Data-Gouv-ML/pcri-informations-sur-les-projets-laureats huggingface dataset:
Environmental Control of Development (ENCODE)

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
Call:  (ERC-2011-ADG_20110310, 2011)
Start date: 2012-01-01
End date: 2017-05-31
Duration (months): 65.0
Total project cost (EUR): 2483870.0
EU funding (EUR): 2483870.0
Participants: 1
Project status: CLOSED

Plant development is highly plastic, with major variations in form determined by the environment. An excellent example is shoot branching, where the body plan of the shoot system conferred by one genotype can range from a single unbranched stem, to a highly ramified bush, depending on the growth conditions. In recent years we have investigated the hormonal network that allows environmentally sensitive changes in shoot branching in Arabidopsis. Through the analysis of a set of monogenic mutants with clear effects on both the number of shoot branches produced and on its responsiveness to environmental inputs, we have developed a model for shoot branching control involving interactions between three systemically transported plant hormones. In collaboration with Prusinkiewicz (Calgary), we have built a computational implementation of this model, which captures the phenotypes of wild-type plants and, through the manipulation of single biologically plausible model parameters, our mutant phenotypes. While there is still much to learn about individual network components, the mechanistic framework we have established is sufficiently well developed to allow network-level investigation. We therefore propose an ambitious project to use natural allelic variation in shoot branching and its environmental sensitivity as in vivo differently parameterized versions of the shoot branching regulatory network, which can be compared with parameter space exploration in our computational model. By investigating the properties of shoot branching in diverse genotypes and in the computational model parameter space, we will identify trait correlations that will contribute to understanding the architecture of the regulatory network. This approach will simultaneously test the validity of our current model and provide new hypotheses for investigation. Furthermore, the rapidly moving genomics tools available in Arabidopsis will allow us to elucidate the genetic basis for key network properties.

Keywords: developmental plasticity
Practical statistical approaches for addressing replicability problems in life sciences (PSARPS)

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-2011-ADG_20110310, 2011)
Start date: 2012-03-01
End date: 2018-02-28
Duration (months): 72.0
Total project cost (EUR): 1933200.0
EU funding (EUR): 1933200.0
Participants: 1
Project status: CLOSED

Lack of replicability of scientific discoveries has surfaced too often in recent years, and even reached the attention of the general public. An ignored cause is the inappropriate statistical treatment of two statistical problems: (1) selective inference, manifested in selecting few promising leads following the statistical analysis of the potential many, where ignoring the selection process on estimates, confidence intervals and observed significance; (2) using too optimistic a yardstick of variation with which confidence intervals set and statistical significance of the potential discovery is judged, as a result of ignoring the variability between laboratories and subjects. The first problem becomes more serious as the pool of potential discoveries increases, the second paradoxically becomes more serious as measuring ability improves, which explain why the two problems are more prominent in recent years. Both problems have statistical solutions, but the solutions are not practical as they burden the analysis to a point where the power to discover new findings is exceedingly low. Therefore, unless required by regulating agencies, scientists tend to avoid using these solutions. I propose to develop methods that address such replicablity problems specific to medical research, epidemiology, genomics, brain research, and behavioral neuroscience. The methods include (a) new hierarchical weighted procedures, and model selection methods, that control the false discovery rate in testing; (b) shorter confidence intervals that offer false coverage-statement rate for the selected, both addressing the concern about selective inference; and (c) a compromise between using random effects models for the laboratories and subjects and treating them as fixed, to be aided by multiple laboratory database in behavior genetics and neuroscience. By serving the exact needs of scientists, while avoiding excessive protection, I expect the offered methodologies to become widely adapted.

Keywords: genetic epidemiology,false discovery rate,multiple endpoints,clinical trials,safety
Sorting processes that ensure short and long-range action of Wnts in developing epithelia (WNTEXPORT)

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
Call:  (ERC-2011-ADG_20110310, 2011)
Start date: 2012-07-01
End date: 2017-06-30
Duration (months): 60.0
Total project cost (EUR): 1938845.57
EU funding (EUR): 1938845.57
Participants: 2
Project status: CLOSED

