Data-Gouv-ML/pcri-actions-marie-curie-participations-et-projets-laureats huggingface dataset:
Projet Oncogenic PI3-kinase (Horizon 2020, appel à projets 2018)
Action : Postdoctoral Fellowships - European Fellowships
Panel : Life Sciences
Statut du projet : CLOSED

PI 3-kinase (PI3K) signalling regulates multiple cell functions and is one of the most frequently genetically-activated pathways in cancer. This is mainly due to activating mutations in PIK3CA (the gene encoding the PI3Kα catalytic subunit) or inactivation of the tumour-suppressor PTEN (which opposes PI3K signalling). Solid tumours are most often hypoxic and nutrient-starved. The central premise of my proposal is that PI3K signalling has thus far been predominantly investigated under experimental settings not representative of these cancer-relevant tissue contexts. In our view, this has resulted in an incomplete understanding of PI3K biology in cancer. Based on this assertion, I have formulated two key objectives: (1) To uncover previously-unappreciated signalling mechanisms of oncogenic PIK3CA under cancer-relevant conditions of long-term starvation and/or hypoxia. (2) To understand the mechanism of cell death induced by an innovative, new type of PI3K modulators, generated by the Host Lab, that kill PIK3CA-mutant cancer cells under hypoxic conditions. These objectives will be achieved by, respectively: (1) Biased and unbiased genetic and pharmacological approaches in cells and mice, including probing signalling under conditions of (A) nutrient and/or oxygen starvation (B) sustained low-level signalling due to genetic PIK3CA activation in the heterozygous state and from the endogenous promotor, as is the case in cancer. (2) Using unique small-molecule PI3K pathway modulators developed in the Host Lab, in cell-biological and signalling studies. These objectives will merge my expertise in signalling under nutrient-starved conditions with world-class know-how in PI3K cancer studies and drug development in the Host Lab. This proposal aims to make scientific breakthroughs in understanding cancer-related PI3K signalling, promoting the progression of my career and allowing the Host Lab to achieve its key long-term aim to make PI3K-based cancer therapies work.

Mots clés : signalling, pi 3 kinase, cancer, hedgehog, embryonic development, mouse model, cell biology

Participants :
- University of London (Royaume-Uni) — Coordinator, beneficiary, Enseignement supérieur ou secondaire, subvention : 212933.76 €
Projet PRISM (Horizon 2020, appel à projets 2016)
Action : Postdoctoral Fellowships - European Fellowships
Panel : Information Science and Engineering
Statut du projet : CLOSED

PRISM is about designing, implementing and testing methodologies to better predict transport demand in a city. While plenty solutions exist today for this objective, there is general consensus that, under stress scenarios (e.g. large social events, inclement weather, demonstrations, special days), those approaches are insufficient. With new, smart mobility modes, demand prediction becomes even more important. For example, a one-way car sharing (e.g. DriveNow) or an autonomous mobility on demand service, are highly sensitive to rebalancing operations (moving vehicles to where demand is expected). In fact, bad demand predictions can lead to disastrous outcomes, by placing supply where it is not needed, and removing it from where it is required. PRISM approach is to combine latest research from Transport Engineering and Computer Science, by using Probabilistic Graphical Models (PGMs), a tool that combines Bayesian statistics, graph theory and scientific computing. As a research area, PGMs have already reached a considerable level of solid foundations, community size, and software tools. The Experienced Researcher (ER) has recently returned to Europe, after several years of research in Singapore and USA with the Massachusetts Institute of Technology (MIT), and this Marie SkŁodowska-Curie fellowship will be instrumental for his growth and affirmation in the Danish and European context.

