Data-Gouv-ML/pcri-actions-marie-curie-participations-et-projets-laureats huggingface dataset:
Projet MolecularEVOLUTION (Horizon 2020, appel à projets 2015)
Action : Postdoctoral Fellowships - European Fellowships
Panel : Chemistry
Statut du projet : CLOSED

Cancer continues to be a major cause of death worldwide. While many drugs can reduce the size of tumors, their side effects commonly outweigh their benefits when the drug is administered by conventional methods. One promising approach to overcome this issue is to employ a synthetic enzyme to activate a prodrug into an active drug via a bioorthogonal reaction at the site of a tumor within a patient. Recent work by the group of Prof. E. W. Meijer at the Eindhoven University of Technology on amphiphilic polymers with pendant “sticky” hydrogen bonding moieties and pendant catalytic centers represents state-of-the-art synthetic enzymes. When these polymers are dissolved in dilute aqueous solutions, individual chains fold to form single chain polymer nanoparticles (SCPNs). The folding is thermodynamically driven by hydrophobic interactions and the dynamic aggregation of the “sticky” moieties. Although current SCPNs catalyze bioorthogonal reactions in water, they do not have well-defined high order structure like natural enzymes, instead exhibiting non-cooperative folding and open, elliptical structures. This lack of well-defined high order structure is due to a lack of polymer sequence control, as SCPNs reported to date are random or block copolymers. As a postdoctoral fellow in the Meijer group, I propose to make a new generation of biocompatible SCPNs that feature an aliphatic polycarbonate backbone that undergoes dynamic covalent chemistry in conjunction with the dynamic aggregation of the “sticky” pendant units to “molecularly evolve” the SCPN’s primary structure. This strategy will allow SCPNs to “correct” non-optimal sequences by giving each polymer chain the ability to reshuffle its primary structure, ultimately allowing the SCPNs to achieve lower energy folding states. I predict that the hydrophobic cores of the resulting evolved SCPNs will be more enzyme-like and thus better suited for catalysis and targeted drug therapy applications.


Participants :
- Eindhoven University of Technology (Pays-Bas) — Coordinator, beneficiary, Enseignement supérieur ou secondaire, subvention : 165598.8 €
Projet Tumour T cells (Horizon 2020, appel à projets 2019)
Action : Postdoctoral Fellowships - European Fellowships
Panel : Life Sciences
Statut du projet : SIGNED

Cancer is a global health burden and the second leading cause of death worldwide. In recent years, the development of immunotherapy has revolutionised the approach to cancer therapy. A significant limitation, however, is that it is only effective in a subset of patients and the biggest challenges remain the identification of immunogenic targets on human cancers and overcoming immunosuppression. Neoantigens, which are newly formed antigens that arise from mutated tumour proteins, are promising targets in immunotherapy. With the proposed project, we aim to investigate the immune response against human neoantigens which will be induced in a novel humanised tumour mouse model. This unique mouse model harbours the entire human CD8 TCR repertoire and expresses human HLA-2. We will test whether human neoantigens can elicit spontaneous anti-tumour T cell responses in acute inflammatory versus resting conditions, ultimately leading to tumour rejection. We hypothesise that T cells are not able to reject tumours in absence of acute inflammation, similar to the development of most human cancers. To investigate why neoantigen-specific T cells become dysfunctional and fail to reject tumours, we will characterise the functional state and metabolic phenotype of neoantigen-specific T cells by flow cytometry, metabolomics and TCR sequencing. In addition, we will characterise the TCR repertoire of T cells that cause tumour rejection under acute inflammatory conditions. Lastly, we will compare the therapeutic efficacy of adoptively transferred T cells transduced with newly identified TCRs with neoantigen-based vaccines against large established tumours. Overall, this project will contribute to the understanding of immunosurveillance and establish novel techniques to test predicted neoantigens. The identification of human immunogenic targets has the potential to make a global impact on cancer intervention.

