Data-Gouv-ML/pcri-informations-sur-les-projets-laureats huggingface dataset:
Molecular mechanisms of the regulation of mammary stem cell homeostasis and their subversion in cancer (MAMMASTEM)

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: Italy
Call:  (ERC-2008-AdG, 2008)
Start date: 2009-03-01
End date: 2014-02-28
Duration (months): 60.0
Total project cost (EUR): 2274862.0
EU funding (EUR): 2274862.0
Participants: 1
Project status: CLOSED

Stem cells (SCs) are thought to be integral to the development and progression of cancer, and their eradication may be essential for the cure of cancer. Yet, direct proof is lacking due to our poor understanding of the molecular differences between normal and cancer SCs. We will investigate normal and cancer mammary stem cells (MSCs) by focusing on the role of the cell fate determinant Numb in two signaling axes: Numb:Notch and Numb:p53. Numb is a tumor suppressor in human breast cancer. Its expression is lost, through increased degradation, in ~50% of breast cancers. These Numbneg cancers display overall poorer prognosis. Mechanistically, loss of Numb causes increased Notch signaling and decreased p53 signaling. Thus, Numb controls both an oncogenic pathway (the Numb:Notch axis) and a tumor suppressor one (the Numb:p53 axis). We showed that Numb is asymmetrically partitioned at the first division of normal MSCs and hypothesize that loss of Numb affects the kinetics of division and MSC fate. Our specific aims are to: 1. Define the role of the Numb:Notch and Numb:p53 axes in normal and cancer MSCs. We will exploit our capacity to propagate and isolate MSCs to near-purity, for biological, biochemical and omics approaches. In this task, we will integrate knowledge derived from the analysis of real human cancers and of genetically-defined mouse models. 2. Define the broader biological context of Numb impact in stem cell biology, by analyzing the role of endocytosis in MSC fate determination. This is justified by the fact that Numb is an endocytic protein and that data in Drosophila indicate a complex role of endocytosis in cell fate specification. 3. Identify the E3 ligase responsible for Numb degradation in Numbneg breast tumors, in order to obtain druggable targets to restore Numb levels in these tumors. If successful, our work will elucidate major mechanisms of normal and cancer stem cell regulation, and provide tools for SC-specific therapeutic intervention.

Keywords: stem cells,tumor suppression,oncogene,endocytosis,ubiquitination,signal transduction
Biomolecular computers (BIOMOLECULAR_COMP)

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: Israel
Call:  (ERC-2008-AdG, 2008)
Start date: 2009-01-01
End date: 2013-10-31
Duration (months): 58.0
Total project cost (EUR): 2125980.0
EU funding (EUR): 2125980.0
Participants: 1
Project status: CLOSED

Autonomous programmable computing devices made of biological molecules hold the promise of interacting with the biological environment in future biological and medical applications. Our laboratory's long-term objective is to develop a 'Doctor in a cell': molecular-sized device that can roam the body, equipped with medical knowledge. It would diagnose a disease by analyzing the data available in its biochemical environment based on the encoded medical knowledge and treat it by releasing the appropriate drug molecule in situ. This kind of device might, in the future, be delivered to all cells in a specific tissue, organ or the whole organism, and cure or kill only those cells diagnosed with a disease. Our laboratory embarked on the attempt to design and build these molecular computing devices and lay the foundation for their future biomedical applications. Several important milestones have already been accomplished towards the realization of the Doctor in a cell vision. The subject of this proposal is a construction of autonomous biomolecular computers that could be delivered into a living cell, interact with endogenous biomolecules that are known to indicate diseases, logically analyze them, make a diagnostic decision and couple it to the production of an active biomolecule capable of influencing cell fate.

Keywords: turing machine,finite automaton,molecular computer,dna computing,smart drug.
TFIIH as a crucial actor in genome expression and repair (TRANSREACT)

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: France
Call:  (ERC-2008-AdG, 2008)
Start date: 2009-01-01
End date: 2013-12-31
Duration (months): 60.0
Total project cost (EUR): 1997000.0
EU funding (EUR): 1997000.0
Participants: 1
Project status: CLOSED

