Data-Gouv-ML/pcri-informations-sur-les-projets-laureats huggingface dataset:
Genetic/epigenetic basis of ethnic differences in cancer predisposition (ECAP)

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-2013-ADG, 2013)
Start date: 2014-02-01
End date: 2020-01-31
Duration (months): 72.0
Total project cost (EUR): 2495425.0
EU funding (EUR): 2495425.0
Participants: 1
Project status: CLOSED

Integration of large scale genetic and epigenetic analysis needs to be coupled with well defined biological hypotheses that can be experimentally tested. This project is aimed at developing a novel integrated approach to understand genetic and epigenetic predisposition to cancer with skin as model system. The Caucasian (West European) and Asian (East Asian) populations differ substantially in their predisposition to skin cancer, specifically Squamous Cell Carcinoma (SCC). The underlying mechanisms are poorly understood. As in other organs, skin SCC results from changes in both epithelial and mesenchymal compartments. We will be focusing on two key gene regulatory networks of cells of the two compartments (keratinocytes and dermal fibroblasts), with a key role in skin SCC. The "keratinocyte network" has Notch/p53/p63 as key nodes, while the "dermal fibroblast network" had Notch and AP1 family members. We will pursue two main goals : 1) We will test the hypothesis that a linkage can be established between specific genetic and epigenetic marks in the Caucasian versus Asian populations and differences in expression and function of "keratinocyte and/or dermal fibroblast network genes". 2) We will test the hypothesis that keratinocytes and/or dermal fibroblasts of Caucasian versus Asian individuals differ in their tumor yielding capability, and that these differences in cancer forming capability are due to differences in either "keratinocyte or dermal fibroblast network genes". The applicant is a world leader in epithelial signaling and cancer biology, and is heading interdisciplinary research efforts that bridge the basic and clinical sciences. Together with his bioinformatician and clinician collaborators, he is in an excellent position to attain the high goals of the proposal. The approach has not been attempted before, is only possible within the frame of an advanced ERC grant, and has substantial basic as well as translational/clinical implications.

Keywords: cancer predisposition,skin,squamous cell carcinoma,cancer associated fibroblasts,notch,p53,p63,ap1,egfr.
Lysosomes as targets for cancer therapy (LYSOSOME)

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: Denmark
Call:  (ERC-2013-ADG, 2013)
Start date: 2014-02-01
End date: 2019-01-31
Duration (months): 60.0
Total project cost (EUR): 2499960.0
EU funding (EUR): 2499960.0
Participants: 1
Project status: CLOSED

Knowing that the lysosomes contain a powerful cocktail of hydrolases capable of digesting cells and entire tissues, it is obvious that the maintenance of lysosomal membrane integrity is of utmost importance for all cells, and especially for cancer cells with dramatically increased lysosomal activity. Yet, the mechanisms that regulate lysosomal membrane stability have remained obscure, largely due to the lack of methods sensitive enough to detect partial lysosomal leakage and suitable for screening purposes. We have finally succeeded in developing such a method, which allows me to propose here a project whose major aim is to reveal how cells maintain the integrity of lysosomal membranes. Based on our emerging data that firmly connect heat shock protein 70 and sphingolipid metabolism to lysosomal membrane stability, we will devote a large part of the project to the molecular details of these connections and to the characterization of the effects of new and already approved (cationic amphiphilic drugs) sphingolipid-regulating drugs on lysosomal membrane stability and cell survival. Additionally, we will screen selected siRNA libraries to identify signaling networks and lysosome-associated proteins essential for lysosomal membrane integrity, and small molecule libraries to identify compounds that induce lysosomal cell death. The next step is to identify lysosome-stabilizing mechanisms that are especially important for cancer cell survival. And the ultimate goal is to validate corresponding drug targets and drugs (old and new) for the induction of lysosomal cell death in therapy resistant cancers. As a “by-product” we expect to identify putative drug targets for the treatment of degenerative diseases and lipid storage disorders, where the stabilization of the lysosomal membranes promotes cell survival.
The Physics of Active Particle Suspensions (PHYSAPS)

Framework: FP7 — Ideas
Programme: European Research Council
Theme: European research council
Destination: Advanced grants
Action type: Support for frontier research (ERC)
Panel: Condensed matter physics
Countries involved: United Kingdom
Call:  (ERC-2013-ADG, 2013)
Start date: 2014-02-01
End date: 2020-01-31
Duration (months): 72.0
Total project cost (EUR): 2491601.0
EU funding (EUR): 2491601.0
Participants: 1
Project status: CLOSED

