Data-Gouv-ML/pcri-informations-sur-les-projets-laureats huggingface dataset:
Cis-regulatory variation: Using natural genetic variation to dissect cis-regulatory control of embryonic development. (CISREGVAR)

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: Germany
Call:  (ERC-2012-ADG_20120314, 2012)
Start date: 2013-09-01
End date: 2018-12-31
Duration (months): 64.0
Total project cost (EUR): 2260116.0
EU funding (EUR): 2260116.0
Participants: 1
Project status: CLOSED

Embryonic development is very robust: In the midst of segregating mutations and fluctuating environments, a fertilized egg has the remarkable capacity to give rise to a precisely patterned embryo. The stereotypic progression of development is driven by tightly regulated programs of gene expression. However, this deterministic view from genetics is at odds with an emerging view of transcription from genomics as a “noisy” process, variable and changing both within and between individuals. How variable transcriptional programs can regulate robust embryonic development remains a long-standing question, which this proposal aims to address. By combining population genetics, genomics, and developmental genetics in Drosophila we will dissect the relationship between DNA sequence variation, transcription factor (TF) occupancy, and the regulatory control of developmental gene expression. The backdrop for this work is extensive information generated by my lab on the location and function of over 12,000 developmental cis-regulatory elements, including accurate, predictive models of their spatio-temporal activity. To understand the impact of variation on transcription and development, we will make use of a powerful experimental resource – 192 sequenced Drosophila strains, collected from a highly genetically diverse wild population. The proposed research has three Specific Aims: 1) Perform the first high-resolution study associating SNPs and structural variants (eQTLs) with gene expression variation during embryonic development, 2) Quantify in vivo the relationship between cis-regulatory variation, TF occupancy, and gene expression, 3) Incorporate these data into an integrated, predictive model of transcription. These Aims, together with our cis-regulatory data, will offer unique, mechanistic insights into how cis-regulatory variation impacts developmental gene regulation, and into the molecular bases of robustness in developmental regulatory networks.

Keywords: cis-regulatory networks,development,drosophila,gene expression,chip-seq
Membranous nephropathy : a model for solving organ-specific auto-immunity (OSAI) (OSAI)

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: 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): 2500000.0
EU funding (EUR): 2500000.0
Participants: 1
Project status: CLOSED

Membranous nephropathy (MN) is a paradigm of organ-specific autoimmune disease which affects the kidney glomerulus, resulting in the formation of immune deposits, complement-mediated proteinuria, and renal failure. My group has recently identified 2 causative antigens (neutral endopeptidase and bovine serum albumin) in children, and 2 predisposing genes HLA-DQA1 and PLA2R1 coding for another antigen in adult MN. However, MN is most likely more complex, involving several antigen-antibody systems and immune response genes. To get a comprehensive view of self and food/environmental antigenic targets and of HLA and non-HLA trigger genes, and to design new rapidly acting therapies, I will develop novel technological approaches such as immunopeptidomics, and explore new pathophysiological and therapeutic concepts with 3 major objectives: 1. Identify the immune response targets (epitopes) using unbiased approaches such as HLA-class II peptidomics, random peptide libraries, and sequencing of candidate genes starting with PLA2R1 2. Investigate trigger genes by next generation sequencing (NGS) of the HLA-D locus and of other genes involved in autoimmunity and disease progression, in 150 pairs of donors and recipients with or without recurrence of MN, a situation offering a unique opportunity to analyze effects of genetic background 3. Revisit complement-related innate immunity by NGS sequencing of 18 complement regulatory protein genes in search of variants which may account for disease heterogeneity, by blocking C5b-9 formation with recombinant factor H in 2 murine models of MN, and by searching for C5b-9 antagonists by high-throughput screening of chemical libraries in podocyte cell-based assays. Our project will provide new biomarkers that will be used to set up reliable tests for diagnosis, monitoring, and prediction of outcome and recurrence of MN. It will result in new therapies, improved monitoring and ontology, and better understanding of organ-specific autoimmunity.

