Data-Gouv-ML/pcri-informations-sur-les-projets-laureats huggingface dataset:
Lipid Signaling at the Glutamatergic Synapse: Involvement in Brain Network Function and Psychiatric Disorders (LIPSYD)

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: 2013-04-01
End date: 2018-03-31
Duration (months): 60.0
Total project cost (EUR): 2499390.0
EU funding (EUR): 2499390.0
Participants: 1
Project status: CLOSED

We have recently reported on a novel mode of modulation of neuronal transmission at the glutamatergic junction. This signaling pathway involves lysophosphatidic acid (LPA) acting via presynaptic LPA2 receptors. This is in turn controlled by a molecule which we named plasticity related gene-1 (PRG-1, Bräuer et al., Nat Neurosci 2003) from the postsynaptic side (Trimbuch et al., Cell 2009). PRG-1 is a brain-specific membrane protein related to lipid phosphate phosphatases (LPPs) with a selective expression in neurons (Geist et al., CMLS 2011). We detected an important role of LPA-synthesizing pathways in bioactive signaling at the synapse acting via ATX and etablished nano-particles as LPA-biosensor using the characteristic spectral shift allowing detection in 2-photon imaging. We provide insights into the oligomeric assembly of PRG-1 in the membrane and assessed LPA-binding, uptake and intracellular interaction partners of the molecule. Animals lacking one PRG-1 allele exhibit a broad spectrum of behavioral pathology indicative of altered brain network function and psychiatric disorders. These changes are already present in animals lacking only 50% of PRG-1. A point mutation at R345T which appears to result in loss-of-function when re-expressed in the mouse was found in 5925 healthy individuals with a heterozygous frequency of approximately 0.86% (about 4.500.000 European citizens). Individuals carrying this loss-of-function mutation revealed functional alterations of sensory gating involved in psychiatric disorders. We plan to continue our studies on (1) synthesis and action of LPA, (2) molecular function of PRG-1 in bioactive lipid signaling, and (3) the role of PRG-1 signaling in brain network function and psychiatric disorders. Characterization of the molecular basis of this novel modulatory signaling pathway and its role in brain network function will be important for our understanding of its role in health and disease.

Keywords: translational neuroscience
Dynamics and Homeostasis of Germinal Zones in the Adult Vertebrate Brain (SYSTEMATICS)

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: 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): 2499855.0
EU funding (EUR): 2499855.0
Participants: 1
Project status: CLOSED

Neural stem cells (NSCs) are self-renewing and multipotent progenitors generating neurons and glia in the adult vertebrate brain. The success of NSC maintenance and mobilization varies widely among species, brain territories, pathological conditions and individual environment, with important physiological impacts. On these grounds, our proposal aims to define the cellular, molecular and systems components controlling the formation of NSC-containing GZs and sustaining the dynamics of GZ reservoirs during an animal’s life, in the context of environmental challenge. We will rely on a novel and powerful model system, the dorsal telencephalon of the adult zebrafish, which harbors a large and superficially located GZ, enriched in NSCs and capable of efficient NSC recruitment. Our previous work highlighted the general relevance of this model, which harbors, like in mammals, quiescent NSCs of glial identity, and can be subject along life to pathological attrition, silencing, or amplification. This system was also instrumental in our identification of Notch signaling as a key control factor of NSC quiescence, a major parameter of GZ equilibrium. To dissect the mechanistic fundaments underlying homeostasis of this GZ, we propose here a combination of cutting edge approaches including the genetic modification and profiling of single NSCs in situ, the mathematical modeling of NSC clonal behavior in physiological and pathological states, and the development of novel optical tools to image for the first time the behavior of NSC populations and in intact, live adult vertebrate. This multidisciplinary and multi-scale approach will reveal the single-cell and population rules governing GZ dynamics, robustness and drifts in healthy and diseased conditions, and will feed these mechanisms with molecular support. More generally, it will generate a quantitative framework to probe the molecular and cellular effects of pathological and environmental challenges on NSC behavior.

