Data-Gouv-ML/pcri-actions-marie-curie-participations-et-projets-laureats huggingface dataset:
Projet TIGER (Horizon 2020, appel à projets 2014)
Action : Postdoctoral Fellowships - European Fellowships
Panel : Life Sciences
Statut du projet : CLOSED

Transposable elements (TEs) are DNA sequences that are able to spread within and between genomes. While transposition may lead to evident harmful effects, TEs can also positively impact the host genome by, for instance, donating intrinsic regulatory elements such as promoters. The main goal of this research project is to understand the regulatory changes that TEs engage within host genomes. While in mammals TE-derived promoters are often observed, only recently Drosophila TEs were described as potential platforms of gene regulatory networks, opening a new field for important discoveries. Since TEs are extremely active in fruit flies and Drosophila is found worldwide, TE copies that are population-specific are observed. Drosophila constitutes therefore a perfect model to study the impact of TEs in the host transcriptome. We hypothesize that Drosophila TEs are able to act as gene promoters and cause differential gene expression between wild-derived strains. Our first aim is to discover strain-specific TE-derived promoters involved in differential gene expression between Drosophila melanogaster populations by using a genome-wide high throughput sequencing method named RAMPAGE. In our second aim we will determine how histone modifications regulate TE-derived promoters by producing chromatin maps for each strain studied. The comparison of full sites (sites containing the insertion of a TE in one population) with empty sites (sites devoid of a TE insertion in another population) allow us to clearly demonstrate the impact and regulation of TE promoters.

Mots clés : gene regulation, transposable elements, exaptation, comparative genomics, drosophila, plasticity, adaptation, genome wide high throughput sequencing

Participants :
- Université Claude Bernard - Lyon 1 (France) — Coordinator, beneficiary, Enseignement supérieur ou secondaire, subvention : 185076.0 €
Projet GOMB-TBI (Horizon 2020, appel à projets 2014)
Action : Postdoctoral Fellowships - European Fellowships
Panel : Life Sciences
Statut du projet : CLOSED

Traumatic Brain Injury (TBI) is the leading cause of death and disability in young adults. Hours or days after the primary injury, secondary injury will develop. This secondary injury is responsible for most in-hospital deaths after TBI. Early interventions to prevent secondary injury are currently targeted at reducing intracerebral pressure and promoting cerebral blood flow (CBF), aiming to improve brain oxygenation and reduce ischaemia. However, there is increasing evidence that other mechanisms besides ischaemia are important in the development of secondary damage. Because our brain depends on glucose for functioning, alterations in cerebral glucose metabolism provide insight into the causes of secondary brain damage. The influence of plasma glucose has been studied, but the relation between body and brain glucose metabolism after TBI is unclear. In addition, there are indications that local neuroinflammation influences local glucose metabolism. New techniques, such as positron emission tomography (PET) with 18-Fluorodeoxyglucose (18FDG) and cerebral microdialsyis, allow detailed study of brain metabolism after TBI. During this project we aim to study the causes and consequences of alterations in brain glucose metabolism using 18FDG PET and microdialysis. We will study the influence of alterations in oxygen supply, neuroinflammation and body glucose on alterations in glucose metabolism. Thereafter, the consequences of alterations in glucose metabolism on brain tissue will be studied, using structural magnetic resonance imaging (MRI) and diffusion tensor imaging (DTI). This will provide novel insights into the underlying mechanisms of secondary injury following TBI and its long term consequences. These data should provide a basis for the design and assessment of future neuroprotective therapies.

Mots clés : glucose metabolism, traumatic brain injury

Participants :
- University of Cambridge (Royaume-Uni) — Coordinator, beneficiary, Enseignement supérieur ou secondaire, subvention : 97727.4 €
Projet EDiPSPrevent (Horizon 2020, appel à projets 2020)
Action : Postdoctoral Fellowships - European Fellowships
Panel : Life Sciences
Statut du projet : SIGNED