Wnts are signaling proteins that act both at short and long range in developing tissues. Several proteins, such as Wntless, are specifically devoted to Wnt secretion, indicating that Wnts may follow a distinct secretory route. Moreover, Wnts carry two lipid modifications, which are likely to interfere with diffusion in the extracellular space. Much of our work will focus on the trafficking of Wingless (the main Drosophila Wnt), which forms a concentration gradient in wing imaginal discs. To chart the route taken by Wingless from the ER to responding cells, we will devise techniques (e.g. BirA-dependent in vivo biotinylation) to pulse label endogenously expressed Wingless in the secretory pathway and at the cell surface. Wingless routing will also be investigated in conditions that alter Evi/Wntless trafficking. We will capitalize on our observation that Wingless and Wntless are present on exosomes in conditioned medium. These exosomes will be purified and characterized by mass spectrometry and the resulting information will be used to devise rigorous functional assays. Similar approaches will be used to identify and characterize proteins that associate with soluble Wingless, which is also present in conditioned medium. Our proposed approaches will also enable us to assess, for the first time, the function of exosomes in an intact animal. Once secreted, Wingless and associated proteins spread in the extracellular space while remaining associated with the epithelial surface. We will use single molecule imaging in a reconstituted system along with mathematical modeling to test the hypothesis that the glypican-Wnt interaction is sufficiently strong to ensure surface retention while allowing diffusion in two dimensions. Finally we will use biochemical approaches and molecular genetics in Drosophila and mice to investigate the mode of action of Notum, a glypican-modifying enzyme that could be relevant to the progression of Wnt signaling dependent cancers.

Keywords: morphogen,wnt,pattern formation,glypicans,notum,diffusion models,single molecule imaging,rnai,exosomes
Modelling Cancer Traits in Drosophila (FLIESCAN)

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: Spain
Call:  (ERC-2011-ADG_20110310, 2011)
Start date: 2012-07-01
End date: 2017-06-30
Duration (months): 60.0
Total project cost (EUR): 2406000.0
EU funding (EUR): 2406000.0
Participants: 1
Project status: CLOSED

Despite significant advance, cancer treatment remains suboptimal. Anatomical and physiological differences between humans and simple model organisms like Drosophila are many and major, and preclude the modelling of key aspects of the disease as it proceeds in vertebrates. However, malignant tumors in vertebrates and flies are made of cells that have derailed from their normal course of development, grow out of control, become immortal, invasive, and kill the host. Moreover, like most solid human tumors, Drosophila malignant tumors display chromosomal instability and copy number variation. In addition, some of them are characterized by the upregulation of germline genes, a distinct feature of certain human cancers. Drosophila tumor models offer an unprecedented opportunity to study these basic malignant traits, which characterize human tumors, in a genetically tractable organism, applying sophisticated genome-wide and comprehensive functional assays at a rate and with a level of detail that are not possible in vertebrates. The goal of this project is twofold: (1) to identify new paths of intervention to inhibit tumor growth, and (2) to determine the origin and function of aneuploidy and changes in gene copy number in malignant growth. We are expectant that the results obtained during the course of this project might eventually have a real impact in human health.

Keywords: modelling cancer in drosophila.
Uncovering and understanding RNA through Massively Parallel Sequencing (RNA-MAPS)

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: Spain
Call:  (ERC-2011-ADG_20110310, 2011)
Start date: 2012-04-01
End date: 2017-12-31
Duration (months): 69.0
Total project cost (EUR): 2056638.0
EU funding (EUR): 2056638.0
Participants: 1
Project status: CLOSED

The overarching goal of the proposal presented here is the use of massively parallel sequencing for the identification of novel genetic and epigenetic factors playing role in RNA processing. Specifically, we plan to focus on the role of long non-coding RNAs and histone modifications in splicing regulation during cell differentiation. Towards that end, we plan to monitor RNA and chromatin changes across many time points through RNASeq and ChIPSeq in two cell differentiation models: 1) the induced transdifferentiation of human pre-B cells into macrophages, and 2) organ morphogenesis during fly development. By investigating, through these time course experiments, patterns of molecular co-variation—for instance, between inclusion levels of alternative exons and histone modifications—we can learn how these factors participate, and eventually cooperate, to modulate the condition specific abundance of the alternative splice forms. We plan therefore to develop statistical methods to infer significant patterns of molecular co-variation through the analysis of datasets profiling RNA and chromatin structure across many data points. Based on these findings, we plan to develop a mathematical model of splicing in which the relative abundance of alternative splice forms is predicted from the relevant genetic and epigenetic factors. To facilitate the storage, organization, access, and analysis of the data produced through the project we propose to develop a robust, efficient, and scalable software system. The system will be open source, so that it can be used and enhanced by other researchers. Realizing that the current model for the storage of publicly available biomolecular data, based on centralized repositories, may not be longer sustainable, we will design our software system assuming a peer-to-peer like network of distributed RNASeq data and resources, across which bioinformatics analyses will be transparently performed.

