Data-Gouv-ML/pcri-informations-sur-les-projets-laureats huggingface dataset:
Novel Approaches to Determine Molecular Mechanisms of Pathogenesis in Tuberculosis (TB-PATH)

Framework: FP7 — Ideas
Programme: European Research Council
Theme: European research council
Destination: Advanced grants
Action type: Support for frontier research (ERC)
Panel: Immunity and infection
Countries involved: United Kingdom
Call:  (ERC-2011-ADG_20110310, 2011)
Start date: 2012-04-01
End date: 2017-03-31
Duration (months): 60.0
Total project cost (EUR): 1522491.41
EU funding (EUR): 1522491.41
Participants: 2
Project status: CLOSED

I initiated and developed an unbiased comprehensive study using whole genome array analysis of the transcriptome in blood of tuberculosis (TB) patients and provided global knowledge of the immune response and potential factors leading to TB pathogenesis. Using larger cohorts of TB patients and controls than previous studies, together with complementary analytical approaches of modular, pathway and gene level analysis, we identified a striking interferon (IFN)-inducible neutrophil-driven signature of active TB. This IFN-inducible gene signature correlated with extent of radiographic disease and was represented by Type I IFN as well as IFN-gamma-inducible genes. We propose to apply the knowledge obtained from our study of human TB to study in depth the potential role of Type I IFNs and Type I IFN-inducible genes in TB pathogenesis in susceptible genetic strains of mice infected with virulent Mycobacterium tuberculosis (MTb) strains. We propose to develop a modular tool to study complex transcriptional data in blood from mouse models of disease, as has been done for human disease, to allow accurate comparison of mouse models with human TB, and allow rapid analysis of the immune response at the transcriptional level to reflect pathogenesis, but also in the study of MTb-infected mice where potential pathways of pathogenesis have been perturbed. Based on our findings in human TB we propose to test the hypothesis that Type I IFN and genes induced by this pathway during TB, including Tripartite motif-containing proteins (TRIMs), are important determinants of pathogenesis. This will be achieved by their elimination or perturbation in susceptible TB models and in MTb-infected macrophages, dendritic cells, and neutrophils to define molecular mechanisms contributing to their role in TB pathogenesis.

Keywords: immune response in infection and disease immunity and infection host response in tuberculosis
Tissue Damage Control Regulates The Pathogenesis of Immune Mediated Inflammatory Diseases (DAMAGECONTROL)

Framework: FP7 — Ideas
Programme: European Research Council
Theme: European research council
Destination: Advanced grants
Action type: Support for frontier research (ERC)
Panel: Immunity and infection
Countries involved: Portugal
Call:  (ERC-2011-ADG_20110310, 2011)
Start date: 2012-04-01
End date: 2017-03-31
Duration (months): 60.0
Total project cost (EUR): 2306196.8
EU funding (EUR): 2306196.8
Participants: 1
Project status: CLOSED

We propose to study evolutionarily conserved stress-responsive protective mechanisms that limit the extent of tissue damage caused by pathogens or by the innate as well as adaptive immune response elicited by those pathogens, which, without a countervailing response would lead to irreversible tissue damage and disease. We refer to these protective mechanisms as “tissue damage control”, and will argue they are an essential component of immunity that allows the effector mechanisms involved in pathogen clearance to operate without causing disease. This proposal aims at identifying and characterizing the mechanism of action of stress-induced genetic programs conferring tissue damage control and to relate those to the pathogenesis of different immune mediated inflammatory diseases. We hypothesize that these genetic programs share as a common denominator their regulation by a restricted number of evolutionary conserved transcription factors that act as “master regulators” of different protective responses to specific forms of stress. We will use “loss” and “gain” of function approaches targeting these master regulators in mice to characterize their function and identify stress-responsive genes conferring tissue metabolic adaptation, cytoprotection and/or tissue regeneration, all of which are components of tissue damage control. Expression of these master regulators likely impacts the pathogenesis of immune mediated inflammatory conditions, as tested under this proposal for infectious as well as autoimmune-like diseases. This proposal should unveil an essential component of immunity that uncouples pathogen clearance from tissue damage and disease, namely tissue damage control, providing new therapeutic targets to suppress the pathogenesis of a broad range of immune mediated inflammatory diseases.

