Data-Gouv-ML/pcri-informations-sur-les-projets-laureats huggingface dataset:
Development and differentiation of CD8 T lymphocytes (CD8 T CELLS)

Framework: FP7 — Ideas
Programme: European Research Council
Theme: European research council
Destination: Advanced grants
Action type: Support for frontier research (ERC)
Panel: Immunity and infection
Countries involved: France
Call:  (ERC-2008-AdG, 2008)
Start date: 2009-02-01
End date: 2014-05-31
Duration (months): 64.0
Total project cost (EUR): 1969644.0
EU funding (EUR): 1969644.0
Participants: 1
Project status: CLOSED

CD8 T lymphocytes have a fundamental role in ensuring the control of different types of intracellular pathogens including bacteria, parasites and most viruses. This control may fail due to several reasons. The current aggressive anti-cancer therapies (or rarely certain congenital immune deficiencies) induce CD8 depletion. After bone-marrow transplantation, long time periods are required to ensure T cell reconstitution particularly in the adult. This long lag-time is due to the long-time periods required for hematopoietic precursors to generate T lymphocytes and to a thymus insufficiency in the adult. However, even when CD8 T cells are present CD8 immune responses are not always adequate. Certain chronic infections, as HIV, induce CD8 dysfunction and it is yet unclear how to generate efficient CD8 memory responses conferring adequate protection. To address these questions this project aims 1) To find strategies ensuring the rapid reconstitution of the peripheral and the gut CD8 T cell compartments a) by studying the mechanisms involved HSC division and T cell commitment; b) by isolating and characterizing progenitors we previously described that are T cell committed and able of an accelerated CD8 reconstitution c) by developing new strategies that may allow stable thymus transplantation and continuous thymus T cell generation. 2) To determine the mechanics associated to efficient CD8 memory generation a) by evaluating cellular modifications that ensure the efficient division and the remarkable accumulation and survival of CD8 T cells during the adequate immune responses as compared to inefficient responses b) by studying CD8 differentiation into effector and memory cells in both conditions. These studies will use original experiment mouse models we develop in the laboratory, that allow to address each of these aims. Besides state of the art methods, they will also apply unique very advanced approaches we introduced and are the sole laboratory to perform.

Keywords: pre-t cells,t cell reconstitution,thymus transplants,cd8 division,cd8 differentiation.
Dissection of environmentally-mediated epigenetic silencing (ENVGENE)

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: United Kingdom
Call:  (ERC-2008-AdG, 2008)
Start date: 2009-01-01
End date: 2013-12-31
Duration (months): 60.0
Total project cost (EUR): 2450000.0
EU funding (EUR): 2450000.0
Participants: 1
Project status: CLOSED

We intend to achieve a step change in our understanding of the mechanistic basis of epigenetic regulation. We will capitalize on a plant epigenetic silencing system, vernalization, which has many features that allow the complete dissection of different facets of epigenetic regulation. In addition, the silencing is quantitatively modulated by the environment enabling dissection of how external cues mediate epigenetic silencing. We will combine genetics, molecular biology and biochemical approaches with computational modelling to allow us to translate the extensive nuts and bolts information into an understanding of how the engine works. A particular strength of modelling will be its predictive nature and ability to distinguish between key components and those with subsidiary or redundant roles. The system we will use is vernalization, the cold-induced Polycomb-silencing of the target locus, FLC. We will dissect the many phases of vernalization: the triggering of FLC repression by prolonged cold; the nucleation and epigenetic stability of chromatin changes at FLC; and the spreading of the silencing yet spatial restriction to FLC. Our goal will be a full understanding of the complexity involved in the epigenetic silencing of this locus, described in a quantitative model that reveals how the silencing is induced by temperature and how individual components of the silencing network are integrated into a robust whole. This ambitious goal, which will uncover fundamental concepts important to gene regulation in many organisms, will be achieved through a tight integration of molecular analysis and computational modelling, enabling efficient cycling between experimentation, prediction and validation.

