Data-Gouv-ML/pcri-informations-sur-les-projets-laureats huggingface dataset:
Modeling Assays Platform "MAP" for hazard ranking of engineered nanoparticles (ENPs) (MOD-ENP-TOX)

Framework: FP7 — Cooperation
Programme: Nanosciences, Nanotechnologies, Materials and new Production Technologies - NMP
Destination: Nanosciences and Nanotechnologies
Action type: Collaborative project
Countries involved: Belgium,France,Switzerland,Taiwan, Province of China
Call:  (FP7-NMP-2012-SMALL-6, 2012)
Start date: 2013-01-01
End date: 2015-12-31
Duration (months): 36.0
Total project cost (EUR): 1385241.2
EU funding (EUR): 1000000.0
Participants: 4
Project status: CLOSED

MOD-ENP-TOX project is a multidisciplinary project aiming to accomplish the following objectives: (i) to develop a novel and rational “Modelling Assay Platform (MAP)” which can be used as a « Risk Indicator » tool to predict the toxicity of metal-based NPs (MeNPs), and (ii) to demonstrate the feasibility of a MAP prototype – on a shortlist of MeNPs - which can be further developed to screen the toxicity of a large number ENPs. Based on the concept of Integrating Testing Strategies (ITS), the proposed generic MAP combines two main and complimentary paradigms: (1) a novel Computational Modeling Package (CMP) based on structural, mechanistic, as well as kinetic modeling tools and (2) an innovative screening (IS) strategy that allows performing multiplexed streamlined assays for calibration, refinement and validation of the computed models. First a series of classification algorithms will be applied to identify MeNPs with similar toxicity patterns, then computational modelling tools will be developed to establish a more rational relationship between MeNPs descriptors and their toxicity in a dynamic and quantitative way. An in-vitro/in-vivo IS paradigm will be developed as a scalable assessment tool to calibrate and validate the predictive power of the CMP using subsets of the training set or independent set of MeNPs (validation set) respectively.

Keywords: computational software package,high throughput screening-high content imaging,metal-based nano-particles,modeling assays platform,nanoparticle-protein coronas.
Harvesting the power of a new model organism: stem cells, regeneration and ageing in Macrostomum lignano (MACMODEL)

Framework: FP7 — Ideas
Programme: European Research Council
Theme: European research council
Destination: Starting grants
Action type: Support for frontier research (ERC)
Panel: Genetics,Genomics,Bioinformatics and Systems Biology
Countries involved: Netherlands
Call:  (ERC-2012-StG_20111109, 2012)
Start date: 2012-11-01
End date: 2017-10-31
Duration (months): 60.0
Total project cost (EUR): 1499723.0
EU funding (EUR): 1499723.0
Participants: 1
Project status: CLOSED

The ‘stem-cell theory’ of ageing posits that the functional decline in adult stem cells is one of the factors contributing to ageing. Importantly, the number of stem cells does not diminish with age in many tissues but rather there are intrinsic and extrinsic changes that affect their functionality. Is it possible to reverse these changes? Experiments in the emerging model Macrostomum lignano suggest that this is indeed the case. Remarkably, induced regeneration in this animal leads to extended lifespan: repeated amputation, followed by regeneration, results in animals that live far beyond the median lifespan of 205 days. Regeneration in M. lignano is facilitated by stem cells called neoblasts, and it appears that regeneration resets the ‘ageing program’ in these animals. Due to its high regeneration capacity, small size, transparency and clear morphology, ease of culture, short generation time and amenability to genetic manipulation, M. lignano has great potential as a model organism for stem cell research. I have recently started developing genomic and genetic tools and resources for this model, and at present my group has generated a draft genome assembly, produced de novo transcriptome assembly, discovered several neoblast marker genes and made the first stable transgenic lines in this animal. Here I propose to study molecular mechanisms underlying rejuvenation in M. lignano, and to further advance M. lignano as a model organism through development of missing genetic tools and resources. I will address how young, aged and regenerated worms differ in their gene and small RNA expression profiles, and what are the differences and variation levels between neoblasts of young, old and regenerated animals. The biological roles of the identified candidate genes and their effects on the lifespan and neoblast activity will be investigated. In parallel, methods for efficient transgenesis and gene manipulation will be developed, and the genome annotation improved.

