Data-Gouv-ML/pcri-informations-sur-les-projets-laureats huggingface dataset:
Dynamic signalling networks in Diabetic Nephropathy (DN) – New avenues to a personalized therapy.- (DNCURE)

Framework: FP7 — Ideas
Programme: European Research Council
Theme: European research council
Destination: Consolidator grants
Action type: Support for frontier research (ERC)
Panel: Physiology, Pathophysiology and Endocrinology
Countries involved: Germany
Call:  (ERC-2013-CoG, 2013)
Start date: 2014-06-01
End date: 2020-01-31
Duration (months): 68.0
Total project cost (EUR): 1999920.0
EU funding (EUR): 1999920.0
Participants: 2
Project status: CLOSED

Dynamic signalling networks in Diabetic Nephropathy (DN) – New avenues to a personalized therapy.- We have developed an exquisite experimental platform that facilitates the systematic unravelling of the signalling networks leading to (1) the initiation, (2) the progression and (3) the potential regeneration of podocytes in DN, paving the way to novel therapeutic strategies: (1) DN initiation: Identification of signalling cascades leading to microalbuminuria: Molecular By combining transgenic Drosophila lines carrying secreted fluorescent proteins to monitor the barrier function in vivo with a genome-wide siRNA screen we will establish a unique system to directly identify gene networks contributing to microalbuminuria. (2a) DN progression: Molecular fingerprinting of podocyte degeneration: Based on a transgenic fluorescent mouse model, we have pioneered a highly efficient podocyte purification method from type1 and type 2 diabetic mice allowing us to develop a precise molecular genetic, quantitative proteomic and micro RNA fingerprint from freshly isolated podocytes from diabetic and non-diabetic mice. (2b) DN progression: We established a proteomic approach to measure site-specific phosphorylation dynamics in primary podocyte cultures originating from transgenic mice that are TORC1 deficient, TORC2 deficient or TORC1 hyperactive (TSC1 KO) solely in the podocytes. (3) Potential role of podocyte regeneration in DN: Finally, to target mechanisms that could potentially reverse the disease process (by repopulating lost podocytes), we invented a strategy to quantitatively monitor podocyte turnover from different stem cell niches allowing us to precisely assess and potentially manipulating the capacity of podocyte regeneration in DN.

Keywords: diabetic nephropathy,podocyte,proteinuria
mTOR pathophysiology in rare human diseases (RARITOR)

Framework: FP7 — Ideas
Programme: European Research Council
Theme: European research council
Destination: Consolidator grants
Action type: Support for frontier research (ERC)
Panel: Physiology, Pathophysiology and Endocrinology
Countries involved: France
Call:  (ERC-2013-CoG, 2013)
Start date: 2015-02-01
End date: 2020-01-31
Duration (months): 60.0
Total project cost (EUR): 1998000.0
EU funding (EUR): 1998000.0
Participants: 1
Project status: CLOSED

The mammalian Target Of Rapamycin (mTOR) is a master regulator of growth. mTOR is a protein kinase that exists in two distinct complexes in the cell and transduces virtually all anabolic signals from the environment: nutrients, such as glucose and amino acids, growth factor peptides, such as insulin and insulin like growth factors, oxygen, mitochondrial metabolites, energy status. mTOR is required to sustain cell responses to nutrient availability including cell growth, proliferation, macromolecule biosynthesis, and suppress autophagy. During the past ten years we have generated and characterized a wide panel of mouse mutants in the mTOR pathway. We were involved in revealing specific phenotypes that increased our knowledge of mTOR roles in pathophysiology: mutants with small cells, mutants resistant to tumorigenesis in specific tissues and after specific oncogenic insults, mutants mimicking caloric restriction and promoting longevity, mutants with muscle dystrophy, mutants with altered insulin action. The overall goal of our research proposal for the next five years is twofold. From one hand we want to better understand fundamental processes including cell size control and organismal longevity. To this end we want to determine the molecular targets of the mTORC1/S6 kinase cassette that may explain the alterations in cell size and lifespan when these kinases are deregulated (project 1). From the other hand we want to understand and cure rare human genetic diseases that arise from pathological changes in the activity of the mTOR pathway in children or that may benefit from therapeutical intervention on this pathway. These diseases include Tuberous Sclerosis Complex, PEComas and hemangiomas (project 2), metabolic diseases (projects 3), lysosomal storage diseases (project 4). The translational approaches in this proposal will stem from a close interaction with multiple Medical Dept. in our shared research campus of the Necker Children Hospital.

