Data-Gouv-ML/pcri-informations-sur-les-projets-laureats huggingface dataset:
Sudden Cardiac Death and Electrical Dyssynchrony Mediated by Purkinje-His Dysfunctional Activity (SYMPHONY)

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: 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): 2489646.0
EU funding (EUR): 2489646.0
Participants: 1
Project status: CLOSED

Cardiovascular disease is the first cause of mortality in the whole world (WHO 2008), responsible for 700000 deaths each year in Europe; a huge burden on healtcare. Half of this mortality is due to heart failure (HF), which can be caused or further aggravated by electrical dyssynchrony. The other half of cardiac mortality occurs suddenly, essentially due to ventricular tachyarrhythmias. The main objectives of SYMPHONY are (i) to advance our fundamental understanding in the mechanisms underlying SCD and electrical dyssynchrony in HF, with a strong focus on the specialized ventricular conduction network, and (ii) to improve current preventive, diagnostic and treatment methods for these life-threatening cardiac electrical disorders. SYMPHONY is a multidisciplinary project that will benefit from a wide array of state-of-the-art methodologies and expertise, both in fundamental and clinical sciences. A large mammalian species, the sheep, will be used for a detailed characterization of the properties of the conduction network in health and disease. Importantly, a limited number of explanted human hearts will be available on which all these techniques will equally be applicable. From our clinical work, SYMPHONY will benefit from cutting edge tools in epicardial and catheter mapping allowing simultaneous mapping of the Purkinje system and ventricular substrate. The gathered data will be fed into large-scale computer models that will allow personalized investigations into the mechanisms of SCD and electrical dyssynchrony. SYMPHONY has a significant potential for industrial valorisation and is likely to introduce new targets for interventions, and new methods for risk stratification and prevention. Therefore we can affirm that this unprecedented, comprehensive and translational project will lead to major advances in scientific knowledge, will have a significant impact on healthcare budgets and, most importantly, will dramatically improve quality of life and patient care.

Keywords: arrhythmias,sudden cardiac death,dyssynchrony,heart failure,catheter ablation,cardiac resynchronization therapy
An interdisciplinary genome-wide study of posttranscriptional regulation by small RNAs: from individual interactions to networks and evolution (POSTTRANS)

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: Israel
Call:  (ERC-2012-ADG_20120314, 2012)
Start date: 2013-02-01
End date: 2019-01-31
Duration (months): 72.0
Total project cost (EUR): 2329360.0
EU funding (EUR): 2329360.0
Participants: 1
Project status: CLOSED

Deciphering the interactions within and between the three major components of living organisms, DNA, RNA and Protein, is at the heart of biological research. New large-scale experimental methods have dramatically advanced genome-wide detection of protein-protein, protein-DNA, protein-RNA and protein-mediated RNA-RNA interactions. However, at present there is no large-scale method that could detect all RNA-RNA interactions independent of a mediator protein, or when the mediator protein is unknown. Attaining such a method is of utmost importance and is very timely, as it is now evident that RNA-RNA interactions play central roles in cellular life. In particular, hundreds of expressed small RNA (sRNA) molecules were discovered in both pro- and eukaryotes, many of which act as posttranscriptional regulators of gene expression by base-pairing with their mRNA targets. It seems that in many organisms the layer of posttranscriptional regulation is as widespread as transcription regulation, presenting a major challenge towards achieving functional and mechanistic understanding of this regulation level. Here we propose to develop an innovative methodology for genome-wide detection of the sRNA targetome, all mRNA targets of cellular sRNAs. This new methodology combines in vivo structural probing with deep sequencing and is independent of protein considerations. We will apply this method to deciper the sRNA targetome of the model organism Escherichia coli, which encodes over 100 sRNAs. We will use the sRNA targetome data as the foundation for a systematic ‘bottom-up’ computational analysis of multifaceted aspects of sRNA-mediated posttranscriptional regulation, encompassing the basic underlying rules of sRNA-mRNA target recognition, the design principles of the posttranscriptional regulatory network and its integration with the transcriptional and metabolic networks, and the evolution of posttranscriptional regulation.

