Data-Gouv-ML/pcri-informations-sur-les-projets-laureats huggingface dataset:
RNA-mediated Transcriptional Gene Silencing in Humans (RNAMEDTGS)

Framework: FP7 — Ideas
Programme: European Research Council
Theme: European research council
Destination: Consolidator grants
Action type: Support for frontier research (ERC)
Panel: Genetics, Genomics, Bioinformatics and Systems Biology
Countries involved: France
Call:  (ERC-2013-CoG, 2013)
Start date: 2014-03-01
End date: 2019-08-31
Duration (months): 66.0
Total project cost (EUR): 1999974.0
EU funding (EUR): 1999974.0
Participants: 1
Project status: CLOSED

More than 70% of the human genome synthesizes non-coding RNA that is believed to regulate gene expression. While there is ample evidence from model systems that small RNAs are the lynchpin of powerful mechanisms that silence transcription, the demonstration of transcriptional gene silencing (TGS) mediated by a small RNA in humans is lacking. We have recently shown that the HIV-1 LTR is controlled by premature termination of transcription and TGS mediated by a small RNA derived from the stem-loop structure, TAR, that forms the 5’ end of HIV-1 transcripts. This pathway depends on Microprocessor, Xrn2, Setx and Rrp6. Cleavage of TAR by Microprocessor has major consequences 1) it provides a substrate for Rrp6, which generates a small RNA that represses HIV-1 transcription, 2) it creates an entry site for Xrn2 and termination factors that lead to premature termination of transcription. Loss of Microprocessor or Rrp6 leads to recruitment of RNAPII to the LTR and activation of transcription. These findings not only provide the first evidence showing that small RNA-mediated TGS acts in human cells, but they also uncovered a new mechanism of gene regulation involving premature termination of transcription by RNAPII. Several important questions now need to be answered. What is the mechanism underlying small RNA-mediated TGS? Does small RNA-mediated TGS operate at human genes? What is the contribution of TGS coupled to premature termination in the global control of transcription? We will use a battery of biochemical and molecular approaches to dissect the molecular mechanism of RNA-mediated TGS. The global importance of small RNA-mediated TGS and premature termination of transcription in the control of human gene expression will be addressed using complementary genome-wide approaches. RNA-mediated TGS coupled to premature termination, if confirmed as a widespread mechanism controlling transcription, will fundamentally change our perspective of transcriptional control in humans

Keywords: transcription,gene silencing,termination,small rna,epigenetics
NMR Spectroscopy of very large complexes: the atomic details of the mRNA degradation machinery (MRNA-DECAY)

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: Germany
Call:  (ERC-2013-CoG, 2013)
Start date: 2014-05-01
End date: 2020-04-30
Duration (months): 72.0
Total project cost (EUR): 1966800.0
EU funding (EUR): 1966800.0
Participants: 2
Project status: CLOSED

The cellular environment is extremely complex and contains thousands of different bio-molecules. To determine how these bio-molecules assemble into a highly organized molecular system has remained a major challenge. Here, we aim to unravel how dozens of proteins assemble into a large molecular machinery that degrades mRNA in an efficient and regulated manner. On an atomic level, we will determine the static structures of the enzymes involved in the mRNA degradation pathways. In parallel, we will develop and exploit novel methods in NMR spectroscopy to correlate molecular motions with catalytic activity. Especially for the 450 kDa eukaryotic exosome complex, these studies will significantly push the limits of what is currently achievable. On a molecular level, we will reconstitute the mRNA degradation machinery from purified components in a stepwise manner. In this challenging approach, we will use NMR spectroscopy to follow how the enzymes engage in a network of interactions that regulate the mRNA degradation process. These studies will also provide us with the unique possibility to reproduce complex cellular behavior in a well defined and easy to manipulate in vitro system. On a microscopic level the mRNA degradation machinery assembles into cytoplasmic processing bodies. The role of these conserved cellular foci is a matter of debate and we aim to determine both the atomic details that result in this self-organization as well as the catalytic advantages that result from this clustering. Our study will provide a very detailed and accurate description of how essential and central molecular processes in mRNA degradation are regulated and modulated. The level of detail that we aim to achieve is currently not available for any cellular pathway of such complexity. In that regard, our projects also provide knowledge and methodology required to study additional and complex cellular functions.

