Data-Gouv-ML/pcri-informations-sur-les-projets-laureats huggingface dataset:
ATP-sensitive potassium channels: from atomic structure to human disease (KATP-DIABETES)

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: United Kingdom
Call:  (ERC-2012-ADG_20120314, 2012)
Start date: 2013-09-01
End date: 2018-08-31
Duration (months): 60.0
Total project cost (EUR): 2478420.0
EU funding (EUR): 2478420.0
Participants: 1
Project status: CLOSED

We are currently experiencing a fast-growing diabetes pandemic. Both type 2 diabetes and rare monogenic forms of diabetes, such as neonatal diabetes, are characterised by impaired insulin secretion. This project seeks to resolve the fundamental mechanisms underlying insulin secretion and its failure in diabetes. We have shown that activating mutations in the ATP-sensitive potassium (KATP) channel cause neonatal diabetes, which has enabled children with this disease to switch from insulin injections to oral sulphonylurea drugs (which block their open KATP channels and stimulate insulin release). The most severe mutations also cause neurological symptoms that, for unknown reasons, are less well treated by sulphonylureas. We aim to: obtain a detailed mechanistic understanding of how nucleotides and drugs regulate KATP channel activity by combining state-of-the-art structural and functional approaches; define how drug therapy affects glucose homeostasis in neonatal diabetes; and explore how activating KATP channel mutations affect glucagon release from pancreatic alpha-cells. We will also investigate how severe KATP channel mutations cause neurological symptoms (such as developmental delay, reduced sensitivity to general anaesthetics and impaired eye movements) and determine how these might be alleviated by drug therapy. While underpinned by my previous work, this project takes my research in new directions, including structural analysis of eukaryotic membrane proteins, stimulus-secretion coupling in other types of islet cell, and neurological studies in humans as well as animal models. It involves a broad multidisciplinary approach, addresses questions of fundamental scientific importance, and has a strong translational element. We expect our studies will be of direct benefit to patients with neonatal or type 2 diabetes.

Keywords: diabetes,insulin secretion,potassium channels,neurological disorders,integrative physiology
Chromosome self-clearing completes sister chromatid separation (SELFCC)

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: United Kingdom,United Kingdom
Call:  (ERC-2012-ADG_20120314, 2012)
Start date: 2013-04-01
End date: 2018-09-30
Duration (months): 66.0
Total project cost (EUR): 2490464.4
EU funding (EUR): 2490464.4
Participants: 2
Project status: CLOSED

In this research program, we propose the new concept that sister chromatid separation in mitosis is completed as a result of the dynamic intrinsic structural changes of chromosomes, i.e. through cycles of regional chromosome stretching and recoiling, which we call the self-clearing mechanism of chromosomes. By developing several novel methods, we will establish this new concept and demonstrate that the self-clearing of chromosomes is an essential mechanism allowing complete removal of sister chromatid cohesion, and that it is a fundamentally conserved function from yeast to vertebrates. To maintain genetic integrity, eukaryotic cells must duplicate their chromosomes and subsequently segregate them to opposite poles of the cell, prior to cell division. Cohesion is established between sister chromatids during S phase and marks sister pairs to ensure proper chromosome segregation in the next mitosis. However, the cohesion must be eventually removed to allow sister chromatids to separate and segregate to opposite poles. Although recent studies have revealed how the removal of cohesion is initiated, it is still elusive how this removal is completed. Our project will address mechanisms promoting this process and will open up a new direction of research, regarding dynamic chromosome organization, in particular its compaction and condensation. At present, the structural basis for chromosome compaction and condensation is poorly understood. Our project will shed new light on this inscrutable scientific problem by revealing the process of chromosome self-clearing. The outcome of our research will give important clues to fundamental mechanisms for chromosome segregation and will contribute to our understanding of human diseases, such as cancer and congenital disorders, which are characterized by chromosome instability and aneuploidy.