Understanding how the genetic information of a cell is retrieved but also protected from insults, is a major challenge facing modern molecular biology. Indeed, one of the most important developments in human genetics over the last decade, has been the realization that diseases such as cancer but also ageing stem from some dis-regulation in the expression and preservation of the genetic information. TFIIH is a multiprotein complex that is essential in transcription and DNA repair. Mutations in some of its subunits are responsible of a UV sensitivity phenotype in yeast and drosophila. In human, this results in the rare DNA repair deficient genetic disorder, xeroderma pigmentosum (XP), which is characterized by photosensitivity and an increased risk of skin cancers. Two further disorders involving mutation in TFIIH subunits, Cockayne syndrome (CS) and trichothiodystrophy (TTD) are also defective in repair of UV damage, but present quite different clinical features such as brittle hair, neurological and developmental retardation, middles sun sensitivity and no susceptibility to solar carcinogenesis. The clinical complexity of these syndromes cannot be explained solely by deficiencies in DNA repair and emerging evidences indicate that it may also result from a dys-regulation of the transcriptional program under the control of hormones. The goal of this proposal is to investigate the DNA repair/transcription disorders involving mutations in TFIIH. This research will not only assists afflicted XP, CS, TTD and normal individuals in prevention and ultimately cures of hormonal dependent diseases and cancer (the clinical point of view), but more generally will provide an improved understanding of the mechanisms that regulate the expression of protein coding genes and the maintenance of genome integrity (the fundamental research point of view).

Keywords: tfiih,nucleotide excision repair,mrna transcription,genome integrity
Molecular Analysis of Hepatitis C Virus Neutralization and Entry For the Development of Novel Antiviral Immunopreventive Strategies (HEPCENT)

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: France,Germany
Call:  (ERC-2008-AdG, 2008)
Start date: 2009-04-01
End date: 2014-12-31
Duration (months): 69.0
Total project cost (EUR): 2447357.0
EU funding (EUR): 2447357.0
Participants: 2
Project status: CLOSED

Hepatitis C virus (HCV) infection is a leading cause of chronic liver disease world-wide. HCV-induced end-stage liver disease such as liver cirrhosis and hepatocellular carcinoma represent a major concern in global health. Treatment options for chronic hepatitis C are limited and no vaccine against HCV infection is available. Vaccine development is hampered by several obstacles. High viral variability and escape from host immune responses render antigen selection a major challenge. Antigen selection requires thorough studies to identify conserved T cell and neutralization epitopes and to decipher neutralization mechanisms, aiming to discover the optimal viral target for immune responses counteracting HCV escape strategies. At the same time it is important to develop antigen presentation systems that are efficient in patients with impaired antiviral immune responses, as often observed during chronic hepatitis C. While most vaccine development programs are based on improving HCV cellular immunity, it is essential to associate, in a same vaccine formulation, immunogens able to induce broad spectrums neutralizing and cellular responses. Owing to recent progresses in the field, here we propose a project aiming to overcome the current limitations in vaccine development by addressing the improvement of B cell responses targeting HCV infection. This will be achieved by a detailed investigation of: 1) mechanisms of antibody-mediated neutralization and escape, 2) impact of lipoproteins associating with the viral particle during assembly/release and counteracting neutralization and 3) cell entry steps that can potentially be targeted by antibodies, including those that are not induced naturally. Thus, through the combined expertise of the team in molecular virology, immunology, clinical hepatology and vectorology, we aim to rationalize the development of B cell immunogens and neutralizing antibodies for novel antiviral immunopreventive strategies targeting HCV infection.

Keywords: hepatitis c,vaccine,neutralisation,lipoprotein,cell entry,assembly,receptor,antibody
Computations by Neurons and Populations in Visual Cortex (CORTEX)

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: United Kingdom
Call:  (ERC-2008-AdG, 2008)
Start date: 2009-04-01
End date: 2014-03-31
Duration (months): 60.0
Total project cost (EUR): 2499921.0
EU funding (EUR): 2499921.0
Participants: 1
Project status: CLOSED

