Data-Gouv-ML/pcri-informations-sur-les-projets-laureats huggingface dataset:
Towards evidence-based genomic medicine: filling the evidence gaps through modelling studies (GENOMICMEDICINE)

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: Netherlands
Call:  (ERC-2012-StG_20111109, 2012)
Start date: 2014-01-01
End date: 2018-12-31
Duration (months): 60.0
Total project cost (EUR): 1368912.8
EU funding (EUR): 1368912.8
Participants: 2
Project status: CLOSED

At increasingly high rate, genome-wide association and whole genome sequencing studies unravel genetic variants implicated in common diseases such as coronary heart disease, cancer, dementia and type 2 diabetes. One of the major promises is that these advances will lead to more personalized medicine, in which preventive and therapeutic interventions are targeted to individuals based on their genetic profiles. There is increasing interest in the early adoption of novel applications and many commercial applications are already marketed without supporting empirical evidence. Already now, regulatory agencies like the US Food and Drug Administration face substantial gaps in empirical evidence, which hamper proper recommendations. The increasing interest in genomic medicine, the evidence gaps and the scarcity of research budgets are strong incentives to search for novel strategies that make the process of translation research more efficient and effective. This project aims to investigate modelling approaches that can be used to predict the expected outcomes of empirical studies on the basis of published epidemiological and intervention studies. This approach can be used to 1) identify genomic applications that are promising and warrant further empirical research, and 2) fill in evidence gaps by identifying applications that are not expected to improve health or health care. When they are valid, precise and simple, modelling studies can optimize the process of translational research so that time and money are allocated to the most promising applications. In this project, I will 1) characterize empirical studies in translational research in terms of the main outcome measures used and their key determinants; 2) develop simulation models that predict outcome measures; 3) investigate how accuracy and precision of the estimates vary with varying model complexity; and 4). investigate the generalizability of the modelling approaches.

Keywords: genetic risk prediction,translational research,technology assessment,modeling
Evolution of Developmental Gene Pathways (EVODEVOPATHS)

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: Israel
Call:  (ERC-2012-StG_20111109, 2012)
Start date: 2012-10-01
End date: 2017-09-30
Duration (months): 60.0
Total project cost (EUR): 1500000.0
EU funding (EUR): 1500000.0
Participants: 1
Project status: CLOSED

The staggering diversity of the living world is a testament to the amount of variation available to the agency of natural selection. While it has been assumed that variation is entirely uniform and unbiased, recent work has challenged this notion. Evolutionary developmental biology seeks to understand the biases on variation imposed by developmental processes and their distinction from selective constraints. Metazoan development is best described by developmental gene pathways which are composed of transcription factors, signaling molecules, and terminal differentiation genes. A systematic comparison of such pathways across species would reveal the patterns of conservation and divergence; however this has not yet been achieved. In the EvoDevoPaths project we will develop a new approach to unravel pathways using both single-cell and tissue-specific transcriptomics. Our aim is to elucidate the evolution of developmental gene pathways using intricate embryology in the nematode phylum, a single-cell transcriptomic method we have developed, and sophisticated computational approaches for pathway comparisons. We will ask how variation is distributed across the specification and differentiation modules of a pathway using the nematode endoderm pathway as a model system. We further propose that the evolutionary change in the tissue specification pathways of early cell lineages is constrained by the properties of cell specification pathways. To test this hypothesis we will, for the first time, determine early developmental cell lineages from single cell transcriptomic data. Finally, we will attempt to unify the molecular signatures of conserved stages in disparate phyla under a framework in which they can be systematically compared. This research collectively represents the first time that developmental gene pathways are examined in an unbiased manner contributing to a theory of molecular variation that explains the evolutionary processes that underlie phenotypic novelty.

Keywords: nematode,evo-devo,dndoderm,developmental gene pathways,single cell transcriptomics
Actin as the Master Organizer of Nuclear Structure and Function (NUCLEARACTIN)

Framework: FP7 — Ideas
Programme: European Research Council
Theme: European research council
Destination: Starting grants
Action type: Support for frontier research (ERC)
Panel: Molecular and Structural Biology and Biochemistry
Countries involved: Finland
Call:  (ERC-2012-StG_20111109, 2012)
Start date: 2012-11-01
End date: 2018-08-31
Duration (months): 70.0
Total project cost (EUR): 1491484.0
EU funding (EUR): 1491484.0
Participants: 1
Project status: CLOSED

