Data-Gouv-ML/pcri-informations-sur-les-projets-laureats huggingface dataset:
Architecture and logic of the eukaryotic cell cycle (SYNTHECYCLE)

Framework: FP7 — Ideas
Programme: European Research Council
Theme: European research council
Destination: Starting grants
Action type: Support for frontier research (ERC)
Panel: Cellular and Developmental Biology
Countries involved: France
Call:  (ERC-2012-StG_20111109, 2012)
Start date: 2013-01-01
End date: 2017-12-31
Duration (months): 60.0
Total project cost (EUR): 1691554.8
EU funding (EUR): 1691554.8
Participants: 1
Project status: CLOSED

Our knowledge of the functioning of eukaryotic cells has emerged from thorough investigation of the molecular mechanisms driving cellular events. However, the complexity of the underlying regulatory networks has made it difficult to understand the core control of essential functions. In the same way that model organisms were chosen for their ease of manipulation or simplicity, model pathways need to be developed to decipher the design principles of regulatory circuits. Using fission yeast, I demonstrated the possibility to replace cell cycle control by a simple synthetic system in vivo and proposed a novel paradigm for the core cell cycle engine. This established the foundation for the proposed projects, which use a synthetic approach to dissect the organisation, complexity and evolution of cellular reproduction. Our work will focus on four axes of research. First, we will investigate the properties of the cyclin dependent kinase (CDK) circuit that ensure reproducibility of cell cycle sequence between cells. Next, we will assess CDK activity dynamics and study their role in progression through cell cycle transitions as well as in the maintenance of population homogeneity. Third, we will investigate the rationale behind the complexity in cell cycle control observed in modern cells, as my previous work has demonstrated that entire branches of the network are dispensable. This will finally lead us to take a unique approach to explore evolutionary principles, assessing how cells operating with simplified CDK circuits adapt and overcome defects in cell cycle progression. These studies relying on mathematical modelling and synthetic rewiring of cell cycle control will shed light on fundamental aspects of this essential process and bring new perspectives to our understanding of its evolution. As cell cycle progression is a foundation of cellular life, our work will have important implications for multicellular organisms and pathological situations.

Keywords: fission yeast,evolution,microfluidics,circuit dynamics
Multistage-Multifunctional Porous Silicon Nanovectors for Directed Theranostics (POROUS SILICON NANOV)

Framework: FP7 — Ideas
Programme: European Research Council
Theme: European research council
Destination: Starting grants
Action type: Support for frontier research (ERC)
Panel: Diagnostic tools, therapies and public health
Countries involved: Finland
Call:  (ERC-2012-StG_20111109, 2012)
Start date: 2013-01-01
End date: 2017-12-31
Duration (months): 60.0
Total project cost (EUR): 1499603.0
EU funding (EUR): 1499603.0
Participants: 1
Project status: CLOSED

The progress of nanotechnology during the last decades has had a strong impact to the current research of biomedical applications, in particular against dreadful diseases such as cancer. It is estimated that more than 12 million cases of cancer are diagnosed every year worldwide. Multidrug resistance, rapid elimination by the immune system, enzymatic degradation, and poor targeting efficiency are still the major obstacles of the nanomedicines used in cancer therapy. The integration of imaging and therapeutic agents into a single carrier (theranostics) allows simultaneously detection, diagnostics, and treatment of the diseases, which may enhance both expectancy and quality of life of the patients. In the proposed project a systematic approach is taken towards developing and testing of novel multistage–multifunctional nanovectors based on the fusion between stage-2 nanoporous silicon nanoparticles and stage-1 polymersomes (fused materials = protocells, cell-like particles) for directed (targeted/personalized) therapy and multimodal imaging. With this approach it is aimed to decouple the quadruple functions of the protocell nanovectors in order to generate relevant preclinical information for rapid translation into the clinic: sufficient multifunctionality to avoid biological barriers, recognition of their targets, accounting for non-invasive in vivo imaging and delivery of therapeutics. The overall distinct and final milestones are: to ligand-anchored, co-loading of drug(s)-dye(s), and dual radiolabelling of the precisely tailored protocell nanovectors for simultaneously targeting the tumour vasculature cells, stimulating the immune system response and multimodal imaging in vivo. It is also aimed to evaluate the suitability and effectiveness of the designed nanodevices by employing in vitro models and in vivo imaging techniques and to achieve a comprehensive and deeper understanding on the cellular interactions between the protocell nanovectors and the cancer cells.

