Data-Gouv-ML/pcri-informations-sur-les-projets-laureats huggingface dataset:
Transatlantic fluxes of Saharan dust: changing climate through fertilising the ocean? (DUSTTRAFFIC)

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: Netherlands
Call:  (ERC-2012-StG_20111109, 2012)
Start date: 2012-10-01
End date: 2017-09-30
Duration (months): 60.0
Total project cost (EUR): 1972839.14
EU funding (EUR): 1972839.14
Participants: 1
Project status: CLOSED

Massive amounts of dust (~1 Billion Ton) are blown from the Sahara into and over the Atlantic Ocean every year. This dust strongly alters the atmosphere through blocking incoming solar radiation [cooling the atmosphere] and trapping outgoing heat that was reflected at the earth’s surface [warming the atmosphere]. In addition, aerosols carry huge amounts of metals and nutrients that can boost marine life, but also vast amounts of microbes, spores, and pathogens that are harmful for both marine- and terrestrial (including human!) life. The net effect of cooling/warming and ocean fertilisation/poisoning is presently far from understood as it depends on a complex set of parameters related to dust emission, dispersal, and deposition. In order to quantify these parameters, I propose to develop and apply a novel approach to study the transatlantic flux of Saharan dust and its environmental effect on the ocean by deploying a transect of seven ocean moorings with a dust-collecting surface buoy below the Saharan dust plume from NW Africa to the Caribbean. Sampling dust in air as well as under water at a biweekly resolution for initially one complete year will for the first time allow to: 1) quantify the seasonal variability in Saharan dust export into the Atlantic, 2) distinguish between high-altitude summer plumes versus low-level winter trade-wind transport, 3) quantify source-to-sink changes in particle size and the related (metal, nutrient, and biological-) composition of the dust, and 4) determine the in situ bio-availability of the associated nutrients and their potential fertilisation of the photic zone. These unique, seasonally and spatially resolved data will bridge the gap between the bi-weekly sediment-trap record off Cape Blanc (NW Africa, since '85) and the daily dust fluxes recorded on Barbados (Caribbean, since '73). Subsequently, the data can be extrapolated back in time in marine sediments, which are an archive for dust transport and carbon pump in the past.

Keywords: ocean fertilisation
Bacterial Cell Morphogenesis (BACEMO)

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: 2013-02-01
End date: 2019-01-31
Duration (months): 72.0
Total project cost (EUR): 1650050.0
EU funding (EUR): 1650050.0
Participants: 1
Project status: CLOSED

In bacteria, the though external cell wall and the intracellular actin-like (MreB) cytoskeleton are major determinants of cell shape. The biosynthetic pathways and chemical composition of the cell wall, a three dimensional polymer network that is one of the most prominent targets for antibiotics, are well understood. However, despite decades of study, little is known about the complex cell wall ultrastructure and the molecular mechanisms that control cell wall morphogenesis in time and space. In rod-shaped bacteria, MreB homologues assemble into dynamic structures thought to control shape by serving as organizers for the movement and assembly of macromolecular machineries that effect sidewall elongation. However, the mechanistic details used by the MreB cytoskeleton to fulfil this role remain to be elucidated. Furthermore, development of high-resolution microscopy techniques has led to new breakthroughs this year, published by our lab and others, which are shaking the model developed over the last decade and re-questioning the MreB “actin cytoskeleton” designation. The aim of this project is to combine powerful genetic, biochemical, genomic and systems biology approaches available in the model bacterium Bacillus subtilis with modern high-resolution light microscopic techniques to study the dynamics and mechanistic details of the MreB cytoskeleton and of CW assembly. Parameters measured by the different approaches will be combined to quantitatively describe the features of bacterial cell morphogenesis.

Keywords: bacterial cytoskeleton,mreb proteins,bacterial cell wall,bacillus subtilis,peptidoglycan,protein interactions,high-resolution fluorescence microscopy,tirfm,cell morphogenesis,systems biology
Cell migration in gut homeostasis and cancer invasion - role of microenvironment (STARLIN)

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: 2017-12-31
Duration (months): 60.0
Total project cost (EUR): 1499600.0
EU funding (EUR): 1499600.0
Participants: 1
Project status: CLOSED