‘Active matter’ is matter that is intrinsically out of equilibrium. In particular, an ‘active suspension’ is made up of self-propelled particles or droplets dispersed in a liquid. Active matter is not in thermal equilibrium even in the absence of external driving, and display fascinating properties. Thus, e.g., a so- lution of the filament-forming protein actin and the ‘molecular motor’ protein myosin can ‘burn’ ATP as fuel to produce a gel that flows in the absence of any external pressure gradient; while a suspension of swimming bacteria can have a viscosity that is lower than that of the suspending liquid. There is yet no gener- ally accepted statistical mechanics of active matter, where the absence of detailed balance means that small differences in microscopic dynamics can in principle lead to very different macroscopic behaviour. Moreover, there is no a priori reason to believe that a reduced description in terms of just a few macroscopic parameters (such as effective temperature and density) is possible. I propose a systematic pro- gramme of experiments to discover when and how microscopic dynamics affect the macroscopic behaviour of active suspensions, whether any of their behaviour has analogues in suspensions of passive particles and droplets, and how activity can be described using coarse-grained variables. To ensure that the experiments can be tightly coupled to theory and simulations, I will use well-characterised, model systems of active particles. Developing model systems is therefore a subsidiary, but crucial, goal of my programme. Some of these systems will be designed to be as similar as possible in their passive properties, but quite distinct in terms of their microscopic dynamics – a ‘luxury’ that is typically only available to theo- rists and simulators. Experimenting with such model systems should reveal what phenomena are generic to activity, and what phenomena are specific to particular kinds of microscopic dynamics.
The Role of Lipolysis in the Pathogenesis of Cancer-associated Cachexia (LIPOCHEX)

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: Austria
Call:  (ERC-2013-ADG, 2013)
Start date: 2014-04-01
End date: 2020-03-31
Duration (months): 72.0
Total project cost (EUR): 2499446.0
EU funding (EUR): 2499446.0
Participants: 1
Project status: CLOSED

Cachexia is a complex syndrome characterized by massive loss of body weight due to uncontrolled loss of adipose tissue and skeletal muscle. The wasting occurs during late stages of many unrelated chronic diseases and frequently leads to the death of affected individuals. Cachexia is most common in cancer, where an estimated 25% of patients die from cancer-associated cachexia (CAC) rather than from the cancer. Despite the tremendous impact of CAC on morbidity and mortality, the underlying molecular mechanisms are poorly understood. Recently, we demonstrated that lipase-catalyzed triacylglycerol (TG) catabolism is required for the pathogenesis of CAC. Mice lacking adipose triglyceride lipase, the rate-limiting enzyme for TG hydrolysis (lipolysis), were completely protected from loss of both adipose tissue and muscle in two forms of cancer. This implies an essential role of the lipolytic process in the pathogenesis of CAC. Here we propose to elucidate the causal role of lipases and their coregulators in CAC development. We will determine mechanisms involved and pursue novel treatment strategies. Our objectives are to: - Investigate how different cancers in mice regulate tissue-specific lipolysis; - Elucidate the functional role of lipases and their coregulators in the pathogenesis of CAC; - Assess whether pharmacological inhibition of specific lipases prevents or delays CAC; - Study the effects of cancer-induced lipolysis on energy dissipating pathways and epigenetic control. The project enters a largely unexplored field: the role of lipid metabolism in the pathogenesis of CAC. The work will heavily rely on the characterization of induced mutant mouse models with CAC and require extensive collaboration with experts in pathology and large-scale systems analytics. The results are expected to yield new mechanisms of disease development and provide novel therapeutic targets to prevent the devastating and prevalent consequences of CAC.
From Structure Property to Structure Process Property Relations in Soft Matter – a Computational Physics Approach (MOLPROCOMP)

Framework: FP7 — Ideas
Programme: European Research Council
Theme: European research council
Destination: Advanced grants
Action type: Support for frontier research (ERC)
Panel: Condensed matter physics
Countries involved: Germany
Call:  (ERC-2013-ADG, 2013)
Start date: 2014-02-01
End date: 2020-01-31
Duration (months): 72.0
Total project cost (EUR): 2025000.0
EU funding (EUR): 2025000.0
Participants: 1
Project status: CLOSED