Keywords: arabidopsis,environment,vernalization,polycomb
Traces in the bones: reconstructing the lost soft anatomy of the earliest vertebrates through ultra-high resolution synchrotron scanning. (BONE SCAN)

Framework: FP7 — Ideas
Programme: European Research Council
Theme: European research council
Destination: Advanced grants
Action type: Support for frontier research (ERC)
Panel: Evolutionary, population and environmental biology
Countries involved: Sweden,France
Call:  (ERC-2008-AdG, 2008)
Start date: 2009-04-01
End date: 2014-03-31
Duration (months): 60.0
Total project cost (EUR): 1046782.0
EU funding (EUR): 1046782.0
Participants: 2
Project status: CLOSED

Early vertebrate evolution involved a series of drastic structural reorganisations as new features were added and elaborated. The fossil record illuminates this evolutionary history more directly than inferences from the diversity of living forms, but the fossils usually consist only of bones whereas many of the most important and interesting changes occurred in the soft anatomy. Traditional approaches to reconstructing the musculature and other soft tissues of fossil vertebrates rely on subjective tools, like the visual identification of rough bone textures thought to indicate muscle attachments, and generally leave a lot to be desired. Here I propose a wholly novel and radically more objective approach to the identification of soft-tissue contacts, using holotomographic synchrotron CT at sub-micron resolutions to identify these contacts by the three-dimensional micro-architecture of the bone. A pilot study has already shown that such scans (performed at the ESRF synchrotron facility in Grenoble) are capable of imaging key features such as arrested growth surfaces and probable Sharpey s fibres in 380 million year old fossils. We will undertake a systematic review of the three-dimensional bone micro-architectures associated with different soft-tissue contacts in living vertebrates, and the use this as a key to reconstruct the soft-tissue contacts on fossil bones with unprecedented accuracy. This will permit us to produce far more reliable reconstructions of the soft anatomy than has hitherto been possible. Our findings will inform other areas of palaentology, particularly functional morphology, and will also be of great importance to evolutionary developmental biology.

Keywords: morphology,palaeontology,histology,vertebrate,evolution,phylogeny,patterning
IMPROVED RETROGRADE LENTIVIRAL VECTORS FOR GENE THERAPY IN MOTOR NEURON DISEASES (IRLVGTMND)

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: United Kingdom
Call:  (ERC-2008-AdG, 2008)
Start date: 2009-04-01
End date: 2014-08-31
Duration (months): 65.0
Total project cost (EUR): 2000000.0
EU funding (EUR): 2000000.0
Participants: 1
Project status: CLOSED

Lentiviral vectors can be targeted to specific cell types by varying the envelope proteins, a process called pseudotyping. The rabies-G pseudotyped lentivectors are useful for distal targeting of neurons because they are retrogradely transported to the nucleus where they integrate and express the transgene, as first demonstrated by us. Motor neuron (MN) diseases are incurable neurodegenerative diseases causing progressive paralysis and premature death. Most amyotrophic lateral sclerosis (ALS) cases are sporadic, but there are rare inherited forms one of which being due to mutations in the superoxide dismutase (SOD1) gene. Spinal muscular atrophy (SMA) is the second commonest genetic disease affecting children and is due to mutations in the survival motor neuron (SMN1) gene. In mouse models for ALS (SOD1 mutant mouse) or SMA (SMNDelta7 mouse) when we delivered in various muscle groups rabies-G pseudotyped lentiviral vectors expressing either vascular endothelial growth factor or short interfering RNA targeted to a mutated SOD1 gene or the normal SMN1 gene we corrected motor defects and extended survival. Despite these successes, experiments with rabies-G pseudotyped vectors in non-human primates have failed to give good efficiency of transduction of MNs so as to translate this approach to the clinic. Also SMN-1 targeted replacement produced only a marginal increase in survival despite sparing MNs. In this grant we propose: 1) To investigate the molecular pathway of retrograde transport of the rabies-G lentiviral vectors. This might allow us to increase the efficacy of gene transfer with these vector systems. 2) To design novel lentiviral vectors with tropism to the neuromuscular junction (NMJ) so as to try to increase the efficiency/specificity of gene transfer to MNs. 3) To utilise the new NMJ-targeted lentiviral vector derived in (2) to simultaneously deliver several neuroprotective proteins to MNs and test its efficacy in animal models of ALS and SMA.

