Data-Gouv-ML/pcri-informations-sur-les-projets-laureats huggingface dataset:
Linking glutamatergic spinal cord and brainstem neuronal circuits to the control of locomotor behavior (NEURONSINMOTION)

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-2010-AdG_20100317, 2010)
Start date: 2011-08-01
End date: 2016-07-31
Duration (months): 60.0
Total project cost (EUR): 2500000.0
EU funding (EUR): 2500000.0
Participants: 1
Project status: CLOSED

Locomotion is an essential motor act that for the most part is controlled by neuronal circuits in the spinal cord itself, called central pattern generators (CPGs), although their activity is turned on from centers in the brainstem. Understanding the operation of CPG circuits in mammals has been a significant challenge to neuroscientists over the last 50 years. The CPG for walking generates rhythm, as well as the precise patterns of muscular activity. The neural assembly that is directly involved in generating the locomotor rhythm is completely unknown. There is strong evidence from pharmacological and lesion studies showing that glutamatergic neurons are responsible for this function. Here, I propose to identify these key glutamatergic neuronal CPG circuits. As a first step we will use state-of-the-art RNA-sequencing to obtain the complete transcriptome of glutamatergic subpopulations in the ventral spinal cord of the mouse to define new postnatally expressed molecular markers. To link glutamatergic neuronal subpopulations to the locomotor behavior we will use transgenic mouse systems to incorporate light-activated switches in a cell specific way. These tools will provide a new basis for functional and network studies needed to understand the CPG operation. We also propose to use mouse models with optogenetic switches to provide a molecular identification of the glutamatergic locomotor command systems and their integration in the CPG. Our analysis will provide a unified characterization of the neuronal organization of the mammalian CPG and its immediate control from the brain. Understanding the locomotor CPG and its control in mammals is of outmost importance for improving rehabilitation of spinal cord injured patients and designing new repair strategies.

Keywords: motor control,neuronal networks,glutamate
Next Generation Genetics of Cancer Predisposition (NGG)

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: Finland
Call:  (ERC-2010-AdG_20100317, 2010)
Start date: 2011-06-01
End date: 2016-05-31
Duration (months): 60.0
Total project cost (EUR): 2483525.0
EU funding (EUR): 2483525.0
Participants: 1
Project status: CLOSED

Unravelling genetic components of human tumor predisposition has contributed significantly to our understanding on molecular basis of cancer, and cancer prevention in the context of hereditary tumor susceptibility is one of the early examples of benefits from genetic disease information. Research into cancer susceptibility is of great importance, and as shown in this proposal Finland provides unique interdisciplinary possibilities to take the field forward. Indeed, in the near future ability to recruit very small groups of patients with a potentially novel cancer susceptibility phenotype will be more relevant than ever. Such materials have been resistant to previous gene identification approaches but lend themselves towards success by exomic and whole genome sequencing. Important discoveries are anticipated in the following fields of research to be conducted under NGG: 1) Identification of rare high-penetrance Mendelian cancer predisposition conditions, and the respective susceptibility genes. One should note that the impact of a gene discovery for basic understanding of key cellular processes is not related to the frequency of the predisposition condition (e.g. RB, LKB1, P53 etc). 2) Identification of moderate penetrance cancer susceptibility genes. Such phenotypes have been difficult to approach with traditional gene identification methods because large pedigrees with multiple affected individuals and few or no phenocopies are not easily identified. Also, the current GWAS approaches are not ideal to detect these loci due to relative rarity of the responsible variants. 3) Characterization of common variants associated with cancer susceptibility.

Keywords: cancer predisposition,marker,translational,prevention,diagnosis,treatment
Connecting the activities of c-Myc in genome regulation, cellular growth control and oncogenesis (MYCNEXT)

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: Italy
Call:  (ERC-2010-AdG_20100317, 2010)
Start date: 2011-07-01
End date: 2016-06-30
Duration (months): 60.0
Total project cost (EUR): 2494000.0
EU funding (EUR): 2494000.0
Participants: 1
Project status: CLOSED