Treatments for schizophrenia are inadequate, and intervening prior to disease onset is a novel approach to improve patient outcomes. Clinical studies using positron emission tomography (PET) have revealed that patients with chronic schizophrenia consistently show an increase in dopamine synthesis capacity in the striatum. This dysfunction is also evident in people at-risk of developing schizophrenia, specifically in those who are later diagnosed with this disorder. Normalizing this increase in pre-synaptic dopamine therefore reflects an extremely promising target for new treatments of schizophrenia. I developed a novel animal model of schizophrenia – Enhanced Dopamine in Prodromal Schizophrenia (EDiPS) – which replicates the pre-synaptic dopaminergic dysfunction seen so robustly in patients. In this project, I propose to firstly use state-of-art preclinical PET to examine pre-synaptic dopamine in EDiPS animals. This will confirm its translatability to the findings in the clinical population. Through a secondment, I will assess other key aspects of dopamine neurotransmission in these animals, focussing on the source of dopaminergic innervation to the striatum – the midbrain. As a complementary objective, I will assess any difference between male and female EDiPS animals for each of these outcomes. This is especially relevant to schizophrenia, which is a sexually dimorphic disorder. The second objective of this fellowship is to trial a novel approach to normalise the increase in pre-synaptic dopamine in EDiPS animals, through a Trace Amino Acid Receptor 1 (TAAR1) agonist. I will trial the TAAR1 agonist both acutely in adult EDiPS animals, and when given chronically during development, to simulate an intervention in the at-risk population. This will be the first study to examine the effects of a TAAR1 agonist in the developing brain. The scientific outcomes of this fellowship will have real-world implications for the treatment of patients with schizophrenia.

Mots clés : animal models, dopamine, dorsal striatum

Participants :
- Imperial College London (Royaume-Uni) — Coordinator, beneficiary, Enseignement supérieur ou secondaire, subvention : 212933.76 €
Projet Kidney-Treg (Horizon 2020, appel à projets 2019)
Action : Postdoctoral Fellowships - European Fellowships
Panel : Life Sciences
Statut du projet : CLOSED

Tregs are a subtype of T cells exerting immunosuppressive functions that are vital to prevent autoimmunity. Recently, tissue-resident Tregs have been proposed to be phenotypically and functionally distinct from the generic Tregs in circulation. Systemic Treg supplementation and depletion studies strongly support a role for Tregs in protection from injury and promotion of tissue repair in models of kidney diseases, highlighting the potential of harnessing Tregs in these pathologies. However, due to the systemic nature of the Treg manipulation in these studies, it is unknown if the effect resides in systemic impacts or in tissue-based impacts. The aim of this project is to characterise Tregs located in the kidney and to expand the kidney-resident Treg population, without impacting the systemic population, in order to evaluate their specific impact on the physiology and pathologies of the kidney. First, I will characterise the kidney-resident Tregs using state-of-the-art molecular biology techniques, such as scRNAseq, and an innovative mouse model of cell fate mapping based on a photoactivatable Cre-recombinase. Second, I will evaluate their specific functions in physiology and pathologies of the kidney using a mouse model of tissue-specific Treg expansion uniquely available in the host laboratory. As well as the novel biology exploring the potential functions of kidney-resident Tregs, the distinction between systemic and kidney-based effects is critical to develop new therapeutic tools aiming to target kidney-resident Tregs. The induction of tissue-specific tolerance for kidney autoimmunity or transplantation, without inducing systemic immune suppression, constitute a promising and feasible alternative to existing immunosuppressive therapies. The knowledge and experience gained from this project combined with my scientific and personal development will give me all the skills I need to achieve my objective to pursue an exciting scientific career in academia.

Mots clés : tregs, tissue resident t cells, kidney, transplantation, autoimmunity

Participants :
- UK Research and Innovation (Royaume-Uni) — Coordinator, beneficiary, Recherche, subvention : 224933.76 €
Projet ProTeCT (Horizon 2020, appel à projets 2018)
Action : Postdoctoral Fellowships - Global Fellowships
Panel : Life Sciences
Statut du projet : CLOSED

Trichomoniasis, caused by the protozoan parasite Trichomonas spp., is the most common, non-viral, sexually transmitted infection in the world. Only two closely related antibiotic drugs are approved for its treatment. The accelerating emergence of resistance to current antibiotics and no alternative treatment options pose an increasing threat to public health, resulting in an urgent need for novel effective anti-parasitic compounds. This project focuses on Trichomonas proteasome that is an underexploited enzyme critical for parasite survival. In this proposal, the proteasome will be functionally and structurally characterized. The substrate specificity of each subunit will be determined and fluorescent substrates that can monitor activity of each subunit will be designed. Libraries of proteasome inhibitors will be screened and hit compounds will be analyzed in co-crystallization studies with Tv proteasome. Ultimately, biochemical and structural data will be used to rationally design inhibitors for treatment of trichomoniasis.