Keywords: sister chromatid cohesion,condensin,cohesin,sister chromatid separation,mitosis,budding yeast,dt40
Function and computation in three-layer cortex (CORTEX SIMPLEX)

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: Germany
Call:  (ERC-2012-ADG_20120314, 2012)
Start date: 2013-02-01
End date: 2018-01-31
Duration (months): 60.0
Total project cost (EUR): 2496111.0
EU funding (EUR): 2496111.0
Participants: 1
Project status: CLOSED

Understanding brain function is one of the outstanding challenges of modern biology. Many studies focus on mammalian neocortex, a modular and versatile structure that operates equally well with different sensory inputs and for perception, planning as well as action. Neocortex, however, is remarkably complex. It contains many cell types, six layers, networks with local and long-range connections, and its study is technically challenging. We propose here to address central issues of cortical computation using a simpler experimental system. Neocortex evolved from a more primitive cortex, likely present in the ancestors of all amniotes. Extant reptiles are closest to this putative ancestor: their cortex contains only three layers, two of which are nearly exclusively neuropilar. Reptilian cortex is also closest to mammals’ old cortices (piriform and hippocampus). Like in mammals, reptilian cortex is modular. Its design, however, is considerably simpler and more ubiquitous than in mammals. Indeed, so far as we know, reptilian primary olfactory and visual cortices are very similar to one another. Finally, certain reptiles such as turtles have evolved biochemical and metabolic adaptations to resist long periods of anoxia. Thus, their brains can be studied ex vivo over long periods, giving experimenters access to the entire brain with an intact retina or nasal epithelium. We will use this system to study cortical computation, primarily in visual and olfactory areas. Using electrophysiological, imaging, molecular, behavioral and computational methods, we will discover the representational strategies of these two cortices in vivo, the functional architecture of their microcircuits and the computations that they carry out. This understanding of generic and ancient units of cortical computation will illuminate our studies of more complex and sophisticated cortical circuits.

Keywords: cerebral cortex cortical circuits turtle vision olfaction computation
Epilepsies of the temporal lobe: emergence, basal state and paroxysmal transitions (HEP)

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: France
Call:  (ERC-2012-ADG_20120314, 2012)
Start date: 2013-10-01
End date: 2018-09-30
Duration (months): 60.0
Total project cost (EUR): 1985057.0
EU funding (EUR): 1985057.0
Participants: 1
Project status: CLOSED

This proposal focuses on a human disease: epilepsy of the temporal lobe. This syndrome has a relatively stereotyped history. Focal seizures emerge, with a delay of several years in the human, after an initial insult that results in neuronal death. We will use physiology, imaging, anatomy and transcriptomic techniques to ask how an epileptic brain emerges, to define different neuronal cell types in the basal epileptic state and to examine factors associated with the paroxysmal transition to a seizure. Specifically we will ask whether a loss of cholesterol homeostasis is involved in the initial sclerotic neuronal death. We will ask whether proteoglycans deposited in the extracellular space as a generalised wound healing response force the establishment of aberrant synaptic contacts and so facilitate the slow process of epileptogenesis. We will then study the basal state of an epileptic brain. We will establish the physiology, anatomy, connectivity and transcriptome of functionally distinct neurons defined by different contributions to epileptiform activities in human epileptic brain slices. Finally we will seek to establish what sudden changes in field potential, ionic homeostasis, cellular firing and synaptic interactions are associated with the paroxysmal moment of transition to seizure.
The importance of gene and genome duplications for natural and artificial organism populations (DOUBLE-UP)

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: Belgium
Call:  (ERC-2012-ADG_20120314, 2012)
Start date: 2013-10-01
End date: 2018-09-30
Duration (months): 60.0
Total project cost (EUR): 2217525.0
EU funding (EUR): 2217525.0
Participants: 1
Project status: CLOSED