Mots clés : neoantigens, cancer, immunology, t cells, immunometabolism, humanised mouse model, tumour microenvironment, cancer immunotherapy, adoptive cell transfer

Participants :
- Max Delbrück Center for Molecular Medicine (Allemagne) — Coordinator, beneficiary, Recherche, subvention : 174806.4 €
Projet PolyP-FXII in cancer (Horizon 2020, appel à projets 2015)
Action : Postdoctoral Fellowships - European Fellowships
Panel : Life Sciences
Statut du projet : TERMINATED

Cancer is a leading cause of venous thrombosis. Tumor-driven procoagulant mechanisms and therapies for interference with cancer-associated thrombosis are poorly developed and are associated with life-threatening bleeding complications. Coagulation factor XII is a protease that is essential for thrombus formation while being dispensable for hemostatic processes that terminate blood loss. Challenging the dogma of a coagulation balance, targeting factor XII protects from thromboembolic disease without interfering with hemostasis. The inorganic polymer polyphosphate activates factor XII with implications for thrombosis. In addition to their roles in coagulation, polyphosphate and factor XII have mitogenic activities and contribute to cell proliferation. I have recently characterized the mechanisms of polyphosphate-driven coagulation and discovered a critical function of polyphosphate/factor XII in prostate cancer-driven thrombosis. The current investigations will explore functions and mechanisms of polyphosphate/factor XII for cancer-driven coagulation and tumor growth using cancer cells in culture, genetically altered murine models and cancer patient materials. I aim to understand activation, regulation and functions of the polyphosphate/factor XII-pathway for venous thromboembolic disease as well as tumor growth. In a translational approach, I will analyze novel polyphosphate/factor XII-inhibitors for interference with cancer-driven thrombosis and tumor proliferation. The applied project will give a comprehensive insight into the function of polyphosphate/factor XII in malignancy and will offer a novel and unique opportunity for a safe anticoagulation therapy with minimal or no bleeding risk with additional anti-cancer activities.

Mots clés : vascular biology, blood coagulation, thrombosis, plasma contact system, factor xii, polyphosphate, cancer

Participants :
- Universität Hamburg (Allemagne) — Coordinator, beneficiary, Enseignement supérieur ou secondaire, subvention : 159460.8 €
Projet GDCOLCA (Horizon 2020, appel à projets 2017)
Action : Postdoctoral Fellowships - European Fellowships
Panel : Life Sciences
Statut du projet : CLOSED

Cancer is the leading cause of death in the world. Immunotherapy is having a major impact in counteracting these cancer-related deaths, since the activity of anti-tumour immune cells can be enhanced to kill cancer. Unfortunately, immunotherapy does not work for every patient, so we must understand how other immune cells participate in cancer progression to design new immunotherapies that may benefit a greater number of patients. One particular type of immune cell, called gamma/delta T cells, was recently shown by my Host to promote breast cancer metastasis via IL-17, an important pro-tumour cytokine. However, the significance of gamma/delta T cells and IL-17 in other cancer metastasis settings remains unclear. In this proposal, I will address this point using a newly developed sophisticated colorectal cancer metastasis model. This novel mouse model shows 100 percent penetration of metastasis, of which 80 percent is to the liver, similar to human colorectal metastasis. Using this metastasis model, I will: 1. Clarify characteristics of gamma/delta T cells in colorectal cancer metastasis, 2. Assess if depletion of gamma/delta T cells by a neutralizing antibody as well as crossing the model with gamma/delta T cell-deficient mice would reduce the occurrence of metastasis, and 3. Examine the involvement of BTNL1, which is a specific activator for anti-tumorigenic IFN-producing gamma/delta T cells in the intestine. The role of BTNL1 in any cancer setting and the importance of IL-17-producing gamma/delta T cells in colon cancer metastasis is largely unexplored. Addressing our goal to understand the role of these gamma/delta T cells in colon cancer metastasis, I will newly acquire expertise and technical skills in both immunology and cancer biology as well as have experience in excellent collaboration with several laboratories. This proposal will identify additional targets for immunotherapy that may help patients with metastatic colon cancer.