Mots clés : transport demand modeling, multi output machine learning, probabilistic graphical models

Participants :
- Technical University of Denmark (Danemark) — Coordinator, beneficiary, Enseignement supérieur ou secondaire, subvention : 212194.8 €
Projet DELETER (Horizon 2020, appel à projets 2020)
Action : Postdoctoral Fellowships - European Fellowships
Panel : Life Sciences
Statut du projet : CLOSED

PROteolysis TArgeting Chimeras (PROTACs) are molecules with therapeutic potential that induce degradation of target proteins involved in disease. PROTACs are composed of a ligand that binds an E3 ubiquitin ligase, chemically linked to a ligand for the target protein. Formation of a ternary complex between ligase, PROTAC and target protein leads to ubiquitination of the target, which is then recognised by the proteasome and degraded. The vast majority of PROTAC degraders developed to date recruit either the VHL or Cereblon E3 ligases, and only ~1% of the >600 known E3 ligases have been harnessed by this type of molecule. However, a given E3 ligase may not always form ternary complexes productive to ubiquitination for every target, and considerations such as organelle, cell type and tissue specificity warrant exploration of E3 ligases beyond those for which ligands currently exist. In this Fellowship, I will pursue the DCAF family of E3 ligases to expand the PROTAC toolbox. Two DCAF proteins have been successfully hijacked by degraders such as PROTACs, validating the family as exploitable for targeted protein degradation, and most DCAF proteins contain a WD40 repeat domain that is ligandable i.e. tractable to small molecule binding. Certain DCAF proteins also display organelle and tissue specificity. Beyond their potential for PROTAC development, DCAF proteins are therapeutically relevant in their own right and have been implicated in diseases such as cancer. DELETER will explore this high-potential yet understudied family of E3 ligases structurally, functionally and biophysically. High-quality recombinant proteins and relevant reagents produced in this project will be used to engage in screening campaigns to identify ligands that will be developed into PROTACs and inhibitors. The information, reagents and compounds generated for DCAFs will expand the scope of targeted protein degradation and has potential to increase the number of targets degradable by PROTACs.

Mots clés : e3 ligase, targeted protein degradation, protac, dcaf, x ray crystallography, structural biology

Participants :
- University of Dundee (Royaume-Uni) — Coordinator, beneficiary, Enseignement supérieur ou secondaire, subvention : 212933.76 €
Projet TURBOMUD (Horizon 2020, appel à projets 2020)
Action : Postdoctoral Fellowships - European Fellowships
Panel : Environment and Geosciences
Statut du projet : SIGNED

Paleoseismology is a relatively recent branch of earthquake-related studies but, since its birth, it is rapidly expanding back in time the earthquakes (EQs) catalogues worldwide. Its contribution to historical and geological EQs detection has shed light on one of the most crucial challenges of modern geology: high magnitude EQs recurrence and our ability to “predict” them. Only this way, improving the characterization of seismic hazard by estimating magnitude and recurrence interval between large events, one would be able to mitigate the seismic risk and implement proper prevention policies for the nearby population. The TURBOMUD proposal is aiming to expand and refine this knowledge for the Gulf of Cadiz (GoC) accretionary wedge, using a large dataset collected during the most recent and previous expeditions carried out in the region. An innovative research plan has been designed, which will conjugate mud volcanism and turbidites occurrence, to better estimate the seismic hazard for this convergent area. With the help of unique material and data, including two long sediment cores obtained with the seafloor drill rig MeBo, several gravity cores, as well as bathymetric and seismic surveys, an extensive study on the GoC paleoseismology will be implemented. Specifically, several statistical techniques will be used to post-process the data, which will allow to test synchronicity of EQ-related events. Following a pioneering approach, the proponent is planning to apply and integrate the classical methods for the study of turbidite deposits to the suites of techniques used to describe mud volcanoes’ episodicity, in order to pinpoint past EQ events. The novel idea of joining these two ways of studying subduction zones EQs will provide an enhanced understanding as well as a more exhaustive mean of EQ risk assessment for this region. Given the uncertainties in the available paleoseismological methods, the TURBOMUD project will contribute to a major advance in this field.