Neurons in primary visual cortex (area V1) receive feedforward inputs from thalamic afferents and lateral inputs from other cortical neurons. Little is known about how these components interact to determine the responses of a V1 neuron. One camp ascribes most responses to feedforward mechanisms. The other camp ascribes them mostly to lateral interactions. We propose that these two apparently opposed views can be simply reconciled in a single framework. We hypothesize that area V1 can operate both in a feedforward regime and in a lateral interaction regime, depending on the nature of the stimulus and on the cognitive task at hand, and that the transition from one regime to the other is governed by synaptic inhibition. We will test these hypotheses by recording from individual V1 neurons while monitoring the activity of nearby populations of cortical neurons via multiprobe electrodes. In Aim 1 we will relate the activity of V1 neurons to that of nearby populations. We will use simple measures of correlation and nonlinear models that predict individual spikes to measure how responses depend on a feedforward contribution (the receptive field ) and on a lateral contribution (the connection field ). We will test our first hypothesis, concerning the role of the stimulus in changing this dependence. In Aim 2 we will extend these results to a behaving animal. We will record from V1 of mice performing a 2-alternative forced-choice psychophysical task, and we will test our second hypothesis, concerning the role of the cognitive task in determining the operating regime of the cortex. In Aim 3 we will seek a biophysical interpretation of the functional mechanisms and effective connectivity revealed by the previous Aims. We will test our third hypothesis, concerning the role of synaptic inhibition. The tools involved will include intracellular recordings and optical stimulation in transgenic mice whose cortical neurons are sensitive to light.

Keywords: cerebral cortex,neural circuits
Proteomics v3.0: Development, Implementation and Dissemination of a Third Generation Proteomics Technology (PROTEOMICS V3.0)

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: Switzerland
Call:  (ERC-2008-AdG, 2008)
Start date: 2009-04-01
End date: 2014-03-31
Duration (months): 60.0
Total project cost (EUR): 2400000.0
EU funding (EUR): 2400000.0
Participants: 1
Project status: CLOSED

Quantitative proteomics is a key technology for the life sciences in general and for systems biology in particular. So far, however, technical limitations have made it impossible to analyze the complete proteome of any species. It is the general goal of this proposal to develop, implement, apply and disseminate a new proteomic strategy that has the potential to generate quantitative proteomic datasets at an unprecedented depth, throughput, accuracy and robustness. Specifically, the new technology will identify and quantify every protein in a proteome. The title of the project Proteomics v3.0 was chosen to indicate the transformation of proteomics into its third phase, after 2D gel electrophoresis and LC-MS/MS based shotgun proteomics. Proteomics v3.0 is based on two sequential steps, emulating the strategy that has been immensely successful in the genomic sciences. In the first step the proteomic space is completely mapped out to generate a proteomic resource that is akin to the genomic sequence database. In the second step rapid and accurate assays will be developed to unambiguously identify and quantify any protein of the respective proteome in a multitude of samples. These assays will be made publicly accessible to support quantitative proteomic studies in the respective species. The strategy will first be implemented and tested in the yeast S. cerevisiae. In a later stage of the project it will be extended to the more complicated human proteome and include the development of assays that also probe the state of modification, splice forms and other types of protein variants generated by a specific open reading frame. Overall, the project will transform quantitative proteomics from a highly specialized technology practiced at a high level in a few laboratories worldwide into a commodity technology accessible, in principle to every group.
Molecular Mechanism of Oxygen Sensing by Enzymes (MOOSE)

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: United Kingdom
Call:  (ERC-2008-AdG, 2008)
Start date: 2009-03-01
End date: 2014-02-28
Duration (months): 60.0
Total project cost (EUR): 3000000.0
EU funding (EUR): 3000000.0
Participants: 1
Project status: CLOSED

The hypoxic response in humans is regulated by enzymes that catalyse the post-translational hydroxylation of hypoxia inducible factor (HIF). Prolyl-hydroxylation signals for HIF-alpha degradation whilst asparaginyl-hydroxylation blocks the transcriptional activity of HIF. The absolute requirement of the HIF hydroxylases for oxygen enables them to act as hypoxia sensors. The overall goal of the proposed programme is to capitalize on recent advances in this field arising from the joint Schofield and Ratcliffe laboratories, in a multidisciplinary chemistry-biology approach aimed at opening new horizons both for the basic molecular understanding, and for the therapeutic manipulation, of the human transcriptional response to hypoxia. The specific objectives of the proposed programme will be pursued via defined and syngergistic work packages and include (i) To develop and apply state-of-the-art methods for monitoring oxygen-dependant hydroxylation within cells that will enable us to examine the role of the hydroxylases as signal integration points for redox factors; (ii) To define the existence and nature of the structural and kinetic features that underpin the physiological function of HIF hydroxylases in oxygen homeostasis; (iii) To define the extent and biological roles of post-translational hydroxylation in human cells; (iv) To develop novel templates for selective inhibition and activation of individual human HIF hydroxylases. We will follow a multidisciplinary approach ranging from kinetic and high-resolution structural analyses on the hydroxylases to studies in animal cells. We aim that the results will not only be of use in ongoing pharmaceutical attempts to modulate the natural hypoxic response for the treatment of ischemic disease and cancer, but will serve as a paradigm for biomedicinal analyses of signalling systems.