The long-term establishment of ancient organisms that have undergone whole genome duplications has been exceedingly rare. On the other hand, tens of thousands of now-living species are polyploid and contain multiple copies of their genome. The paucity of ancient genome duplications and the existence of so many species that are currently polyploid provide an interesting and fascinating enigma. A question that remains is whether these older genome duplications have survived by coincidence or because they did occur at very specific times, for instance during major ecological upheavals and periods of extinction. It has indeed been proposed that chromosome doubling conveys greater stress tolerance by fostering slower development, delayed reproduction and longer life span. Furthermore, polyploids have also been considered to have greater ability to colonize new or disturbed habitats. If polyploidy allowed many plant lineages to survive and adapt during global changes, as suggested, we might wonder whether polyploidy will confer a similar advantage in the current period of global warming and general ecological pressure caused by the human race. Given predictions that species extinction is now occurring at as high rates as during previous mass extinctions, will the presumed extra adaptability of polyploid plants mean they will become the dominant species? In the current proposal, we hope to address these questions at different levels through 1) the analysis of whole plant genome sequence data and 2) the in silico modelling of artificial gene regulatory networks to mimic the genomic consequences of genome doubling and how this may affect network structure and dosage balance. Furthermore, we aim at using simulated robotic models running on artificial gene regulatory networks in complex environments to evaluate how both natural and artificial organism populations can potentially benefit from gene and genome duplications for adaptation, survival, and evolution in general.

Keywords: genome duplication gene regulatory networks genome evolution
Chromatin Fiber and Remodeling Factor Structural Studies (CFRFSS)

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: Switzerland
Call:  (ERC-2012-ADG_20120314, 2012)
Start date: 2013-01-01
End date: 2018-12-31
Duration (months): 72.0
Total project cost (EUR): 2500000.0
EU funding (EUR): 2500000.0
Participants: 1
Project status: CLOSED

DNA in higher organisms is organized in a nucleoprotein complex called chromatin. The structure of chromatin is responsible for compacting DNA to fit within the nucleus and for governing its access in nuclear processes. Epigenetic information is encoded chiefly via chromatin modifications. Readout of the genetic code depends on chromatin remodeling, a process actively altering chromatin structure. An understanding of the hierarchical structure of chromatin and of structurally based, remodeling mechanisms will have enormous impact for developments in medicine. Following our high resolution structure of the nucleosome core particle, the fundamental repeating unit of chromatin, we have endeavored to determine the structure of the chromatin fiber. We showed with our X-ray structure of a tetranucleosome how nucleosomes could be organized in the fiber. Further progress has been limited by structural polymorphism and crystal disorder, but new evidence on the in vivo spacing of nucleosomes in chromatin should stimulate more advances. Part A of this application describes how we would apply these new findings to our cryo-electron microscopy study of the chromatin fiber and to our crystallographic study of a tetranucleosome containing linker histone. Recently, my laboratory succeeded in providing the first structurally based mechanism for nucleosome spacing by a chromatin remodeling factor. We combined the X-ray structure of ISW1a(ATPase) bound to DNA with cryo-EM structures of the factor bound to two different nucleosomes to build a model showing how this remodeler uses a dinucleosome, not a mononucleosome, as its substrate. Our results from a functional assay using ISW1a further justified this model. Part B of this application describes how we would proceed to the relevant cryo-EM and X-ray structures incorporating dinucleosomes. Our recombinant ISW1a allows us to study in addition the interaction of the ATPase domain with nucleosome substrates.