Unlike previously thought the nucleus is a highly compartmentalized organelle. Both the genome and processes associated with it show non-random distribution within the nucleus. This compartmentalization has a fundamental impact on nuclear processes. However, the mechanisms driving this organization are poorly understood. I hypothesize that actin plays a key role in this process. Nevertheless, the true potential of nuclear actin has not been fully appreciated, due to two fundamental open questions in this field, namely 1) what is the biological significance of nuclear actin and 2) what is the molecular mechanism by which actin operates in the nucleus? I intend to address these key questions by manipulating actin specifically in the nucleus, and by identifying nuclear actin binding partners, respectively. My lab has recently identified the nuclear import mechanism for actin, which offers us a unique tool to manipulate nuclear actin. We will therefore create cell lines with decreased/increased nuclear actin, and analyze the consequences by using cell biological and gene expression tools, combined with deep sequencing. This will disclose the genes that depend on actin for their expression, and reveal the biological significance of nuclear actin in organizing the general nuclear landscape. To unravel the mechanisms by which actin functions in the nucleus, we will implement a novel multi-readout, fluorescence microscopy screen to identify nuclear actin binding proteins, which will be analyzed by different biochemical methods. This approach will reveal how actin is connected to nuclear machineries, and what biochemical features of actin are required to power the essential nuclear processes. These techniques will significantly broaden our understanding on the nuclear functions of actin, and thus likely reveal molecular mechanisms that regulate nuclear organization, which are highly relevant to basic biological processes, such as cell differentiation and epigenetics.

Keywords: actin,transcription
Consequences of helminth-bacterial interactions (COHABIT)

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: Switzerland
Call:  (ERC-2012-StG_20111109, 2012)
Start date: 2013-04-01
End date: 2018-03-31
Duration (months): 60.0
Total project cost (EUR): 1480612.0
EU funding (EUR): 1480612.0
Participants: 1
Project status: CLOSED

Throughout evolution both intestinal helminths and commensal bacteria have inhabited our intestines. This "ménage à trois" situation is likely to have exerted a strong selective pressure on the development of our metabolic and immune systems. Such pressures remain in developing countries, whilst the eradication of helminths in industrialized countries has shifted this evolutionary balance—possibly underlying the increased development of chronic inflammatory diseases. We hypothesize that helminth-bacterial interactions are a key determinant of healthy homeostasis. Preliminary findings from our laboratory indicate that helminth infection of mice alters the abundance and diversity of intestinal bacteria and impacts on the availability of immuno-modulatory metabolites; this altered environment correlates with a direct health advantage, protecting against inflammatory diseases such as asthma and rheumatoid arthritis. We intend to validate and extend these data in humans by performing bacterial phlyogenetic and metabolic analysis of stool samples collected from a large cohort of children living in a helminth endemic region of Ecuador. We further propose to test our hypothesis that helminth-bacterial interactions contribute to disease modulation using experimental models of infection and disease. We plan to develop and utilize mouse models to elucidate the mechanisms through which bacterial dysbiosis and helminth infection influence the development of chronic inflammatory diseases. These models will be utilized for germ-free and recolonization experiments, investigating the relative contribution of bacteria versus helminthes to host immunity, co-metabolism and disease modulation. Taking a trans-disciplinary approach, this research will break new ground in our understanding of the crosstalk and pressures between intestinal helminth infection and commensal bacterial communities, and the implications this has for human health.
Towards a mechanistic understanding of mRNA localization (RNPLOCALIZATION)

Framework: FP7 — Ideas
Programme: European Research Council
Theme: European research council
Destination: Starting grants
Action type: Support for frontier research (ERC)
Panel: Molecular and Structural Biology and Biochemistry
Countries involved: Germany
Call:  (ERC-2012-StG_20111109, 2012)
Start date: 2013-01-01
End date: 2018-12-31
Duration (months): 72.0
Total project cost (EUR): 1442400.0
EU funding (EUR): 1442400.0
Participants: 2
Project status: CLOSED