The entire intestinal epithelium is renewed every week due to cell division in the crypts coupled with cell migration towards the villi and loss of cells by apoptosis at the tip of villi. Uncoupling cell proliferation from apoptosis and possibly from cell migration can lead to pathologies such as cancer. In carcinoma in situ, the basement membrane (BM) represents a physical barrier that prevents spreading of the primary tumor to adjacent tissues. It is believed that cancer cells perforate BM, but stromal cells such as carcinoma-associated fibroblasts (CAFs) also secrete matrix proteinases. Thus, the question is who is invading whom – do cancer cells invade the stroma or is the stroma invading tumor cells? Here we propose an innovative multi-disciplinary approach, at the interface of cancer cell biology and physics, combined with recent advances in optics aimed to unravel the fundamental mechanisms of cell migration in 3D environments during intestinal homeostasis and tumor invasion. Our specific aims are: 1. Determine the mechanism of epithelial cell migration in gut homeostasis. Using intestinal slice cultures and two-photon microscopy we will determine if epithelial cells migrate using cellular protrusions, are pushed by dividing cells, or are transported by underlying fibroblasts and BM. 2. Examine if cancer cells and CAFs cooperate to break the BM. We will use a 3D in vitro model to determine which cell type is degrading BM and if distinct sub-populations of CAFs have different functions. 3. Explore how cancer cells and CAFs cooperate during invasion of the stroma. 3D chemoattraction assays will be used to determine if CAFs can guide cancer cells towards blood vessels. 4. Characterize cooperation of cancer cells and CAFs in vivo. Using intravital imaging we will analyze interactions between cancer cells and CAFs in the primary tumor. Ortotopic mouse models will be used to determine if a specific sub-population of CAFs can trigger metastasis of colon cancer.

Keywords: cell migration,cell invasion,in vivo imaging,filopodia,cancer cells-fibroblast interaction,3d in vitro assays
Targeting downstream effectors of Wnt signaling in colorectal cancer (COLONCAN)

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: 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): 1499044.8
EU funding (EUR): 1499044.8
Participants: 1
Project status: CLOSED

Colorectal cancer (CRC) is one of the most common cancers of the western world. The underlying initiating mutation for the majority of CRC is within the Adenomatous Polyposis Coli (Apc) gene. The APC protein performs an important role in controlling the levels of Wnt signalling by targeting beta-catenin for degradation. Loss of the APC protein leads to the activation of Wnt signaling target genes such as c-Myc which is required for phenotypes causes by Apc loss. However, despite the clear importance of APC loss and deregulated Wnt signalling, additional events are required for the development of CRC such as KRAS and P53 mutations.The impact of these changes on the development of CRC and response to therapy is not well understood. Furthermore, identification and testing of potential novel targets and therapies is hampered by lack of a preclinical model that faithfully recapitulates the course of the human disease. This proposal has two aims: 1. Assess the impact of cooperating mutations with Apc and assess how they alter sensitivities of Apc deficient cells. 2. Develop mouse models of invasive and metastatic colorectal cancer that recapitulate the human disease. We will use ‘state of the art’ methodologies to identify the changes in signaling output conferred by these cooperating mutations. Genetic mouse models of invasive and metastatic colorectal cancers will be generated through the acquisition of additional mutations and genomic instability. These studies will produce predictions on therapeutic combinations that will be tested in mouse models in vitro and in vivo that may identify new treatment regimens for patients with late stage CRC.

Keywords: colorectal cancer,apc,cooperating mutations,wnt signalling,mek and mtor inhibitors,mouse models of cancer,tumour invasion and metastasis
Synthetic Metabolism in Plants: Elucidating Vinblastine Biosynthesis and Implementing Strategies to Overproduce Complex Plant Metabolites (SYNPLANTMET)

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: 2013-02-01
End date: 2018-01-31
Duration (months): 60.0
Total project cost (EUR): 1497920.0
EU funding (EUR): 1497920.0
Participants: 2
Project status: CLOSED