Keywords: mtor,signal transduction,nutrition,rare diseases
Unravelling the unicellular prehistory of metazoans with functional analyses and single-cell genomics (PREMETAZOANEVOLUTION)

Framework: FP7 — Ideas
Programme: European Research Council
Theme: European research council
Destination: Consolidator grants
Action type: Support for frontier research (ERC)
Panel: Evolutionary, Population and Environmental Biology
Countries involved: Spain
Call:  (ERC-2013-CoG, 2013)
Start date: 2014-05-01
End date: 2019-04-30
Duration (months): 60.0
Total project cost (EUR): 1967535.0
EU funding (EUR): 1967535.0
Participants: 1
Project status: CLOSED

How multicellular animals (metazoans) emerged from their single-celled ancestor remains a long-standing evolutionary question. Recent genome data has shown that the unicellular ancestor of metazoans already had a complex gene repertoire for genes involved in cell adhesion, cell signaling and transcriptional regulation, including integrins, cadherins, T-box genes, and protein tyrosine kinases. Thus, besides a few metazoan-specific genes, gene co-option and, probably, an increase in gene regulation played important roles into the origin of Metazoa. However, the lack of genetic tools among metazoan’s closest relatives has so far precluded further investigations at the molecular level. Our recent establishment, for the first time, of transgenesis methodologies in two close unicellular relatives of metazoans (both the ichthyosporean Creolimax fragrantissima and the filasterean Capsaspora owczarzaki), allow us to approach these questions in ways that were not previously possible. Thus, we aim to push forward these two model systems and infer, by cell biology and functional genomics, the ancestral function of those genes key to multicellularity in order to understand how they were co-opted for new multicellular functions. In addition, we will analyze the regulation of the different cell stages and the colony formation (syncitial and aggregative multicellularity) in these two organism by functional genomics and identify when and how the metazoan histone code (an important regulatory layer of gene expression) evolved by analyzing the histone code in these taxa. Finally, to understand the ecology, distribution and adaptation of these unicellular taxa we will obtain the complete genome sequence of uncultured lineages by using single-cell genomics. This research will not only markedly improve our understanding of a major biological question (the origin of metazoan multicellularity) but will also generate new data relevant to a broad range of researchers.

Keywords: multicellularity,protists,metazoans,opisthokonts,comparative genomics,single-cell genomics,functional analyses,non-model organisms,transcriptions factors,gene regulation,ichthyosporeans.
Building the Neuronal Microtubule Cytoskeleton (NEUROMT)

Framework: FP7 — Ideas
Programme: European Research Council
Theme: European research council
Destination: Consolidator grants
Action type: Support for frontier research (ERC)
Panel: Cellular and Developmental Biology
Countries involved: Netherlands
Call:  (ERC-2013-CoG, 2013)
Start date: 2014-11-01
End date: 2020-10-31
Duration (months): 72.0
Total project cost (EUR): 2000000.0
EU funding (EUR): 2000000.0
Participants: 1
Project status: CLOSED

