein interaction in complex organisms.


Participants :
- University of Zurich (Suisse) — Coordinator, beneficiary, Enseignement supérieur ou secondaire, subvention : 175419.6 €
Projet SpatialOrganoids (Horizon 2020, appel à projets 2019)
Action : Postdoctoral Fellowships - European Fellowships
Panel : Life Sciences
Statut du projet : CLOSED

Cell-to-cell heterogeneity in biological systems has been broadly studied in unicellular organisms and mammals. Furthermore, non-genetic, in addition to genetic heterogeneity has been recently proposed to support tumour growth and to induce resistance to cancer therapy. However, the molecular events on a spatial and temporal level that lead to the emergence of tumour heterogeneity are largely unknown. To address this question, I will study breast cancer, which shows the highest cancer incidence in women and is characterised by extensive intra- and inter-patient heterogeneity in cellular and molecular phenotypes. As model system, I select 3D organoid cultures, which are gaining popularity in cancer research due to their ability to reconstruct tumour-like molecular features and to recapitulate treatment response. Here, I propose experimental and computational time-course analyses of breast cancer organoids to understand molecular and spatial determinants that underlie the emergence of heterogeneity in cancer cell phenotypes. On the experimental side, I will use imaging mass cytometry and perturbation experiments to capture and validate spatio-temporal changes in cellular phenotypes, interactions and signalling networks. Statistical modelling will quantify dynamic changes in phenotypic heterogeneity over the time-course of organoid growth. Finally, I will predict the emergence of intra-organoid heterogeneity across multiple organoid lines, which allows me to derive targeted treatment strategies. In sum, the proposed work will disentangle and perturb the spatio-temporal emergence of phenotypic intra-tumour heterogeneity, which is characteristic of breast cancer tissues.

Mots clés : imaging mass cytometry, breast cancer organoids, spatial data analysis

Participants :
- University of Zurich (Suisse) — Coordinator, beneficiary, Enseignement supérieur ou secondaire, subvention : 191149.44 €
Projet mRNAstress (Horizon 2020, appel à projets 2018)
Action : Postdoctoral Fellowships - European Fellowships
Panel : Life Sciences
Statut du projet : CLOSED

Cells are frequently exposed to stress conditions, which can disrupt cellular homeostasis and result in cell death. To minimize the damage and adapt to the stress condition, eukaryotic cells employ a highly conserved signaling pathway, the integrated stress response, which integrates a variety of intrinsic and extrinsic stress signals to reprogram mRNA translation. Consequently, translation of most mRNAs is inhibited to conserve energy, while a select group of stress-related mRNAs is preferentially translated to promote recovery and restore homeostasis. This preferential translation of stress-related mRNAs depends on special sequence elements called upstream open reading frames (uORF), but the molecular mechanisms behind this process remain largely unclear. To investigate the translational reprogramming during cellular stress, I will exploit recent advances in single-molecule imaging of mRNA translation in living human cells. First, to understand how uORFs facilitate the preferential translation of stress-related transcripts in stressed cells, I will apply single-molecule imaging of mRNA translation to measure the translational dynamics at different start codons of uORF-containing reporter mRNAs. Next, I will test how the translational reprogramming is affected by the formation of stress-inducible ribonucleoprotein granules (stress granules). To this end, I will combine the single-molecule imaging of mRNA translation with imaging and optogenetic manipulation of stress granules. Last, to complement the single-molecule imaging approach, the same reporter mRNAs will be subjected to proximity-dependent labelling assays in order to identify novel factors that facilitate stress-induced translation. Together, this project will provide important insights into the regulation of mRNA translation during cellular stress. This will also expand our understanding of pathological conditions that involve misregulation of the integrated stress response.

Mots clés : mrna translation, cellular stress, single molecule imaging, live cell imaging

Participants :
- Friedrich Miescher Institute (Suisse) — Coordinator, beneficiary, Recherche, subvention : 191149.44 €
Projet DeCoDe Platy (Horizon 2020, appel à projets 2020)
Action : Postdoctoral Fellowships - European Fellowships
Panel : Life Sciences
Statut du projet : CLOSED

Cells in multicellular organisms show a huge diversity of shape, size, and function, yet are all descended from the same totipotent zygote. As development progresses, cells lose their ability to contribute to different fates, instead committing to a narrower subset of expression programs. This stepwise reduction of differentiation potential has been illustrated in Waddington’s epigenetic landscape (“Waddington lineage”). The specific gene expression programs of cell types are governed by Core Regulatory Complexes (CoRCs), where transcription factors cooperate to maintain their own expression and the effector genes that give rise to the cellular phenotype. Cell types exist as terminal or transitory states of the Waddington lineage, and it is yet unclear whether and to what extent transitory developmental and terminal cell types involve similar or distinct regulatory principles and effector modules. I will reconstruct the Waddington lineage of Platynereis dumerilii, an indirectly developing marine invertebrate with a wealth of transitory developmental and terminal cell types. I will gather single-cell RNA-seq and chromatin accessibility data for multiple developmental stages and computationally identify putative cell types. I will map these onto locations in the animal body using the in-situ expression patterns of lineage and cell type markers, and exploit unique electron microscopy data to explore the connection between gene expression and subcellular morphology. After connecting successive stages computationally, I will validate the resulting Waddington lineage with functional experiments, disrupting the expression of effector genes in the terminal cell types with CRISPR/Cas9. By combining gene expression, chromatin accessibility, cellular lineage information, functional genomics, spatial localization, and, uniquely, subcellular morphology, we will shed light on animal development and the regulatory mechanisms that govern cell types.


