Data-Gouv-ML/pcri-informations-sur-les-projets-laureats huggingface dataset:
Identification and targeting of somatic changes initiating sporadic cancers (ISIS)

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: Germany
Call:  (ERC-2012-ADG_20120314, 2012)
Start date: 2013-03-01
End date: 2018-08-31
Duration (months): 66.0
Total project cost (EUR): 2499982.14
EU funding (EUR): 2499982.14
Participants: 1
Project status: CLOSED

Cancer drugs are extremely ineffective, generally because current therapies do not address cellular heterogeneity. While hypothesis-driven research and functional genomics identify ever more novel putative therapeutic targets, the scientific community lacks rationales to attack the cellular heterogeneity in cancer, to select among the targets the most promising, and to design combination therapies. In particular, these all fail to provide successful adjuvant therapy settings after curative resection of the primary tumour before the onset of manifest metastasis. Here I propose a novel way to address cancer cell heterogeneity and to develop a rationale for the design of adjuvant therapies. The proposal rests upon the premises that (i) cancer initiation is causally associated with genetic changes, (ii) early, functionally relevant genetic changes -particularly involving DNA loss- have the highest probability to be shared among the progeny of a monoclonal, yet genetically unstable, cancer, and (iii) subsequent, cumulative genetic changes must either add to the fitness of the cell or at least be neutral to enable progression. The proposal is then built upon our observation that a subgroup of disseminated cancer cells (DCCs) displays normal karyotypes and DNA changes smaller than 10 Mb whilst primary tumours and more advanced DCCs harbour multiple additional chromosomal changes at the time of analysis. I suggest that although these karyotypically normal DCCs are the putative “loser cells” in cancer progression - since they are arrested in bone marrow - they are central to uncovering the early genetic changes of an individual cancer. With these cells we will identify for the first time the catalogue of initiating changes of sporadic cancers in a systematic way. We will then test the function of the early aberrations and perform functional viability screens to develop novel systemic therapies that target the Achilles’ heel of a given cancer: its shared critical alteration.

Keywords: disseminated cancer cells,stratified therapies,metastasis
Evolutionary strategy for plant breeding (EVOBREED)

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-2012-ADG_20120314, 2012)
Start date: 2013-10-01
End date: 2018-09-30
Duration (months): 60.0
Total project cost (EUR): 2497061.99
EU funding (EUR): 2497061.99
Participants: 1
Project status: CLOSED

Large proportions of eukaryotic genomes consist of transposable elements (TEs), predominantly of retrotransposons. They are generally considered as intra-chromosomal parasites. However, their periodical activity bursts influenced organization of host genomes and contributed to beneficial traits. Remarkably, number of transposon generated phenotypic innovations was subsequently selected by humans during plant domestication and breeding. Therefore, retrotransposons could be also considered as attractive endogenous source of genetic variation. Unfortunately so far there is no experimental/technological means to exploit this potential in a controlled fashion. Recently my laboratory revealed surprisingly selective epigenetic, environmental and developmental mechanisms controlling retrotransposition in Arabidopsis. Here, I intend to build on this knowledge and establish well controlled retrotransposition system a crop plant to liberate its innate genetic diversity buried in silenced TEs. To achieve this, I propose a stepwise strategy with the following three objectives: 1. Deeper understanding of molecular mechanisms and environmental cues controlling retrotransposition in Arabidopsis thaliana and use this model plant to develop universal methodology for detection of retrotransposition. 2. Transfer the knowledge and methodologies to non model plant. I propose to use Arabidopsis lyrata as close relative of A. thaliana, however with 50% enlarged genome due to expansion of retrotransposon populations. 3. Using methodologies and experimental conditions developed for A. thaliana and A. lyrata we will apply them to maize where we can also take advantage of genetic resources (mutants in epigenetic regulation) in conjunction with responses to selected abiotic stresses. If the progress towards above listed objectives was swift, I will initiate collaboration with a corn breeding company to create EVOBREED generated population for evaluation of its phenotypic diversity.