The c-myc proto-oncogene is a general driving force in cancer. The cmyc product (Myc) is a transcription factor that binds thousands of genomic loci. However, the identity of the Myc-target genes that influence tumor development, as well as the mechanisms through which Myc acts on these genes, remain most elusive questions in the field. We will use next-generation DNA sequencing to create a multi-layered set of genome-wide profiles. We will analyze cultured mouse cells and developing tumors, the latter in a transgenic model of Myc-induced lymphoma. The profiles will include (i.) quantitative mapping of the RNA transcriptome (coding, non-coding and small RNAs), (ii.) protein-DNA interaction profiles, (iii.) epigenome profiling, (iv.) 3D-folding of genomic DNA, (v.) mutational analysis. These datasets will provide broad views and will answer pointed questions about the action of Myc. We will address the hypothesis that many Myc target genes may not be regulated at the level of net mRNA accumulation, but rather of co-transcriptional processing events. We will provide maps for the RNA-Polymerase II complex, transcriptional co-factors and histone-modifying enzymes. We will whether the Myc-binding sites that do not map within promoters may act as enhancers and/or replication origins. We will address the hypothesis that Myc contributes to reprogramming of the genome independently from its localized effects on target genes. We will also ask which genes are targets of mutations and/or epigenetic silencing in Myc-induced lymphoma. High-throughput functional genomics will be used to address which genes suppress or promote Myc-induced lymphoma. Altogether, our data will provide an unprecedented level of insight into Myc function and into the early stages of tumor progression.

Keywords: lymphoma,c-myc
Role of microRNA dysregulation in Alzheimers Disease (MIRNA_AD)

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: Belgium
Call:  (ERC-2010-AdG_20100317, 2010)
Start date: 2011-05-01
End date: 2016-04-30
Duration (months): 60.0
Total project cost (EUR): 2500000.0
EU funding (EUR): 2500000.0
Participants: 1
Project status: CLOSED

Alzheimer's Disease (AD) is a major health problem in aging societies. Remarkable progress in the study of the rare genetic forms of the disease has lead to the identification of several key players like APP and the secretases, but the molecular basis of sporadic AD remains largely unresolved. The convergence of several factors (multicausality) has to be considered. miRNAs are crucially involved in normal brain functioning and integrity. Evidence obtained from analyzing a limited number of brains indicates that miRNA expression is affected in sporadic AD. We propose the hypothesis that such changes can affect normal functioning of neurons increasing their susceptibility to AD. We will document in 3 brain regions in >100 sporadic AD patients and in >100 controls alterations in miRNA expression and explore whether similar alterations can be detected in cerebrospinal fluid. This part of the study will firmly establish which miRNAs are altered in AD. We will then investigate the functional relevance of those miRNAs by gain and loss of function experiments in brains of zebra fish and mice. We will determine the target genes of the miRNA with genetic and proteomic approaches, and establish the functional networks controlled by those miRNA. We anticipate that this will lead to complete novel insights in the role of miRNAs in AD and in maintenance of brain integrity. Our work is likely to have diagnostic relevance for AD and will identify novel drug targets for the disease.

Keywords: alzheimer,micro-rna
Eukaryotic genomic origins, parasites, and the essential nature of mitochondria (EUKORIGINMIT)

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-2010-AdG_20100317, 2010)
Start date: 2011-03-01
End date: 2017-02-28
Duration (months): 72.0
Total project cost (EUR): 1998703.0
EU funding (EUR): 1998703.0
Participants: 1
Project status: CLOSED

Understanding the origin and evolution of eukaryotes, their genomes and organelles, are among the most important and exciting challenges facing biology. However, determining ancient gene origins tests methods and data to their limits, and it is unrealistic to expect progress to be easy. A comparative cross-disciplinary approach involving sophisticated phylogenetics allied with mathematical understanding, offers the best hope of obtaining robust hypotheses for gene and genomic origins. It is also necessary to look beyond the narrow focus of a few model organisms, and to thoughtfully embrace a wider selection of eukaryotic diversity. Over the past few years, my lab has studied the genomes and mitochondrial homologues (mitosomes and hydrogenosomes) of parasitic protozoa that represent significant health hazards in both the developed and developing world. These microbial eukaryotes will provide the model systems for investigations which aim to deliver major progress in understanding the importance of lateral gene transfer for eukaryotic genome origins and flux, for understanding how parasites exploit their host cells, and for identifying the essential functions of organelles related to mitochondria, which now appear to be vital components of all eukaryotic cells.