Microtubules (MTs) are one of the major cytoskeletal components of the cell, essential for many fundamental cellular and developmental processes, such as cell division, motility and polarity. In large and highly polarized cells like neurons, MTs have been regarded as essential structures for stable neuronal morphology and serve as tracks for long-distance transport; however, fundamental new insights into the role of neural MTs have emerged. New findings demonstrate that the MT cytoskeleton plays an active role during different phases of neuronal development: MTs determine axon formation, control polarized cargo trafficking, and regulate the dynamics of dendritic spines, the major sites of excitatory synaptic input. Failures in MT function have been linked to various neurological and neurodegenerative diseases and recent studies highlight MTs as a potential target for therapeutic intervention. How neuronal MTs are formed and stabilized during neuronal polarity and differentiation is largely unknown, and whether this requires the centrosome is under debate. The overall aim of this proposal is to investigate basic mechanisms responsible for organizing the microtubule cytoskeleton during neuronal development. Here, we will take a multidisciplinary approach and combine biochemistry, neurobiology, molecular engineering, and advanced microscopy to study the role of MTs at three stages of neuronal differentiation. We propose to determine: i) the role of (non-)centrosomal MT nucleation during early development, ii) the mechanism by which dendrites organize MTs into anti-parallel arrays, iii) the relation between MTs spine entry and cargo transport in mature neurons. We anticipate that these studies will uncover how the MT cytoskeleton is built and organized at different phases of neuronal development, which will be relevant for understanding polarized transport, synaptic processes and associated neurodegenerative disorders.

Keywords: cytoskeleton,microtubule,neuron polarity,neuron development,axon,dendrite,dendritic spines,transport,motor proteins,neurodegenerative disorders
Disabling Radiotherapy resistance in Cancer Treatment (DIRECT)

Framework: FP7 — Ideas
Programme: European Research Council
Theme: European research council
Destination: Consolidator grants
Action type: Support for frontier research (ERC)
Panel: Diagnostic Tools, Therapies and Public Health
Countries involved: Netherlands,New Zealand
Call:  (ERC-2013-CoG, 2013)
Start date: 2014-05-01
End date: 2019-04-30
Duration (months): 60.0
Total project cost (EUR): 1830510.0
EU funding (EUR): 1830510.0
Participants: 2
Project status: CLOSED

Cancer is a devastating disease affecting 1 in 3 people in their lifetime. The incidence is rising because of our aging population and causes a huge economic impact on our society because of hospitalization and lost productivity. Radiotherapy alone or in combination with surgery and/or chemotherapy is used in ~50% of all patients and uses ionizing radiation to induce DNA breaks that are lethal to cells. While significant progress has been made, radiotherapy is often limited because of side-effects in normal tissues and tumor control often fails because of resistance and metastases. Novel treatment paradigms are urgently needed. Among the key classical biological factors that determine radiation response in normal and tumor cells are the 4R; Reoxygenation, Repopulation, Redistribution and Repair. They are determined by intrinsic (genetic) as well as extrinsic factors from the tumor microenvironment and underlie tumor heterogeneity a hallmark of cancers and a decisive factor in clinical response. Yet, standard cancer treatments are largely based on the flawed assumption that tumors are homogenous within and between patients. We hypothesized that NOTCH signaling and tumor hypoxia cause tumor heterogeneity and are tumor selective therapeutic targets. First we will study key biological mechanisms that determine intra tumor heterogeneity, second we will establish their role in therapy response and third we will exploit this knowledge to enhance radiotherapy and provide proof of concept of a highly innovative approach to selectively activate cancer therapeutics targeting the NOTCH stem cell pathway in therapy resistant tumor cells without adverse effects in normal tissues. DIRECT interrogates the molecular details of key cancer therapy response parameters providing opportunities for the next generation of tumor cell specific treatments that improve disease outcome.

Keywords: tumor heterogeneity,hypoxia,lineage tracer,notch,stem cells,radiation sensitizer,nitroimadazole,bioreductive prodrug,nitroreductase,live imaging,cell cycle
DNA Replication Stress in Cancer (RESTRECA)

Framework: FP7 — Ideas
Programme: European Research Council
Theme: European research council
Destination: Consolidator grants
Action type: Support for frontier research (ERC)
Panel: Molecular and Structural Biology and Biochemistry
Countries involved: Switzerland
Call:  (ERC-2013-CoG, 2013)
Start date: 2014-10-01
End date: 2019-09-30
Duration (months): 60.0
Total project cost (EUR): 1846500.0
EU funding (EUR): 1846500.0
Participants: 1
Project status: CLOSED