Keywords: nanoporous silicon,drug delivery,targeted therapy,in vitro/vivo interactions,biodistribution,biocompatibility,multifunctionalization,biomaterials,polymersomes,nanodevice,cancer,theranostic
REwiring the nucleus TowaRds plant ImmuNity (RETRAIN)

Framework: FP7 — Ideas
Programme: European Research Council
Theme: European research council
Destination: Starting grants
Action type: Support for frontier research (ERC)
Panel: Applied life sciences and biotechnology
Countries involved: United Kingdom
Call:  (ERC-2012-StG_20111109, 2012)
Start date: 2013-01-01
End date: 2017-12-31
Duration (months): 60.0
Total project cost (EUR): 1393084.0
EU funding (EUR): 1393084.0
Participants: 1
Project status: CLOSED

Plant pathogenic microbes cause significant economic damage to global food crop production systems. Pathogens are specialised microbes that manipulate the host defense circuitry to suppress immunity and promote virulence. Interestingly, many of the processes that determine immunity or susceptible interactions, take place in the host nucleus. With the identification of vast repertoires of (nuclear) secreted pathogen proteins (effectors) and host signaling components that extert their functions in the nucleus, this host compartment is now considered an important interface where outcomes are decided. This proposal aims to unravel the molecular mechanisms that underpin infection outcomes in the nucleus. A powerfull approach that will combine quantitative proteomics with gene expression analyses will be used to (i) detect pathogen effectors in the host nucleus in situ and (ii) identify changes in the nuclear proteome during infection. I will then use Yeast two Hybrid and immunoprecipitation to identify effector host targets before placing these components in a nuclear immune signalling context. New information on effector-induced changes in the host nuclear proteome coupled to immune signalling, will then be used to rationalise implementation of two synthetic approaches towards resistance. I will design synthetic (non)host targets that are immune to effector induced modifications and function towards immunity. In addition, identification of key effectors and targets will be used to design new R-gene like specificities, embodied in synthetic Nucleotide-Binding Leucine Rich Repeat proteins (sNB-LRR). Overall, this work will impact studies on host-microbe interactions and importantly, will provide proof of concept for two new synthetic breeding strategies in plants.

Keywords: nucleus,immunity,phytophthora capsici,plants
Neuroprotection in Multiple Sclerosis: From Molecular Imaging to Screenable Models (NEMESIS)

Framework: FP7 — Ideas
Programme: European Research Council
Theme: European research council
Destination: Starting grants
Action type: Support for frontier research (ERC)
Panel: Neurosciences and neural disorders
Countries involved: Germany
Call:  (ERC-2012-StG_20111109, 2012)
Start date: 2012-12-01
End date: 2017-11-30
Duration (months): 60.0
Total project cost (EUR): 1487200.0
EU funding (EUR): 1487200.0
Participants: 1
Project status: CLOSED