Keywords: flatworms,macrostomum,model organisms,neoblasts,single-cell transcriptome,regeneration,rejuvenation,ageing,transgenics,reverse genetics,forward genetics,microrna
Blood vessels as a target for infection (VIP)

Framework: FP7 — Ideas
Programme: European Research Council
Theme: European research council
Destination: Starting grants
Action type: Support for frontier research (ERC)
Panel: Immunity and infection
Countries involved: France
Call:  (ERC-2012-StG_20111109, 2012)
Start date: 2013-01-01
End date: 2018-12-31
Duration (months): 72.0
Total project cost (EUR): 1500000.0
EU funding (EUR): 1500000.0
Participants: 1
Project status: CLOSED

One of the major challenges in bacterial infectious disease relates to infections taking place in the bloodstream (septicemia). Despite availability of antibiotics these types of infections lead to extremely severe conditions such as septic shock or meningitis requiring a better understanding of mechanisms of disease. The common denominator of these conditions is the interaction of pathogens with the blood vessels and the subsequent alteration of the vessels biological properties. The aim of this project is to understand how such pathogens cause these dramatic alterations. This raises both biomedical and basic scientific questions that will be addressed in this project. How can these bacteria survive and multiply in the bloodstream? How do they interact with the endothelium? How do they affect vessel integrity and homeostasis? How can bacteria exit the vessel lumen to access the cerebrospinal fluid? Neisseria meningitidis is used as an experimental model in this project because it is a stereotypical example of septicemia and meningitis causing pathogen and because of the availability of experimental tools for its genetic manipulation. A central hypothesis of the project is that the ability of this bacterium to bind to endothelium and proliferate in aggregates inside the microvasculature, a process we refer to as vascular colonization, is central to the disease process. Our experimental approach is to generate innovative tools to reproduce the specific environment encountered by the bacteria in the bloodstream: blood flow generated shear stress, the specific geometry of the microcirculation, the human endothelium and its tissue environment. To meet these challenges we are using a multidisciplinary approach exploiting recent findings from the fields of physics, chemistry, microbiology, vascular biology and immunology. With this work we hope to unravel important pathophysiological mechanisms with implication for the management and treatment of sepsis and meningitis.

Keywords: septicemia and meningitis
Fitness drivers in long-distance migrants: the interacting roles of physiology, social biology, ecological and physical environments (STATEMIG)

Framework: FP7 — Ideas
Programme: European Research Council
Theme: European research council
Destination: Starting grants
Action type: Support for frontier research (ERC)
Panel: Evolutionary, population and environmental biology
Countries involved: United Kingdom
Call:  (ERC-2012-StG_20111109, 2012)
Start date: 2013-02-01
End date: 2019-01-31
Duration (months): 72.0
Total project cost (EUR): 1499223.6
EU funding (EUR): 1499223.6
Participants: 1
Project status: CLOSED

Long distance migration in birds is among the most dramatic and exciting phenomena in nature. However despite many years of study, there are still huge gaps in our understanding of how this behaviour shapes individual ecology and influences population processes. For example, we have very little understanding of how migratory animals manage trade offs within and among seasons and how these in turn drive variation in productivity, survival or breeding phenology. Increased understanding in this area has important implications for ecology, evolution conservation and management Our lack of progress in this area is almost inevitable given the complex nature of migration. Migration is sequential in nature, meaning that an animal’s state in one season is heavily influenced by previous conditions. Therefore the costs/benefits of behaviours can be carried over into subsequent seasons and thus the processes regulating fitness may not occur at the time it is being expressed. This also means that regulating processes and response can also be separated spatially making it even harder to identify cause. These effects are likely to be emphasized in migrants because fuelling flights and breeding also places huge physiological demands on migratory birds. Yet few studies have linked the stress incurred during migration with subsequent fitness. Integrating mechanism and function would provide very important insights into the ecology and evolution of migration. In order to progress we need to able to follow large numbers of individuals throughout their annual cycles, tracking the different conditions they experience and how this influences their state at each point in time. I would use state of the art technologies and statistical tools to follow migratory geese throughout the year and integrate, for the first time, how interactions among physiological, social, ecological and climatic environments underpin state and in turn fitness across the annual cycle.