DNA replication is a crucial, but potentially dangerous process in every cellular division. A failure to maintain the integrity of replicating chromosomes leads to genome instability, an early event in tumorigenesis. Most common anti-cancer drugs also interfere with DNA synthesis, by largely undefined mechanisms. My lab specializes in the structural and molecular characterization of DNA replication stress in higher eukaryotes, combining standard cell and molecular biology with specialized single molecule analysis of replication intermediates. The first aim of our research is to gain mechanistic information about the elusive impact of oncogene activation on DNA replication. By direct structural analysis of tissue culture models of tumorigenesis, we have recently uncovered specific defects in DNA synthesis associated with DNA damage checkpoint activation. We plan to expand these studies to compare the effect of different oncogenes and to identify cellular factors modulating oncogene-induced genotoxicity. We are also elucidating the cytotoxic mechanisms of anti-cancer drugs that challenge DNA replication. Comparing the molecular consequences of chemotherapeutic treatments in control cells and cells lacking cancer-related factors, we plan to uncover how precisely different drugs interfere with replication and which cellular players mediate their cytotoxicity. We plan to complement these studies with a proteomic-based screen, to identify novel factors modulating replication of a damaged template. Finally, we plan to analyze replication features in different populations of stem cells, as the cellular response to replication stress was recently proven essential for stem cell maintenance. We aim to provide mechanistic insight into the constitutive activation of the DNA damage response reported in embryonic stem cells. We also plan to expand these investigations to hematopoietic stem cells, where we recently observed similar phenomena upon stimuli-induced proliferation.

Keywords: genome instability,dna replication stress,single molecule approaches,electron microscopy,dna damage checkpoints,oncogenes,chemotherapeutic drugs,stem cells
Spectroscopy of exotic nuclei in a Magnetic Active Target (SPECMAT)

Framework: FP7 — Ideas
Programme: European Research Council
Theme: European research council
Destination: Consolidator grants
Action type: Support for frontier research (ERC)
Panel: Fundamental Constituents of Matter
Countries involved: Belgium
Call:  (ERC-2013-CoG, 2013)
Start date: 2014-06-01
End date: 2020-05-31
Duration (months): 72.0
Total project cost (EUR): 1944900.0
EU funding (EUR): 1944900.0
Participants: 1
Project status: CLOSED

SpecMAT aims at providing crucial experimental information to answer key questions about the structure of atomic nuclei: - What are the forces driving the shell structure in nuclei and how do they change in nuclei far from stability? - What remains of the Z = 28 and N = 50 “magic numbers” in 78Ni? - Do we understand shape coexistence in nuclei, and what are the mechanisms controlling its appearance? The position of natural and “intruder” shells will be mapped in two critical regions, the neutron-rich nuclei around Z = 28 and the neutron-deficient nuclei around Z = 82. The centroids of the shell strength are derived from the complete spectroscopy of those systems in nucleon-transfer measurements. This method will be applied for the first time in the region of neutron-deficient Pb nuclei. In SpecMAT (Spectroscopy of exotic nuclei in a Magnetic Active Target) a novel instrument will overcome the present challenges in performing such measurements with very weak beams of unstable nuclei. It combines high luminosity, high efficiency and a very large dynamic range and allows detection of both charged-particle and gamma-ray radiation. The instrument owns its remarkable performances to a number of advanced technologies concerning the use of electronics, gaseous detectors and gamma-ray detectors in a magnetic field. The SpecMAT detector will be coupled to the HIE-ISOLDE facility for the production and post-acceleration of radioactive ion beams in construction at CERN in Geneva. HIE-ISOLDE will provide world-unique beams thanks to the use of the proton injector of the CERN complex. If successful, SpecMAT at HIE-ISOLDE will produce specific results in nuclear structure which cannot be reached by other programmes elsewhere. Such results will have a significant impact on the present theories and models of the atomic nucleus.