The localization of mRNAs has been increasingly recognized as a prominent mode of regulation of gene expression in eukaryotes. Localized RNAs can have crucial roles during animal development, in the maintenance of cell polarity and in nervous system function. Studies of RNA localization in model organisms have revealed many components of the process, some of which are conserved across eukaryotes. The correct cytoplasmic localization of mRNAs and their transport and silencing in messenger ribonucleoprotein particles (mRNPs), is dependent on the earliest steps of mRNA processing in the nucleus. The core nuclear mRNP particles associate with further components in the cytoplasm, forming large and dynamic multimolecular assemblies, underlying the various steps or mRNA maturation, transport, silencing and eventual localized translation. Even though many components of these large mRNP particles are known, their detailed molecular organization and regulation is poorly understood. Our aim is to gather structural information of mRNP complexes involved in RNA localization in the fruit fly Drosophila, currently the best-studied model system. We will use a multidisciplinary approach, combining biochemistry, protein crystallography and fly genetics, to tackle the complex structure-function relationships regulating mRNA localization. Our work will elucidate the structural details and molecular mechanisms of how mRNP complexes regulate mRNA localization during development. Given that mRNA localization is a conserved process, our results are expected to elucidate the mechanistic and structural details of a conserved regulatory pathway with fundamental and often medically relevant roles in the cell.

Keywords: structural biology,x-ray crystallography,rna localization,drosophila development
The Role of Ectopic Adipocyte Progenitors in Age-related Stem Cell Dysfunction, Systemic Inflammation, and Metabolic Disease (AGEINGSTEMCELLFATE)

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): 1496444.0
EU funding (EUR): 1496444.0
Participants: 1
Project status: CLOSED

Ageing is accompanied by ectopic white adipose tissue depositions in skeletal muscle and other anatomical locations, such as brown adipose tissue and the bone marrow. Ectopic fat accrual contributes to organ dysfunction, systemic insulin resistance, and other perturbations that have been implicated in metabolic diseases. This research proposal aims to identify the regulatory cues that control the development of ectopic progenitor cells that give rise to this type of fat. It is hypothesized that an age-related dysfunction of the stem cell niche leads to an imbalance between (1) tissue-specific stem cells and (2) fibroblast-like, primarily adipogenic progenitors that reside within many tissues. Novel methodologies that assess stem/progenitor cell characteristics on the single cell level will be combined with animal models of lineage tracing to determine the developmental origin of these adipogenic progenitors and processes that regulate their function. Notch signalling is a key signalling pathway that relies on direct physical interaction to control stem cell fate. It is proposed that impaired Notch activity contributes to the phenotypical shift of precursor cell distribution in aged tissues. Lastly, the role of the stem cell niche in ectopic adipocyte progenitor formation will be analyzed. External signals originating from the surrounding niche cells regulate the developmental fate of stem cells. Secreted factors and their role in the formation of ectopic adipocyte precursors during senescence will be identified using a combination of biochemical and systems biology approaches. Accomplishment of these studies will help to understand the basic processes of stem cell ageing and identify mechanisms of age-related functional decline in tissue regeneration. By targeting the population of tissue-resident adipogenic progenitor cells, therapeutic strategies could be developed to counteract metabolic complications associated with the ageing process.

Keywords: circulating factors,stem cell niche biology,ectopic adipogenesis
Glomerulonephritis and Focal Segmental Glomerulosclerosis as a Model to Investigate the Link between Inflammation and Kidney Disease: From Basic Mechanisms to Clinical Application (TARGET GLOMDIS)

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: 2013-03-01
End date: 2018-02-28
Duration (months): 60.0
Total project cost (EUR): 1364466.0
EU funding (EUR): 1364466.0
Participants: 1
Project status: CLOSED

Rapidly progressive glomerulonephritis (RPGN) and focal and segmental glomerulosclerosis (FSGS) are severe kidney diseases responsible for irreversible renal failure, which is a major risk factor for mortality. Despite the aggressiveness of immunosuppressive protocols applied, treatments against RPGN have limited effectiveness. Similarly, there is no specific treatment for FSGS. We built this research project on novel identification of molecular pathways and markers of pathogenic glomerular epithelial cells (GEC). Although major roles of endothelial activation with immune-mediated insult and imbalance between coagulation and fibrinolysis have been demonstrated, our findings reinforce this paradigm that “activation” of resident glomerular cells play a key role in disease and extend the concept by examining interactions between surrounding cellular systems. We hypothesize that abnormal activation of G-protein coupled receptors (GPCRs) and EGFR may synergize to switch the phenotype of GECs from healthy to pathological. We propose that coagulation and dysfunction of the capillary barrier, may provide GPCR ligands to receptors present in target cells such as GECs. GPCRs, themselves implicated in GN, are known to transactivate the EGFR. The EGFR has the potential to amplify actions of GPCRs in GECs, leading to cytoskeletal rearrangement, and cell death. We hypothesise that interactions between “switched GECs” and T cells are essential for the perpetuation of the immuno-inflammatory response in such glomerular diseases, after the potentially groundbreaking discovery that lymphocytes display functional EGFR, sensitive to ligands produced by pathological GECs. Finally, we will harness this knowledge for a better identification of patients at risk of glomerular demolition. Our project should identify complementary therapeutic pathways that could then be targeted on top of current immunosuppressive regiments. We also propose that this approach would be beneficial to FSGS.