Keywords: chromatin,nucleosome,dna,histone,remodeling,epigenetics
Meiotic recombination: How, where and why? Mechanisms and Implications (HOTMEIOSIS)

Framework: FP7 — Ideas
Programme: European Research Council
Theme: European research council
Destination: Advanced grants
Action type: Support for frontier research (ERC)
Panel: Molecular and Structural Biology and Biochemistry
Countries involved: France
Call:  (ERC-2012-ADG_20120314, 2012)
Start date: 2013-09-01
End date: 2018-08-31
Duration (months): 60.0
Total project cost (EUR): 2491899.0
EU funding (EUR): 2491899.0
Participants: 1
Project status: CLOSED

During meiosis, homologous recombination plays a mechanical role by connecting homologous chromosomes, thus allowing proper chromosome segregation during the first meiotic division. In most species, the absence of meiotic recombination leads to sterility. In addition, recombination generates new combinations of alleles, increases genome diversity and plays a major role in genome evolution. Meiotic recombination is initiated by the programmed induction of DNA double-strand breaks (DSBs), but how these events are controlled at the molecular level and how they are constrained by selective pressures during evolution is not understood. Our recent historical discovery that the Prdm9 gene controls the localization of recombination in the mouse and human genomes revolutionizes our view on this process, with one main unanticipated finding: the highly dynamic and fast evolution of Prdm9 and of meiotic DSB sites in the genome. Understanding meiotic recombination clearly requires the development of novel approaches to analyze this process from both molecular and evolutionary perspectives. To this aim, we will develop an extensive analysis of Prdm9 as its activity, role, regulators and sites of action in the genome need to be identified and understood in order to gain insight into its dynamics and evolution. We will develop a unique and challenging strategy to overcome the limitation of laboratory mice and pioneer the analysis of Prdm9 and recombination activity in wild mice. We thus aim at making a breakthrough in the field by bringing molecular genetics and evolutionary biology together, to grasp the significance of meiotic recombination for genome evolution and sexual reproduction in eukaryotes.

Keywords: meiosis,recombination
Understanding and exploiting complex glycan metabolism in the human microbiota (HUMAN MICROBIOTA)

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,France
Call:  (ERC-2012-ADG_20120314, 2012)
Start date: 2013-05-01
End date: 2019-04-30
Duration (months): 72.0
Total project cost (EUR): 2491013.6
EU funding (EUR): 2491013.6
Participants: 2
Project status: CLOSED

The human large bowel is colonized by a community of microbes, the microbiota, which has a significant impact on human health and nutrition through the production of short chain fatty acids, and by interactions with the host immune system. The major nutrients available to these organisms are dietary glycans that are not metabolized by mammalian enzymes in the small intestines. Dietary and nutraceutical strategies can, potentially, be deployed to encourage the dominance of beneficial microbes in the microbiota (e.g. those producing health promoting SCFAs such as propionate and butyrate, and bacteria that have an anti-inflammatory impact through its interaction with the human immune system), ensuring that this microbial ecosystem has a positive influence on human health. This approach, however, is greatly restricted by a critical lack of understanding of the mechanisms by which complex glycans are metabolized by the microbiota. Significantly, the wealth of genomic and metagenomic microbiota sequence data now available, presents an exciting and unparalleled opportunity to make decisive advances in our understanding of glycan metabolism in the human large bowel. This project seeks to capitalize on this genomic information, in harness with recent functional data from my lab., to understand the mechanisms by which complex glycans are metabolized by the human microbiota. At a generic level, by providing insight into glycan resource allocation in the microbiota, this ERC advanced fellowship will make a significant contribution to protein evolutionary biology. The microbiota represents a highly concentrated reservoir of microbes that is continuously exposed to an extensive repertoire of diverse and highly complex glycans, the metabolism of which is essential for bacterial survival.