Keywords: genomics,molecular cell biology,mathematics,evolution,minimal mitochondria,parasites
KRAB/KAP1-mediated gene regulation in mammalian physiology and human diseases (KRABNKAP)

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: Switzerland
Call:  (ERC-2010-AdG_20100317, 2010)
Start date: 2011-04-01
End date: 2016-03-31
Duration (months): 60.0
Total project cost (EUR): 2499996.03
EU funding (EUR): 2499996.03
Participants: 1
Project status: CLOSED

This project aims at exploring the roles or KRAB/KAP1-mediated gene regulation in mammalian physiology and the possible impact of its dysfunctions on human health. The proper control of gene expression is paramount to all biological events, and is orchestrated through a sophisticated balance of activating and repressing influences. The mouse and human genomes contain around four hundred genes encoding KRAB-containing zinc finger proteins (KRAB-ZFPs), a family of tetrapod-restricted sequence-specific DNA-binding transcriptional repressors. Even though these KRAB-ZFPs represent the single largest group of transcriptional regulators encoded by higher vertebrates, their functions remain largely unknown. Nevertheless, it has been established that they share an essential cofactor, the histone methyltransferase- and histone deacetylase-recruiting KAP1, and act by triggering the formation of heterochromatin. KAP1 is ubiquitous, and KRAB-ZFPs are present in most if not all cells, albeit along distinctly cell type-, stage- and state-specific patterns, suggesting that KRAB/KAP1 gene regulation influences a very large number of physiological events. A few years ago, we launched a program aimed at addressing this hypothesis through a combination of genetic, functional and molecular studies focused on two paradigmatic organs, the lympho-hematopoietic system and the liver. Our preliminary results confirm that KRAB/KAP1-mediated transcriptional control is a master regulator of mammalian homeostasis. Accordingly, we now propose to dissect the regulatory networks orchestrated by KAP1 and KRAB-ZFPs in these two systems, to identify their gene targets and the mechanisms of their control, and to probe their possible implication in human pathologies targeting these organs.
Evolution of LNA Aptamers (EVOLNA)

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: Denmark
Call:  (ERC-2010-AdG_20100317, 2010)
Start date: 2011-04-01
End date: 2016-03-31
Duration (months): 60.0
Total project cost (EUR): 2497720.0
EU funding (EUR): 2497720.0
Participants: 1
Project status: CLOSED

Aptamers are single-stranded oligonucleotides which are able to target peptides, proteins, small molecules or live cells by virtue of their well-defined three-dimensional shapes. Aptamers are typically generated by evolution of specific sequences against a given target by in vitro evolution using the process known as SELEX. Progress of this field with respect to drug development has so far been hampered by the relative large size and poor biostability of evolved aptamers composed of unmodified nucleotides, necessitating tedious and extensive post-SELEX truncation and modification approaches. LNA (locked nucleic acid) is a prominent nucleotide modification which is in the process of revolutionizing gene silencing and RNA detection. LNA however has never been included in de novo aptamer evolution. EVOLNA is an ambitious but coherent research program with the objective of transforming the field of aptamer technology. The vision is to enable evolution of aptamers that per se possess most of the desired properties, thereby alleviating the need for extensive post-SELEX procedures. This will be realized by combining the unique properties of LNA with innovative methods for LNA aptamer evolution. LNA aptamer technology is envisioned to enable evolution of aptamers displaying maximum chemical diversity, minimum size and high biostability. The developed strategies will be applicable not only towards evolution of therapeutic aptamers, which will be the main subject of this program, but also towards evolution of aptamers for biosensing, diagnostic and imaging applications. The program is at the very frontier of biotechnology research and spans the areas of chemistry, molecular biology and drug research.

Keywords: nucleic acid chemical biology,locked nucleic acid,aptamer
Transcription and the maintenance of genome integrity (TRANSINTEG)

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-2010-AdG_20100317, 2010)
Start date: 2011-05-01
End date: 2016-04-30
Duration (months): 60.0
Total project cost (EUR): 1950000.0
EU funding (EUR): 1950000.0
Participants: 2
Project status: CLOSED

Maintaining genome integrity is crucial, especially in protein-encoding genes. DNA damage in genes can give rise to harmful mutations, but it can also directly obstruct the progress of transcribing RNA polymerase II (RNAPII), thereby blocking gene expression. Not surprisingly, repair pathways have evolved that specifically target lesions that stop RNAPII during its journey across a gene, so-called transcription-coupled repair pathways. As an alternative and ¿last resort¿, damage-stalled RNAPII can also be permanently removed by ubiquitylation/degradation, clearing the gene for repair by other means. Together, transcription-coupled repair and RNAPII ubiquitylation constitute an essential axis in the response to DNA damage. Conversely, while transcription is essential and therefore protected by a variety of mechanisms, it also itself comes at a cost for genome integrity. For example, high levels of transcription are correlated with breaks at fragile chromosome sites, mutagenesis and elevated levels of DNA recombination. Research into how the genome-destabilizing effects of transcription are minimized is still at an early stage, but insight into this research area is essential for our general appreciation of the regulatory mechanisms at play in the interface between transcription and other DNA-related processes, as well as for the understanding of processes underlying genome instability. This proposal describes how funding from the ERC will enable us to use a multi-disciplinary approach to shed new light on fundamental and disease-relevant processes, which are crucial for maintaining genome integrity during active transcription.