Keywords: lentiviral vector,retrograde transport,rabies-g,neurodegenerative diseases,amyotrophic lateral sclerosis,spinal muscular atrophy,neuromuscular junction,targeting,bidirectional expression
The molecular complexity of the complement system (COCO)

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-2008-AdG, 2008)
Start date: 2009-04-01
End date: 2014-03-31
Duration (months): 60.0
Total project cost (EUR): 1700000.0
EU funding (EUR): 1700000.0
Participants: 1
Project status: CLOSED

The complement system is a regulatory pathway in mammalian plasma that enables the host to recognize and clear invading pathogens and altered host cells, while protecting healthy host tissue. This regulatory system consists of ~30 large multi-domain plasma and cell-surface proteins, that act in concert through an interplay of proteolysis and complex formations on target membranes. We study the molecular events on membranes that ensure initiation and amplification of the response, protection of host cells and activation of immune responses leading to cell lysis, phagocytosis and B-cell stimulation. In the past few years, we have resolved the structural details of the large complement proteins involved in the central, aspecific labelling and amplification step; with recent data we revealed the structural basis of the assembly and activity of the protease complex associated with this step. These insights into the central aspecific reaction, and the experiences gained on working with these large multi-domain proteins and complexes, give us an excellent starting point to addres the questions of specificity, protection and activation of immune cells. The goal of the proposal is to elucidate the multivalent molecular mechanisms of recognition, regulation and immune cell activation of the complement system on target membranes. We will use protein crystallography and electron microscopy to study the interactions and conformational changes involved in protein complex formation, and (single-molecule) fluorescence to resolve the multivalent molecular events, the conformational states and transitions that occur on the membrane. The combined data will provide mechanistic insights into the specifity of immune clearance by the complement system. Understanding the molecular mechanisms of complement activation and regulation will be instrumental in developing more potent therapeutics to control infections, prevent tissue damage and fight tumours by immunotherapies.

Keywords: complement system
AP-1 (Fos/Jun) Functions in Physiology and Disease (AP-1-FUN)

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: Spain
Call:  (ERC-2008-AdG, 2008)
Start date: 2009-11-01
End date: 2015-10-31
Duration (months): 72.0
Total project cost (EUR): 2500000.0
EU funding (EUR): 2500000.0
Participants: 1
Project status: CLOSED

Our research interests lie in breaking new ground in studying mechanism-based functions of AP-1 (Fos/Jun) in vivo with the aim of obtaining a more global perspective on AP-1 in human physiology and disease/cancer. The unresolved issues regarding the AP-1 subunit composition will be tackled biochemically and genetically in various cell types including bone, liver and skin, the primary organs affected by altered AP-1 activity. I plan to utilize the knowledge gained on AP-1 functions in the mouse and transfer it to human disease. The opportunities here lie in exploiting the knowledge of AP-1 target genes and utilizing this information to interfere with pathways involved in normal physiology and disease/cancer. The past investigations revealed that the functions of AP-1 are an essential node at the crossroads between life and death in different cellular systems. I plan to further exploit our findings and concentrate on utilising better mouse models to define these connections. The emphasis will be on identifying molecular signatures and potential treatments in models for cancer, inflammatory and fibrotic diseases. Exploring genetically modified stem cell-based therapies in murine and human cells is an ongoing challenge I would like to meet in the forthcoming years at the CNIO. In addition, the mouse models will be used for mechanism-driven therapeutic strategies and these studies will be undertaken in collaboration with the Experimental Therapeutics Division and the service units such as the tumor bank. The project proposal is divided into 6 Goals (see also Figure 1): Some are a logical continuation based on previous work with completely new aspects (Goal 1-2), some focussing on in depth molecular analyses of disease models with innovative and unconventional concepts, such as for inflammation and cancer, psoriasis and fibrosis (Goal 3-5). A final section is devoted to mouse and human ES cells and their impact for regenerative medicine in bone diseases and cancer.

