Data-Gouv-ML/pcri-informations-sur-les-projets-laureats huggingface dataset:
Structure-Function Analysis of the Chemokine Interactome for Therapeutic Targeting and Imaging in Atherosclerosis (ATHEROPROTECT)

Framework: FP7 — Ideas
Programme: European Research Council
Theme: European research council
Destination: Advanced grants
Action type: Support for frontier research (ERC)
Panel: Physiology, Pathophysiology and Endocrinology
Countries involved: Germany,Germany
Call:  (ERC-2009-AdG, 2009)
Start date: 2010-04-01
End date: 2016-03-31
Duration (months): 72.0
Total project cost (EUR): 2500000.0
EU funding (EUR): 2500000.0
Participants: 2
Project status: CLOSED

Atherosclerosis is characterized by chronic inflammation of the arterial wall. Mononuclear cell recruitment is driven by chemokines that can be deposited e.g. by activated platelets on inflamed endothelium. Chemokines require oligomerization and immobilization for efficient function, and recent evidence supports the notion that heterodimer formation between chemokines constitutes a new regulatory principle amplifying specific chemokine activities while suppressing others. Although crucial to inflammatory disease, this has been difficult to prove in vivo, primarily as chemokine heterodimers exist in equilibrium with their homodimer counterparts. We introduce the paradigm that heteromerization of chemokines provides the combinatorial diversity for functional plasticity and fine-tuning, coining this interactome. Given the relevance of chemokine heteromers in vivo, we aim to exploit this in an anti-inflammatory approach to selectively target vascular disease. In a multidisciplinary project, we plan to generate covalently-linked heterodimers to establish their biological significance. Obligate heterodimers of CC and CXC chemokines will be designed using computer-assisted modeling, chemically synthesized and cross-linked, structurally assessed using NMR spectroscopy and crystallography, and subjected to functional characterization in vitro and reconstitution in vivo. Conversely, we will develop cyclic beta-sheet-based peptides binding chemokines to specifically disrupt heteromers and we will generate mice with conditional deletion or knock-in of chemokine mutants with defects in heteromerization or proteoglycan binding to be analyzed in models of atherosclerosis. Peptides will be used for molecular imaging and chemokine heteromers will be quantified in cardiovascular patients.

Keywords: atherosclerosis,chemokines,interactomics,drug discovery
Vesicular glutamate transporters as molecular regulators of neural communication (SYNVGLUT)

Framework: FP7 — Ideas
Programme: European Research Council
Theme: European research council
Destination: Advanced grants
Action type: Support for frontier research (ERC)
Panel: Neurosciences and neural disorders
Countries involved: Germany
Call:  (ERC-2009-AdG, 2009)
Start date: 2010-04-01
End date: 2015-03-31
Duration (months): 60.0
Total project cost (EUR): 2413200.0
EU funding (EUR): 2413200.0
Participants: 1
Project status: CLOSED

This proposal describes experiments aimed at defining the multiple roles of vesicular glutamate transporters (VGLUTs) in central synapses. Classically, VGLUTs transport glutamate from the cytoplasm into synaptic vesicles. Deletion of these genes disrupts synaptic glutamate release and their expression suffices to determine neurons as glutamatergic. We recently discovered that VGLUTs control additional key parameters such as quantal size and vesicular release probability, suggesting that they are fundamental regulators of synaptic strength and synaptic plasticity. To study these novel functions, we will first address whether the number of VGLUTs per vesicle (VGLUT content) can affect the amount of stored glutamate and in addition, the probability of vesicle release. We will subsequently explore the underlying mechanisms. Second, we will test the hypothesis that different VGLUT paralogs contribute to functional differences in discrete synapse populations, as implied by our preliminary data and the distribution pattern of the two main paralogs VGLUT1 and VGLUT2 in the brain. Subsequently, we will perform structure function studies on VGLUTs in native synapses to identify the underlying molecular interactions. Finally, the little understood VGLUT3 paralog is expressed mainly in subclasses of cholinergic, dopaminergic and GABAergic neurons, but no evidence exists that demonstrates VGLUT3 s role in glutamate release. We will address whether VGLUT3 is used to co-release glutamate with other neurotransmitters, and will test whether presence of glutamate in synaptic vesicles interferes with the storage or release of other neurotransmitters. Our studies will yield important insights into how these transporters operate, and how modulation of VGLUTs affects synaptic encoding and brain function. Because of observed profound regulation of VGLUTs in schizophrenia, depression and Parkinsons disease, these findings will also contribute to diagnosis and treatment of mental illness.