Keywords: auto-immunity,membranous nephropathy,pathogenic epitopes,biomarkers,gwas,patients cohorts,random peptide libraries,protein and gene arrays,podocyte,molecular signatures,disease ontology
Distributed Propulsion and Ultra-high By-pass Rotor Study at Aircraft Level (DISPURSAL)

Framework: FP7 — Cooperation
Programme: Transport (including Aeronautics)
Destination: Aeronautics and air transport
Action type: Collaborative project
Countries involved: Germany,Russian Federation,Germany,France
Call:  (FP7-AAT-2012-RTD-L0, 2012)
Start date: 2013-02-01
End date: 2015-01-31
Duration (months): 24.0
Total project cost (EUR): 788536.2
EU funding (EUR): 591300.0
Participants: 4
Project status: CLOSED

The objectives defined in “Flightpath 2050” as well as the limited availability of fossil fuels call for significant reductions in fuel consumption in the air transport sector. Novel propulsion concepts are thus a field of intense research, with particular trends that emerge: hybrid energy sources may not only be more efficient, but open up new degrees of freedom in terms of airframe-engine integration. The power plant system can be fully or partially embedded in the airframe, and thus exploit the benefits of boundary layer ingestion and wake filling, which have proven to allow lower power requirements. However, despite the established advantages of such integrated propulsion concepts, little effort has been expended to examine the practical implementation in realistic aircraft systems. The project DisPURSAL investigates the impact of novel propulsion concepts in a holistic manner, covering the aspects of power generation and drive chain architectures as well as engine-airframe integration together with the impact on aircraft performance and emissions. The project is set up around two case studies, namely a “distributed propulsion concept” with multiple propulsive devices, and a “propulsive fuselage concept” featuring a propulsive device encircling the fuselage. Starting from the definition of realistic operational and systems requirements, initial concept exploration and down-selection define a baseline and feed into a multi-disciplinary design optimization process, which quantifies the efficiency potentials at aircraft level. Detailed numerical flow simulation is used to evaluate the strong interaction of airframe and propulsion. DisPURSAL shows the potential of distributed propulsion and highlights synergy effects with turbo-electric aircraft architectures. A technology roadmap derived in the project will contribute to establish distributed propulsion as a serious option for future air transport and sustain the competitiveness of the European aviation industry.

Keywords: distributed propulsion,propulsive fuselage,aircraft level assessment,wake-filling,boundary layer ingestion,numerical experimentation,multi-disciplinary design optimization,technology roadmap
The Evolution and Development of Complex Morphologies (CARNOMORPH)

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-2012-ADG_20120314, 2012)
Start date: 2013-06-01
End date: 2018-05-31
Duration (months): 60.0
Total project cost (EUR): 2499997.0
EU funding (EUR): 2499997.0
Participants: 1
Project status: CLOSED

Plant and animal organs display a remarkable diversity of shapes. A major challenge in developmental and evolutionary biology is to understand how this diversity of forms is generated. Recent advances in imaging, computational modelling and genomics now make it possible to address this challenge effectively for the first time. Leaf development is a particularly tractable system because of its accessibility to imaging and preservation of connectivity during growth. Leaves also display remarkable diversity in shape and form, with perhaps the most complex form being the pitcher-shaped (epiascidiate) leaves of carnivorous plants. This form has evolved four times independently, raising the question of whether its seeming complexity may have arisen through simple modulations in underlying morphogenetic mechanisms. To test this hypothesis, I aim to develop a model system for carnivorous plants based on Utricularia gibba (humped bladderwort), which has the advantage of having one of the smallest genomes known in plants (~2/3 the size of the Arabidopsis genome) and small transparent pitcher-shaped leaves amenable to imaging. I will use this system to define the morphogenetic events underlying the formation of pitcher-shaped leaves and their molecular genetic control. I will also develop and apply computational modelling to explore hypotheses that may account for the development of U. gibba bladders and further test these hypotheses experimentally. In addition, I will investigate the relationship between U. gibba bladder development and species with simpler leaf shapes, such as Arabidopsis, or species where the epiascidiate form has evolved independently. Taken together, these studies should show how developmental rules elucidated in current model systems might be extended and built upon to account for the diversity and complexity of tissue forms, integrating evo-devo approaches with a mechanistic understanding of morphogenesis.

Keywords: morphogenesis,modelling,growth,shape
Design Principles of Microtubule Cytoskeleton Architectures during Cell Division (SPINDLEDESIGN)

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-2012-ADG_20120314, 2012)
Start date: 2013-07-01
End date: 2019-06-30
Duration (months): 72.0
Total project cost (EUR): 2497115.0
EU funding (EUR): 2497115.0
Participants: 2
Project status: CLOSED