Keywords: zebrafish,adult neural stem cells
Glycosylation: Programmes for Observation, Inhibition and Structure-based Exploitation of key carbohydrate-active enzymes (GLYCOPOISE)

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-2012-ADG_20120314, 2012)
Start date: 2013-05-01
End date: 2019-04-30
Duration (months): 72.0
Total project cost (EUR): 2500000.0
EU funding (EUR): 2500000.0
Participants: 1
Project status: CLOSED

The development of new approaches to dissect the diverse roles for carbohydrates in living cells is a major challenge for modern cell biology. The huge diversity of carbohydrates is reflected in a multiplicity of function; in addition to acting as energy sources, carbohydrates play major roles in structure, signalling and epigenetics. The work programme will build upon the applicant’s excellence in the mechanistic and structural enzymology of carbohydrate-active enzymes to tackle the key challenges of modern cellular glycobiology. Our vision is to provide fundamental structural and mechanistic-dissection of key proteins and their complexes and to use these as the foundation to deliver enzyme inhibitors as tools to probe the cellular function of specific glycans. The programme’s three strands will each scale a major pinnacle of carbohydrate biochemistry. Strand 1 will focus on mammalian glycosidases involved in glycocerebroside metabolism and genetic disease. We will unlock new 3-D information for glycocerebrosidase 2 (GBA2) and use these together with GBA1 to design and exploit novel and specific enzyme inhibitors as mechanistic and cellular probes, novel chaperones and imaging agents. Strand 2 will focus on the key endoplasmic reticulum enzyme endomannosidase, both its mechanistic novelty and its exploitation to perturb cellular glycans to unlock its biological roles and deliver compounds for anti-viral therapeutics. Strand 3 will probe the modification and elaboration of specific human N-glycans and their role in cell surface receptor biology. It will focus on the GlcNAc transferase V catalysed formation of polylactosamine epitopes and their regulation of growth factor signalling at the cell surface both in health and cancerous tissues. GlycoPOISE will both answer cardinal structural and chemical mechanistic questions in the enzymology of glycobiology and inform strategies for the observation and inhibition of carbohydrate-active enzymes and their exploitation

Keywords: glycosylation enzyme carbohydrate chemical biology
A Novel Non-Invasive Prenatal Diagnosis for Genetic Disorders (NIPD)

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: Cyprus
Call:  (ERC-2012-ADG_20120314, 2012)
Start date: 2013-05-01
End date: 2019-04-30
Duration (months): 72.0
Total project cost (EUR): 2500000.0
EU funding (EUR): 2500000.0
Participants: 2
Project status: CLOSED

Non-Invasive Prenatal Diagnosis (NIPD) has been one of the most fascinating research fields during the last decade. The identification of small amounts of fetal DNA in maternal circulation has opened new possibilities for NIPD. Up until today, two methods have achieved accurate and validated NIPD methods for trisomy 21. The first NIPD for trisomy 21 was based on next generation sequencing and the second was developed by our group and is based on a MeDIP real time qPCR. However, nothing has been achieved for the NIPD of other genomic disorders caused by pathogenic copy number changes or mutations. The primary goal of this proposal is to develop, validate and provide to clinical practice a novel NIPD method, which will enable fast, sensitive, accurate, robust and cost effective NIPD of the great majority of genetic disorders caused by either pathogenic copy number changes of genomic segments or single and small size mutations. Initially, biomarkers with differential methylation between fetal and maternal DNA located within the entire human exome will be identified using methylation DNA immunoprecipitation and whole-exome massive parallel sequencing. Then a novel MeDIP exome NGS NIPD method for the great majority (~85%) of genetic disorders will be developed and validated. The method will undergo a blind evaluation study using 300 normal and abnormal maternal peripheral blood samples of pregnant women at 10-12 week of gestation. The intellectual property which may arise will be protected by filing internationally PCT patent(s) followed by dissemination of the results of the project. The new method will not only provide a greater number of highly accurate prenatal diagnoses of genetic disorders, but will do so without any risk for the fetus. Thus, the provision of such prenatal diagnoses may be provided to all pregnant women. The proposed proposal goes beyond the current state of the art and provides multiple medical, social and economic benefits.

Keywords: non invasive prenatal diagnosis (nipd),fetal-specific dna methylation markers,methylated dna immunoprecipitation (medip),differentially methylated regions (dmrs)
Role of Liver Estrogen Receptor in female Energy Metabolism, Reproduction and Aging: What About Your Liver Sexual Functions? (WAYS)

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-2012-ADG_20120314, 2012)
Start date: 2013-04-01
End date: 2019-03-31
Duration (months): 72.0
Total project cost (EUR): 1445381.0
EU funding (EUR): 1445381.0
Participants: 1
Project status: CLOSED