Keywords: synaptic transmission plasticity
Coordinated regulation of actin dynamics in cell motility and morphogenesis : from molecules to reconstituted biomimetic assays (FORCEFULACTIN)

Framework: FP7 — Ideas
Programme: European Research Council
Theme: European research council
Destination: Advanced grants
Action type: Support for frontier research (ERC)
Panel: ERC Advanced Grant Interdisciplinary Panel
Countries involved: France,Germany,Germany
Call:  (ERC-2009-AdG, 2009)
Start date: 2010-05-01
End date: 2015-10-31
Duration (months): 66.0
Total project cost (EUR): 2434195.0
EU funding (EUR): 2434195.0
Participants: 3
Project status: CLOSED

An impressive variety of motile and morphogenetic processes are driven by site-directed polarized asssembly of actin filaments. In the past ten years, breathtaking advances coming from cell biology, cell biophysics, and biochemistry have brought insight into the molecular bases for production of force and movement by site-directed actin polymerization. Yet, we do not know, with the detail sufficient to understand how force is produced, by which molecular mechanisms the filaments are nucleated or created by branching. We do not know by which elementary steps insertional polymerization of barbed ends of filaments against the membrane is performed by different protein machineries, nor how these machineries work in a coordinated fashion. Here we propose a multiscale and interdisciplinary approach of the mechanisms used by the major actin nucleators to organize the motile response of actin. The elementary reactions involved in the processive walk of formin at the growing barbed ends of filaments and the role of ATP hydrolysis in force production will be analyzed by a combination of biochemical solution studies and physical methods using functionalized GUVs and optical tweezers. The multifunctionality of WH2 domains involved in actin sequestration, filament nucleation severing and processive elongation will be similarly examined in an interdisciplinary perspective from structural biology at atomic resolution to physics at the mesoscopic scale. Biochemical and structural methods and single molecule measurements (TIRFM) will shed light into the elementary steps and structural mechanism of filament branching. Biomimetic assays with functionalized GUVs associated with biophysical methods like FRAP or fluorescence correlation spectroscopy will elucidate how different filament initiating machineries segregate in the membrane as a consequence of their interactions with growing filaments and function in a coordinated fashion during actin-based motility.

Keywords: actin,polymerization,self-organized system,force production,single molecule,interdisciplinary approach of the molecular basis of cell motility
The balance of ubiquitin conjugation and deconjugation (UBIQUITIN BALANCE)

Framework: FP7 — Ideas
Programme: European Research Council
Theme: European research council
Destination: Advanced grants
Action type: Support for frontier research (ERC)
Panel: Molecular and Structural Biology and Biochemistry
Countries involved: Netherlands
Call:  (ERC-2009-AdG, 2009)
Start date: 2010-02-01
End date: 2015-01-31
Duration (months): 60.0
Total project cost (EUR): 2299720.0
EU funding (EUR): 2299720.0
Participants: 1
Project status: CLOSED

Ubiquitin conjugation is one of the most important signaling systems in the eukaryotic cell. Different types of mono- and polyubiquitin chains determine the fate of target proteins by redirecting them for degradation, relocalization or interaction with new partners. The type of ubiquitin modification on any target is determined by the interplay between the conjugating E2/E3 complexes on the one hand and deubiquitinating enzymes on the other. In practice, it is the balance between conjugating and deconjugating systems that determines the result of the various ubiquitination signals. For three different regulatory systems that are critical for correct genome maintenance, we are now in a position to study not just the individual process of conjugation or deconjugation in isolation, but rather, reconstitute the entire reaction on a defined physiological target. These three target systems, histone H2A, PCNA and P53, can be mono-ubiquitinated by a defined E3-ligase, poly-ubiquitinated by a second ligase and deconjugated by defined deubiquitinating enzymes in a reaction that is affected by known allosteric modulators. Our unique collection of tools to study these systems in vitro allows reconstitution of the full reaction, to trap intermediates, and to study their interaction from atomic detail to kinetic reactivity. Using X-ray crystallography of critical intermediates and kinetic analysis of individual reactions by FRET and surface plasmon resonance, we can address how the mono-, poly and deubiquitinating reactions affect each other. By answering mechanistic questions on the relative effect of the forward and backward reaction components and their modulators we will provide a solid basis for drug design studies that target these pathways against cancer development.