Keywords: small rna,posttranscriptional regulation,differential deep sequencing,bacteria
Telling the full story: how neurons send other signals than by classical synaptic transmission (DCVFUSION)

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: Netherlands
Call:  (ERC-2012-ADG_20120314, 2012)
Start date: 2013-05-01
End date: 2019-04-30
Duration (months): 72.0
Total project cost (EUR): 2439315.0
EU funding (EUR): 2439315.0
Participants: 2
Project status: CLOSED

The regulated secretion of chemical signals in the brain occurs principally from two organelles, synaptic vesicles and dense core vesicles (DCVs). Synaptic vesicle secretion accounts for the well characterized local, fast signalling in synapses. DCVs contain a diverse collection of cargo, including many neuropeptides that trigger a multitude of modulatory effects with quite robust impact, for instance on memory, mood, pain, appetite or social behavior. Disregulation of neuropeptide secretion is firmly associated with many diseases such as cognitive and mood disorders, obesity and diabetes. In addition, many other signals depend on DCVs, for instance trophic factors and proteolytic enzymes, but also signals that typically do not diffuse like guidance cues and pre-assembled active zones. Hence, it is beyond doubt that DCV signalling is a central factor in brain communication. However, many fundamental questions remain open on DCV trafficking and secretion. Therefore, the aim of this proposal is to characterize the molecular principles that account for DCV delivery at release sites and their secretion. I will address 4 fundamental questions: What are the molecular factors that drive DCV fusion in mammalian CNS neurons? How does Ca2+ trigger DCV fusion? What are the requirements of DCV release sites and where do they occur? Can DCV fusion be targeted to synthetic release sites in vivo? I will exploit >30 mutant mouse lines and new cell biological and photonic approaches that allow for the first time a quantitative assessment of DCV-trafficking and fusion of many cargo types, in living neurons with a single vesicle resolution. Preliminary data suggest that DCV secretion is quite different from synaptic vesicle and chromaffin granule secretion. Together, these studies will produce the first systematic evaluation of the molecular identity of the core machinery that drives DCV fusion in neurons, the Ca2+-affinity of DCV fusion and the characteristics of DCV release sites.

Keywords: regulated secretion,dense core vesicles,snare-proteins,munc18,munc13,vesicle docking,membrane fusion,exocytosis,ldcv
NANOSCALE ANALYSIS OF PROTEIN ISLANDS ON LYMPHOCYTES (NANO-ISLANDS)

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: 2013-05-01
End date: 2018-12-31
Duration (months): 68.0
Total project cost (EUR): 2244000.0
EU funding (EUR): 2244000.0
Participants: 1
Project status: CLOSED

To detect foreign invaders and to communicate with other cells of the immune system, B lymphocytes carry a multitude of receptor proteins on their surface. In the past, it was thought that most of these receptors are randomly distributed on the cell surface and only become organized upon lymphocyte activation. Recent studies showed, however, that many of these surface proteins are pre-organized in nanoscale protein islands (here called nano-islands) with a size of 50-150 nanometer (nm). We have developed a Fab-proximity ligation assay (Fab-PLA) which allows us to study the organization of membrane proteins at 10-20 nm distances. With this method, we discovered that the B cell antigen receptor (BCR) of the classes IgM and IgD are located in different class-specific nano-islands. Due to the technical limitations of classical biochemistry (detergent lysis), light microscopy (diffraction limit of 250 nm) and electron microscopy (fixation artifacts), the nanoscale organization of membrane proteins is not well studied. With the Fab-PLA method, we can, for the first time, explore this unknown 200-20 nm space and analyze the composition and stability of the different nano-islands on the B cell surface. We also will develop new methods such as proximity biotinylation and proximity proteomics to better study these nanostructures and learn more about their role in B lymphocyte activation and human diseases such as lymphomas and autoimmune diseases. Although more than 50% of all drugs target membrane proteins, the nanoscale organization of these proteins is poorly characterized. To learn more about the nano-islands organization of membrane proteins is thus of utmost importance for a better understanding of the action of these drug treatments and to improve them. Our study may also provide better markers for specific disease stages and could lead to new drugs influencing nanoscale membrane processes.

Keywords: membrane organisation,nanoscale membrane analysis
Individual stochasticity and population heterogeneity in plant and animal demography (INDSTOCH)

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: Netherlands
Call:  (ERC-2012-ADG_20120314, 2012)
Start date: 2013-06-01
End date: 2018-05-31
Duration (months): 60.0
Total project cost (EUR): 1496655.0
EU funding (EUR): 1496655.0
Participants: 1
Project status: CLOSED

Variation among individuals in reproduction, survival, and other demographic traits, is universal. It has two potential sources: heterogeneity (differences among individuals in their vital rates) and individual stochasticity (random differences resulting from the application of the same vital rates to identical individuals). The goal of the proposed research is to incorporate individual stochasticity and heterogeneity into demographic models for plants, animals, and humans. The project has three components: (1) a study of variation in longevity, focusing on perturbation analysis of Markov chain models for mortality, (2) an analysis of the reward structure of populations, to quantify individual stochasticity in reproduction and other properties, and (3) the development of models to incorporate heterogeneity and stochasticity into branching process models and diffusion models. These three topics will be integrated using matrix population models, integrodifference equation models, and Markov chain models for the life cycle.