Keywords: transcription factors,bone pathophysiology,liver pathology,skin physiology,inflammation,stem cells,cancer
DNA damage and the connection with cancer, premature aging and longevity (DAMAGE)

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-2008-AdG, 2008)
Start date: 2010-01-01
End date: 2014-12-31
Duration (months): 60.0
Total project cost (EUR): 2000000.0
EU funding (EUR): 2000000.0
Participants: 1
Project status: CLOSED

We study DNA damage and genome stability and its impact on human health using nucleotide excision repair (NER) as paradigm. Patients with NER defects present a perplexing clinical heterogeneity ranging from extreme cancer predisposition to dramatic neurodevelopmental deficits. To elucidate the underlying mechanism we adopted an integral strategy from gene to patient and contributed to resolving the NER reaction in vitro and its dynamic organization in vivo, using molecular genetics, advanced life cell imaging and photobleaching. Mouse NER mutants revealed an unexpected link between DNA damage and (premature) aging, as strong as the DNA damage-cancer connection. We found a striking correlation between type/severity of the repair defect and degree of premature aging, with some mutants dying of aging in 3 weeks! Pathological and functional analysis and expression profiling confirmed that this is bona fide aging. Conditional mutants allowed targeting accelerated aging to specific organs/stages of development e.g. dramatic aging only in brain. Expression profiling revealed that short-lived repair mutants mount a survival response that attempts to extend lifespan by investing in defenses at the expense of growth. The ambitious objective of this multi-disciplinary proposal is to obtain an integral understanding of the biological/medical impact of DNA damage and the important survival response, with emphasis on rational-based prevention and intervention strategies for cancer and other aging-related diseases using the rapidly aging mouse mutants as tools. Triggering the survival response at adulthood is expected to postpone many aging-related diseases including cancer and to strongly improve quality of life at later age. We already identified compounds that influence rapid aging in mice and demonstrated the potency of the survival response to withstand ischemia reperfusion damage. Thus, this proposal addresses the major medical challenges faced by our society.

Keywords: genome stability mechanisms,dna damage,repair syndromes,mouse models,longevity,progeria.
Organelle homeostasis: How are membrane fission and fusion machineries coordinated to regulate size and copy number of a lysosomal compartment? (ORGANELL)

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: Switzerland
Call:  (ERC-2008-AdG, 2008)
Start date: 2009-09-01
End date: 2015-08-31
Duration (months): 72.0
Total project cost (EUR): 2310000.0
EU funding (EUR): 2310000.0
Participants: 1
Project status: CLOSED

Yeast vacuoles (lysosomes) will serve as an excellent model system: Vacuoles change copy number and size in the cell cycle and upon shifts of media; due to their large diameter (up to 5 µm) these changes can be assayed by fluorescence microscopy and are amenable to genetic screening. Moreover, an in vitro system for vacuole fusion exists and we recently succeeded in reconstituting also cell-free vacuole fission with purified organelles. We will first build an experimental toolkit for vacuole fission to characterize this reaction in detail. Several approaches will be combined: (1) Identification of fission proteins by mutant screening, as well as by candidate approaches, and their localization relative to the fission site; (2) further developing a system reconstituting in vitro fission and efficient methods to quantitate it. (3) creating organelle chips to synchronously study fission on multiple single vacuoles immobilized in a defined orientation. (4) time-resolved confocal microscopy of fission proteins in vivo and in vitro; (5) biochemical characterization of fission protein associations and their changes during fission. These approaches will identify the vacuolar fission apparatus and help to elucidate its functioning. In a second step we will explore how the fission apparatus physically and functionally interacts with the already well-defined vacuolar membrane fusion machinery. We will characterize the impact of cell cycle regulators and signaling pathways on these interactions. These studies will be pioneering in that they will lead us to a comprehensive description of an organelle fission process and of how membrane fission and fusion components are coordinated to control size and copy number of an organelle.