Keywords: nmr spectroscopy,enzyme function,molecular machine,mrna degradation,structural biology,methyl trosy,protein dynamics,protein-rna complexes,processing bodies
Functional diversity of single neurons in anatomically complex cortical networks (NEUROHUBS)

Framework: FP7 — Ideas
Programme: European Research Council
Theme: European research council
Destination: Consolidator grants
Action type: Support for frontier research (ERC)
Panel: Neurosciences and Neural Disorders
Countries involved: Israel
Call:  (ERC-2013-CoG, 2013)
Start date: 2014-10-01
End date: 2019-09-30
Duration (months): 60.0
Total project cost (EUR): 2000000.0
EU funding (EUR): 2000000.0
Participants: 1
Project status: CLOSED

A fundamental quest in Neuroscience research is to reveal the function(s) of single neurons and networks. Understanding function seems to be on relatively solid grounds at the periphery where both anatomy and physiology converge in a simplified manner. However, as one ascends higher into the central nervous system, anatomy and physiology become increasingly more complex and functions become difficult to study. To reveal function, we will take a structure/function approach that synergizes between anatomical, physiological and behavioral methods. Namely, we will study the physiology of identified neurons to a rich set of stimuli bearing different behavioural contingencies and in the context of their anatomical boundaries. Specifically, my proposal aims to uncover function and structure of the mouse auditory cortex. First, we will redefine local and distant functional architecture in the auditory cortex using novel tracing techniques. Second, we will test a specific hypothesis whereas individual cortical neurons are multifunctional and part of distinct but multiple sub-networks. Third, we will use novel genetic techniques to tag and manipulate distinct cortical processing streams that are active during natural behaviors and specific learning paradigms. These experiments will answer whether specific sub-networks are instructive, permissive or necessary for perception. Finally, we will study how single neurons and sub-networks change in face of perceptual learning. As a whole, the main premise of this grant is to set the stage for, and eventually crystallize the experimental means to tease out functional diversity of single neurons in complex anatomical networks. Charting these basic principles for single neurons will impact how we study neuronal function and plasticity not only in the auditory system but across the mammalian brain.

Keywords: plasticity,perceptual learning
Unconventional pairing in ultracold Fermi gases (UPFERMI)

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: Germany
Call:  (ERC-2013-CoG, 2013)
Start date: 2014-10-01
End date: 2019-09-30
Duration (months): 60.0
Total project cost (EUR): 1925525.0
EU funding (EUR): 1925525.0
Participants: 1
Project status: CLOSED

We explore unconventional ways how ultracold fermions pair and form collective quantum phases exhibiting long-range order, such as superfluidity and magnetically order. Specifically, we plan to realize and study pairing with orbital angular momentum and pairing induced by long-range interaction. Besides the fundamental interest in unravelling unconventional pairing mechanisms and the interplay between superfluidity and quantum magnetism, our project will also lead to gaining experimental control over topologically protected quantum states. This will pave the way for future topological quantum computers, which are particularly robust to environmental decoherence. Our project addresses three different aspects: (1) We plan to realize p-wave superfluids in two dimensions. This quantum phase exhibits topological excitations (vortices) with anyonic statistics and an isomorphism to the fractional quantum-Hall effect. We will investigate the unusual properties of p-wave superfluids, such as Majorana fermions, i.e. quasiparticles being their own anti-particles, which are predicted to be localized at vortices. This will boost the long-standing efforts in the cold atoms and condensed matter communities to understand topological states of matter. (2) We aim to realize d-wave pairing in optical lattices using a novel experimental approach. d-wave pairing is closely related to high-Tc superconductivity in the cuprates and we are interested in exploring its interplay with magnetic order. Superfluidity and magnetic order are antagonistic phenomena from a conventional BCS-theory point-of-view and hence several fundamental questions will be answered. (3) We plan to induce long-range interactions using a high-finesse optical cavity leading to a light-induced pairing mechanism. We will search for Cooper pairing in spin-polarized Fermi gases mediated by the interaction of Fermions with a quantized light field. This provides access to a new class of combined light-matter quantum states.

Keywords: ultracold atoms,quantum gases,fermi gases,optical lattices,quantum simulation
Cellular Destruction Mechanisms that Create New Lives (SPERMDESTRUCT)

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: Israel
Call:  (ERC-2013-CoG, 2013)
Start date: 2014-05-01
End date: 2019-04-30
Duration (months): 60.0
Total project cost (EUR): 2000000.0
EU funding (EUR): 2000000.0
Participants: 1
Project status: CLOSED