In mammals, the liver is the peripheral integrator of nutrient availability and energetic needs of the entire organism. We recently demonstrated that dietary amino acids (AA) activate liver Estrogen Receptors (ER) and that, in case of food scarcity, the lowered circulating AA decrease liver ER activity and reduce IGF-1 synthesis with the consequent blockage of the estrous cycle. Here, we hypothesize that in females liver ERa is also a sensor of the endogenous signalling induced by transitions among reproductive stages and a key organizer for the changes required to adapt energy metabolism to reproductive necessities. Thus, we propose that in mammals liver ERa is regulated by reproductive functions and that, in case of ovary malfunctioning, the altered estrogenic signalling causes metabolic impairment leading to local and perhaps systemic disruption of energy homeostasis. To demonstrate our theory, we will explore: i) the molecular pathways activating liver ERa and the related ERa transcriptome by genome-wide analytical tools; ii) the hepatic metabolism and the systemic consequences of liver ER pharmacological and genetic manipulations by means of metabolomic technologies; iii) the association between altered signalling on liver ER and the onset of metabolic disorders; iv) the molecular interactions between ER and PPAR activity and the effect of estrogens on liver autophagy. WAYS research is facilitated by a series of tools such as ER conditional KO, reporter mice, arrays of genes known as target of liver ERa, and others generated by our laboratory in collaboration with EU groups in previous EU programs. The vision of the liver as a functional unit with reproductive organs constitutes a paradigm shift in our understanding of woman physiology; thus, the full comprehension of liver ERa activity and regulation will be a critical step for the conception of new therapies for several diseases affecting women including the metabolic syndrome or the non-alcoholic steatosis.

Keywords: estrogen receptors,liver,energy metabolism,reproduction,woman aging,nafld,pharmacology,in vivo imaging,genomics,bioinformatics
A combined evolutionary and proteomics approach to the discovery, induction and application of antiviral immunity factors (ANTI-VIROME)

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: 2013-04-01
End date: 2018-03-31
Duration (months): 60.0
Total project cost (EUR): 1915200.0
EU funding (EUR): 1915200.0
Participants: 1
Project status: CLOSED

Humans are equipped with a variety of intrinsic immunity or host restriction factors. These evolved under positive selection pressure for diversification and represent a first line of defence against invading viruses. Unfortunately, however, many pathogens have evolved effective antagonists against our defences. For example, the capability of HIV-1 to counteract human restriction factors that interfere with reverse transcription, uncoating and virion release has been a prerequisite for the global spread of AIDS. We are just beginning to understand the diversity and induction of antiretroviral factors and how pandemic HIV-1 group M (major) strains evolved to counteract all of them. Here, I propose to use a genetics, proteomics and evolutionary approach to discover and define as-yet-unknown antiviral effectors and their inducers. To identify novel antiviral factors, we will examine the capability of all primate genes that are under strong positive selection pressure to inhibit HIV and its simian (SIV) precursors. This examination from the evolutionary perspective of the invading pathogen will also reveal which adaptations allowed HIV-1 to cause the AIDS pandemic. Furthermore, complex peptide-protein libraries representing essentially the entire human peptidome, will be utilized to identify novel specific inducers of antiviral restriction factors. My ultimate aim is to unravel the network of inducers and effectors of antiviral immunity - the "Anti-Virome" - and to use this knowledge to develop novel effective preventive and therapeutic approaches based on the induction of combinations of antiviral factors targeting different steps of the viral life cycle. The results of this innovative and interdisciplinary program will provide fundamental new insights into intrinsic immunity and may offer alternatives to conventional vaccine and therapeutic approaches because most restriction factors have broad antiviral activity and are thus effective against various pathogens.

Keywords: siv
Downhill Folding Protein Modules as Conformational Rheostats: Roles in Molecular Biology and Applications as Biosensors (MOLRHEOSTAT)

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: Spain
Call:  (ERC-2012-ADG_20120314, 2012)
Start date: 2013-05-01
End date: 2018-04-30
Duration (months): 60.0
Total project cost (EUR): 2290318.64
EU funding (EUR): 2290318.64
Participants: 2
Project status: CLOSED

Protein folding and function is a perfect arena towards growing the grassroots of quantitative and synthetic biology. This is so because all cellular processes controlled by proteins can ultimately be traced back to physico-chemical properties encoded in their aminoacid sequences. MOLRHEOSTAT is framed within these goals, focusing on the investigation of novel connections between protein folding and function via a multidisciplinary approach that combines experiment (single molecule spectroscopy, high-resolution NMR, protein engineering and design), theory and computer simulations. Conventionally, proteins are portrayed as conformational switches that fold and function by flipping between an on-state (native, active) and an off-state (inactive, unfolded) in response to stimuli. However, last years have witnessed the discovery of protein modules that undergo continuous conformational changes upon unfolding (downhill folding). MOLRHEOSTAT aims at investigating the functional and technological implications of downhill folding. The goal is to determine whether downhill folding modules can be exploited to build conformational rheostats; that is, proteins that continuously modulate a signal or response at the single molecule level by tuning their folding conformational ensemble. Conformational rheostats could open a new realm of applications as synthetic biomolecular devices as well as regulatory mechanisms for controlling complex biochemical processes carried out by macromolecular assemblies. These ideas will be explored on two specific objectives: 1) Implementation of a general approach for building high-performance, ultrafast, single-molecule sensors based on downhill protein folding modules. 2) Analysis of the roles of conformational rheostats in the regulation of three fundamental processes in molecular biology (coordination in protein networks, DNA sliding and homing-to-target of transcription factors, and molecular springs in macromolecular assemblies).