The microtubule cytoskeleton provides an intracellular coordinate system and a mechanical scaffold for a multitude of essential cellular functions. The design principles underlying the dynamic organisation and function of the microtubule cytoskeleton are not understood. Using an in vitro reconstitution approach, we will determine the rules that govern which combination of mechano-chemical elements gives rise to specific large-scale organisation of the microtubule cytoskeleton. We will reconstitute the architecture of bipolar spindles that are essential for the segregation of the genetic material during cell division. For the in vitro reconstitutions, we will use candidate proteins suggested to be crucial by the literature and we will identify as yet unknown proteins with critical activities. We will investigate key fundamental questions: In which region of the multidimensional biochemical parameter space is bipolarity encoded, which is essential for successful cell division? What are the molecular mechanisms that determine size scaling of spindles or of spindle substructures? How do chromosomes position themselves correctly within spindles and how are spindles positioned properly within cells? To validate that the answers obtained from our in vitro reconstitutions are also applicable to the cytoskeleton in vivo, the reconstituted systems will be quantitatively compared to living cells at the global and single molecule level. The results of our experiments will develop theoretical models of cytoskeleton architecture and function. The overall goal of the project is to understand at a mechanistic level how the self-organised architecture of the microtubule cytoskeleton, and its collective dynamic and mechanical properties, derive from the complex interplay between its mechano-chemical constituents. This will link the functional properties of a system to the fundamental biochemistry and biophysics of the system’s components.

Keywords: systems biochemistry,cytoskeleton architecture,in vitro reconstitution
Flow in the tumor microenvironment: Linking mechanobiology with immunology (LYMPHIMMUNE)

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: Switzerland
Call:  (ERC-2012-ADG_20120314, 2012)
Start date: 2013-05-01
End date: 2016-12-31
Duration (months): 44.0
Total project cost (EUR): 2217581.66
EU funding (EUR): 2217581.66
Participants: 1
Project status: CLOSED

Tumors often engage the lymphatic system to invade and metastasize. The tumor-draining lymph node (dLN) may be an immune privileged site that protects the tumor from host immunity, and lymph flow draining tumors is often increased, enhancing communication between the tumor and the sentinel node. In addition to increasing transport of tumor antigens and regulatory cytokines to the lymph node, increased lymph flow in the tumor margin causes mechanical stress-induced changes in stromal cells that stiffen the matrix and alter the immune microenvironment of the tumor. In this proposed project, we will investigate the interplay between lymphatic drainage and flow-induced mechanotransduction in the tumor stroma that may synergize to promote tumor immune escape by appropriating lymphatic mechanisms of peripheral tolerance. We will address the hypothesis that lymphatic drainage and flow-induced mechanotransduction in the tumor stroma synergistically promote tumor immune escape by altering the immune microenvironment, and that targeting lymphatic drainage from the tumor may represent a new avenue for tumor immunotherapy. For the latter, we will develop strategies to limit or block lymphatic flow in the tumor microenvironment and characterize their ability to improve the efficacy of tumor immunotherapy by dampening local immunosuppression in the tumor stroma and tumor-draining lymph node (dLN). We will combine in vivo mouse models and intravital imaging with engineered in vitro microenvironments and nanoparticle-based targeting strategies in three broad aims designed to constitute several PhD and postdoctoral projects.

Keywords: lymphatic vessel,lymph node,chemokines,fibroblasts,mechanical stress,therapeutic cancer vaccine,cross-presentation,immune tolerance,interstitial flow
High resolution and chemical genetic approaches to RNA silencing mechanisms (FRONTIERS OF RNAI-II)

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: Switzerland
Call:  (ERC-2012-ADG_20120314, 2012)
Start date: 2013-07-01
End date: 2018-06-30
Duration (months): 60.0
Total project cost (EUR): 2251600.0
EU funding (EUR): 2251600.0
Participants: 1
Project status: CLOSED

In eukaryotes, silencing small (s)RNAs, including micro (mi)RNAs and small interfering (si)RNAs, regulate many aspects of biology, including cell differentiation, development, hormonal responses, or defense. In particular, many plant and metazoan miRNAs play crucial roles in embryonic/post-embryonic development; the precise timing and localization of their expression is thus crucial to their action. Hence, specific miRNA repertoires underlie specific cell identities, and deviations from such repertoires often have deleterious consequences such as cancer. Many miRNAs also help organisms to adapt to stress, thus, given their importance in virtually all aspects of biology, understanding how, when and where miRNAs exert their actions is of paramount importance. To date, however, the few approaches to miRNA-mediated silencing in whole organisms have not taken into account the exquisite definition, in space and time, of their biogenesis and action, leading to an inaccurate view of the biology of these molecules at the systems level. Using the root system of the model plant Arabidopsis thaliana, we propose to explore, at single-cell and subcellular resolution levels, the biology of the main miRNA effector protein, ARGONAUTE 1 (AGO1) in intact tissues. Using a combination of state-of the-art technologies for single-cell forward genetics, protein purification and RNA/polysome profiling, we will establish a functional spatiotemporal map of the root AGO1-sRNAome and identify cell-specific modifiers of sRNA biogenesis and action. As a complement to the above approaches, chemical genetics will isolate small molecules allowing direct and specific manipulation of AGO1-dependent sRNA pathways in planta. RNA silencing modifier compounds will also accelerate forward and reverse approaches of RNA silencing in plants with sensitized genetic backgrounds, and uncover novel connections between miRNA/siRNA and physiological or metabolic pathways.