Mots clés : mud volcanism, turbidites, paleoearthquakes, radiocarbon dating, fluid seepage

Participants :
- Spanish National Research Council (Espagne) — Coordinator, beneficiary, Recherche, subvention : 160932.48 €
Projet NERVASION (Horizon 2020, appel à projets 2020)
Action : Postdoctoral Fellowships - European Fellowships
Panel : Life Sciences
Statut du projet : SIGNED

Pancreatic ductal adenocarcinoma (PDAC) is an exceptionally aggressive cancer with a 5-year survival rate below 10%. It is resistant to traditional treatments and unresponsive to immunotherapy. New insights into the biology of PDAC are needed to identify novel therapeutic targets. Nerve invasion, defined as the presence of cancer cells along nerves and within different layers of nerve fibres, is a hallmark feature of PDAC. Patients that show signs of nerve invasion have a worse prognosis, higher risk of tumour recurrence, and suppressed anti-tumour immune responses. During PDAC, nerves form a dynamic microenvironment in which glial cells, neurons, stroma cells, cancer cells, and immune cells interact. The mechanistic basis of this communication and its effects on cancer progression remain undefined. Thus, in this project, cutting-edge transcriptomics technology preserving spatial information will be applied to human and murine PDAC tumour tissue sections. The cellular and molecular pathways dysregulated explicitly within cancer-invaded nerves will be identified, and the therapeutic potential of their targeting will be controlled in vitro and in vivo. The findings generated within this project could provide novel treatment strategies for PDAC and essential insights into the basic biology of cancer-nerve-immune interactions during tumorigenesis.

Mots clés : tumor microenvironment, cellular niches, immune cells, nerves

Participants :
- Board of the Swiss Federal Institutes of Technology (Suisse) — Coordinator, beneficiary, Enseignement supérieur ou secondaire, subvention : 191149.44 €
Projet PARAISO (Horizon 2020, appel à projets 2020)
Action : Postdoctoral Fellowships - European Fellowships
Panel : Environment and Geosciences
Statut du projet : SIGNED

Parasitic trophic interactions have been largely excluded in food web studies, but recent research has highlighted their integral role in affecting food web properties. Previous efforts to unravel trophic interactions between parasites and their hosts have used stable isotope analysis of whole tissues (bulk SIA, 13C and 15N), but these studies show considerably higher variability in the isotopic differences between parasites and their resources than usually observed for free-living species. This variability, combined with likely effects on the isotopic composition of infected hosts further confound trophic interactions within food webs. PARAISO aims to make a significant contribution to our understanding of parasitic trophic interactions and their potential to affect the isotopic composition of infected hosts through an innovative integrated approach combining field sampling and laboratory feeding experiments with the simultaneous analysis of bulk SIA and compound-specific stable isotope analysis of amino acids (CSIA-AA). This novel technique allows for the detection of changes in individual amino acids during trophic transfer and for comparison of source vs trophic amino acids to identify the trophic level of individual animals. Combining field samplings, laboratory-based feeding experiments with four common coastal parasite-host systems, and the use of bulk SIA and CSIA-AA will allow for determination of isotopic changes caused by dietary shifts or parasitic infections in both hosts and parasites. With this novel interdisciplinary approach using cutting-edge technologies, PARAISO will significantly advance our understanding of trophic transfer during parasite-host interactions. Through successful implementation of this project, the gained skills and dissemination actions will considerably contribute to EU excellence in isotope ecology and ecological parasitology and place the applicant in a powerful position to continue her career.

Mots clés : stable isotope analyses, trophic parasite host interactions, feeding experiments, csia aa, bulk sia

Participants :
- Dutch Research Council (Pays-Bas) — Coordinator, beneficiary, Recherche, subvention : 187572.48 €
Projet LINKERS (Horizon 2020, appel à projets 2019)
Action : Postdoctoral Fellowships - European Fellowships
Panel : Life Sciences
Statut du projet : CLOSED

Parkinson disease (PD) is the most common movement disorder. Dysfunction of basal ganglia circuits in PD leads to characteristic motor deficits including bradykinesia, with hypometria and reduced EMG activity, tremor, and frequently gait disorders with start hesitation or freezing of gait (FOG) associated with increased falling. On the one hand, there is a large literature on the postural adjustments during gait initiation and the biomechanics of ongoing gait in healthy and patient populations. On the other hand, neuronal recording in the pallidum, subthalamic nucleus (STN), substantia nigra pars reticulata (SNpr) and mesencephalic locomotor region (MLR) demonstrate activity related to movement and locomotion in rats, cats, primates and humans. DBS, particularly STN- and MLR-DBS, can effectively alleviate postural and locomotor deficits in PD, although the neural mechanisms and the precise role of each structure in locomotion is still matter of debate. The aim of this study is to characterize the association between STN and MLR neuronal activity and the biomechanical parameters of locomotion and gait initiation. I will characterize these associations in PD patients using neuro-muscular, neuro-kinematic and neuro-neuronal (STN-STN, MLR-MLR) coherence in different locomotor paradigms under different treatment conditions. This study will make an important contribution to a poorly studied but important aspect of motor control in PD. From a knowledge transfer point of view, it will provide important information to clinicians and researchers using DBS to ameliorate postural difficulties and FOG. From an interdisciplinary point of view, it will help neurologists to refine diagnosis as well as foster the core of knowledge and help targeting new avenues of treatment to rehabilitation professionals involved in the non-invasive treatments of PD.