Keywords: glomerulonephritis,podocyte,egfr,rare disease,chronic kidney disease
Specificity Drift in The Kinome During Cancer Development and Evolution (KINOMEDRIFT)

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: Denmark,Denmark
Call:  (ERC-2012-StG_20111109, 2012)
Start date: 2012-11-01
End date: 2016-10-31
Duration (months): 48.0
Total project cost (EUR): 1700000.0
EU funding (EUR): 1700000.0
Participants: 2
Project status: CLOSED

Cellular signaling networks have evolved to enable swift and accurate responses, even in the face of genetic or environmental perturbation. While we can readily assess dynamics in phosphorylation sites, our ability to model and predict the associated networks of kinases are hampered by the fact that we lack information on catalytic specificity for around 60% of the 538 human protein kinases (kinome). This translates into an even bigger gap in kinase-substrate relationships, where a phosphorylating kinase is only known for 20% of all known phosphorylation sites. The importance of closing these gaps is underlined by the fact that kinases are the target of about 75% of current world-wide drug development programs, and it is increasingly evident that they must be targeted in combinations, as elucidated by network models. While genomic studies are revealing large numbers of mutations in kinases in most cancers, algorithms that can assess which of these are important for tumor growth and disease progression are missing. Thus, there is a critical need for algorithms that can predict how such lesions affect the catalytic specificity of kinases. These challenges must be resolved before we can predict how combinations of genetic alterations affect networks and thereby drive complex phenotypes and diseases. The main objective of this grant is to explore the specificity space of kinases through a combination of experimental and computational approaches. We shall investigate how specificity in cellular signaling systems may be altered during both natural evolution and cancer development. We will develop a new generation of network biology algorithms to enable interpretation of mutations in the kinase domain. In combination with semi-automated specificity and mass-spectrometry interaction screening of hundreds of kinases, we shall deploy these algorithms to specifically identify drift in natural selection of kinase specificity as well as in fast evolving cancer genomes.

Keywords: kinome biology,kinase specificity,evolution,cancer development,network biology,kinase inhibitors
Functional protein dynamics studied by solution- and solid-state NMR spectroscopy (PROTDYN2FUNCTION)

Framework: FP7 — Ideas
Programme: European Research Council
Theme: European research council
Destination: Starting grants
Action type: Support for frontier research (ERC)
Panel: Molecular and Structural Biology and Biochemistry
Countries involved: France
Call:  (ERC-2012-StG_20111109, 2012)
Start date: 2013-04-01
End date: 2019-01-31
Duration (months): 70.0
Total project cost (EUR): 1490557.0
EU funding (EUR): 1490557.0
Participants: 1
Project status: CLOSED

Proteins are highly flexible objects that perform their functions by sampling a wide range of conformations. The characterization of such motions is, therefore, crucial to establish the link between protein structure and function. In this project we will use advanced nuclear magnetic resonance in solution state and solid state to characterize functionally important motions in two challenging classes of proteins. The first target of these studies will be a large molecular chaperone of close to 1MDa in size. Conformational changes and dynamics are a prerequisite for the function of this assembly, as it binds, encloses and folds unfolded substrate proteins. Atomic-resolution structures of such large objects frozen in their crystal lattice do not provide access to dynamic information nor insight into the folding process itself. Here, we will exploit the complementary advantages of solid- and solution-state NMR spectroscopy to probe the dynamics, allostery and binding in a ≈1MDa object. Furthermore, we will study how the chaperone cage influences folding, by observing in real time and at atomic resolution how substrate proteins achieve their native fold inside and outside this large molecular edifice. We will furthermore study the mechanism of substrate translocation across membranes by characterizing structure, interactions and dynamics in a solute carrier protein. The dynamics of integral membrane proteins is currently poorly understood. This relates to the need to address membrane protein dynamics in an environment that closely resembles the native membrane. NMR techniques on proteoliposomes as well as nanodiscs are uniquely suited to get insight into native dynamics. We will use such techniques to relate the process of substrate translocation to inherent protein dynamics over a wide range of time scales. The development of novel NMR methods will be an integral part of these studies, and will allow us to probe protein motion at unprecedented detail.

Keywords: protein dynamics,protein folding,membrane proteins,solid-state nmr methods