Nature produces a spectacularly diverse array of complex molecules that are exploited for many applications. Elucidating the biosynthetic pathways that are used to construct these complex molecules allows implementation of metabolic engineering or synthetic biology strategies that can dramatically improve production levels of these compounds. Moreover, identifying the biosynthetic genes facilitates study of the unprecedented biochemistry harboured within these specialised metabolic pathways. Unfortunately, research progress in plant specialised metabolism has lagged, in large part due to the complexities of plant systems. This has hampered the application of state-of-the-art synthetic biology approaches that can exploit this rich metabolism. The availability of inexpensive sequence data makes this an outstanding time to revisit difficult questions in plant metabolism. My group has recently obtained RNA-seq data for 24 tissues for Catharanthus roseus, which produces vinblastine, an anti-cancer drug that is arguably one of the most complex natural products found in plants. Moreover, my group has recently pioneered the implementation of gene silencing technology in C. roseus, which provides, for the first time, the means to rapidly assess C. roseus gene function in planta. This ensures that we will have a reasonably high-throughput platform by which we can assess gene candidates identified by hierarchical clustering analysis. In Objective 1, we outline a plan to identify vinblastine biosynthetic gene candidates using our transcriptome data and then screen these candidates for function in planta. We also propose a series of in vitro assays by which to characterise promising gene candidates biochemically. In Objective 2, we propose to reconstitute portions of the vinblastine pathway in Saccharomyces cerevisiae (yeast) and the model plant Nicotiana benthamiana (tobacco) to create high-yielding platforms for production of valuable plant metabolites.

Keywords: biosynthesis,alkaloid,terpene,enzymology,synthetic metabolism
Coevolution of bacteria and conjugative plasmids (COEVOCON)

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: 2013-02-01
End date: 2018-01-31
Duration (months): 60.0
Total project cost (EUR): 1233610.0
EU funding (EUR): 1233610.0
Participants: 2
Project status: CLOSED

Horizontal gene transfer (HGT) is a fundamental process of bacterial evolution, accelerating adaptation to novel environments and providing access to new ecological niches. However, two of the three mechanisms of HGT, transduction and conjugation, both rely on semi-autonomous vectors (lysogenic phages and conjugative plasmids, respectively), creating the potential for coadaptation between microbe and vector. I here focus on conjugative plasmids. These encode their own replication and transfer, and as such are capable of pursuing their own fitness interests, which need not be aligned with those of their bacterial host. My thesis is that bacterial adaptation by conjugation must therefore be viewed as a co-evolutionary, rather than simply an evolutionary process as achieved to date. In this proposal I take an experimental evolution approach to derive an empirically founded understanding of bacteria-plasmid coevolutionary processes. In particular, I focus on the effects (on the pattern and process of bacteria-plasmid coevolution) of ecological variables identified in population models as crucial to the persistence of conjugative plasmids: environmental heterogeneity, spatial structure, and between-species transfer. Drawing on coevolutionary theory, I highlight that the ecological conditions expected to favour plasmid persistence may often drive the breakdown of bacteria-plasmid coadaptation. Additionally, I will determine the consequences of bacteria-plasmid coevolution for the structuring of microbial communities.

Keywords: experimental evolution horizontal gene transfer coevolution conjugative plasmid bacteria
Metastability of proteins during tumor metastasis (METAMETA)

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: Germany
Call:  (ERC-2012-StG_20111109, 2012)
Start date: 2013-03-01
End date: 2018-02-28
Duration (months): 60.0
Total project cost (EUR): 1366800.0
EU funding (EUR): 1366800.0
Participants: 1
Project status: CLOSED

Mutational heterogeneity bestows tumors with the phenotypic plasticity and adaptability required for expansion. On the other hand, mutations destabilize proteins – lower stability (metastability) of the tumor proteome must be the inevitable consequence. We set out to systematically investigate this biochemical aspect of metastasis aiming to uncover and therapeutically exploit specific vulnerabilities resulting from protein destabilization. We will approach this goal by cataloging associations between metastasis-promoting proteins and molecular chaperones. Chaperones are obvious candidates to stabilize the proteome, therefore we will prepare a BAC-based mouse model of metastasis, where the contribution of 63 chaperones, comprising the entire murine HSP70 superfamily, to metastasis development will be individually investigated. The role of metastasis-relevant chaperones at the molecular level will be elucidated using mass spectrometry, complemented by next-generation sequencing of metastatic exome. In parallel, a novel proteomics-based method to evaluate aberrant complex formation in tumor cells will be established. Because of the high heterogeneity of cancer, molecularly tailored and combined therapies are needed. To this end, we will capitalize on insights regarding the role of chaperones in metastasis by identifying proteasomal degradation activators able to support or replace the activity of individual chaperones from the HSP70 superfamily. Finally, we will validate the potential of combined, yet specific manipulation of the folding and degradation machineries to suppress metastasis development.