From cell biology to polymer photovoltaics, (self-)assembly processes that give rise to morphology and functionality result from non-equilibrium processes, which are driven by both, external forces, such as flow due to pressure gradients, inserting energy, or manipulation on a local molecular level, or internal forces, such as relaxation into a state of lower free energy. The resulting material is arrested in a metastable state. Most previous work has focused on the relationship between structure and properties, while insight into the guiding principles governing the formation of a (new) material, has been lacking. However, a comprehensive molecular level understanding of non-equilibrium assembly would allow for control and manipulation of material processes and their resulting properties. This lag of knowledge can be traced to the formidable challenge in obtaining a molecular picture of non-equilibrium assembly. Non-equilibrium processes have been studied extensively on a macroscopic level by non-equilibrium thermodynamics. We take a novel route approaching the challenge from a molecular point of view. Recent advances in experimental, but especially computational modeling, now allow to follow (supra-) molecular structural evolution across the range of length and time scales necessary to comprehend, and ultimately control and manipulate macroscopic functional properties of soft matter at the molecular level. Soft matter is particularly suited for that approach, as it is “slow” and easy to manipulate. We take the computational physics route, based on simulations on different levels of resolution (all atom, coarse grained, continuum) in combination with recent multiscale and adaptive resolution techniques. This work will initiate the way towards a paradigm change from conventional Structure Property Relations (SPR) to molecularly based Structure Process Property Relations (SPPR).

Keywords: non equilibrum structures,soft matter,computer simulations,multiscale modeling
Outer Membrane Vesicles (OMVs) from “Vaccinobacter”: A Synthetic Biology approach for effective vaccines against infectious diseases and cancer (OMVAC)

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: Italy
Call:  (ERC-2013-ADG, 2013)
Start date: 2014-06-01
End date: 2019-05-31
Duration (months): 60.0
Total project cost (EUR): 2612828.0
EU funding (EUR): 2612828.0
Participants: 3
Project status: CLOSED

This proposal intends to apply Synthetic Biology to create a new bacterial species, Vaccinobacter, devoted to the production of multivalent, highly effective vaccines. The project originates from the evidence that Outer membrane Vesicles (OMVs) naturally produced by all Gram-negative bacteria can induce remarkable protective immunity, a property already exploited to develop anti-Neisseria vaccines now available for human use. OMV protection is mediated by the abundance of Pathogen-Associated-Molecular Patterns (PAMPs), known to play a key role in stimulating innate immunity. Moreover, OMVs can be engineered by delivering recombinant proteins to bacterial periplasm and outer membrane. Intrinsic adjuvanticity and propensity to be manipulated potentially make OMVs an ideal vaccine platform, particularly indicated when antigen combinations (for pathogens with genetic variability) and strong potentiation of immunity (for the elderly and cancer) are needed. However, full exploitation of OMVs as vaccines is prevented by: i) presence of potentially reactogenic compounds such as LPS, virulence factors, and toxins, ii) presence of several irrelevant proteins, which dilute immune responses, iii) lack of broadly applicable molecular tools to load OMVs with foreign antigens. Scope of the project is to provide novel solutions to solve these limitations and demonstrate the unique performance OMVs as vaccines by testing them on complex pathogens and cancer. Main project activities are: 1) remodelling of E. coli genome to create “Vaccinobacter”, a “living factory” of OMVs deprived of all unnecessary components but carrying the relevant immune potentiators, 2) characterization and optimization of the immune stimulatory properties of OMVs, 3) development of novel methods to incorporate foreign antigens into Vaccinobacter-derived OMVs, 4) loading of OMVs with selected pathogen- and cancer-derived antigens and demonstration of their protective efficacy in appropriate animal models.
Engineering of biomimetic surfaces: Switchable micropatterns for controlled adhesion and touch (SWITCH2STICK)

Framework: FP7 — Ideas
Programme: European Research Council
Theme: European research council
Destination: Advanced grants
Action type: Support for frontier research (ERC)
Panel: Products and process engineering
Countries involved: Germany
Call:  (ERC-2013-ADG, 2013)
Start date: 2014-02-01
End date: 2019-10-31
Duration (months): 69.0
Total project cost (EUR): 2482800.0
EU funding (EUR): 2482800.0
Participants: 1
Project status: CLOSED

Nature has, in the course of evolution, found many fascinating solutions to “engineering problems”. The proposed work aims at three-dimensional (3D) surface structures inspired by insects, spiders and geckoes. Based on the PI’s earlier work on passive structures, the new challenge addressed by this interdisciplinary project is to design and investigate active, switchable 3D micropatterns, whose adhesion and touch can be tuned at will and modified on demand. The resulting features will bend or tilt in response to external stimuli (especially temperature, electric field and stress) and thereby create a responsive surface structure. Theoretical modelling and simulation of the relevant mechanics will be a major effort to establish “structure-property relationships” for switchable patterned surfaces, to guide the choice of structure parameters and to establish new multifunctional design rules for targeted applications. Emphasis will be placed on the novel aspect of interaction with soft, compliant objects, with a view to creating future opportunities for interaction with soft matter and skin. Talented junior scientists – with both experimental and theoretical background - will be heavily involved as an opportunity to promote their career opportunities in this modern field of materials research. A final objective will be the exploration of the transferability of patterning techniques to larger-scale areas. Overall, such switchable micropatterns will likely open up revolutionary new possibilities in various technologies: robotic grippers with careful, benign “touch” of delicate objects, medical adhesives that become sticky on reaching body temperature, and active devices that can respond and send signals to touching fingers. The successful project will thus lay the scientific foundations for innovative devices and solutions that will improve our competitiveness and the living conditions of an ageing society.