Keywords: plant genetics,plant epigenetics,transposons
Protist evolution in suboxic worlds (PROTISTWORLD)

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: France
Call:  (ERC-2012-ADG_20120314, 2012)
Start date: 2013-09-01
End date: 2019-08-31
Duration (months): 72.0
Total project cost (EUR): 2039812.27
EU funding (EUR): 2039812.27
Participants: 1
Project status: CLOSED

How and when eukaryotes evolved remain major open questions. Also the phylogenetic relationships and the emergence order of major eukaryotic lineages remain unresolved, despite progress in phylogenomic analyses based on genome and transcriptome data across the eukaryotic tree. However, this information is biased towards multicellular taxa. Yet, environmental molecular analyses have uncovered a vast diversity of protists (broadly, microbial eukaryotes), many of which have uncertain phylogenetic position. Phylogenomics also suggests that endosymbiosis (e.g. mitochondrial acquisition) played a key role in eukaryotic evolution, shaping their genomes and leading to innovations. The first eukaryotes likely evolved in anoxic or transition-to-oxic (suboxic) environments, which may hold clues as to the occurring selective constraints, prior to colonizing new niches thanks to oxygen-respiring mitochondria. Despite so, little is known about the diversity and mode of evolution of eukaryotes in suboxic worlds, including microbial mats and stromatolites, where many inter-species interactions are likely to exist. I propose an integrative interdisciplinary approach to gain significant knowledge about early eukaryotic evolution according to the following hypotheses: i) High diversity suboxic environments, such as microbial mats, hide novel divergent protist lineages. ii) The study of natural fossilization processes of microbial eukaryotes in calcifying microbial mats such as stromatolites will lead to the definition of biosignatures in the past fossil record and to establish reference dates for the origin of eukaryotes and/or particular eukaryotic taxa. iii) Phylogenomic analysis of divergent protist lineages from suboxic environments will help resolving the eukaryotic tree of life and dating major splits in eukaryotic lineages. iv) Protist symbiosis with prokaryotes is widespread in suboxic worlds and that (endo)symbiotic-gene transfer has an important impact in protist evolution.

Keywords: protist diversity and evolution,environmental microbiology,phylogenomics,microbial fossil record,stromatolite
Celiac disease: from lincRNAs to disease mechanism (CD-LINK)

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: Netherlands
Call:  (ERC-2012-ADG_20120314, 2012)
Start date: 2013-02-01
End date: 2018-11-30
Duration (months): 70.0
Total project cost (EUR): 2319914.0
EU funding (EUR): 2319914.0
Participants: 1
Project status: CLOSED

Celiac disease affects at least 1% of the world population. Its onset is triggered by gluten, a common dietary protein, however, its etiology is poorly understood. More than 80% of patients are not properly diagnosed and they therefore do not follow a gluten-free diet, thereby increasing their risk for disease-associated complications and early death. A better understanding of the disease biology would improve the diagnosis, prevention, and treatment of celiac disease. This project investigates the disease mechanisms in celiac disease by using predisposing genes and genetic variants as disease initiating factors. Specifically, it will investigate if long, intergenic non-coding RNAs (lincRNAs) are causally involved in celiac disease pathogenesis by regulating protein-coding genes and pathways associated with the disease. This project is based on two important observations by my group: (1) Our genetic studies, which led to identifying 39 celiac disease risk loci, suggest that the mechanism underlying the disease is largely governed by dysregulation of gene expression. (2) We uncovered a previously unrecognized role for lincRNAs that provides clues as to exactly how genetic variation causes disease, as this class of biologically important RNA molecules regulate gene expression. The research will be performed in CD4+ T cells, a severely affected cell type in disease pathology. I will first use celiac disease-associated protein-coding genes to delineate their regulatory pathways and then study the transcriptional programs of lincRNAs present in celiac disease loci. Next I will combine the information and investigate if the expressed lincRNAs modulate the pathways and affect T cell function, thereby discovering if lincRNAs are a missing link between non-coding genetic variation and protein-coding genes. Our findings may well lead to potential therapeutic targets and provide a solid scientific basis for new diagnostic markers, particularly biomarkers, based on genetics.

Keywords: celiac disease,lincrna,systems genetics,eqtl analyses,celiac disease pathogenesis,gene expression,genetic risk model,t cells,lymphoid tissues
Overpowering helminth-mediated immune-modulation is a route towards vaccine development against these major animal pathogens (HELIVAC)

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-2012-ADG_20120314, 2012)
Start date: 2013-06-01
End date: 2018-11-30
Duration (months): 66.0
Total project cost (EUR): 2486332.76
EU funding (EUR): 2486332.76
Participants: 1
Project status: CLOSED