Keywords: infection,autoimmunity,tissue damage,stress response,transcription,disease
Impact of stress-induced transposon activities on human disease (TRANSPOSOSTRESS)

Framework: FP7 — Ideas
Programme: European Research Council
Theme: European research council
Destination: Advanced grants
Action type: Support for frontier research (ERC)
Panel: ERC Advanced Grant Interdisciplinary Panel
Countries involved: Germany
Call:  (ERC-2011-ADG_20110310, 2011)
Start date: 2013-01-01
End date: 2018-12-31
Duration (months): 72.0
Total project cost (EUR): 1940725.0
EU funding (EUR): 1940725.0
Participants: 1
Project status: CLOSED

The evolutionary success of transposable elements (TEs) is underscored by the finding that about 45% of the human genome is TE-derived. However, recent high throughput approach studies indicate that the impact of TE-associated activities was seriously underestimated. The first objective is to investigate the impact of TE-derived activities on the human genome in general and on disease mechanisms in particular, based on the central premise that some of these activities are stress-induced. To model how a vertebrate-specific transposon responds to stress signals in human cells, I will study molecular interactions of the Sleeping Beauty (SB) transposon with host cellular mechanisms to understand how stress-signalling and response triggers transposon activation. My second aim is to decipher the relationship between stress-induced activation of endogenous TEs and TE-derived regulatory sequences and human disease. I aim at investigating conditions and the consequences of activation of a particular copy of the MERmaid transposon located in the Sin3B transcriptional corepressor, frequently observed in cancer. The impact of global epigenetic remodelling will be investigated in the model of a complete (induced pluripotency) and partial (trans-differentiation) epigenetic reprogramming. In parallel, I aim at translating experience accumulated in TE research to cutting-edge technologies. First, the SB transposon will be adopted as a safe, therapeutic vector to treat age-dependent blindness (AMD). Second, a mutagenic SB vector will be used in a forward genetic screen to decipher a genetic network that protects against hormone-induced mammary cancer. The anticipated output of my research programme is a refined understanding of the consequences of environmental stress on our genome mediated by TE-derived sequences. The project is expected to provide an effective bridge between basic research and clinical- as well as technological translation of a novel gene transfer technology.

Keywords: transposable elements,induced pluripotency,hormone dependent breast cancer,age related macular degeneration
Gene therapy and nanotechnology based CNS targeted vectors (GTNCTV)

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: United Kingdom
Call:  (ERC-2011-ADG_20110310, 2011)
Start date: 2012-03-01
End date: 2017-10-31
Duration (months): 68.0
Total project cost (EUR): 2499958.8
EU funding (EUR): 2499958.8
Participants: 1
Project status: CLOSED

Targeting therapeutic genes selectively into the central nervous system (CNS) is a crucial precondition for translation of gene therapy strategies into human trials. The current multidisciplinary proposal integrates expertise identified as essential in the effective acceleration of research to overcome bottlenecks in the field including: 1) Inefficiency of therapy delivery to the CNS because of factors like the blood-brain barrier (BBB); 2) Poor understanding of disease mechanisms at the molecular and cellular levels. These problems must be overcome to develop fully effective treatments for neurological disorders. Currently the adeno-associated (AAV)-based system is one of the most refined and effective gene delivery systems for neuronal cells. In contrast to all other systems, it has been possible to engineer AAV9 to deliver genes through the BBB to the CNS by intravascular (IV) administration. However, following IV delivery, these vectors also target liver and other tissues, with significant potential for untoward effects. This has prompted us to adopt two major strategies: i) targeting of AAV9 vectors at the level of transcription by insertion of hybrid motor neuron specific promoters into the vector genome; ii) development of a CNS-targeted delivery approach based on state-of-the art nanoparticle-mediated encapsulation of AAV9 vectors. We anticipate that engineering strategies with the ability to restrict transgene expression to CNS tissue will significantly overcome various existing hurdles in CNS gene therapy development. Our objectives are to: 1) explore mechanisms leading to penetration of scAAV9 vectors through BBB since the exact mechanism of AAV9 diffusion through BBB is unknown; 2) design novel targeted strategies with enhanced tropism to CNS; 3) use CNS targeted vectors to investigate mechanisms of motor neuron death linked to mutations in RNA processing genes; 4) utilise CNS-targeted systems to test therapeutic strategies for motor neuron diseases.

Keywords: gene therapy,viral vectors,nanoparticles,targeting,neurodegenerative diseases,amyotrophic lateral sclerosis,spinal muscular atrophy
Mitochondrial calcium signalling: molecules, roles and pharmacological targeting (MITOCALCIUM)

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: Italy
Call:  (ERC-2011-ADG_20110310, 2011)
Start date: 2012-04-01
End date: 2017-03-31
Duration (months): 60.0
Total project cost (EUR): 2432400.0
EU funding (EUR): 2432400.0
Participants: 1
Project status: CLOSED