Keywords: materials engineering,mechanical engineering,shaping,biomaterials
Dynamic architecture of the RNA polymerase I transcription initiation machinery (POL1PIC)

Framework: FP7 — Ideas
Programme: European Research Council
Theme: European research council
Destination: Advanced grants
Action type: Support for frontier research (ERC)
Panel: Molecular and Structural Biology and Biochemistry
Countries involved: Germany
Call:  (ERC-2013-ADG, 2013)
Start date: 2014-02-01
End date: 2019-01-31
Duration (months): 60.0
Total project cost (EUR): 2459090.0
EU funding (EUR): 2459090.0
Participants: 1
Project status: CLOSED

RNA polymerase (Pol) I and Pol III synthesize non-translated RNAs including rRNA, 5S RNA, and tRNAs for ribosome assembly and protein synthesis. Pol I and Pol III transcription initiation machineries are carefully regulated in healthy cells, while misregulation of Pol I and Pol III transcription is observed in a variety of cancers. We propose to study the structure and dynamics of the Pol I transcription initiation machinery in a broad and interdisciplinary analysis that combines an integrated structural biology approach with in vitro and in vivo functional analysis, proteomics approaches, integrative modelling and fluorescence microscopy studies. The project builds on our on-going efforts in studying Pol III transcription and first results in the analysis of Pol I transcription, where crystals of the 14-subunit Pol I enzyme diffracting to at least 3.5 Å resolution have been obtained. We will determine the crystal structure of Pol I as second eukaryotic DNA-dependent RNA polymerase structure, and we will also co-crystallize Pol I with nucleic acids and Pol I-specific general transcription factors. A particular focus of the project will be the structural and functional characterization of the Pol I transcription pre-initiation complex (Pol I PIC) that is considerably smaller and compacter as the Pol II PIC. Structural data combined with results from chemical cross-linking and biochemical interaction assays will be used for integrative modeling of the structure and dynamics of Pol I PICs. Fluorescence (cross-) correlation spectroscopy (FCS/FCCS) will monitor Pol I PIC assembly in vivo. Structural information will direct the site-specific fluorescence labeling of Pol I PIC components to monitor conformational changes during Pol I PIC assembly and transcription in vitro. Our results will provide comprehensive, structural, and mechanistic insights into Pol I transcription and the possible role of Pol I in cancer.

Keywords: rna polymerase i,pol i-specifc general transcription factors,transcription pre-initiation complex,integrated structural biology & modeling,conformational dynamics,fluorescence microscopy
Functional wiring of the core neural network of innate fear (COREFEAR)

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,Australia
Call:  (ERC-2013-ADG, 2013)
Start date: 2014-03-01
End date: 2019-02-28
Duration (months): 60.0
Total project cost (EUR): 2493839.22
EU funding (EUR): 2493839.22
Participants: 2
Project status: CLOSED

Fear is an emotion that exerts powerful effects on our behavior and physiology. A large body of research implicates the amygdala in fear of painful stimuli, but virtually nothing is known about the circuits that support fear of predators and social threats, despite their primal importance in human behavior and pathology. Unlike painful stimuli, predator and social threats activate the medial hypothalamus, a cluster of highly conserved brain nuclei that control motivated behavior. Intriguingly, predator and social threats recruit largely non-overlapping nuclei in the medial hypothalamus, and we have recently demonstrated that separate medial hypothalamic circuits are essential for predator and social fear. We aim to build a functional wiring diagram of predator and social fear in the mouse that will explain how these fears are triggered, coordinated, and remembered. Such a functional wiring diagram will reveal the network logic of innate fear and put us in a position to selectively intervene in fear processing. Electrical stimulation of the medial hypothalamus in humans elicits panic responses and pharmacological agents that block these circuits will offer unexplored therapeutic approaches to treat anxiety disorders such as panic, social phobia, and post-traumatic stress disorder. Moreover, the relatively simple architecture of the medial hypothalamic fear network and its robust and direct behavioral readout in the mouse will be a powerful platform to test the role of several fundamental circuit features that are common to a wide range of behavioral networks, but whose function remains unknown, including the role of feedback loops, sparse cellular encoding of behavior, and overlapping processing of distinct behavioral responses. In this way, the project will provide the first circuit-level understanding of predator and social fear and answer a series of fundamental questions about how neural networks control behavior.