Mots clés : metastasis, gamma delta t cells, colon cancer

Participants :
- Cancer Research UK (Royaume-Uni) — Coordinator, beneficiary, Recherche, subvention : 195454.8 €
Projet BaCTher (Horizon 2020, appel à projets 2014)
Action : Postdoctoral Fellowships - Global Fellowships
Panel : Life Sciences
Statut du projet : CLOSED

Cancer is the second cause of death in the western world and it is expected to become the leading one in developing countries in the next future. The long-term outcome of BaCTher is the improvement of the cancer treatment that can overcome the intrinsic limitations of the current therapies through the development of a new promising therapeutic strategy. The specific hypothesis behind the proposed research is that an attenuated Salmonella enterica serovar Typhimurium (STMΔznuABC) is able to influence the tumor microenvironment (TME) reprogramming or re-educating the immune response, and inducing a shift from protumorigenic inflammation to anticancer immunity, which results in a tumor growth control. This hypothesis is based on the observation that: 1) there is compelling scientific evidence of the effect of bacteria, and in particular Salmonella, against cancer growth; 2) STMΔznuABC is able to reduce cancer growth and to increase the average life expectancy in a mammary adenocarcinoma Balb/c mice model; 3) STMΔznuABC is able to penetrate and proliferate into the tumor cells inhibiting the proliferation of tumor cells at 24h post-treatment. Three specific aims are designed to: 1) investigate the relationship between STMΔznuABC and TME; 2) characterize the mechanism of STMΔznuABC antitumor activity; 3) validate the results obtained in the preliminary studies using alternative in vivo models. The Experienced Researcher (ER), from the Istituto Superiore di Sanità (ISS), Italy, will spend one year at the Cancer Immunobiology Section of the Cancer and Inflammation Program (CIP), Center for Cancer Research (CCR), division of the National Cancer Institute (NCI), Bethesda, MD USA, for mutual exchange of skills and know-how that will be transferred back to the beneficiary organisation (ISS), contributing to the establishment of a wider long-term collaboration between the ER and host institutions.

Mots clés : cancer therapy, attenuated salmonella, tumor microenvironment, immune response

Participants :
- Government of the United States of America (Etats-Unis) — Partner, organization partner, Organismes publics (hors enseignement & recherche), subvention : 0.0 €
- Istituto Superiore di Sanità (Italie) — Coordinator, beneficiary, Recherche, subvention : 164203.8 €
Projet TRPLigDrugConj (Horizon 2020, appel à projets 2016)
Action : Postdoctoral Fellowships - European Fellowships
Panel : Chemistry
Statut du projet : CLOSED

Cancer remains a leading cause of death and morbidity worldwide. Prostate cancer (PC) is among the most frequently diagnosed non-skin cancers. Despite major advances in the understanding of cancer biology and development of candidate therapeutic agents, there is still an urgent need of exploiting innovative chemotypes and disrupting novel signalling pathways. Evidence suggests that targeted therapies may provide an original means of selectively modulating diseased prostate cells. Herein we propose the validation and devlopment of an unprecedented approach to tackle PC, addressing the overexpressed transient receptor potential vanilloid channel V1 (TRPV1) with ligand-drug conjugates. This strategy provides a pioneering technological advance by aiming at the disruption of calcium signalling, while selectively targeting cancer cells for the delivery of cytotoxic payloads. The approach will additionally yield chemical probes for studying TRPV1 biology and for whole-animal optical imaging of TRPV1-overexpressed cancer cells.

Mots clés : targeted therapeutics, chemical biology, cancer

Participants :
- University of Lisbon (Portugal) — Coordinator, beneficiary, Recherche, subvention : 160635.6 €
Projet EnCAge (Horizon 2020, appel à projets 2017)
Action : Postdoctoral Fellowships - European Fellowships
Panel : Life Sciences
Statut du projet : CLOSED