Helminth (worm) pathogens cause >55% of all animal diseases which result in enormous losses to the global agricultural economy. Since the use of chemical products to treat worms is not sustainable in the long term because of the continual emergence of drug-resistant parasites and consumer concerns about what they eat, control by vaccines is the most appropriate way forward. However, there are presently no vaccines for any animal or human helminth pathogen. We hypothesise that the ability of helminth parasites to suppress the protective arm of the immune response explains why we have been unsuccessful in developing efficacious vaccines against these pathogens. During helminth infection the function of innate immune cells, dendritic cells (DCs) and macrophages, is manipulated by the parasite to create a T helper (Th) cell 2-driven immune response that is beneficial to its survival, while simultaneously suppressing the immunoprotective Th1-driven response. This helminth-induced immune modulation is induced by the secretion of specific parasite immunomodulatory molecules. Focusing on the helminth that causes animal and human fascioliasis (liver fluke disease), we will ‘turn-the-table’ on this parasite by targeting its immunomodulatory mechanisms and develop vaccine formulations that induce potent protective Th1-inducing humoral and cellular immune responses. The project involves both innovative and discovery approaches in the search for novel helminth immunomodulatory molecules, and a translational element that will bring these findings into a useful veterinary medicine application for the end-users, farmers and consumers. The breakthrough of this project, therefore, will not only be the development of a vaccine against liver fluke disease, but also the opening of a new route towards the control of many other major helminth pathogens of both animals and humans.

Keywords: helminths,worms,trematodes,liver fluke,fasciola
A novel direct role of non coding RNA in DNA damage response activation (DDRNA)

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: Italy
Call:  (ERC-2012-ADG_20120314, 2012)
Start date: 2013-06-01
End date: 2018-05-31
Duration (months): 60.0
Total project cost (EUR): 2329200.0
EU funding (EUR): 2329200.0
Participants: 1
Project status: CLOSED

DNA, if damaged, cannot be replaced. If not replaceable, it must be repaired. The so-called “DNA damage response” (DDR) is a coordinate set of evolutionary conserved events that arrest the cell-cycle (DNA damage checkpoint function) in proliferating cells and attempts DNA repair. Until DNA damage has not been repaired in full, cell proliferation is not resumed in normal cells. DNA damage is a physiological event. Ageing and cancer are both associated with DNA damage accumulation. In the past, we contribute to better understand the mechanisms and the consequences of DNA damage generation and DDR activation in both settings. We have recently identified a completely hitherto undiscovered level of control of DDR activation, so far considered a proteinaceous only signaling cascade. We have discovered that short RNA species are detectable at DNA damage sites and are necessary for DDR activation at DNA lesions. These RNA species are generated by an evolutionary-conserved RNA processing machinery. However, they serve purposes never reported before. We believe that our findings change radically our understanding of DDR modulation in mammals and disclose a fertile unspoilt ground for exciting investigations.

Keywords: dna damage response,non coding rna,genome stability,dicer,drosha.
Induction of juvenile-like plasticity in the adult brain (IPLASTICITY)

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: Finland
Call:  (ERC-2012-ADG_20120314, 2012)
Start date: 2013-04-01
End date: 2018-03-31
Duration (months): 60.0
Total project cost (EUR): 2500000.0
EU funding (EUR): 2500000.0
Participants: 1
Project status: CLOSED

Neuronal networks are tuned to optimally represent external and internal milieu through neuronal plasticity during critical periods of juvenile life. After the closure of the critical periods, plasticity is considered to be much more limited. In a series of landmark studies, we have shown that critical period-like plasticity can be reactivated in the adult mammalian brain by pharmacological treatment with the antidepressant fluoxetine. These ground-breaking studies establish a new principle, induced juvenile-like plasticity (iPlasticity) and define a new class of drugs, iPlastic drugs. For optimal results, iPlastic drug must be combined with physical or psychological rehabilitation, which guide the plastic networks and together allow better adaptation towards changing environment. iPlasticity may facilitate functional recovery after brain injury and underlie the enhanced efficacy of combined antidepressant treatment and psychotherapy. We have uncovered iPlasticity as an exciting new concept and established experimental models to study the molecular, cellular and network level mechanisms underlying it. We will here focus on the role of neurotrophin BDNF, because our previous and unpublished work clearly shows that BDNF and its receptors TrkB and p75 are essential and sufficient for iPlasticity. We have found that a major developmental reorganization in TrkB signalling takes place coinciding with the end of critical periods, and its reversal may underlie iPlasticity. We will utilize our resources as a leading lab in BDNF effects in adult brain and through novel controlled transgenic models, genomics and proteomics, we will reveal the role of BDNF signalling through TrkB and p75 in brain maturation, iPlasticity and brain disorders. Understanding the neurobiological background of iPlasticity will be vital for iPlastic drug development and the numerous translational applications of iPlasticity clearly in sight.