Apoptosis, the major form of programmed cell death (PCD), is executed by caspases. However, activation of caspases can also promote a variety of vital cellular processes. Furthermore, cell death can sometimes proceed in the absence of apoptotic caspases by triggering alternative cell death (ACD) pathways. The main goal of my proposal is to delineate the molecular mechanisms, pathways and components underlying three distinct, evolutionarily conserved, cellular destruction processes, all associated with the Drosophila sperm life cycle, and to screen blood DNA samples from fertility clinics for mutations in human homologous genes. The first process, termed germ cell death (GCD), eliminates about 25% of the pre-meiotic germ cells through an ACD pathway. In the second process, the bulk cytoplasmic contents of the terminally differentiating spermatids are removed in a process called ‘individualization’, which involves active caspases. The third process occurs immediately after fertilization to selectively eliminate the sperm mitochondrial derivative. Similar cellular processes are also instrumental for the development and homeostasis of a variety of tissues and organs in essentially all multicellular organisms. Therefore, not only will this study enhance our understanding of male germ cell maturation and function, this unique system also provides an opportunity to study these important cellular processes using physiological conditions. The extraordinary degree of anatomical and molecular conservation of spermatogenesis in animals with flagellated sperm also signifies the extension of these studies to human patients. Although human infertility is a major health problem affecting 7% of men world-wide, we are still rather ignorant about the genetic causes of male infertility. My proposed approach, therefore, is feasible and efficient, and can overcome technical, practical, and ethical limitations associated with large-scale studies in humans.

Keywords: drosophila,spermatogenesis,programmed cell death,alternative cell death,caspase-dependent vital cellular processes,mitochondrial turnover,ubiquitin,selective autophagy,human male infertility
Epigenetic Control of Mammalian Reproduction (EPIREPRO)

Framework: FP7 — Ideas
Programme: European Research Council
Theme: European research council
Destination: Consolidator grants
Action type: Support for frontier research (ERC)
Panel: Genetics, Genomics, Bioinformatics and Systems Biology
Countries involved: France
Call:  (ERC-2013-CoG, 2013)
Start date: 2014-06-01
End date: 2019-05-31
Duration (months): 60.0
Total project cost (EUR): 1999416.0
EU funding (EUR): 1999416.0
Participants: 1
Project status: CLOSED

By standing at the crossroads of generations, germ cells ensure species continuity. At the time of fertilization, the oocyte and spermatozoon carry the genetic material but also non-genetically encoded, epigenetic information. Gametic epigenetic modifications have immediate effects on gametic production and fertility. They also have long-term consequences on somatic phenotypes when transmitted to the progeny. Our team has previously made some important contributions to the emergence of these concepts. Here we propose to explore further the epigenetic control of mammalian reproduction, with a specific emphasis on DNA methylation-related events. How are DNA methylation patterns shaped? How do they impact on germ cell identity and integrity? How much gametic DNA methylation is transmitted to the progeny and how does this influence phenotypes across generations? Our projects can be subdivided into three interconnected themes, which are at the heart of mammalian developmental biology and are not usually investigated as a common effort: 1) Trans and cis determinants of de novo DNA methylation, 2) DNA methylation and transposon control, and 3) DNA methylation and genomic imprinting. Our approach is mainly fundamental, using the mouse as a mammalian model, and will involve a powerful combination of genetics, cellular and developmental biology, with large-scale genomic and biochemical strategies. We are also extending our research to humans, in the hope of uncovering new causes of impaired or malignant gametogenesis. Correct DNA methylation patterns are paramount for the generation of functional gametes capable of forming viable and healthy offspring, but also for the regulation of pluripotency states and the maintenance of genome architecture and function in somatic cells. Our work therefore not only impacts on the field of reproduction and development, but also on stem cell biology and cancer.

Keywords: epigenetics,reproduction,development,gametes,dna methylation,genomic imprinting,transposons
Dark matter of the human transcriptome: Functional study of the antisense Long Noncoding RNAs and Molecular Mechanisms of Action (DARK)

Framework: FP7 — Ideas
Programme: European Research Council
Theme: European research council
Destination: Consolidator grants
Action type: Support for frontier research (ERC)
Panel: Genetics, Genomics, Bioinformatics and Systems Biology
Countries involved: France
Call:  (ERC-2013-CoG, 2013)
Start date: 2014-12-01
End date: 2020-11-30
Duration (months): 72.0
Total project cost (EUR): 1998883.73
EU funding (EUR): 1998883.73
Participants: 1
Project status: CLOSED

98% of the human genome is non-protein coding raising the question of the role of the dark matter of the genome. It is now admitted that pervasive transcription generates thousands of noncoding transcripts that regulate gene expression and have broad impacts on development and disease. Among the long non coding (lnc)RNAs, antisense transcripts have been poorly studied despite their putative regulatory importance. Several functional examples include X-chromosome inactivation, maintenance of pluripotency and transcriptional regulation. However, no systematic study has yet addressed the comprehensive functional description of human antisense ncRNA, mainly because of technological issues and their low abundance. Indeed, in budding yeast S. cerevisiae, our group showed the existence of an entire class of antisense regulatory lncRNA extremely sensitive to RNA decay pathways, impinging their study so far. The roles for yeast antisense lncRNAs in shaping the epigenome raises important questions: What are the molecular and biochemical mechanisms by which antisense lncRNAs carry out their functions and are they functionally conserved in human cells? We propose that the dark side of the non-coding genome is another layer of gene regulation complexity that needs to be deciphered. With this proposal, we aim to draw the first exhaustive catalog of human antisense lncRNA in various cell types and tissues using up to date High throughput technologies and bioinformatics pipelines. Second, we propose to determine the functional role of antisense lncRNA on genome expression and stability in the context of cellular stress and cancer. We anticipate that powerful and modern genetic tools such DNA-mediated gene inactivation (ASO) and TALEN approaches will allow precise antisense genes manipulation never achieved so far. Our project is strongly supported by preliminary data indicating an unexpected large number of hidden antisense lncRNA in human cells controlled by RNA decay pathways.