Multiple Sclerosis (MS) is an inflammatory CNS disease that affects more than 2.5 million individuals worldwide. Damage to axonal connections determines the functional deficits of MS patients. How axons are damaged in MS is only incompletely understood. Using in vivo multiphoton imaging we have discovered a novel axon loss process that underlies axonal damage in experimental and human neuroinflammatory lesions. We have termed this process Focal Axonal Degeneration (FAD). FAD is characterized by a sequence of morphologically defined stages that ultimately result in axonal fragmentation. Notably, intermediate stages of FAD can persist for several days in vivo and still recover spontaneously. In this proposal I want to explore the biological and medical significance of FAD by addressing its: 1. Functional Characteristics I want to analyze two key aspects of axonal function, the ability to transport cargoes and the ability to propagate action potentials, in experimental neuroinflammatory lesions to better understand the in vivo relation between structural and functional deficits during axon damage. 2. Molecular Mechanisms I want to deploy new molecular imaging approaches to directly monitor the redox potential, calcium and ATP levels of axons and their mitochondria in experimental neuroinflammatory lesions. This will allow us to reveal the key effector mechanisms of FAD and the sequence in which they are activated in vivo. 3.Therapeutic Opportunities I plan to make use of advances in automated imaging and microfluidics to develop new in vivo assays for high-throughput screening of therapeutic interventions. This will help us to identify novel strategies for limiting progression and improving recovery of axon damage. The proposed project should provide new insights into the functional and molecular underpinnings of axon damage in vivo, establish new tools and models to study it and guide the development of therapeutic strategies that can prevent or reverse it.

Keywords: multiple sclerosis,axon degeneration,experimental autoimmune encephalomyelitis,in vivo microscopy
The Past, Present and Future of Neotropical Biodiversity (NEOTROPICS)

Framework: FP7 — Ideas
Programme: European Research Council
Theme: European research council
Destination: Starting grants
Action type: Support for frontier research (ERC)
Panel: Evolutionary, population and environmental biology
Countries involved: Sweden
Call:  (ERC-2012-StG_20111109, 2012)
Start date: 2013-01-01
End date: 2017-12-31
Duration (months): 60.0
Total project cost (EUR): 1499855.0
EU funding (EUR): 1499855.0
Participants: 1
Project status: CLOSED

The American tropics – the Neotropics – comprise more species than any other region on Earth, including thousands of species used as crops, medicines and crafts. Understanding the evolution of this biodiversity and predicting the effects of climate and habitat changes on species losses constitute a major scientific challenge. This project will: 1) Estimate the rates of historical migration, speciation and extinction among and within all major Neotropical biomes and regions, thereby identifying key areas for ‘evolutionary’ conservation (i.e., those necessary for biotic interchange and vegetation shifts, and those that may function as ‘species pumps’ to the rest of the continent). 2) Test competing hypotheses of speciation (soil specialisation, temperature increases, polyploidy, habitat shifts, range expansion) for the two main centres of Neotropical biodiversity: the tropical Andes and Amazonia. 3) Produce new estimates on species losses due to on-going climate and habitat changes based on our new findings in 1) and 2) above. To achieve these goals we will develop novel bioinformatics pipelines that will greatly improve our use of biological databases. We will analyse DNA sequences, georeferences and biotic traits for tens of thousands of plant and animal species. Our tools will enable continuously up-to-date inferences and allow the easy integration of new data by students and researchers interested in the evolution of particular species groups or biomes. This is a multi-disciplinary project that requires a wide range of skills in molecular phylogenetics, bioinformatics, field botany, ecology and palaeontology. It will greatly profit from the well-established scientific network I have built up in my career, the vast collections of Neotropical species deposited at European natural history collections, and the excellent laboratory and cultivation facilities available in Gothenburg, Sweden.

Keywords: tropical biodiversity,evolution,climate change,conservation,biological databases,phylogenetic inference,species distribution modelling.
Discovering Gene-Drug Interactions in Breast Cancer With a Systematic and Genetically Tractable Model (GENES, DRUGS AND BREAST CANCER)

Framework: FP7 — Ideas
Programme: European Research Council
Theme: European research council
Destination: Starting grants
Action type: Support for frontier research (ERC)
Panel: Genetics,Genomics,Bioinformatics and Systems Biology
Countries involved: Austria
Call:  (ERC-2012-StG_20111109, 2012)
Start date: 2013-05-01
End date: 2018-04-30
Duration (months): 60.0
Total project cost (EUR): 1497982.0
EU funding (EUR): 1497982.0
Participants: 2
Project status: CLOSED