Capillary endothelial cells (ECs) are not just passive conduits for delivering blood. Rather, ECs also play tissue-specific functions by providing highly specialized sets of angiocrine factors that control tissue homeostasis, regulate stem cell self-renewal, and guide organ regeneration without provoking fibrosis. However, it is not known whether tissue-specific instructive functions of ECs are lost during ageing. Moreover, the causal role of EC ageing in age-associated tissue dysfunction has not been directly studied so far. The use of aged mice to study age-related tissue alterations and to develop new drugs is not practical, since it is expensive, time consuming and does not allow for high throughput screenings. Thus, it is key to develop more convenient experimental systems that recapitulate the phenotype of aged cells. Hutchinson-Gilford progeria syndrome (HGPS) is a rare disease caused by progerin, a mutant form of the nuclear protein prelamin A that induces premature ageing. Remarkably, HGPS mimics many of the characteristics of human ageing, and progerin has also been detected at low levels in aged tissues of non-HGPS individuals. Thus, HGPS experimental models have proven to be very useful for the study of physiological ageing. This proposal will study age-dependent and tissue-specific alterations in ECs using a mouse model of HGPS. Furthermore, the candidate will use mice with EC-specific expression of progerin to assess the causal role of EC ageing in age-related impairment of organ regeneration, modelled by liver repair after injury. Finally, the applicant will develop an in vitro system to identify mechanisms through which progerin-induced EC ageing may elicit fibrotic responses that could compromise organ repair, and to test compounds to prevent or reverse the acquisition of an aged EC phenotype. These studies will open new potential therapeutic approaches to tackle age-related disorders, one of the most prominent health issues in European societies.

Mots clés : hutchinson gilford progeria syndrome, microvascular endothelial cells, fibrosis, organ regeneration

Participants :
- Ministry of Health (Espagne) — Coordinator, beneficiary, Recherche, subvention : 170121.6 €
Projet RAMSES (Horizon 2020, appel à projets 2015)
Action : Postdoctoral Fellowships - European Fellowships
Panel : Chemistry
Statut du projet : CLOSED

Carbohydrate recognition is fundamental in varied biological processes such as cellular differentiation, cell–cell interactions, immune defence and inflammatory response; consequently it plays key roles in tumour growth and metastasis, adhesion of viruses and bacteria to host cells and in immune and inflammatory disorders. It is well established that carbohydrate-binding molecules will have a strong impact on the development of new diagnostic and imaging methods and give rise to new opportunities for drug discovery. However the ab initio design of synthetic receptors for monosaccharides still remains an elusive objective, in particular if recognition is to take place in highly competitive polar media. This project aims to rationally design and synthesize single helically folded aromatic oligoamide capsules containing metal ions in order to achieve high affinity and selectivity for monosaccharides in polar media and to further develop them into functional fluorescent sensors. By introducing metal ions into foldamer frameworks a highly innovative class of receptors will be created which are expected to have exceptional binding abilities in polar media. The devised strategy consists in an iterative design process that exploits the modular structure of folded synthetic oligomer sequences in conjunction with structural characterization to inform subsequent refinements. Starting with a slightly larger than needed cavity possessing first-principles design that takes into account features such as size, shape and hydrogen bonding ability, the cavity size can iteratively be reduced while increasing shape complementarity with the substrate. With this evolutionary process the sequence will quickly converge towards a highly selective receptor for the target, which after replacement of key building blocks by fluorescent analogues, will be converted into a highly selective sensor.

Mots clés : foldamers, molecular recognition, monosacharrides

Participants :
- Centre national de la recherche scientifique (France) — Coordinator, beneficiary, Recherche, subvention : 185076.0 €
Projet CuZnSyn (Horizon 2020, appel à projets 2019)
Action : Postdoctoral Fellowships - European Fellowships
Panel : Chemistry
Statut du projet : CLOSED

Carbon dioxide (CO2) is a greenhouse gas that is significantly contributing to climate change. In tandem with advances in sequestering carbon, beneficial uses for CO2 are of high societal importance for developing a sustainable future. One attractive use of CO2 is in its conversion to energy dense fuels (green energy vectors). One such fuel is methanol, made from CO2 via hydrogenation in conjunction with a multimetallic catalyst. The current best industrial (heterogeneous) catalyst incorporates copper and zinc-oxide nanoparticles with an alumina support. A special synergy is observed between the copper (active site) and zinc (reaction promoter), but these species and their connection is poorly defined and remains debated. This project aims to isolate proximal copper and zinc centres, the fundamental building block for the construction of critical copper–zinc interfaces, within a well-defined, and highly tuneable ligand framework. Once isolated, the binding, activation and interconversion of key intermediates along the CO2 hydrogenation pathway will be meticulously analysed. Work package 1 involves the synthesis and characterisation of a series of 12 ligands that encompass a range of stereo-electronic profiles, and subsequent isolation of CuZn complexes using these ligands. Work package 2 will use the complexes to study the activation and interconversion of key intermediates along the CO2 hydrogenation pathway to gain mechanistic understanding. Finally, work package 3 will test the most active complexes as catalysts for the direct hydrogenation of CO2 to methanol. The combination of my skills (multimetallic systems) and the host groups (mechanistic studies) make achieving the project aims realistic. The knowledge harnessed from gaining deep mechanistic understanding of the synergy between copper and zinc during CO2 hydrogenation will be invaluable in developing the next generation of catalysts for methanol production, adding value to a deleterious waste streams.