Keywords: stochastic population models,population heterogeneity,matrix population models
Identification of Novel Targeted Therapies for Renal Cancer (ONCOTREAT)

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,United Kingdom
Call:  (ERC-2012-ADG_20120314, 2012)
Start date: 2013-09-01
End date: 2019-08-31
Duration (months): 72.0
Total project cost (EUR): 2247890.24
EU funding (EUR): 2247890.24
Participants: 2
Project status: CLOSED

Overall, kidney cancers are the eighth most common cancer and the incidence of the most common form (renal cell carcinoma, RCC) has been increasing steadily over the past 30 years. If detected early, surgical removal of RCC can be curative but the prognosis for metastatic disease is very poor. RCC is resistant to conventional therapy and recently introduced targeted therapies form the mainstay of treatment for metastatic disease. The rationale for the use of targeted therapies (e.g. antiangiogenic tyrosine kinase inhibitors) in RCC was derived from functional investigations of the mechanism of tumourigenesis in the rare inherited RCC syndrome von Hippel-Lindau disease. Whilst currently available targeted therapies can extend progression free survival in advanced RCC they are not curative and better treatments are urgently required. Large scale genomic studies of RCC are in progress and will greatly enhance current knowledge of the molecular pathology of RCC. However, experience from other cancers suggests that the results of genomic analyses of cancer are complex and identifying the key “gatekeeper genes” is frequently challenging. ONCOTREAT is based on the hypothesis that (a) the identification of the genetic basis of inherited forms of RCC will highlight those genes and pathways that are critical for tumourigenesis and (b) that selective targeting of cells deficient in inherited RCC gene function will enable advances in the treatment of inherited and sporadic RCC. The objectives of ONCOTREAT are to: 1. Identify novel inherited RCC genes 2. Generate and characterise human cell line models for inherited RCC genes 3. Identify candidate therapeutic agents that, in in vitro studies, selectively target human cell line models of inherited RCC genes dysfunction 4. Evaluate candidate therapeutic agents identified from in vitro studies in in vivo investigations to identify agents that target cancers deficient in inherited RCC gatekeeper genes.

Keywords: renal cell carcinoma inherited
Mutation and Recombination in the Cattle Germline: Genomic Analysis and Impact on Fertility (DAMONA)

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: 2013-03-01
End date: 2018-02-28
Duration (months): 60.0
Total project cost (EUR): 2258000.0
EU funding (EUR): 2258000.0
Participants: 1
Project status: CLOSED

Mutation and recombination are fundamental biological processes that determine adaptability of populations. The mutation rate reflects the equilibrium between the need to adapt, the burden of mutation load, the “cost of fidelity”, and random drift that determines a lower limit in achievable fidelity. Recombination fulfills an essential mechanistic role during meiosis, ensuring proper chromosomal segregation. Recombination affects the rate of creation and loss of favorable haplotypes, imposing 2nd-order selection pressure on modifiers of recombination. It is becoming apparent that recombination and mutation rates vary between individuals, and that these differences are in part inherited. Both processes are therefore “evolvable”, and amenable to genomic analysis. Identifying genetic determinants underlying these differences will provide insights in the regulation of mutation and recombination. The mutational load, and in particular the number of lethal equivalents per individual, remains poorly defined as epidemiological and molecular data yield estimates that differ by one order of magnitude. A relationship between recombination and fertility has been reported in women but awaits confirmation. Population structure (small effective population size; large harems), phenotypic data collection (systematic recording of > 50 traits on millions of cows), and large-scale SNP genotyping (for genomic selection), make cattle populations uniquely suited for genetic analysis. DAMONA proposes to exploit these unique resources, combined with recent advances in next generation sequencing and genotyping, to: (i) quantify and characterize inter-individual variation in male and female mutation and recombination rates, (ii) map, fine-map and identify causative genes underlying QTL for these four phenotypes, (iii) test the effect of loss-of-function variants on >50 traits including fertility, and (iv) study the effect of variation in recombination on fertility.

Keywords: de novo mutation,recombination,loss of function mutation,qtl mapping,embryonic lethal,fertility
Epithelial cells in inflammation (EPINFLAM)

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: 2013-05-01
End date: 2018-04-30
Duration (months): 60.0
Total project cost (EUR): 2500000.0
EU funding (EUR): 2500000.0
Participants: 1
Project status: CLOSED