Mots clés : trichomoniasis, proteasome, inhibitor

Participants :
- Czech Academy of Sciences (Rép. Tchèque) — Coordinator, beneficiary, Recherche, subvention : 237756.24 €
- University of California System (Etats-Unis) — Partner, organization partner, Enseignement supérieur ou secondaire, subvention : 0.0 €
Projet TropicalModuli (Horizon 2020, appel à projets 2017)
Action : Postdoctoral Fellowships - European Fellowships
Panel : Mathematics
Statut du projet : CLOSED

Tropical geometry is the geometry of the combinatorial objects associated to degenerations and compactifications of algebraic (or analytic) varieties. As in algebraic geometry, the tropical geometry of moduli spaces is one of the richest and most fundamental parts of this field, with many of the features of tropical geometry only being visible through the prism of moduli spaces. The experienced researcher proposes to extend the foundations of tropical moduli theory, building on his prior work on tropical moduli stacks, and to explore new applications of these combinatorial techniques to classical problem in arithmetic and algebraic geometry. During the fellowship the experienced researcher will focus on the following three types of moduli spaces: - The universal Picard variety, with applications to Brill-Noether theory (universally over the moduli space of curves), as well as to theta-characteristics, spin curves, and Prym varieties. - Moduli of (higher) differentials, with applications to Eliashberg's problem on the compactification of the double ramification locus and the compactification of strata of abelian and quadratic differentials. - Moduli of G-admissible covers with the goal of developing a tropical approach to the regular inverse Galois problem.

Mots clés : tropical geometry, moduli spaces, stacks, logarithmic structures, picard varieties, brill noether theory, abelian differentials, flat surfaces, g admissible covers

Participants :
- University of Warwick (Royaume-Uni) — Coordinator, beneficiary, Enseignement supérieur ou secondaire, subvention : 195454.8 €
Projet TubInTrain (Horizon 2020, appel à projets 2019)
Action : Doctoral Networks - Joint Doctorates
Panel : Life Sciences
Statut du projet : SIGNED

TubInTrain is a Consortium of 7 beneficiaries and 14 partners from 6 European countries joining their forces to train 13 Early Stage Researchers (ESRs) for n European Joint Doctorate. TubInTrain mission is to: - develop an Elite European Doctorate School to train ESRs in the context of neurodegeneration as well as in essential scientific, entrepreneurial and management skills; - create a multidisciplinary and multi-sectorial network for long-term cooperation in the research training of internationally oriented scientists for the global workplace; - train a new generation of cutting-edge researchers/professionals for employment by highly attractive European Institutions. The ESRs will work on an integrated innovative research project focused on the microtubules breakdown associated to neurodegenerative diseases and neurotoxicity. Despite the constant improvement in medical treatments, a significant leap in therapies for such diseases has been lacking for a long time. This calls for an ever-renewing effort in the investigation of their basic pathological mechanisms. This objective will be achieved through fertile collaborations between the partners, which have diverse expertise, ranging from computational chemistry to neurobiology. The Consortium will manage the recruitment/supervision/assessment processes. Each ESR will be co-supervised by two Beneficiaries, delivering the double degree, and a Partner. Two secondments are planned to improve the ESR research and training programs with management skills. ESRs will benefit of lectures/Training Schools/Workshops integrating the local graduate programs. This process coaches ESRs to: rise to challenges, be flexible/adaptable, achieve valuable attributes for today’s knowledge-based environment, be ready for creative and leadership roles in industry/academy/public sectors. All the know-how built up among the Consortium will spread out to external groups through exposures, public engagement, network and outreach activities

Mots clés : tubulin, microtubules, molecular modeling, fiber diffraction, organic synthesis, alpha synuclein, aggregation