Mots clés : locomotion, coupled biomechanics and neurophysiology signals

Participants :
- Institut du cerveau (France) — Coordinator, beneficiary, Recherche, subvention : 196707.84 €
Projet ParkIFNAR (Horizon 2020, appel à projets 2019)
Action : Postdoctoral Fellowships - European Fellowships
Panel : Life Sciences
Statut du projet : CLOSED

Parkinsonian disorders (PDs) affect more than 1.2 million people in Europe with an estimated cost of €13.9 billion annually and have no cure. PDs have long been characterized by decreased motor activity, which is caused by the loss of dopaminergic neurons. Several disturbed processes have been described such as proteostasis, mitochondrial function and neuroinflammation, but its molecular mechanisms and their interactions are essentially unknown. There are recent evidences of alterations in the interferons’ (IFN) signalling involved in the neuroinflammatory processes of PDs. The host lab discovered the essential role of IFNβ signalling in the neuronal homeostasis of PD. The IFNβ receptor (IFNAR) plays a key role in the control of IFNβ cellular responses. However, the regulatory mechanisms, at level of its membrane subunits IFNAR 1 and 2, and especially its soluble receptor sIFNAR2 have not been characterized in PD-associated neuroinflammatory context. Most remarkably, the host lab has also identified a new mutation in IFNAR1 associated with a family of PD patients, and I have found that PDs present lower serum levels of sIFNAR2 than controls indicating dysregulation in this pathway. Based on our findings, I hypnotise that a defective IFNβ-IFNAR signalling is associated with PD pathology and this could be partly mediated by the function of sIFNAR2 as this protein is able to modulate the endogenous IFNβ and interplay with membrane-expressed IFNAR1 or IFNAR2. Fulfilling the tasks of this proposal will have strong potential to reveal the mode of action of sIFNAR2, as IFNβ-IFNAR signalling regulator, and as a novel molecule with intrinsic activities in maintaining & restoring the neuronal homeostasis and therefore could identify novel targets for treatment of PD. Through this MSCA-IF I would benefit from a unique training and expertise in one of the most cutting-edge laboratories of the research proposed here, and it will impact extremely my future scientific career.

Mots clés : parkinson disease, ifn, soluble ifn  receptor, neuronal homeostasis, ifn  signaling regulation, neuroinflammation, pd mice model, neuronal and glia cultures, crispr, cas9, rna seq, chip seq

Participants :
- University of Copenhagen (Danemark) — Coordinator, beneficiary, Enseignement supérieur ou secondaire, subvention : 207312.0 €
Projet PARNANT (Horizon 2020, appel à projets 2018)
Action : Postdoctoral Fellowships - European Fellowships
Panel : Life Sciences
Statut du projet : CLOSED