Keywords: migration,carry over effects,oxidative stress,social network
Identity and functions of polyphosphate polymerases in eukaryotes (EUROPOLYPS)

Framework: FP7 — Ideas
Programme: European Research Council
Theme: European research council
Destination: Starting grants
Action type: Support for frontier research (ERC)
Panel: Cellular and Developmental Biology
Countries involved: Switzerland,Germany
Call:  (ERC-2012-StG_20111109, 2012)
Start date: 2013-01-01
End date: 2017-12-31
Duration (months): 60.0
Total project cost (EUR): 1434822.0
EU funding (EUR): 1434822.0
Participants: 2
Project status: CLOSED

Inorganic polyphosphate (polyP), a linear polymer of dozens to thousands of orthophosphate units, has been found in virtually every pro- and eukaryotic cell. PolyP regulates blood clotting, inflammation and bone formation in humans, symbiotic interactions in plants and stress responses in bacteria. The molecular functions of this high-energy polymer however remain largely enigmatic and its synthesis has only been characterized in prokaryotes. Systematic investigation of polyP functions in higher organisms has so far been hampered by our complete lack of knowledge about the molecular machinery required for polyP synthesis, transport, storage and signalling. Here, I propose a multi-disciplinary approach to dissect the origins and functions of polyP in eukaryotes. Using a candidate approach, I have identified the polyP polymerase in Arabidopsis thaliana, and a closely related human enzyme. I propose to dissect the architecture and catalytic mechanism of the plant polyphosphate polymerase, and study its distribution in cells and tissues. Using genetics, we will next analyse the contribution of polyP synthesis to plant metabolism, growth and development. In parallel, we will develop biosensors to visualize the transport, storage and re-mobilisation of polyP in living cells. Together, these experiments should yield traceable phenotypes and novel tools that will enable us for the first time to design and evaluate polyP-specific genetic screens. By this means, we hope to identify other players involved in polyP metabolism, transport, storage, re-mobilisation and signalling. We will translate our findings from Arabidopsis to animal models, and study the evolution of this ancient polymer. I envision that our work will uncover a fundamental metabolic pathway, and may spur the design of crops that require less phosphate fertilizer, small molecule inhibitors against human parasites, and novel drugs that target inflammatory disease and osteoporosis.

Keywords: arabidopsis,gene discovery,energy metabolism,phosphate metabolism,thiamine metabolism,polymerases,membrane transport,plant growth,embryo development,inflammatory disease,blood clotting
Order in Disorder: Context-dependent strategies for integrating peptide-mediated interactions (ORDER IN DISORDER)

Framework: FP7 — Ideas
Programme: European Research Council
Theme: European research council
Destination: Starting grants
Action type: Support for frontier research (ERC)
Panel: Genetics,Genomics,Bioinformatics and Systems Biology
Countries involved: Israel
Call:  (ERC-2012-StG_20111109, 2012)
Start date: 2012-12-01
End date: 2018-05-31
Duration (months): 66.0
Total project cost (EUR): 1499808.0
EU funding (EUR): 1499808.0
Participants: 1
Project status: CLOSED