Keywords: ubiquitin,dna damage,genome stability,pcna,h2a,p53,kinetics,mechanism
Structural studies of the eukaryotic ribosome by X-ray crystallography (EUKARYOTIC RIBOSOME)

Framework: FP7 — Ideas
Programme: European Research Council
Theme: European research council
Destination: Advanced grants
Action type: Support for frontier research (ERC)
Panel: Molecular and Structural Biology and Biochemistry
Countries involved: Switzerland
Call:  (ERC-2009-AdG, 2009)
Start date: 2010-07-01
End date: 2015-06-30
Duration (months): 60.0
Total project cost (EUR): 2446725.0
EU funding (EUR): 2446725.0
Participants: 1
Project status: CLOSED

The ribosome is a large cellular organelle that plays a central role in the process of protein synthesis in all organisms. Currently, structural information at atomic resolution exists only for bacterial ribosomes and some of their functional complexes. Eukaryotic ribosomes are larger and significantly more complex than their bacterial counterparts. They consist of two unequal subunits with a combined molecular weight of approximately 4 million Daltons and contain 70-80 different protein molecules and four different RNAs. Currently the only structural information on eukaryotic ribosomes is available from cryo electron microscopic reconstructions in the nanometer resolution range, which is insufficient to derive information about the function of the eukaryotic ribosome at the atomic level. The aim of this proposal is to use X-ray crystallography to obtain structural and functional information on the eukaryotic ribosome and its functional complexes at high resolution. The key targets of the structural work will be: i) the structure of the small ribosomal subunit, ii) the structure of the large ribosomal subunit, and iii) structures of complexes involved in the initiation of protein synthesis. Besides the obvious fundamental importance of this research for understanding protein synthesis in eukaryotes the proposed studies will also be the prerequisite for understanding the structural basis of the regulation of protein synthesis in normal cells and how it is perturbed in various diseases. Finally, comparing the structures of bacterial and eukaryotic ribosomes is important for understanding the specificity of various clinically used antibiotics for the bacterial ribosome.
Integrated Quantum Sensors (ISENSE)

Framework: FP7 — Cooperation
Programme: Information and Communication Technologies
Destination: Future and emerging technologies
Action type: Collaborative project
Countries involved: United Kingdom,United Kingdom,Germany,France,Italy,Germany,Austria,Germany,United Kingdom,France
Call:  (FP7-ICT-2009-C, 2009)
Start date: 2010-07-01
End date: 2014-12-31
Duration (months): 54.0
Total project cost (EUR): 3329055.0
EU funding (EUR): 2451999.0
Participants: 10
Project status: CLOSED

The central aim of iSense is to deliver breakthrough enabling technologies and knowledge to push long-anticipated sensor and quantum ICT applications using cold atoms to a broadly accessible and commercially exploitable level. To achieve this goal, iSense is structured in two highly interlinked and temporally overlapping phases: In the phase 1 iSense will create a science and technology platform introducing novel integrated optics concepts for cold atom production and interrogation. Phase 2 will pursue the establishment of commercial cold atom devices for a wide variety of integrated quantum sensors as well as in information and communication technologies (ICT). Starting with the realization of an integrated high-precision gravity sensor and strong technology dissemination activities this phase will lay the foundations for applications-specific broadening and wide use of the technol-ogy platform beyond the extension of this project. The long term vision is a modular, scalable and portable quantum technology family based on cold atoms, adaptable to a wide variety of applications in diverse working envi-ronments. Potential applications include fundamental physics tests, quantum ICT devices, satel-lite geodesy, oil / mineral prospecting and communication network timing.