Keywords: protein aggregation,molecular chaperones,proteome
Deciphering cytosolic antibacterial immunity: from triggering bacteriolysis to Aim2 inflammasome activation (CYTOBACLYSIS)

Framework: FP7 — Ideas
Programme: European Research Council
Theme: European research council
Destination: Starting grants
Action type: Support for frontier research (ERC)
Panel: Immunity and infection
Countries involved: France
Call:  (ERC-2012-StG_20111109, 2012)
Start date: 2012-11-01
End date: 2018-10-31
Duration (months): 72.0
Total project cost (EUR): 1404687.6
EU funding (EUR): 1404687.6
Participants: 1
Project status: CLOSED

Bacteria replicating within host cells either multiply in membrane-bound compartment or escape into the host cytosol. The host cytosol has long been considered as a safe haven for bacteria. However, the host cytosol is armed with an array of innate immune receptors detecting cytosolic invasion. Furthermore, the macrophage cytosol displays a bacteriolytic activity, which is inducible by IFN. Surprisingly, the molecular mechanisms of this innate immune effector response are still largely uncharacterized. A ubiquitously expressed antimicrobial peptide, ubiquicidin has been described in the macrophage cytosol. Its relevance, its connection with macrophage-specific bacteriolytic activity and with IFN, remain to be deciphered. While cytosol-adapted bacteria are largely resistant to the bactericidal activity of the macrophage, lysis of a single bacterium triggers activation of the Aim2 inflammasome. Cytosolic bacteriolysis is thus key to orchestrate inflammasome-mediated innate immune responses. We propose here to characterize the bacteriolytic effector mechanisms, the regulation of this response and of the Aim2 inflammasome by IFN in infected macrophages. We will use two complementary bacterial models: F. tularensis, a cytosol-adapted bacterium and S. typhimurium sifA mutant, a bacterium lysed in the macrophage cytosol. We will develop three synergistic approaches: i) the generation of novel tools to monitor cytosolic bacteriolysis ii) hypothesis-driven investigations on the antimicrobial activity of the macrophage cytosol focusing on ubiquicidin to uncover the mechanisms of processing and targeting of this antimicrobial peptide iii) screening of IFN-inducible genes to identify novel players involved in the cytosolic bacteriolytic activity and in inflammasome regulation. We believe this project should reveal the innate immune effector mechanisms of the macrophage cytosol i.e. how the macrophage kills cytosolic bacteria and orchestrates further immune responses.

Keywords: bacteriolysis,cytosolic immunity,francisella,tularemia,salmonella,macrophage,interferon,inflammasome,aim2
Factor XII and the contact system: cross-talk between thrombosis and inflammation (F12)

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: Sweden
Call:  (ERC-2012-StG_20111109, 2012)
Start date: 2013-08-01
End date: 2019-07-31
Duration (months): 72.0
Total project cost (EUR): 1488780.0
EU funding (EUR): 1488780.0
Participants: 2
Project status: CLOSED

Combinations of proinflammatory and procoagulant reactions are the unifying principle for a variety of disorders affecting the cardiovascular system. Factor XII (FXII, Hageman factor) is a plasma protease that initiates the contact system. This system starts a cascade of procoagulant and proinflammatory reactions via the intrinsic pathway of coagulation, and the bradykinin-producing kallikrein-kinin system, respectively. The biochemistry of the contact system in vitro is well understood, however its in vivo functions are just beginning to emerge. We have previously demonstrated that FXII is essential for thrombus formation while being dispensable for hemostatic processes that terminate blood loss. Challenging the dogma of a coagulation balance, targeting factor XII protected from cerebral ischemia without interfering with hemostasis. In contrast, excess FXII activity is associated with a life threatening inflammatory disorder, Hereditary angioedema. We recently have identified platelet polyphosphate (an inorganic polymer) and mast cell heparin as in vivo FXII activators with implications on the initiation of thrombosis and edema. The current investigations will explore roles of the FXII-driven contact system at the intersection of procoagulant and proinflammatory pathways using genetically altered murine models. We aim to understand activation, regulation and functions of the system for ischemic heart disease, vascular leakage in Hereditary angioedema, allergic airway inflammation as well as procoagulant reactions driven by bacterial infections in skin and lung. A key aspect of this proposal will be analysis of common principles, interactions and cross-talk between coagulation and inflammation, to identify novel therapeutic targets. Elucidating the FXII-driven contact system offers the exciting opportunity to develop strategies for safe interference with both thrombotic and inflammatory diseases.

Keywords: thrombosis and hemostasis blood coagulation anticoagulation vascular permeability