Peptide-mediated protein interactions are emerging as key regulators of many important regulatory processes in the cell. Short motifs, usually embedded into disordered regions of the protein, interact with specific sets of protein partners in a transient way and allow efficient and malleable propagation of signals towards their targets. While regular protein interactions have been intensively studied, many aspects of peptide-mediated interactions have not yet been elucidated. The aim of this proposal is to improve our understanding of the basic strategies that are employed by peptide-mediated interactions to achieve different types of outcomes in different settings, and how the context of the peptide influences this outcome. Towards this aim, we will establish two complementary strategies, namely (1) a significant extension of our modeling tools for peptide-protein complex structures that will allow modeling of effects of the surrounding flexible linker, and (2) the establishment of an experimental lab that will allow us to independently validate and complement our modeling results. Targeted modulation of peptide affinity, specificity, and linker length and sequence, using both computational design as well as experimental in vitro evolution, will dissect different contributions to the functional outcome of a peptide-mediated interaction within its context. We can thus study in detail the interplay of the interaction with additional features in the linker sequence, such as posttranslational modification sites, as well as additional peptide binding motifs and interactions. Interactions mediated by intrinsically disordered regions are omnipresent. Their accurate characterization, modeling and manipulation holds therefore many promises towards applications for the development of better drugs and basic insights for better fundamental understanding of the underlying basis of regulatory interactions.

Keywords: computational structural biology,structural modeling of protein interactions,binding affinity and specificity,inhibitory peptides,intrinsically disordered proteins
NLRs AS TRANSCRIPTIONAL REGULATORS (TRANSCRIPTIONALNLRS)

Framework: FP7 — Ideas
Programme: European Research Council
Theme: European research council
Destination: Starting grants
Action type: Support for frontier research (ERC)
Panel: Immunity and infection
Countries involved: Switzerland
Call:  (ERC-2012-StG_20111109, 2012)
Start date: 2013-03-01
End date: 2018-02-28
Duration (months): 60.0
Total project cost (EUR): 1499154.0
EU funding (EUR): 1499154.0
Participants: 1
Project status: CLOSED

MHC molecules are central to our immune system and are therefore also involved in several pathologies. MHCII transcription is controlled by proximal promoter sequences, which are cooperatively bound by several factors forming the ‘MHC enhanceosome’. Upon recruitment to this complex, the NLR family member CIITA promotes MHCII transcription. We recently found that our mice deficient for the NLR NLRC5 exhibit markedly reduced MHCI expression in lymphocytes. Importantly, endogenous NLRC5 occupies H-2 proximal promoter regions and drives gene transcription. We now plan to characterize novel NLR-mediated transcriptional regulatory pathways controlling MHC expression. We will investigate the enhanceosome and the transcriptional regulators interacting with NLRC5 as well as the role of NLRC5 in gene expression more broadly. We will also address the function of NLRC3, which is homologous to CIITA and NLRC5, by using novel conditional knockout mice. Our preliminary data indicate that conventional Nlrc3-KO mice show embryonic lethality and that NLRC3 can localize to the nucleus, supporting the hypothesis that it acts as an essential transcriptional regulator. We will therefore investigate NLRC3 function in immunity and reproduction, paying particular attention to the regulation of non-classical MHCI molecules known to play a role in embryogenesis. Interestingly, we identified RFX7, which is homologous to the enhanceosome component RFX5, as an interactor of NLRC3. Although RFX7 has been associated with leukemia development, this factor remains functionally uncharacterized, and we plan to study its role by generating knockout mice. Novel aspects of MHC transcriptional regulation are emerging, highlighting a combinatorial system wherein NLRs play a more general role than realized so far. A better understanding of the mechanisms regulating MHC transcription is fundamental to design novel therapeutic approaches relevant to immune disorders, malignancies, and infertility.