Keywords: protein folding,engineering and design,conformational transitions,biological regulation,molecular sensors,single-molecule spectroscopy,nmr,laser spectroscopy,computer simulations
Genetics of mosquito resistance to pathogens. (ANOPATH)

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: France
Call:  (ERC-2012-ADG_20120314, 2012)
Start date: 2013-03-01
End date: 2019-02-28
Duration (months): 72.0
Total project cost (EUR): 2307800.0
EU funding (EUR): 2307800.0
Participants: 1
Project status: CLOSED

Malaria parasite infection in humans has been called “the strongest known force for evolutionary selection in the recent history of the human genome”, and I hypothesize that a similar statement may apply to the mosquito vector, which is the definitive host of the malaria parasite. We previously discovered efficient malaria-resistance mechanisms in natural populations of the African malaria vector, Anopheles gambiae. Aim 1 of the proposed project will implement a novel genetic mapping design to systematically survey the mosquito population for common and rare genetic variants of strong effect against the human malaria parasite, Plasmodium falciparum. A product of the mapping design will be living mosquito families carrying the resistance loci. Aim 2 will use the segregating families to functionally dissect the underlying molecular mechanisms controlled by the loci, including determination of the pathogen specificity spectra of the host-defense traits. Aim 3 targets arbovirus transmission, where Anopheles mosquitoes transmit human malaria but not arboviruses such as Dengue and Chikungunya, even though the two mosquitoes bite the same people and are exposed to the same pathogens, often in malaria-arbovirus co-infections. We will use deep-sequencing to detect processing of the arbovirus dsRNA intermediates of replication produced by the RNAi pathway of the mosquitoes. The results will reveal important new information about differences in the efficiency and quality of the RNAi response between mosquitoes, which is likely to underlie at least part of the host specificity of arbovirus transmission. The 3 Aims will make significant contributions to understanding malaria and arbovirus transmission, major global public health problems, will aid the development of a next generation of vector surveillance and control tools, and will produce a definitive description of the major genetic factors influencing host-pathogen interactions in mosquito immunity.

Keywords: anopheles gambiae,malaria,plasmodium falciparum,genetic mapping,qtl,functional analysis
Innovative Modelling to Optimise Control of Childhood Anaemia across Africa (IMCCA)

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: Switzerland
Call:  (ERC-2012-ADG_20120314, 2012)
Start date: 2013-10-01
End date: 2018-09-30
Duration (months): 60.0
Total project cost (EUR): 2494800.0
EU funding (EUR): 2494800.0
Participants: 1
Project status: CLOSED

Anaemia affects two-third of all preschool-aged children in Africa. Malnutrition, malaria and helminth infections are among the main factors contributing to anaemia in this age group, however their relative contribution across the continent is not well understood. Spatially explicit estimates of anaemia risk are important measures of child morbidity and mortality. The goal of the project is to develop Bayesian geostatistical methodology for very large, non-stationary data and employ it to (i) determine the relative contribution of malaria, helminth infections and malnutrition on anaemia and severe anaemia burden among pre-school children; (ii) obtain spatially explicit estimates of the risk of anaemia, severe anaemia and number of affected children; (iii) characterize co-endemicity patterns of anaemia, malaria, helminth infection and malnutrition; and (iv) quantify the contribution of severe anaemia to child mortality. This research will contribute novel statistical methodologies in (i) spatial analysis of very large non-stationary geostatistical data, (ii) variable selection within a non-stationary model for very large geostatistical data, (iii) modelling disease co-endemicity from spatially misaligned surveys arising from independent regression models and (iv) meta-analyses of heterogeneous large spatial data by coupling geostatistical with mathematical transmission models. Applications of geostatistical methodology will help optimising interventions to combat anaemia by generating (i) the first anaemia risk map and number of affected preschool children across Africa which will guide efficient allocation of nutrient supplements and fortified foods; (ii) anaemia co-endemicity maps and estimates of the relative contribution of anaemia risk factors to design integrated interventions based on local conditions; and (ii) estimates of the anaemia-related mortality across Africa.

Keywords: geostatistics,bayesian,non-stationarity,anaemia,malaria,neglected diseases,markov chan monte carlo