Participants :
- European Molecular Biology Laboratory (Allemagne) — Coordinator, beneficiary, Recherche, subvention : 174806.4 €
Projet YEFF (Horizon 2020, appel à projets 2016)
Action : Postdoctoral Fellowships - European Fellowships
Panel : Life Sciences
Statut du projet : CLOSED

Cellular and developmental processes rely on the precise activity of the proteins that constitute them, and alteration of protein activity often causes disease phenotypes and fitness defects. The relation between protein activity (or expression) and organismal fitness is thus a fundamental genetic property with implications for evolutionary and disease processes. However, a systematic understanding of how protein expression relates to fitness is lacking. Here we propose a comprehensive screen of expression-fitness functions (EFFs) for yeast genes. The proposed inter-disciplinary project will combine cutting-edge methods from synthetic biology, innovative one-step construction of a comprehensive genome-wide library, multiplexed genomics measurements and functional genomics computational analyses to elucidate fundamental patterns of expression-fitness functions. The methodology is based on an inducible degron system that allows for controlled repression of protein levels. Due to a one-fits-all design, the inducible degron can be fused in a one-step transformation procedure to any gene contained in the yeast GFP-fusion library. An all-in-one construction of the library, assessment of library components via deep-sequencing and multiplexed growth and expression assays will allow for the measurement of thousands of yeast gene EFFs in parallel. Computational data analyses will elucidate principal classes of EFFs. Subsequent functional genomics analyses will link principal EFFs to underlying molecular and physiological properties, such as gene’s functions, pathways or cellular localizations, which will therefore provide a foundation to understand the principal causes of how alterations in gene activity translate to impairments of cellular function. The proposed project will therefore open up a new area of systematic, quantitative genetic analysis that should prove crucial in the understanding of human genetic variation and disease.

Mots clés : yeast, gene, expression, fitness, gene regulation, evolution, quantitative genetics, disease

Participants :
- Centre for Genomic Regulation (Espagne) — Coordinator, beneficiary, Recherche, subvention : 170121.6 €
Projet LipTransProMet (Horizon 2020, appel à projets 2018)
Action : Postdoctoral Fellowships - European Fellowships
Panel : Life Sciences
Statut du projet : CLOSED

Cellular membranes of eukaryotic cells vary in their lipid composition, which allows segregation of diverse biological processes and specific enrichment of signaling, enzymatic and structural proteins. Differential enrichment of lipids in different membranes stems from compartmentalized synthesis and degradation of lipids, but also from lipid transport between membranes. Lipid transfer proteins (LTPs) facilitate non-vesicular lipid transport through aqueous spaces, and their dysfunction can lead to diseases. They are crucial for many molecular processes because a large part of the proteome depends on membranes for its function. However, for the majority of the more than 100 LTPs in humans, the lipid cargoes, the integration into metabolism, the mode of action, and the targeted organelles remain unknown. The Gavin group recently performed large screens to identify the lipids bound and transported by LTPs, and during my first months in the host lab, I have been involved in the data analysis of these screens. Our primary objective in the current project is to take the next step by exploring the role of LTPs in lipid metabolism. We will evaluate the effect of LTP knockdown in cell lines with a unique combination of two complementary systems biology approaches: lipidomics and thermal proteome profiling. The integration of these data with previous data from the Gavin group and public databases will highlight lipid metabolic pathways that rely on LTPs for their correct function, and might decipher less obvious connections with other cellular pathways. Moreover, as additional results of this analysis, these data will likely also highlight relevant organelles and maybe even signaling pathways, even further establishing the functions of the LTPs. This project will enhance our insight in the role of non-vesicular transport in lipid metabolism, while the new approach is likely broadly applicable, even for the future study of primary cells from patients.

Mots clés : lipid transfer proteins, lipid metabolism, non vesicular lipid transport, thermal proteome profiling, multi omics data integration, lipidomics, pathway enrichment, network mapping

Participants :
- European Molecular Biology Laboratory (Allemagne) — Coordinator, beneficiary, Recherche, subvention : 162806.4 €
Projet Post-GFC Monetary Policy (Horizon 2020, appel à projets 2014)
Action : Postdoctoral Fellowships - European Fellowships
Panel : Economic Sciences
Statut du projet : CLOSED

Central banks worldwide routinely use models in assessing and forecasting the global and domestic economic outlook in order to determine the most suitable monetary policies. Economies evolve over time and policies that worked in the 1980s might not be viable at the present time, thus models must be flexible to account for these changes. Undoubtedly, it is difficult to identify the exact point in time when a change in macroeconomic behaviour occurs, particularly a change that will trigger a reactive monetary policy to neutralise its negative effects. The current project proposes a new methodology, which due to its local nature can react faster to changes in the process than other existing methodologies. This project aims at breaking new ground in several respects. First, by proposing for the first time a nonparametric local linear estimator of multivariate processes with possible smooth or abrupt changes in the parameters. Second, by developing a user-friendly computational package with the aforementioned functionality. Finally, by investigating the effect for G7 and Eurozone economies of the monetary policies driven by the global financial crisis.

Mots clés : nonparametric statistical methods, kernel smoothing, monetary policy and r programming

Participants :
- Basque Center for Applied Mathematics (Espagne) — Coordinator, beneficiary, Recherche, subvention : 158121.6 €