Keywords: nod-like receptors,regulation of mhc transcription,antigen presentation
The role of pericytes in central nervous system scarring and fibrosis (PERICYTESCAR)

Framework: FP7 — Ideas
Programme: European Research Council
Theme: European research council
Destination: Starting grants
Action type: Support for frontier research (ERC)
Panel: Neurosciences and neural disorders
Countries involved: Sweden
Call:  (ERC-2012-StG_20111109, 2012)
Start date: 2013-02-01
End date: 2018-01-31
Duration (months): 60.0
Total project cost (EUR): 1750000.2
EU funding (EUR): 1750000.0
Participants: 1
Project status: CLOSED

Damage to the central nervous system (CNS) often leads to persistent functional deficits, causing great individual suffering and enormous cost to society. The manifestation of these deficits is believed to be associated with the scar tissue that forms locally at lesions, causing permanent tissue alteration and blocking regeneration. Research on CNS scar tissue has primarily focused on astrocytes and it is often referred to as the glial scar. However, although it has received much less attention, there is also a connective tissue or stromal, non-glial, component of the scar. While studying spinal cord injury-induced scarring, I recently discovered a new subpopulation of perivascular cells, named type A pericytes, as a major source of connective scar tissue. Type A pericytes are embedded in the vascular wall but proliferate and leave the blood vessel upon injury, differentiating into fibroblast-like cells that deposit extracellular matrix to seal the lesion and form the persistent stromal scar core. The aim of the proposal is to determine whether type A pericytes are a general source of pathological connective tissue in the CNS, to understand the nature of type A pericytes, and to uncover the signaling mechanisms mediating their recruitment. By comparing several different injury and disease models the proposed research intends to uncover common mechanisms of scarring and fibrosis and to identify new targets for human treatment after CNS injury.

Keywords: regenerative medicine,scar formation,pericytes,spinal cord injury,stroke,multiple sclerosis,glioblastoma,axonal regeneration,behavior,mesenchymal stem cells,pdgfr beta signaling
Memory B cell immunity in chronic viral infection (IMMUNIBY)

Framework: FP7 — Ideas
Programme: European Research Council
Theme: European research council
Destination: Starting grants
Action type: Support for frontier research (ERC)
Panel: Immunity and infection
Countries involved: Switzerland
Call:  (ERC-2012-StG_20111109, 2012)
Start date: 2013-09-01
End date: 2018-08-31
Duration (months): 60.0
Total project cost (EUR): 1499923.0
EU funding (EUR): 1499923.0
Participants: 2
Project status: CLOSED

This project aims for a quantum leap in the understudied area of memory B cell immunity to chronic viral infection. It provides i) a landscape analysis of primary and memory B cell responses to chronic viral challenge, ii) investigates receptor hypermutation of memory B cells for broadened protection against viral escape variants, and iii) studies the role of memory CD4+ T cells in augmenting memory B cell protection in chronic viral infection. Memory B cells represent a main pillar of immunological memory and account for long-term protection by the hepatitis B virus vaccine, the only one to afford protection against a persistent viral infection in humans. Yet our understanding of memory B cell immunity to chronic viral infection remains rudimentary, owing to a lack of advanced methodology and model systems for its investigation. My laboratory has developed a comprehensive set of tools to overcome these hurdles in the prototypic chronic infection model of lymphocytic choriomeningitis virus (LCMV) in mice. We have at hands the first LCMV-neutralizing monoclonal B cell receptor-expressing mouse (unpublished), and will collaborate with a world-leading lab in B cell biology to exploit their novel mouse model for in vivo tracing of polyclonal antigen-specific memory B cells. Combined with genetically engineered LCMV mutants, multi-parameter flow cytometry, state-of-the-art immunological methods, histopathology and deep sequencing of B cell receptor repertoires, these models will allow for unprecedented cell transfer and viral infection studies in vivo. Our leading expertise in LCMV molecular biology and immunology, combined with our partners’ expertise in B cell biology warrants for a high likelihood of success in this ambitious journey to virgin territory. We expect this project to provide a conceptual basis and incentive to successfully exploit memory B cell immunity in the battle against global hepatitis C virus and human immunodeficiency virus pandemics.

Keywords: memory b cells,persistent viral infection,vaccination,viral immune escape,b cell receptor hypermutation