The cross talk between the host and the microbiota is believed to be the major determinant of health and disease in the gastrointestinal tract. Inflammatory bowel diseases (IBD) are chronic inflammatory conditions of the intestine with unclear aetiology. Deregulation of the cross talk between the intestinal microbiota and the host immune system is considered a main factor contributing to IBD. Genomic studies revealed associations of NOD2 and of genes regulating autophagy and ER stress with an increased risk for IBD. Mutations in these pathways compromise Paneth cell dependent epithelial antibacterial defences causing alterations in the intestinal microbiota, termed dysbiosis. However, mutations in NOD2 or autophagy genes are not sufficient to cause intestinal inflammation in humans or in mice, suggesting that dysbiosis by itself cannot cause inflammation but additional, as yet unidentified, factors are required to precipitate the pathogenesis of IBD in genetically susceptible individuals. Mouse model studies revealed that epithelial specific mutations sensitizing intestinal epithelial cells to apoptosis or necroptosis triggered spontaneous intestinal pathologies with many features of human IBD, including loss of Paneth cells, impaired epithelial antimicrobial defences and chronic intestinal inflammation. We hypothesize that pathways controlling programmed cell death critically contribute to the pathogenesis of IBD by acting on Paneth cells to regulate epithelial antibacterial defences and simultaneously regulating intestinal epithelial cell survival and the integrity of the epithelial barrier. The aims of this research proposal are: a) to dissect the pathways regulating Paneth cell death and the development of dysbiosis in the gut, and b) to elucidate the additional genetic or environmental factors regulating intestinal epithelial barrier integrity that are likely to synergise with Paneth cell dysfunction and dysbiosis to trigger chronic intestinal inflammation.

Keywords: inflammation,pathogenesis of inflammatory bowel disease,programmed cell death,nf-kappab signaling
The role of symplastic communication during root development (SYMDEV)

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,Finland
Call:  (ERC-2012-ADG_20120314, 2012)
Start date: 2013-06-01
End date: 2019-05-31
Duration (months): 72.0
Total project cost (EUR): 2387026.0
EU funding (EUR): 2387026.0
Participants: 2
Project status: CLOSED

The symplastic route composed of plasmodesmata (PD) channels and the transporting phloem tissue (rich in PD) is the major pathway for carbon allocation in plants. How the symplastic transport route is formed during plant ontogeny and what is its significance in conducting and distributing morhogenetic signals to the growing organs is poorly understood at the moment and is addressed here. My laboratory has recently made a breakthrough that facilitates the analysis of symplastic communication. In a genetic screen we identified gain-of-function mutations in a locus that codes for a CALLOSE SYNTHASE isoform CALS3. The cals3-d mutations result in restricted symplastic trafficking through the PD. Using the cals3-d mutations in a vector system that allows cell type specific and inducible control of expression of the transgene, icals3m, we have been able to construct a molecular tool, with which we can regulate the passage of the various signaling molecules between the neighboring cells. This tool has already opened several new lines of research on symplastic communication concerning understanding of the regulation of PD channels, phloem development and symplastically moving signals. By a combination of experimental approaches at molecular, genetic, imaging and theoretically levels we will investigate here: (1) How is symplastic trafficking regulated? (2) What are the (symplastic) signals specifying phloem development? (3) How do the signals emanating from the phloem control root development? (4) Can we predict new regulatory factors controlling symplastic trafficking in space and time, based on the experimental data (on the distribution of symplastic channels, symplastically controlled genes and symplastically mobile molecules)?

Keywords: phloem,procambial development,plasmodesmata,transcription factors
Integrating cancer detection and SURgery Via molecular Imaging (SURVIVE)

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: Netherlands
Call:  (ERC-2012-ADG_20120314, 2012)
Start date: 2013-11-01
End date: 2019-10-31
Duration (months): 72.0
Total project cost (EUR): 2487600.0
EU funding (EUR): 2487600.0
Participants: 1
Project status: CLOSED

The ambitious aim of this ERC-advanced grant proposal is to develop strategies that will connect cancer detection and surgery via tumor-specific molecular imaging techniques. This will lead to personalized patient-, or even tumor-specific treatment strategies. In addition, it will provide a tool for the selection of patients that, following preoperative (neoadjuvant) treatment, would benefit from additional (minimally invasive) surgery and identify patients who may be treated non-operatively. Fine-tuning the relation between tumor diagnosis, neoadjuvant treatment, preoperative planning and minimally invasive image-guided surgery will likely improve radical oncologic surgery while reducing surgical morbidity in cancer patients. The mechanistic aim of the proposal is to develop an integrated multimodal imaging strategy that will more accurately connect tumor biology with surgical resection approaches via the use of tumor-specific molecular imaging agents. The cornerstone of this approach is the unique clinical translation of tumor-targeted imaging agents that are both radioactive (diagnostic imaging) and fluorescently (surgical guidance) labeled. It is expected that the proposed multimodal imaging agents will allow for a significant improvement of both imaging and surgery strategies.

Keywords: molecular imaging,multimodal imaging agents,treatment monitoring,preoperative planning,image-guided surgery,surgical navidation