Keywords: enzymology,glycoside hydrolases,human microbiota,prebiotics,glycanases,human nutrition,plant cell wall degradation
Regulation and Function of CARD9 / BCL10 / MALT1 Signalosomes in Innate Immunity and Inflammation (CBM-INNATE)

Framework: FP7 — Ideas
Programme: European Research Council
Theme: European research council
Destination: Advanced grants
Action type: Support for frontier research (ERC)
Panel: Immunity and infection
Countries involved: Germany
Call:  (ERC-2012-ADG_20120314, 2012)
Start date: 2013-02-01
End date: 2019-01-31
Duration (months): 72.0
Total project cost (EUR): 2440200.0
EU funding (EUR): 2440200.0
Participants: 1
Project status: CLOSED

Acute inflammation is a response to infection or tissue damage that is critical for host protection and tissue homeostasis. However, deregulated or chronic inflammation is harmful to the host and can cause multiple diseases including inflammatory bowel disease, rheumatoid arthritis, cardiovascular diseases, neuroinflammatory disease and cancer. Cells of the innate immune system sense microbial or sterile danger via pattern recognition receptors (PRRs). Subsequently, these PRRs engage intracellular signalling modules to elicit inflammatory effector mechanisms. We have recently identified the CARD9 / BCL10 / MALT1 (CBM) signalosome as a central proinflammatory signalling complex in innate immune cells. This molecular platform responds to stimuli from transmembrane SYK-coupled C-type lectin receptors and from intracellular danger sensors such as RIG-I-like helicases, NOD2 and presumably others to robustly activate NF-κB and MAPK pathways. Innate CBM signalling is engaged upon fungal, bacterial or viral recognition and upon sterile cell injury and it is essential for host protection in humans and mice. Still, it is unclear how the CARD9 / BCL10 / MALT1 signalosome is activated on a molecular level and how CBM responses are transduced to effector cascades. Moreover, although CARD9 polymorphisms are linked to various human inflammatory diseases, the cell type- and signal-specific roles of CBM signalosomes in complex diseases in vivo are unknown. Here we aim to take an integrated genetic, biochemical and in vivo approach to comprehensively dissect the regulation of the CARD9 / BCL10 / MALT1 complex in innate immunity and to define the role of this signalosome in clinically relevant inflammatory diseases. Mechanistic in vitro studies will be combined with the in vivo analysis of CBM function in genetically defined mouse models to gain better insights into the regulation of innate immunity and to pave the way to novel therapeutics for inflammatory diseases.

Keywords: inflammation
Structural mechanism of recognition, signaling and resection of DNA double-strand breaks (ATMMACHINE)

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: Germany
Call:  (ERC-2012-ADG_20120314, 2012)
Start date: 2013-05-01
End date: 2018-04-30
Duration (months): 60.0
Total project cost (EUR): 2498019.0
EU funding (EUR): 2498019.0
Participants: 1
Project status: CLOSED

DNA double-strand breaks are perhaps the most harmful DNA damages and result in carcinogenic chromosome aberrations. Cells protect their genome by activating a complex signaling and repair network, collectively denoted DNA damage response (DDR). A key initial step of the DDR is the activation of the 360 kDa checkpoint kinase ATM (ataxia telangiectasia mutated) by the multifunctional DSB repair factor Mre11-Rad50-Nbs1 (MRN). MRN senses and tethers DSBs, processes DSBs for further resection, and recruits and activates ATM to trigger the DDR. A mechanistic basis for the activities of the core DDR sensor MRN has not been established, despite intense research over the past decade. Our recent breakthroughs on structures of core Mre11-Rad50 and Mre11-Nbs1 complexes enable us now address three central questions to finally clarify the mechanism of MRN in the DDR: - How does MRN interact with DNA or DNA ends in an ATP dependent manner? - How do MRN and associated factors such as CtIP process blocked DNA ends? - How do MRN and DNA activate ATM? We will employ an innovative structural biology hybrid methods approach by combining X-ray crystallography, electron microscopy and small angle scattering with crosslink mass spectrometry and combine the structure-oriented techniques with validating in vitro and in vivo functional studies. The anticipated outcome will clarify the structural mechanism of one of the most important but enigmatic molecular machineries in maintaining genome stability and also help understand the molecular defects associated with several prominent cancer predisposition and neurodegenerative disorders.

Keywords: dna double-strand break repair ataxia telangiectasia hybrid methods