Participants :
- Université Paris-Saclay (France) — Partner, beneficiary, Enseignement supérieur ou secondaire, subvention : 549604.08 €
- University of Barcelona (Espagne) — Partner, beneficiary, Enseignement supérieur ou secondaire, subvention : 501809.76 €
- Osnabrück University (Allemagne) — Partner, beneficiary, Enseignement supérieur ou secondaire, subvention : 505576.8 €
- University of Milan (Italie) — Coordinator, beneficiary, Enseignement supérieur ou secondaire, subvention : 1045998.72 €
- Spanish National Research Council (Espagne) — Partner, beneficiary, Recherche, subvention : 250904.88 €
- Board of the Swiss Federal Institutes of Technology (Suisse) — Partner, beneficiary, Recherche, subvention : 281276.64 €
- Université de Strasbourg (France) — Partner, beneficiary, Enseignement supérieur ou secondaire, subvention : 274802.04 €
Projet CryoMyco (Horizon 2020, appel à projets 2020)
Action : Postdoctoral Fellowships - European Fellowships
Panel : Life Sciences
Statut du projet : CLOSED

Tuberculosis (TB) is a global disease. With over 1.6 million deaths in 2017 alone and an estimated one quarter of the world’s population infected with Mycobacterium tuberculosis (Mtb), the etiological agent, TB is found throughout the world. Mtb is highly successful as a pathogen, in part due to its distinct and hydrophobic outer membrane (OM) and its type VII secretion systems (T7SSs). Although critical for the success of Mtb as a pathogen, the structure and mechanism of T7SSs are still poorly understood. In Mtb, five T7SSs (ESX-1 to 5) perform diverse functions such as immunomodulation, virulence, uptake of nutrients and iron. In T7SSs, four conserved membrane components, EccB/C/D/E assemble into a hexameric inner membrane complex, with a fifth transiently interacting membrane component, MycP. We have previously shown a low resolution, hexameric structure of the EccB/C/D/E membrane complex and recently two models of a dimeric subcomplex have been published. However, little is known on the structure of the entire core complex (including MycP), what is the secretion pore and how is it gated, or how secretion takes place through the OM, making this research proposal timely and necessary. The aim of this fellowship is to elucidate the underlying mechanism of secretion through the diderm cell envelope by: 1 - Elucidating the high-resolution structure of the hexameric T7SS membrane complex of Mtb. 2 - Investigate the molecular and structural mechanisms behind the OM translocation process. The results stemming from this proposal have the potential to aid and steer structure-based drug designs against Mtb. The host lab has pioneered cryo-EM of secretion systems and has state-of-the-art infrastructure and know-how that will provide the fellow with the best possible training and chances of success. With appropriate measures put in place, this project will drive forward mycobacterial research and will serve as a starting platform for identifying new possible drug targets.


Participants :
- Universität Hamburg (Allemagne) — Coordinator, beneficiary, Enseignement supérieur ou secondaire, subvention : 174806.4 €
Projet HADES (Horizon 2020, appel à projets 2019)
Action : Postdoctoral Fellowships - European Fellowships
Panel : Chemistry
Statut du projet : SIGNED

Tuberculosis (TB) is one of the most aberrant causes of global mortality and the molecular mechanisms of its pathogenesis are not well understood. The extrapulmonary dissemination of TB involves requires a crucial virulence factor designated as heparin-binding haemaglutinin adhesin (HBHA). HBHA is a 28 kDa dimeric protein localised at the surface of the Mycobacterium tuberculosis (MTB) that binds dextran sulphate, dermatan sulphate, glycosaminoglycans and heparan-sulphate proteoglycans thus mediating the adhesion with epithelial cells and to extracellular matrix components. Despite a crucial role in the dissemination of TB, a key relevance as strong diagnostic antigen and as therapeutic target, there is currently limited understanding of the structure and mechanism of action of HBHA. The ambitious aim of this proposal is to characterise at high-resolution the mechanisms of function of HBHA in different phases of the life cycle of MTB. To achieve this ambitious target, we will carry out an integrated investigation of solution-state and solid-state NMR nuclear magnetic resonance (NMR) to acquire high-resolution data on the interaction of HBHA with membranes of MTB. The NMR experiments will be complemented with biophysical studies and mutagenesis to accurately define the relationship between structure, dynamics and function of HBHA. Our preliminary data suggest that this ambitious project comes at the most opportune time as we now have tools, materials and knowledge to resolve this important goal for biochemistry and reveal the propeties of a crucial molecule for the mechanism of extrapulmonary dissemination of TB.