Keywords: nuclear structure,nuclear spectroscopy,gaseous detector,gamma-ray detectors
Nano-Particle-Resolved Studies (NANOPRS)

Framework: FP7 — Ideas
Programme: European Research Council
Theme: European research council
Destination: Consolidator grants
Action type: Support for frontier research (ERC)
Panel: Condensed Matter Physics
Countries involved: United Kingdom
Call:  (ERC-2013-CoG, 2013)
Start date: 2014-05-01
End date: 2020-04-30
Duration (months): 72.0
Total project cost (EUR): 2336887.0
EU funding (EUR): 2336887.0
Participants: 1
Project status: CLOSED

Amorphous materials may be classified into three types – thermodynamically stable liquids, metastable (supercooled) liquids and solid glasses. The second type represents the meeting point of many of the great challenges of statistical physics and materials science. What is the mechanism of dynamical arrest, by which structural relaxation become progressively inhibited upon cooling from a liquid to a glass? Can we develop physical pictures of the sequence of fluctuations associated with irreversible relaxation in metastable liquids? How do crystals emerge from these fluctuations? Here we take a structural approach coupled with novel experiments and computer simulations to tackle two specific questions. Firstly, it has long been believed that there should be some structural mechanism underpinning the glass transition, where deeply supercooled liquids continuously transform into solid glasses. Secondly, the fate of the supercooled liquid – whether it crystallises on accessible timescales – should also be related to the local atomic arrangements in the liquid. Tackling the first will lead to insight into the nature of the glass transition - it is not known whether or not there is a true thermodynamic transition to a glass. As for crystallisation, predicted nucleation rates vary wildly with those obtained experimentally in the only system in which both have been compared, little is known beyond trial and error of means by which crystallisation in mixtures can be controlled. In short, our understanding of the fate of supercooled liquids is lacking in a variety of ways. Understanding the glass transition and nucleation is of fundamental importance, and both have important applications for example in metallic glasses and phase change materials. The former are prized for their superior mechanical properties such as extreme toughness while latter underpin emergent technologies such as optical data storage and phase change memory.

Keywords: colloids,glass transition,crystallisation
Recombination in Adaptive Evolution (EVOLRECOMBADAPT)

Framework: FP7 — Ideas
Programme: European Research Council
Theme: European research council
Destination: Consolidator grants
Action type: Support for frontier research (ERC)
Panel: Evolutionary, Population and Environmental Biology
Countries involved: Germany
Call:  (ERC-2013-CoG, 2013)
Start date: 2014-08-01
End date: 2020-07-31
Duration (months): 72.0
Total project cost (EUR): 1998704.0
EU funding (EUR): 1998704.0
Participants: 1
Project status: CLOSED

Meiotic recombination is a key source of genetic diversity with considerable implications for the genomic landscape and evolutionary process. By shuffling parental alleles to produce novel haplotypes, recombination impacts the strength of selection on nearby polymorphisms, and can increase the rate of adaptation in natural populations. Recombination defects can have serious phenotypic consequences: inviable gametes, miscarriages and developmental abnormalities. Strikingly, recombination rate differs by orders of magnitude across the genome, among individuals, sexes, populations and species. Despite recent progress, we know little about how molecular constraints and evolutionary forces interact to shape recombination in natural populations. We will close this knowledge gap using threespine stickleback fish—an exceptional evolutionary model system that bridges molecular genetic studies and adaptive evolution in the wild. This research program combines next-generation genomics with cutting-edge molecular biology and transgenics. We will 1) create kilobase-scale maps of the recombination landscape in adaptively diverging populations; 2) genetically dissect factors cis- and trans-acting factors that cause recombination variation; 3) characterize molecular mechanisms of recombination modifiers using cutting-edge techniques; and 4) test evolutionary theory that predicts natural selection favours recombination suppression in hybrids. This will significantly improve our understanding of recombination and introduce sophisticated genetic engineering techniques that further cement sticklebacks as an evolutionary model organism. Our ultimate goal is to understand how molecular mechanisms and natural selection shape and constrain recombination during adaptive divergence. This research connects a fundamental biological process that underlies severe human diseases with the tempo of adaptation in natural populations

Keywords: meiotic recombination,transgenics,chromosome inversions,adaptive divergence,fitness