Keywords: hypoxia,hypoxic response,ischemic disease,oxygen,iron-oxygenase,oxygen-sensing,post-translational modification,transcriptional regulation.
Genomic and Phenotypic Evolution of Bonobos, Chimpanzees and Humans (TWOPAN)

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: Germany
Call:  (ERC-2008-AdG, 2008)
Start date: 2009-06-01
End date: 2015-05-31
Duration (months): 72.0
Total project cost (EUR): 2199996.0
EU funding (EUR): 2199996.0
Participants: 1
Project status: CLOSED

Humans have two closest living relatives: the well known chimpanzee (Pan troglodytes) and the lesser known bonobo (Pan paniscus). While the lineage leading to humans and the lineage leading to bonobos and chimpanzees split five to seven million years ago, the bonobo and chimpanzee lineages split around one million years ago. Despite such a recent divergence, these two ape species exhibit remarkable phenotypic differences, indicating that inferences about human evolution will require comparative data from both bonobos and chimpanzees. This is also true at the genomic level. For example, in order to understand the extensive variation seen in gene expression within humans, it is necessary to know the extent of variation within closely related species, as well as the level of differences between species. Comparative genomic data is also necessary, for example, to address whether the supposed high rate of human adaptive evolution is exceptional relative to other closely related primates. Thus, in order to better understand patterns of human evolution, we propose to generate a genome sequence for the bonobo and to collect extensive data from chimpanzees and bonobos on: cDNA sequences, variation in coding and non-coding parts of the genomes, expression of mRNAs, microRNAs and proteins in five tissues, and phenotypic parameters in terms of clinical chemistry, and behavioral and cognitive traits. We will combine these data with the extensive data already collected on humans and perform integrated analyses of between- and within-species variation of genomic and phenotypic traits in humans, bonobos and chimpanzees. This will allow us to place the trends seen in human evolution within the context of our closest living relatives and will substantially increase our understanding of how the genomes of humans, bonobos and chimpanzees produce such startlingly different phenotypes.

Keywords: evolutionary genomics,human origins,positive selection,primate cognition and behavior
Neural basis of Drosophila mating behaviours (FRU CIRCUIT)

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: Austria
Call:  (ERC-2008-AdG, 2008)
Start date: 2009-07-01
End date: 2013-09-30
Duration (months): 51.0
Total project cost (EUR): 2492164.0
EU funding (EUR): 2492164.0
Participants: 1
Project status: CLOSED

How does information processing in neural circuits generate behaviour? Answering this question requires identifying each of the distinct neuronal types that contributes to a behaviour, defining their anatomy and connectivity, and establishing causal relationships between their activity, the activity of other neurons in the circuit, and the behaviour. Here, I propose such an analysis of the neural circuits that guide Drosophila mating behaviours. The distinct mating behaviours of males and females are genetically pre-programmed, yet can also be modified by experience. The set of ~2000 neurons that express the fru gene have been intimately linked to both male and female mating behaviours. This set of neurons includes specific sensory, central, and motor neurons, at least some of which are directly connected. Male-specific fruM isoforms configure this circuit developmentally for male rather than female behaviour. In females, mating triggers a biochemical cascade that reconfigures the circuit for post-mating rather than virgin female behaviour. We estimate that there are ~100 distinct classes of fru neuron. Using genetic and optical tools, we aim to identify each distinct class of fru neuron and to define its anatomy and connectivity. By silencing or activating specific neurons, or changing their genetic sex, we will assess their contributions to male and female behaviours, and how these perturbations impinge on activity patterns in other fru neurons. We also aim to define how a specific experience can modify the physiological properties of these circuits, and how these changes in turn modulate mating behaviour. These studies will define the operating principles of these neural circuits, contributing to a molecules-to-systems explanation of Drosophila s mating behaviours.

Keywords: neural circuits,genetics,drosophila,behaviour,imaging,photoactivation