Keywords: splicing,chromatin structure,rnaseq,computational methods
Signal integration and rewiring during tumor development (P38CANCER)

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: Spain
Call:  (ERC-2011-ADG_20110310, 2011)
Start date: 2012-07-01
End date: 2017-12-31
Duration (months): 66.0
Total project cost (EUR): 2497800.0
EU funding (EUR): 2497800.0
Participants: 1
Project status: CLOSED

Cell fate decisions rely on signaling pathways that integrate external signals to coordinate specific intracellular programs. One of these pathways leads to the activation of p38α MAPK, which plays key roles in cell responses to many types of stresses as well as chemotherapeutic agents and oncogenes. Importantly, p38α acts in a cell context-specific and cell type-specific manner to integrate signals that affect cell proliferation, differentiation and survival. Evidence from mouse models and human cell lines indicates that p38α can negatively regulate tumor initiation at different levels. Intriguingly, recent results suggest that p38α activation may also sometimes have pro-tumorigenic functions. The molecular basis for the different functions of p38α are not well understood but it is likely that the network of substrates phosphorylated by p38α plays a major role. This project proposes to investigate molecular mechanisms of p38 MAPK signaling during tumorigenesis including the systematic identification of substrates and how they contribute to the different functions of this pathway. An important part of the studies will focus on the mechanisms underlying the rewiring of p38α signaling to serve pro-tumorigenic functions, including in-depth characterization of how p38α regulates the survival, proliferation and spreading of cancer cells, as well as its role in the interplay between cancer cells and stromal cells. We also plan to investigate the implication of p38α in tumor progression in vivo, using both xenografts and genetically modified mice that we have generated to either inactivate or hyperactivate the p38 MAPK pathway. These models will allow us to analyze the role of this signaling pathway in the regulation of tumor initiation, growth and spreading in different tissues. Taken together, this project will address important questions on cellular signaling and tumor development, which might be also useful for more rational anti-tumoral treatments.

Keywords: map kinase,signaling pathways,cancer cell regulation,mouse models
Nonlinear synaptic integration in morphologically simple and complex neurons (NEUROGAIN)

Framework: FP7 — Ideas
Programme: European Research Council
Theme: European research council
Destination: Advanced grants
Action type: Support for frontier research (ERC)
Panel: Neurosciences and neural disorders
Countries involved: United Kingdom
Call:  (ERC-2011-ADG_20110310, 2011)
Start date: 2012-03-01
End date: 2018-02-28
Duration (months): 72.0
Total project cost (EUR): 2499710.0
EU funding (EUR): 2499710.0
Participants: 1
Project status: CLOSED

Understanding how neurons represent and transform information and perform the computations required to generate complex behaviours is a core aim of neuroscience. Although this knowledge is of fundamental importance and is a prerequisite for understanding many neuronal disorders, the way in which individual neurons process information is poorly understood. This reflects the technical difficulty of measuring rapid synaptic signalling in fine dendritic structures distributed in 3D space. Moreover, defining the transformation between inputs and output firing is complex due to the large number of input combinations involved. To overcome these problems I have recently developed two powerful new tools. A high speed 3D 2-photon acousto-optic lens (AOL) microscope that enables high speed (30 kHz) 3D optical functional imaging with submicron resolution. I will use AOL microscopy with uncaging, electrophysiological and optogenetic approaches to study synaptic integration in cerebellar granule cells, cortical pyramidal cells and fast-spiking interneurons. Comparison of synaptic integration and neuronal computation in these neurons, which include simple and complex morphologies and excitatory and inhibitory cell types, will allow mechanisms to be investigated and principles identified. By measuring [Ca2+] and voltage at many locations within 3D dendritic trees, I will map the spatiotemporal properties of synaptic input in 3D and locate and count regenerative events. By applying AOL microscopy, in vitro and in vivo I will elucidate mechanisms and test how information is processed by neurons during sensory input. I have also developed neuroConstruct, a software tool for modelling neurons and large-scale networks in 3D with a high degree of biological detail. By using in vitro and in vivo data to constrain models we will bridge the gap in our understanding between synaptic and neuronal mechanisms and the input-output transformations that morphologically complex neurons perform.