Mots clés : nuclear magnetic resonance, biochemistry, protein structure, membrane proteins

Participants :
- University of Naples Federico II (Italie) — Coordinator, beneficiary, Enseignement supérieur ou secondaire, subvention : 171473.28 €
Projet TBNANO (Horizon 2020, appel à projets 2018)
Action : Postdoctoral Fellowships - European Fellowships
Panel : Chemistry
Statut du projet : CLOSED

Tuberculosis (TB) is still a major public health problem worldwide. It is estimated that more than one-quarter of the world's population is infected with this airborne infectious disease. Moreover, the increase of multidrug- and extensively drug-resistant TB is alarming. TB is caused by Mycobacterium tuberculosis, an intracellular pathogen that can survive in host cells, mainly in macrophages. The uptake of the antitubercular drugs by infected host cells is limited. The orally or intravenously administered drugs are distributed throughout the body causing side effects and the majority of the drug molecules do not reach their targets. The elimination of the intracellular bacteria could be more efficient with host cell directed delivery. The TBNANO project aims to develop and in vitro evaluate antitubercular agent-loaded nanocapsules decorated with host cell targeting molecules. For this purpose, naturally occurring, biocompatible and biodegradable polysaccharide nanocapsules loaded with a recently approved anti-TB drug (bedaquiline) and antimicrobial peptides will be used. The surface of the nanocapsules will be functionalized with macrophage targeting ligands, such as peptides and mannose derivatives. With such nanotechnology-based drug delivery system, enhanced cellular uptake can be achieved by the host cell macrophages, therefore, the anti-TB agent can reach the intracellular bacteria as site of action. This approach leads to increased bioavailability and selectivity of the drugs while reducing their undesirable side effects. The proposed project could provide a breakthrough step in nanotechnology-based TB treatment to get closer to a world free of TB. Furthermore, this multidisciplinary project provide valuable transfer of knowledge to the host institution, as well as advanced training of the young researcher in the field of nanomaterial science to broaden her expertise in drug delivery systems.

Mots clés : peptide chemistry, biological chemistry, biochemistry

Participants :
- Spanish National Research Council (Espagne) — Coordinator, beneficiary, Recherche, subvention : 172932.48 €
Projet DLL4-LVN (Horizon 2020, appel à projets 2015)
Action : Postdoctoral Fellowships - European Fellowships
Panel : Life Sciences
Statut du projet : CLOSED

Tumor metastasis is responsible for >90% of cancer deaths. A tumor type where the mechanisms driving this process are especially unclear is melanoma, the only cancer where apparently thin lesions (2 mm depth) have a high potential for metastatic dissemination. As a PhD student in P. Agostinis lab (KUL, Belgium) I identified a new strategy using the lysosomotropic agent chloroquine (CQ) to blunt melanoma metastasis, by normalizing the angiogenic vasculature via increased blood endothelial cell (BEC) NOTCH signaling. The complete abolishment of metastasis by CQ urged me to study whether another route of metastasis; the lymphatic system and the sentinel lymph nodes (SLN); was also affected. The importance of this route of metastasis is supported by recent evidence showing that even before the arrival of the tumor cells, the lymph endothelial cells (LEC) and immune cells in the SLN undergo dynamic changes that actively facilitate tumor cell recruitment, metastatic outgrowth and immune tolerance. This phenomenon is referred to as the ‘lymphovascular (pre)metastatic niche’. Pending questions are how the cancer cells, LEC and immune cells crosstalk and how to target them pharmacologically. My preliminary data, obtained during a short term EMBO Fellowship in the lab of M. Soengas (CNIO, Spain) show that CQ affects lymphangiogenesis even more than angiogenesis. These effects are due to an unexpected different wiring of the NOTCH pathway in BEC versus LEC. Activated LECs express high levels of the NOTCH ligand DLL4, which is trapped and inactivated in the endosomal compartment by CQ. Genetic interference in LEC revealed that DLL4 not only regulates lymphangiogenesis, but also the production of mediators of cancer cell homing and immune tolerance. In this project I will address the mechanistic role of DLL4 in the establishment of the lymphovascular niche, correlate DLL4 levels with melanoma patient prognosis and target DLL4 pharmacologically to improve therapeutic outcome.

Mots clés : metastasis, cancer, melanoma, lymph endothelial cells, dll4, pre metastatic lymphovascular niche, immune tolerance

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