Keywords: membrane fission,membrane fusion,organelle homeostasis,yeast
Nanosciences Live in Science Centres and Museums (NANOTOTOUCH)

Framework: FP7 — Cooperation
Programme: Nanosciences, Nanotechnologies, Materials and new Production Technologies - NMP
Destination: Nanosciences and Nanotechnologies
Action type: Coordination and support actions
Countries involved: Germany,Italy,Sweden,Belgium,Belgium,Estonia,Italy,Belgium
Call:  (FP7-NMP-2008-CSA-2, 2008)
Start date: 2009-03-01
End date: 2011-08-31
Duration (months): 30.0
Total project cost (EUR): 1533664.0
EU funding (EUR): 1367516.0
Participants: 14
Project status: CLOSED

The NANOTOTOUCH proposal aims to create innovative environments for the broad public to learn about and to discuss nano research by directly involving the actors of research themselves. We propose to do this by taking the laboratory environment and the research work out of enclosed academic campuses and relocating them right in the midst of the public in science museums and science centres. Three science museums and three science centres will closely cooperate with local university partners to create three permanent Open Nano Lab locations (in Munich, Milan and Gothenburg) and three Nano Researcher Live areas (in Mechelen, Tartu and Naples). In these places the visitors will experience “live” the day-to-day practices and processes of nano research conducted by young scientists. This peer-to-peer dialogue on an equal basis between lay public and nano-researchers not only creates a bidirectional feedback, it also minimises the expert-to-lay bias (“top-down" approach) inherent present science communication processes with authoritative top researchers. In order to prepare the young scientists for this novel method of communication, NANOTOTOUCH also includes a strong communication skills training component. NANOTOTOUCH will also establish new role models for choosing science as a career: young adults thinking of entering science will be able to discuss various aspects with young researchers who themselves made this decision recently, whilst upcoming researchers will learn that communication is a self-evident part of their professional identity. Thus, NANOTOTOUCH pushes science communication to its extreme, merging communication and research in a powerful way and responding to the need for more transparency and accessibility in science. Furthermore, the strong synergetic network approach of the project enables contents and models to be developed for further distribution and implementation in educational and scientific communities.

Keywords: nanotechnology,public understanding of research,public engagement,dialogue,science museums,science centres
Organization of the Conference EURONANOFORUM 2009 "Nanotechnology for Sustainable Economy" (ENF 2009)

Framework: FP7 — Cooperation
Programme: Nanosciences, Nanotechnologies, Materials and new Production Technologies - NMP
Destination: Integration
Action type: Coordination and support actions
Countries involved: Czechia
Call:  (FP7-NMP-2008-CSA-2, 2008)
Start date: 2008-11-01
End date: 2009-10-31
Duration (months): 12.0
Total project cost (EUR): 786414.0
EU funding (EUR): 394300.0
Participants: 1
Project status: CLOSED

The conference EuroNanoForum 2009 will be established as a foremost European congress in Nanotechnology within the framework of the Czech presidency. The conference will address the impact of nanotechnologies on sustainable economy focusing on their applications in resource- and eco-efficient industrial production, environmental protection and remediation, and energy production and conservation in the coming years. It aims to: (i) present the nanotechnology state of the art in the realm of sustainable economy;(ii) facilitate intensive exchange of views, information and experience between researches and representatives of industry, investors as well as policy makers and representatives of civil society; (iii) foster networking and knowledge transfer between different national and European stakeholders; and (iv) promote responsible governance in nanotechnology.

Keywords: conference,nanotechnology,sustainable economy