Keywords: synapse,synaptic integration,interneuron,dendrite,cerebellum,cortex
Radical Medicine: Redefining Oxidative Stress (RADMED)

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-2011-ADG_20110310, 2011)
Start date: 2012-08-01
End date: 2018-07-31
Duration (months): 72.0
Total project cost (EUR): 2298000.0
EU funding (EUR): 2298000.0
Participants: 1
Project status: CLOSED

Oxidative stress, an excess of radical and other reactive oxygen species (ROS), has been suggested as a major disease mechanism. However, the major clinical trials using anti-oxidants have been failures, even suggesting serious side effects. Here, I propose completely different approaches: First, instead of letting radicals form and then scavenge them we will identify their diseases-relevant sources and prevent their formation or specifically repair the damage caused by ROS. Second, we will differentiate beneficial signalling roles of ROS. In combination, this will result in unprecedented precision and molecular specificity. In 2010, I submitted a somewhat related proposal to the ERC and received a comment as being “too focused on essential hypertension”. This proposal has a much broader focus and impact beyond cardiovascular diseases. In the past months we achieved major breakthroughs by identifying a radical/ROS source (NOX4) as fundamental mechanism in stroke, the fastest growing and soon no 1 cause of death. We are also developing in phase II a radical formation inhibitor for neurotrauma. Moreover, our basic research facilitated the development of drug classes re-activating an oxidatively damaged signalling receptor, now in phase III. Further, we identified angiogenesis as a radical/ROS-dependent and protective (!) signalling event. This proposal is just the beginning: our basic science will open up new fields and leap forward in personalized medicine with groundbreaking technologies and approaches. We will contribute to the diagnosis and early identification of patients at risk and to monitor their successful treatment (in vitro/blood-based); to the localization of disease processes (in vivo/molecular imaging) before the onset of symptoms; and to a new generation of more effective, predictable, and mechanism-based drugs. We also expect to later apply our findings and tools to neurobiology and oncology, where ROS also play physiological and pathological roles.

Keywords: redox balance,nadph oxidases,soluble guanylate cyclase,nitric oxide,biomarker,molecular imaging,ischemia-reperfusion injury,clinical study
FUTUREROOTS: Redesigning root architecture for improved crop performance (FUTUREROOTS)

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
Call:  (ERC-2011-ADG_20110310, 2011)
Start date: 2012-08-01
End date: 2017-07-31
Duration (months): 60.0
Total project cost (EUR): 3498588.0
EU funding (EUR): 3498588.0
Participants: 1
Project status: CLOSED

Food security is a pressing global issue. Crop production has to double by 2050 to keep pace with global population growth increasing to 9 billion. This target is challenging given the impact of climate change on water availability and the drive to reduce fertilizer inputs to make agriculture more environmentally sustainable. In both cases, developing crops with improved water and nutrient uptake efficiency would provide the solution. Root architecture critically influences nutrient and water uptake efficiency. Rooting depth impacts the efficient acquisition of soil nitrogen (and water) since nitrate leaches deep into the soil. Phosphate use efficiency could be significantly improved without increasing root depth by manipulating the angle of root growth to explore the top soil where this macronutrient accumulates. The genes that regulate root traits such as angle, depth and density in crops remain to be identified. A key impediment to genetic analysis of root architecture in crops grown in soil has been the ability to image live roots non-invasively. Recent advances in microscale X-ray Computed Tomography (CT) now permit root phenotyping. Major technical and scientific challenges remain before CT can become a high throughput phenotyping approach. This ambitious multidisciplinary research programme will be achieved through six integrated work packages. The first 3 work packages will create high-throughput CT (WP1) and image analysis (WP2) tools that will be used to probe variation in root systems architecture within wheat germplasm collections (WP3). Work packages 4-6 will identify root architectures that improve water (WP4) and nitrate uptake efficiencies (WP5) and pinpoint the genes that regulate these traits. In parallel, innovative mathematical models simulating the impact of root architecture and soil properties will be developed as tools to assess the impact of architectural changes on uptake of other nutrients in order to optimise crop performance (WP6).

Keywords: system biology,mathematic modelling,image analysis,wheat