Keywords: ncrna,chromatin
The endodermis - unraveling the function of an ancient barrier (ENDOFUN)

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: Switzerland
Call:  (ERC-2013-CoG, 2013)
Start date: 2014-06-01
End date: 2019-05-31
Duration (months): 60.0
Total project cost (EUR): 1985443.0
EU funding (EUR): 1985443.0
Participants: 1
Project status: CLOSED

In addition to maintaining homeostasis within their cells, multicellular organisms also need to control their inner, extracellular spaces between cells. In order to do so, epithelia have developed, bearing ring-like paracellular barriers, with specialised membrane surfaces facing either the environment or the inner space of the organism. In animals, such polarised epithelia use specialised protein assemblies, called tight junctions, to seal the extracellular space, which have been a topic of active research for decades. Plant roots need to extract inorganic elements from the soil. A plethora of transporters are expressed in plant roots, yet, as in animals, transporter action is contingent upon the presence of efficient paracellular (apoplastic) barriers. Therefore, an understanding of the development, structure and function of the root apoplastic barrier is crucial for mechanistic models of root nutrient uptake. The endodermis is the main apoplastic barrier in roots, but, in contrast to animals, molecular data about endodermal differentiation and function has been virtually absent. We recently gained insights into the factors that drive endodermal differentiation, largely due to efforts from my research team. Our work has led a foundation of mutants, markers and protocols that provide an unprecented opportunity to test the many supposed roles of the root endodermis. Our preliminary insights indicate that generally accepted views of endodermal function have been overly simplistic. The topic of this proposal is to develop better tools and much more precise molecular analysis of nutrient uptake, centered around the endodermis. I propose to investigate our specific barrier mutants with new tools that allow visualisation of changes in nutrient transport at cellular resolution. The results from this project will provide a new foundation for models of plant nutrition and help us to understand how plants manage, and sometimes fail, to extract what they need from the soil.

Keywords: arabidopsis,root,endodermis,casparian strip,apoplast,cell wall,nutrient transport
Functional Brain Tractography (F-TRACT)

Framework: FP7 — Ideas
Programme: European Research Council
Theme: European research council
Destination: Consolidator grants
Action type: Support for frontier research (ERC)
Panel: Neurosciences and Neural Disorders
Countries involved: France
Call:  (ERC-2013-CoG, 2013)
Start date: 2014-08-01
End date: 2019-07-31
Duration (months): 60.0
Total project cost (EUR): 1999200.0
EU funding (EUR): 1999200.0
Participants: 1
Project status: CLOSED

Single-pulse direct electrical stimulation of cortical regions in patients suffering from focal drug-resistant epilepsy who are explored using intracranial electrodes induces electrophysiological responses. Such cortico-cortical induced potentials can be used to infer functional and anatomical brain connectivity. We will develop methods to analyse those responses using neuroimaging tools in order to create a new probabilistic atlas of functional tractography of the human brain, which will be made freely available to the clinical and neuroscience community. Several thousands of stimulation runs performed in several hundreds of patients will be included in the atlas database to reach a nearly full coverage of the human cortex (inclusion of 540 patients retrospectively and of 172 patients/year prospectively, from 8 French and 1 Czech epilepsy surgery centres). As a proof of concept, we generated for F-TRACT scientific document a preliminary database of 1535 stimulation runs performed in 35 adult patients. To illustrate the potential of our approach, in particular to refine neurobiological models of cognitive systems, we use here this preliminary atlas to demonstrate the asymmetry of the functional connectivity between Wernicke’s area and Broca’s area, two key nodes of the language network. This new atlas of functional tractography will be very useful to understand how the brain works and to develop neurocomputational models at a large scale. It will also allow the development of new clinical tools for the presurgical evaluation of intractable epilepsy. It is very complementary to other structural and functional approaches, such as MRI diffusion and functional mapping derived from metabolic, optical and electromagnetic techniques. The open access to this unique atlas of functional tractography will allow to explore in the future its numerous properties in relation to distributed brain networks in the domains of neuroanatomy, neurocognition and neurophysiopathology.

Keywords: brain atlas,direct electrical stimulation,epilepsy,connectivity,tractography,signal processing,neuroimaging,statistical parametric mapping