Keywords: integrated optics,cold atom sensors
Novel strategies to combat future influenza pandemics (FLUPLAN)

Framework: FP7 — Ideas
Programme: European Research Council
Theme: European research council
Destination: Advanced grants
Action type: Support for frontier research (ERC)
Panel: Diagnostic tools, therapies and public health
Countries involved: Netherlands
Call:  (ERC-2009-AdG, 2009)
Start date: 2010-06-01
End date: 2015-05-31
Duration (months): 60.0
Total project cost (EUR): 2187758.0
EU funding (EUR): 2187758.0
Participants: 1
Project status: CLOSED

The Mexican influenza A virus (H1N1) reminds us that the threat of an influenza pandemic is real. The 1918 Spanish flu virus, also started as a low pathogenic virus that mutated into a highly pathogenic virus within months, causing more than 50 million deaths. The Mexican influenza A virus (H1N1) may follow the same path. FLUPLAN will expand our knowledge of the packaging signals that govern reassortment events between influenza A viruses in general and between the Mexican influenza A virus (H1N1) and circulating human, porcine and highly pathogenic avian influenza A viruses in particular. FLUPLAN will thus lead to fundamental insights in the mechanisms that govern reassortment phenomena, providing a risk assessment concerning the pandemic potential of circulating avian and mammalian influenza A viruses. This will provide us with a panel of possible reassortant viruses of potentially pandemic nature. The MVA vaccine vector system that efficiently induced broad protective immunity against HPAI-H5N1 viruses in macaques, will be used for the preparation of a repository of MVA-H based pandemic vaccine seed viruses.The selection will be based on the reassortant viruses mentioned above, and on a repository of avian influenza viruses of the 16HA subtypes including the Mexican influenza A virus (H1N1) of avian/swine origin. The added value of including a relevant MVA-NP in the immunization schedule to obtain broader and longer protection will be determined in a macaque infection model. Collectively these studies will provide us with a highly versatile system that anticipates on future pandemic events by having seed viruses for vaccine development ready to go on the shelf, for the rapid production of broadly protective pandemic vaccines, which will save time and thus lives.

Keywords: reassortment,influenza,vaccine,mva,macaque,ferret,pandemic preparedness,mexican flu
The role of epigenetic factors in the aetiology of common complex diseases using twins (EPITWIN)

Framework: FP7 — Ideas
Programme: European Research Council
Theme: European research council
Destination: Advanced grants
Action type: Support for frontier research (ERC)
Panel: Applied life sciences and biotechnology
Countries involved: United Kingdom
Call:  (ERC-2009-AdG, 2009)
Start date: 2010-07-01
End date: 2015-06-30
Duration (months): 60.0
Total project cost (EUR): 2498658.0
EU funding (EUR): 2498658.0
Participants: 1
Project status: CLOSED

Twin studies traditionally have been used to assess the relative contributions of genetic and environmental factors. Nearly all common diseases and traits have now been found to be heritable and GWA studies are discovering many novel genes. However 95% of the heritability is not yet identified and discordances within identical (MZ) twin pairs cannot be explained by known environmental factors. The missing heritability could be due to epigenetic factors- which are ideally studied with twins. The proposed study uses MZ twins discordant for 10 important age-related complex disease traits to uncover epigenetic signals that are associated with disease. We will study in detail epigenetic differences using a high throughput Illumina methylation array in the 5% most discordant pairs for the following disease susceptibility traits : obesity (BMI), type II diabetes (insulin resistance) , hypertension (BP), hyperlipidemia (lipid levels), Osteoporosis (BMD), biological aging (white cell telomere levels), Allergy (IgE) , asthma (FEV1), platelet volume (MPV) and smoking. We will use the TwinsUK cohort of 3000 phenotyped MZ twins for a discovery group. For replication of the most significant associations we will use singletons from the 200 extreme highs and lows of the remaining 4000 phenotyped twins as a ‘case’-‘control ‘association study genotyped by the same array. A sub-sample will be genotyped by sequencing. To assess tissue specificity, additional tissues for methylation analysis will be sampled (buccal, fat and skin DNA). Causality will be explored using bioinformatics, cell specificity experiments and longitudinal studies using DNA stored for up to 15 years- as well as parental and offspring DNA. Epigenomics is a major future growth area. This large scale study would enable us to maintain a European lead and act also a valuable future epidemiologic resource and enable important collaborations with other European researchers and cohorts.