Keywords: mirna,sirna,argonaute,cell-specificity,chemical genetics
Attine ANT SymbiomeS (ANTS)

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: Denmark
Call:  (ERC-2012-ADG_20120314, 2012)
Start date: 2013-05-01
End date: 2018-04-30
Duration (months): 60.0
Total project cost (EUR): 2290102.0
EU funding (EUR): 2290102.0
Participants: 1
Project status: CLOSED

The attine fungus-growing ants are prime models for understanding phenotypic adaptations in social evolution and symbiosis. The mutualism has many hallmarks of advanced cooperation in its mating system commitments and functional complementarity between multiple symbiont partners, but potential conflicts between sexes and castes over reproductive priorities, and between hosts and symbionts over symbiont mixing have also been documented. With collaborators at BGI-Shenzhen and the Smithsonian Institution my group has obtained six reference genomes representing all genus-level branches of the higher attine ants and a lower attine outgroup. With collaborators in Denmark and Australia we have pioneered proteomic approaches to understand the preservation of sperm viability in spite of sperm competition and the enzymatic decomposition of plant substrates that the ants use to make their fungus gardens grow. Here, I propose an integrated study focusing on four major areas of attine ant biology that are particularly inviting for in depth molecular approaches: 1. The protein-level networks that secure life-time (up to 20 years) sperm storage in specialized ant-queen organs and the genetic mechanisms that shape and adjust these “sexual symbiome” networks. 2. The ant-fungal symbiome, i.e. the dynamics of fungal enzyme production for plant substrate degradation and the redistribution of these enzymes in fungus gardens through fecal deposition after they are ingested but not digested by the ants. 3. The microbial symbiome of ant guts and other tissues with obligate bacterial mutualists, of which we have identified some and will characterize a wider collection across the different branches of the attine ant phylogeny. 4. The genome-wide frequency of genomic imprinting and the significance of these imprints for the expression of caste phenotypes and the regulation of potential reproductive conflicts.

Keywords: social evolution,conflict and cooperation,omics approaches
Cardiac Connective Tissue: Beat-by-Beat Relevance for Heart Function in Health and Disease (CARDIONECT)

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: 2013-07-01
End date: 2019-06-30
Duration (months): 72.0
Total project cost (EUR): 2498612.4
EU funding (EUR): 2498612.4
Participants: 2
Project status: CLOSED

Cardiac connective tissue is regarded as passive in terms of cardiac electro-mechanics. However, recent evidence confirms that fibroblasts interact directly with cardiac muscle cells in a way that is likely to affect their beat-by-beat activity. To overcome limitations of traditional approaches to exploring these interactions in native tissue, we will build and explore murine models that express functional reporters (membrane potential, Vm; calcium concentration, [Ca2+]i) in fibroblasts, to identify how they are functionally integrated in native heart (myocyte => fibroblast effects). Next, we will express light-gated ion channels in murine fibroblast, to selectively interfere with their Vm (fibroblast => myocyte effects). Fibroblast-specific observation and interference will be conducted in normal and pathologically remodelled tissue, to characterise fibroblast relevance for heart function in health & disease. Based on these studies, we will generate 2 transgenic rabbits (fibroblast Vm reporting / interfering). Rabbit cardiac structure-function is more amenable to translational work, e.g. to study fibroblast involvement in normal origin & spread of excitation across the heart, in pathological settings such as arrhythmogenicity of post-infarct scars (a leading causes of sudden death), or as a determinant of therapeutic outcomes such as in healing of atrial ablation lines (interfering with a key interventions to treat atrial fibrillation). The final ‘blue-skies’ study will assess whether modulation of cardiac activity, from ‘tuning’ of biological pacemaker rates to ‘unpinning’ / termination of re-entrant excitation waves, can be achieved by targeting not myocytes, but fibroblasts. The study integrates basic-science-driven discovery research into mechanisms and dynamics of biophysical myocyte-fibroblast interactions, generation of novel transgenic models useful for a broad range of studies, and elucidation of conceptually new approaches to heart rhythm management.

Keywords: optical mapping,voltage,calcium,optogenetics