Parkinson’s disease (PD) is the second most common neurodegenerative disorder (after Alzheimer's) associated with oxidative stress and aging, and affects an estimated 1% of people worldwide over 60 years of age. The pathogenetic triggers of neurodegenerations are largely unknown. Current therapeutic interventions only partially alleviate symptoms and do not restore normal neuronal function or prevent progressive neurodegenerations. Identifying novel molecular targets and searching for therapeutic agents that block neurodegeneration and promote neuronal restoration is a key challenge in the field. I and the Host have together identified 51 candidate genetic loci associated with age-related neurodegenerations in PD model and PD patients, respectively. These candidate genes are evolutionarily conserved in both vertebrate and invertebrate animals. I hypothesize that some of these genes, via an evolutionarily conserved signal transduction pathway, alleviate the oxidative stress in the dopaminergic neurons and protect them against degeneration. This project combines my (C. elegans genetics) and Host (cell-based PD models) expertise to identify new genetic pathways that mediate protection against neurodegenerations during oxidative stress and aging. I expect that achieved goals of the proposal will be important discovery that should lead to novel therapeutic targeting for Parkinson’s disease, and other neurodegenerative proteinopathies. My long-term goal is to become an independent scientist and establish lab to find novel therapeutic targets and strategies for the diseases associated with oxidative stress, including PD. Gained research experience together with improving my teaching, mentoring and management skills during this fellowship will help me to achieve my goals and transition myself into independence.

Mots clés : c  elegans, ips cell, neurodegeneration, genetics, stress

Participants :
- European Academy of Bolzano (Italie) — Coordinator, beneficiary, Recherche, subvention : 183473.28 €
Projet SC-EpiTranscriptome (Horizon 2020, appel à projets 2017)
Action : Postdoctoral Fellowships - European Fellowships
Panel : Life Sciences
Statut du projet : CLOSED

Past research has identified epigenetic mechanisms including histone modifications as key regulators of transcription and implicated them in cellular differentiation. But while our knowledge about their cell type specific distribution and its influence on transcription has constantly increased, we still know very little about the orchestration of epigenetic and transcriptional changes as they occur during differentiation. To gain a global understanding of the order of events, we aim to identifying changes in gene expression and main transcriptional repressive and promoting histone modifications in cells undergoing differentiation. For this we will develop a novel approach to examine the distribution of histone modifications on a single cell level adapting a method based on antibody targeted micrococcal nuclease (ChIC-seq), which will lead to a modification dependent enzymatic digestion of the DNA. In comparison with existing single cell ChIP approaches this method lacks a precipitation step, leading to minimal material loss per cell, while allowing the use of the variety of histone mark specific monoclonal antibodies. Adapting this approach to the previously described method for co-acquisition of transcriptomic and genomic information from a single cell existing in the lab, will allow the normalization of the histone state using the transcription status of the cell. To analyze the order of changes associated with cell differentiation, we will use single cell RNA seq analysis pipelines (RaceID + StemID) to identify and enrich for cells in between two specific differentiation stages.

Mots clés : single cell transcriptomics, single cell epigenomics, parallel acquisition, cell differentiation, epigenetic gene regulation, method developement

Participants :
- Royal Netherlands Academy of Arts and Sciences (Pays-Bas) — Coordinator, beneficiary, Recherche, subvention : 165598.8 €
Projet CHI-ZEF (Horizon 2020, appel à projets 2016)
Action : Postdoctoral Fellowships - European Fellowships
Panel : Life Sciences
Statut du projet : CLOSED

Patterning of the vertebrate optic vesicle into proximal/optic stalk and distal/neural retina involves midline-derived Hh signalling, which promotes stalk specification. At the neural retina/optic stalk border, the cell adhesion molecule Cdon binds Hh, acting as a decoy receptor to protect the neural retina from Hh activity. How Cdon controls Hh dispersion, what is the destiny of the Hh protein accumulated at the neural retina/optic stalk boundary, whether Cdon participates in the release of Hh from its producing cells or whether Cdon has Hh-unrelated functions in the neural retina are the arising and still unanswered questions I aim to tackle in this proposal. Using the zebrafish as a model system and CRISPR/Cas9 technology I will first generate unprecedented tools to follow in vivo Cdon/Hh interaction, and then address how Cdon, expressed in both the ventral diencephalic midline and the neural retina, shapes the gradient of Hh responsible for proximo-distal patterning of the eye. I expect that the development of this proposal will provide significant advance on how morphogenetic signalling pathways operate, ultimately reverting into the field of regenerative medicine and clinical research related to congenital ocular malformations.

Mots clés : eye morphogenesis, patterning, cell signaling, sonic hedgehog, genome editing

Participants :
- Spanish National Research Council (Espagne) — Coordinator, beneficiary, Recherche, subvention : 158121.6 €