Keywords: ubiquitin,rna polymerase ii,transcription-coupled repair
The neurobiology of schemas: knowledge acquisition and consolidation (NEUROSCHEMA)

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,Netherlands
Call:  (ERC-2010-AdG_20100317, 2010)
Start date: 2011-06-01
End date: 2016-05-31
Duration (months): 60.0
Total project cost (EUR): 3051404.0
EU funding (EUR): 3051404.0
Participants: 2
Project status: CLOSED

This Co-Investigator Application is an interdisciplinary experimental analysis of the neurobiological mechanisms by which we acquire knowledge. Our approach builds on the foundations of contemporary cognitive neuroscience, particularly ideas about the neural mechanisms of declarative memory, and upon recent findings of the participating laboratories (Morris, Fernández) that have each addressed key issues associated with the rapid acquisition and assimilation of new associative information into existing neural ¿schemas¿. Rapid learning depends upon both novelty and prior knowledge. We propose a coordinated program of research concerning the mechanisms of both determinants. First, we will test that novelty, acting via the release of dopamine, has a direct impact on the mechanisms of cellular consolidation in the hippocampus. Second, with respect to prior knowledge, the retention of new event-related associative information requires the process of systems consolidation within declarative memory, as widely studied, but we further suggest that the organisation of knowledge requires more than just stabilising memory traces within neocortical networks. It also involves the integration of distinct memory traces into neural ¿schemas¿ that, once formed, have a major positive influence on future learning. Our experiments to date are supportive and we outline new research to examine the neurobiological basis of schemas. This will involve animal experimentation including novel behavioural tasks, optogenetics and single-cell recording; and functional magnetic resonance imaging of the human brain using new cognitive tasks combined with pharmacology, transcranial magnetic stimulation, model-free analysis methods, and a translational project reaching into real-world education.

Keywords: none
Mechanisms of cell fusion in eukaryotes (ELEGANSFUSION)

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: Israel,United Kingdom
Call:  (ERC-2010-AdG_20100317, 2010)
Start date: 2011-05-01
End date: 2016-04-30
Duration (months): 60.0
Total project cost (EUR): 2380000.0
EU funding (EUR): 2380000.0
Participants: 2
Project status: CLOSED

Membrane fusion is a universal process essential inside cells (endoplasmic) and between cells in fertilization and organ formation (exoplasmic). With the exception of SNARE-mediated endoplasmic fusion the proteins that mediate cellular fusion (fusogens) are unknown. Despite many years of research, little is known about the mechanism of cell-cell fusion. Our studies of developmental cell fusion in the nematode C. elegans have led to the discovery of the first family of eukaryotic fusogens (FF). These fusogens, EFF-1 and AFF-1, are type I membrane glycoproteins that are essential for cell fusion and can fuse cells when ectopically expressed on the membranes of C. elegans and heterologous cells. Our main goals are: (1) To determine the physicochemical mechanism of cell membrane fusion mediated by FF proteins. (2) To find the missing fusogens that act in cell fusion events across all kingdoms of life. We hypothesize that FF proteins fuse membranes by a mechanism analogous to viral or endoplasmic fusogens and that unidentified fusogens fuse cells following the same principles as FF proteins. Our specific aims are: AIM 1 Determine the mechanism of FF-mediated cell fusion: A paradigm for cell membrane fusion AIM 2 Find the sperm-egg fusion proteins (fusogens) in C. elegans AIM 3 Identify the myoblast fusogens in mammals AIM 4 Test fusogens using functional cell fusion assays in heterologous systems Identifying critical domains required for FF fusion, intermediates in membrane remodeling, and atomic structures of FF proteins will advance the fundamental understanding of the mechanisms of eukaryotic cell fusion. We propose to find the Holy Grail of fertilization and mammalian myoblast fusion. We estimate that this project, if successful, will bring a breakthrough to the sperm-egg and muscle fusion fields with potential applications in basic and applied biomedical sciences.

Keywords: cell fusion,caenorhabditis elegans,virus-cell fusion,myoblast fusion,eff-1,aff-1,fertilization,developmental cell fusion in caenorhabditis elegans,ff family of developmental fusogens,membrane