Mots clés : co2 hydrogenation, copper zinc synergy, mechanistic insight

Participants :
- Imperial College London (Royaume-Uni) — Coordinator, beneficiary, Enseignement supérieur ou secondaire, subvention : 224933.76 €
Projet CERTAINTY (Horizon 2020, appel à projets 2019)
Action : Postdoctoral Fellowships - European Fellowships
Panel : Information Science and Engineering
Statut du projet : CLOSED

Carbon fibre reinforced composites (CFRP) have been increasingly used in aeronautical/aerospace structures given their outstanding specific stiffness and strength. However, CFRPs exhibit weak through-thickness strength, making them susceptible to impact damage, a design driver for aerostructures. Induced impact damage may reduce the compressive strength of the structure, and the inherent complex damage mechanisms of CFRP are difficult to predict. With a better predictive capability, structural design could be faster, cost effective and lead to a lighter and more damage tolerant nal structure. In reality, experimental characterisation of these CFRPs reveals appreciable variability of material properties, attributed to a complex heterogeneous microstructure, among others. This action (CERTAINTY) aims at developing the next generation methodology for predicting the mechanical response of CFRPs under impact loading by accounting for uncertainty in material properties and harnessing this in a physically-based damage model across different scales. CERTAINTY will provide a robust computational framework by introducing probabilistic models in contrast to traditional deterministic ones, by employing: Monte Carlo and metamodel techniques when the Monte Carlo approach is not suitable. CERTAINTY will further enable the researcher to establish collaborations with leading industrial partners. Targeted training will enable the researcher to develop a research career as a world expert in the design of CFRP aerostructures quantifying uncertainties associated with damage modelling. By demonstrating how damage mechanisms vary in a CFRP under impact loading, taking fracture toughness and material parameters variability into account in the damage modelling, the researcher and the host will be at the forefront of developing the next generation methodology for designing advanced lightweight aerostructures, delivering a key differentiator for the European aerospace industry.

Mots clés : composite structures, uncertainty quantification, fracture toughness, damage mechanisms, compression after impact, finite element modelling

Participants :
- Queen's University Belfast (Royaume-Uni) — Coordinator, beneficiary, Enseignement supérieur ou secondaire, subvention : 224933.76 €
Projet HierTough (Horizon 2020, appel à projets 2014)
Action : Postdoctoral Fellowships - European Fellowships
Panel : Information Science and Engineering
Statut du projet : CLOSED

Carbon fibre-reinforced polymers (CFRPs) are a rapidly growing class of materials as they possess excellent stiffness and strength in combination with a low density. They are vital in reaching the European objectives to reduce emissions of greenhouse gases and to achieve more efficient material usage . They are becoming highly popular in aerospace and automotive industries, but their introduction is hampered by their low damage tolerance. This fellowship proposes a novel approach to increase the toughness and hence the damage tolerance of CFRPs by intelligently designing the microstructure of the material in a hierarchical manner. The objective is to predict the microstructure that maximises toughness through modelling, to manufacture this microstructure and to validate the predicted toughness experimentally. The translaminar fracture toughness of CFRPs is expected to be increased by 50-100%. This is realistic given the successful examples from nature as well as recent, but preliminary modelling predictions. The fellowship will benefit from synergies between the models developed by the experienced researcher during his PhD and by the supervisor’s group. An extensive and multidisciplinary framework of materials, mechanics and chemistry is uniquely available at Imperial to help to reach the objectives. The outcome of the project will help the EU to gain a competitive edge in the aerospace and automotive industries.

Mots clés : fibre reinforced composites, hierarchical design, toughness

Participants :
- Imperial College London (Royaume-Uni) — Coordinator, beneficiary, Enseignement supérieur ou secondaire, subvention : 91727.4 €