Keywords: twins,epigenetics,complex traits
Interferon-focused Innate Immunity Interactome and Inhibitome (I-FIVE)

Framework: FP7 — Ideas
Programme: European Research Council
Theme: European research council
Destination: Advanced grants
Action type: Support for frontier research (ERC)
Panel: Genetics, Genomics, Bioinformatics and Systems Biology
Countries involved: Austria
Call:  (ERC-2009-AdG, 2009)
Start date: 2010-04-01
End date: 2015-03-31
Duration (months): 60.0
Total project cost (EUR): 1974022.4
EU funding (EUR): 1974022.4
Participants: 1
Project status: CLOSED

After a decade of development in model organisms and later in mammalian cells, mass spectrometry-based functional proteomics approaches have come of age and are ready to enable a systematic study of the innate immune system. We propose to cross the large-scale proteomics and innate immunity disciplines to obtain a functionally annotated map of the molecular machinery involved in viral recognition and leading to the hallmark interferon response, through a three-pronged approach: 1. Map the interactome of innate immunity proteins in macrophages to establish the network of components leading to interferon production; 2. Chart the interactions of molecular patterns, mostly nucleic acids, to identify the receptors and sensors at the non-self/self interface; 3. Study viral pathogenicity factors as molecular jammers of the anti-viral response and elucidate their mode of action to uncover critical nodes (inhibitome). Datasets are integrated and released at regular intervals with embargoed windows allowing a network of collaborators/own laboratory to do in-depth validation. New components at data intersections will be tested through loss-of-function experiments and standardized read-outs for the interferon pathway as well as genetic association with autoimmune diseases. Because of its unbiased/large scope and its cross-validating approaches, wherein the newly mapped circuitry is modeled, challenged by inducers and perturbed by viral agents, i-FIVE has the potential to promote a systems-level understanding of the interferon branch of molecular innate immunity. This insight may in turn create medical opportunities for the treatment of autoimmune disorders, septic shoc, arthritis as well as in boosting anti-viral responses.
Origin of a cell differentiation mechanism and its evolution over 500 million years of life on land (EVO500)

Framework: FP7 — Ideas
Programme: European Research Council
Theme: European research council
Destination: Advanced grants
Action type: Support for frontier research (ERC)
Panel: Cellular and Developmental Biology
Countries involved: United Kingdom
Call:  (ERC-2009-AdG, 2009)
Start date: 2010-10-01
End date: 2015-09-30
Duration (months): 60.0
Total project cost (EUR): 2463835.0
EU funding (EUR): 2463835.0
Participants: 1
Project status: CLOSED

The evolution of the first rooting systems approximately 470 million years ago was a critical event in the history of life on Earth because it allowed the growth of complex multicellular eukaryotic photosynthetic organisms – plants - on the surface of the land. Rooting systems are important because they facilitate the uptake of every chemical element in the plant body with the exception of carbon. The root systems of the first land plants (liverworts) comprised a mass of unicellular tip-growing filaments (rhizoids) that grew from the plant surface into the soil. All root systems that evolved since then similarly comprise a system of tipgrowing filamentous cells located at the interface between the plant and the soil, indicating that the differentiation of filamentous root cells has been critical for root function for the past 470 million years. This proposal aims to characterize the origin and evolution of this essential cellular differentiation process. The proposed research is in three parts: First we propose to define the mechanism that controlled the development of the first land plant root system by identifying genes that control liverwort rooting system (rhizoids) development and characterizing their regulatory interactions. Second we propose to determine if the mechanism that controlled the development of the first land plant root system was inherited from algal ancestors. Third we propose to characterize the mechanism that controls filamentous root hair growth in Arabidopsis in response to environmental factors, and determine if it is conserved among land plants. In combination, these experiments will define the genetic mechanisms underpinning the development and evolution of one of the fundamental developmental processes in land plants.

Keywords: land plant evolution,evolutionary developmental biology,root evolution,cell differentiation,cell growth