Biomedical research has been very successful in finding the individual genes that are deregulated in cancer and it is estimated that ~2% of all genes can be classified as “cancer genes”. However, it has proven challenging to translate this genomics knowledge into effective treatments. One complication is that cancer cells typically carry many molecular aberrations and every tumor displays a unique pattern. This heterogeneity complicates the application of drugs and biologicals as it often interferes with patient response. Thus, unraveling the complex interplay between cancer genes and drugs is of great importance for effective patient-stratified cancer therapy. Besides playing a role in drug resistance, the molecular changes also result in cancer cells becoming uniquely dependent on certain gene products or pathways. These cancer “vulnerabilities” offer opportunities targeted therapies, including those based on oncogene addiction and synthetic lethality. Therefore, these concepts have attracted much interest as they can help bridge the gap between cancer genomics and effective treatments. I propose to identify cancer vulnerabilities and drug resistance mechanisms in breast cancer by developing a genetically tractable model system. Designed to capture relevant constellations of genetic aberrations found in patients, it extends our recently developed, systematic screening platform. Combined with bioinformatics integration of cell line data, this will result in a unique and powerful approach. I aim to identify functional interactions between breast cancer genes and experimental or approved drugs. Detailed characterization of gene-drug interactions will reveal their translational potential for targeting specific cancer vulnerabilities in patients, or as biomarkers. Together, this project aims to improve therapies in breast cancer by identifying patient cohorts that are most likely to benefit from a given drug and revealing novel cancer Achilles’ heels.

Keywords: genetic interactions,drugs,synthetic lethality,breast cancer,drug resistance,patient-stratified medicine
Influence of nutrient starvation on corals' susceptibility to bleaching (INCORALS)

Framework: FP7 — Ideas
Programme: European Research Council
Theme: European research council
Destination: Starting grants
Action type: Support for frontier research (ERC)
Panel: Evolutionary, population and environmental biology
Countries involved: United Kingdom
Call:  (ERC-2012-StG_20111109, 2012)
Start date: 2012-11-01
End date: 2017-10-31
Duration (months): 60.0
Total project cost (EUR): 1285671.0
EU funding (EUR): 1285671.0
Participants: 1
Project status: CLOSED

INCORALS will establish a novel conceptual model that introduces a transition of symbiotic algae from a nutrient limited to a nutrient starved state as a process that renders reef building corals more susceptible to heat stress. Elevated temperatures have been identified as the key driver for coral bleaching, which is the often fatal loss of corals’ symbiotic algae. Thus, studies have estimated that reefs will be lost within the next one hundred years as a result of global warming. High temperatures undoubtedly play a major role in triggering coral bleaching. However, observations made for instance during the 1998 bleaching event, suggest also a connection between the susceptibility of corals to heat stress and anthropogenically elevated nutrient levels. Here, I present evidence that unbalanced ratios of dissolved inorganic nitrogen to phosphorus in the water column perturb the lipid composition of photosynthetic membranes of zooxanthellae and result in an increased susceptibility to thermal bleaching. I have developed a novel conceptual model of coral bleaching that introduces nutrient starvation as a cause for increased heat stress susceptibility. The model clarifies the previously unexplained correlation between the reduction of the thermal bleaching threshold of corals and their exposure to coastal run-off with elevated concentrations of dissolved inorganic nitrogen. INCORALS will conduct an in-depth study of nutrient starvation of reef corals, comparing the impact of nitrogen, phosphorus and iron. INCORALS will combine physiological experiments under tightly controlled laboratory conditions and field-based studies, using a suite of optical methods and cutting-edge molecular techniques to study this yet unexplored cause of coral bleaching and define its relevance for coral ecosystems. The improved understanding of coral bleaching gained during this project is urgently required to develop knowledge-based management strategies to support coral reef resilience.