Keywords: neuronal plasticity
Plasticity and formation of lasting memories in health and disease. Genetic modeling of key regulators in adult and aging mammals and in neurodegenerative disease (MEMORYSTICK)

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: Sweden
Call:  (ERC-2012-ADG_20120314, 2012)
Start date: 2013-03-01
End date: 2018-02-28
Duration (months): 60.0
Total project cost (EUR): 2330974.0
EU funding (EUR): 2330974.0
Participants: 1
Project status: CLOSED

When an adult mammal acquires new skills and new knowledge, the degree to which transition will occur from temporary to permanent memories of such events is governed by factors such as emotional weight and importance of the experiences for survival. To execute the necessary structural synaptic reorganisations needed to permanently embed novel memories in the brain, a complex and precisely orchestrated molecular machinery is activated. We have found that rapid down-regulation of Nogo receptor 1 (NgR1) is one key element needed to allow permanent memories to form. Thus, our MemoFlex mice, with inducible overexpression of NgR1 in forebrain neurons, are severely impaired with respect to the ability to form lasting memories. When transgenic NgR1 is turned off in these mice, the ability to form lasting memories is restored. Several other genes are also involved in the process of consolidation of memories, including prompt activity-driven upregulation of BDNF. Very recently, we have discovered that Lotus, a newly identified negative regulator of NgR1, is also upregulated by activity, thus providing additional efficacy to the process of causing nerve endings to become temporarily insensitive to Nogo when plasticity is needed. Based on our experience with neurotrophic factors and the Nogo signaling system, and using additional transgenic mouse models, including the mtDNA Mutator mouse with premature, yet typical aging, NgR1 KO mice and mice modeling neurodegenerative diseases (such as APPSwePSEN mice and our MitoPark mice to model aspects of Alzheimer’s and Parkinson’s disease, respectively) we will examine the formation of lasting normal and pathological (addiction, posttraumatic stress disorder) memories in adult and aging individuals with and without additional neurodegenerative genotypes known to include cognitive impariment. This research will further the understanding of mechanisms behind memory dysfunction and help the design of memory-improving stratetegies.

Keywords: long-lasting memory formation,nogo receptor,aging,parkinson,alzheimer,structural synapatic plasticity,memory consolidation,nogo signaling
The evolution of simplicity: comparative morphology, embryology and genomics of Xenacoelomorpha, the fourth phylum of deuterostome. (XENOTURBELLA)

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: United Kingdom
Call:  (ERC-2012-ADG_20120314, 2012)
Start date: 2013-06-01
End date: 2019-02-28
Duration (months): 69.0
Total project cost (EUR): 2151540.0
EU funding (EUR): 2151540.0
Participants: 1
Project status: CLOSED

Understanding the origins and evolution of the highly diverse body plans of the ~30 distinct phlya that make up the animal Kingdom is a major programme in biology. Recent research in my lab has demonstrated the existence of a new phylum of animals with a unique bodyplan - the Xenacoelomorpha - whose evolutionary origins are particularly surprising and highly contentious. Our work has elevated these very simple worms from a lowly position at the base of the animal tree to a place right within a group of highly complex animals called the deuterostomes. The deuterostome ‘super-phylum’ includes three other major animal body architectures: the phyla Chordata (including Humans), Echinodermata (starfish and sea urchins) and Hemichordata (acorn worms). All species within the phylum Xenacoelomorpha appear to have lost almost all features that define them as deuterostomes implying a history of extreme evolutionary simplification and loss. The research I propose aims to understand the extraordinary evolutionary path that led to this bizarre phylum of worms and give deep new insights into the origins of phyla. We will use diverse techniques to study the morphology, ultrastructure, embryogenesis and developmental genetics of the Xenacoelomorpha to get a much clearer picture of the extent to which their phenotype is simplified. In parallel we will undertake ab initio sequencing of the genomes of three species of xenacoelomorphs and perform comparative genomics across all deuterostome phyla to discover the genotypic correlates of their phenotypic innovations. In a reversal of the standard evolutionary approach which moves from morphology to genetics, we will use our genomes to discover the genetic novelties associated with all groups of deuterostome and then use data on gene function to link these novelties to their novel biological functions. Our ultimate goal is to uncover the links between genotypic and phenotypic novelty in the evolution of the deuterostomes.

Keywords: comparative genomics,phylogeny,deuterostome