Keywords: lipidomics
Proliferation and Migration under External Constraints (PROMICO)

Framework: FP7 — Ideas
Programme: European Research Council
Theme: European research council
Destination: Starting grants
Action type: Support for frontier research (ERC)
Panel: Physiology, Pathophysiology and Endocrinology
Countries involved: France
Call:  (ERC-2012-StG_20111109, 2012)
Start date: 2013-01-01
End date: 2018-06-30
Duration (months): 66.0
Total project cost (EUR): 1489400.0
EU funding (EUR): 1489400.0
Participants: 1
Project status: CLOSED

Cell proliferation lies at the heart of the threat posed by tumours. It involves cellular growth, division and migration. The tissue surrounding a tumor physically limits its proliferation, which implies that cells that are able to produce effective tumour growth, as well as cells that migrate out of the original tumour, have been able to circumvent this physical limitation. Other factors in tissues, however, can contribute to stop cell proliferation, making it difficult to precisely evaluate the contribution of physical confinement. In this project I propose to specifically address the effect of physical confinement on normal and cancer cells that are dividing and migrating, using new pathophysiologically relevant in vitro approaches. More specifically I propose two main objectives, related to the pathogenic potential of tumour cells: 1) Discover specific mechanisms that allow dividing cells to push surrounding tissue (a process known as mitotic cell rounding) and demonstrate that alterations in this process can lead to spindle assembly defects and eventually to mitotic cell death. This will open a new set of targets to specifically kill dividing tumour cells. 2) Discover specific mechanisms that allow migrating cells to squeeze their nucleus through narrow gaps. The nucleus has been shown to be the main physical barrier to cell migration in tissues, and two types of cells are able to migrate through narrow gaps: immune cells and metastatic cells. By comparing these two types of cells, we hope to uncover mechanisms specific to metastatic cells, thus providing targets for anti-metastatic treatments that would not harm immune cells function. Understanding how cancer cells can achieve efficient proliferation and migration under external constraints will aid the design of new anti-cancer strategies. These strategies would be based on targeting these specific processes identified to be essential for cancer cells to circumvent physical constraints they encounter in vivo.

Keywords: cell mechanics,micro-fabrication,cell morphogenesis,mitotic cell shape,mitotic spindle,cell volume,cell migration,nuclear deformation,transmigration,acto-myosin cortex,membrane transporters
Retinal Gene Alteration in XLRP (REGAIN)

Framework: FP7 — Ideas
Programme: European Research Council
Theme: European research council
Destination: Starting grants
Action type: Support for frontier research (ERC)
Panel: Diagnostic tools, therapies and public health
Countries involved: Germany
Call:  (ERC-2012-StG_20111109, 2012)
Start date: 2013-01-01
End date: 2017-12-31
Duration (months): 60.0
Total project cost (EUR): 1471840.0
EU funding (EUR): 1471840.0
Participants: 1
Project status: CLOSED

In this project the applicant proposes to develop a treatment strategy for a devastating blinding disorder affecting photoreceptor function within the first decade of life, X-linked Retinitis pigmentosa (XLRP). No treatment option exists to date. The proposed treatment strategy is based on the idea of inducing homology directed repair (HDR) of the mutation by promoting the exchange between the endogenous mutated chromosomal sequence and an exogenous repair DNA template at a double strand break (DSB) site in vivo. The treatment will be realized by co-delivery of endonucleases and the template DNA via adeno-associated virus (AAV) based gene transfer. However, This strategy has never been applied in the retina in vivo and therefore, several parameters are unknown, i.e. the average frequency of HDR in photoreceptors, whether DNA repair will take place through HDR or not, and the average length of the DNA conversion tract during HDR. The project includes the following parts: 1. Establishing the HDR frequency in photoreceptors in vivo: it is planned to optimize the frequency by co-delivery of trophic factors for the stimulation of the cellular repair machinery. 2. Inducing a bias of repair events towards HDR: it is planned to use nickases that only cut one DNA strand or will edit the expression profile of sensor proteins in the repair pathway in vitro and in vivo. 3. Optimization of the DNA conversion tract length: the expression profiles of helicases and other repair proteins are edited in vitro and in vivo. 4. Treatment of the PRGR2793delA mouse model: The optimized treatment settings are identified in order to test them for functional and morphological rescue effects. Results from this study will significantly advance the state of the art in targeted gene correction strategies in vivo and patients with XLRP and other hereditary disorders will potentially benefit from it through extrapolating the results for a broader application.

Keywords: homology directed repair,endonucleases,aav,mouse model