Mitochondrial Ca2+ homeostasis is an important component of the calcium-mediated cellular response to extracellular stimuli. It controls key organelle functions, such as aerobic metabolism and the induction of apoptotic cell death, and shapes the spatio-temporal pattern of the cytosolic [Ca2+] increase. While its physiological and pathological relevance is now fully appreciated, lack of molecular insight has severely limited mechanistic understanding and pharmacological targeting. We have now identified the long sought “mitochondrial Ca2+ uniporter” (MCU). This project stems from this ground-breaking result, and with a multidisciplinary approach investigates the biological role of MCU, tackling also its structure/function relationship and possible pharmacological exploitation. Specifically, the project will be divided in five major tasks: i) the elucidation of the subcellular distribution of MCU and of the supramolecular organization of the mitochondrial Ca2+ influx machinery; ii) the clarification of the cross-talk with other signaling pathways, with major focus on regulatory mechanisms based on post-translational modifications (phosphorylation, acetylation, oxidation); iii) the development of suitable heterologous systems, in which wild-type MCU or mutants can be expressed; the purified protein (or the isolated mitochondria) will be utilized in electrophysiological studies to investigate the functional properties of the channel; iv) the elucidation of the protein structure, with the aim of developing specific inhibitors, based on molecular modeling and crystallization of the protein produced in the appropriate heterologous system; v) the generation of conditional and tissue-specific knockout models for investigating MCU function in vivo; the analysis of the phenotype, including the sensitivity to genetic or environmental causes of disease, will provide insight into the role of mitochondrial Ca2+ dysregulation in the pathogenesis and treatment of human disorders.

Keywords: calcium signalling,mitochondria
Novel variation in plant breeding and the plant pan-genomes (NOVABREED)

Framework: FP7 — Ideas
Programme: European Research Council
Theme: European research council
Destination: Advanced grants
Action type: Support for frontier research (ERC)
Panel: ERC Advanced Grant Interdisciplinary Panel
Countries involved: Italy
Call:  (ERC-2011-ADG_20110310, 2011)
Start date: 2012-07-01
End date: 2017-12-31
Duration (months): 66.0
Total project cost (EUR): 2473500.0
EU funding (EUR): 2473500.0
Participants: 2
Project status: CLOSED

The analysis of variation in plants has revealed that their genomes are characterised by high levels of structural variation, consisting of both smaller insertion/deletions, mostly due to recent insertions of transposable elements, and of larger insertion/deletion similar to those termed in humans Copy Number Variants (CNVs). These observations indicate that a single genome sequence might not reflect the entire genomic complement of a species, and prompted us to introduce the concept of the plant pan-genome, including core genomic features common to all individuals and a Dispensable Genome (DG) composed of partially shared and/or non shared DNA sequence elements. The very active transposable element systems present in many plant genomes may account for a large fraction of the DG. The mechanisms by which the CNV-like variants are generated and the direction of the mutational events are still unknown. Uncovering the intriguing nature of the DG, i.e. its composition, origin and function, represents a step forward towards an understanding of the processes generating genetic diversity and phenotypic variation. Additionally, since the DG clearly appears to be for the most part the youngest and most dynamic component of the pan genome, it is of great interest to understand whether it is a major contributor to the creation of new genetic variation in plant evolution and more specifically in the breeding process. We thus aim at: i) defining extent and composition of the pan genome in two plant species, maize and grapevine; ii) identifying the different mechanisms that generate and maintain the dispensable portion in these 2 species; iii) identifying the phenotypic effects of the DG; iv) estimating the rates and modes of creation of new genetic variation due to DG components and whether this could represent an important factor in the breeding process; v) extending our findings to other plant species for which the genome sequence in the meantime may have become available.

Keywords: plant breeding,quantitative traits,structural variation,transposable elements,bioinformatics,mutations,maize,grapevine
Genetics and epigenetics of Type 2 Diabetes physiology (GEPIDIAB)

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,France
Call:  (ERC-2011-ADG_20110310, 2011)
Start date: 2012-11-01
End date: 2017-10-31
Duration (months): 60.0
Total project cost (EUR): 2476324.99
EU funding (EUR): 2476324.99
Participants: 2
Project status: CLOSED

Failure to elucidate Type 2 Diabetes (T2D) physiology frustrates efforts to improve therapeutics. Although GWAS has identified 40 T2D genes, mostly expressed in pancreatic beta-cells, this explains no more than 10% of T2D inheritance. Up to 5% of T2D patients have dominantly inherited maturity-onset diabetes of the young (MODY), characterized by beta-cell dysfunction. Elucidating the genetics of familial early-onset T2D, using Whole-Exome Sequencing (WES) can bring breakthroughs in understanding insulin secretion physiology. DNA methylation, particularly in insulin sensitive tissues may also contribute to T2D. Newly-developed genome-wide methylation arrays can be used to identify associations with these epigenetic elements and T2D. In the proposed project, GEPIDIAB, I will take advantage of our MODY family DNA collection and multi-tissue biobank to 1: identify novel genetic causes of familial T2D (WP1) and 2: identify DNA methylation variation associated with T2D (WP2). In WP1, unresolved MODY-X families will be studied using WES to identify novel sequence changes. Then we will elucidate the cellular and metabolic mechanisms leading to beta-cell dysfunction caused by these novel mutations. In WP2, variation in DNA methylation at 450K sites across the genome will be studied in normoglycemic or diabetic bariatric surgery patients. Five separate tissue samples will be studied to identify tissue-specific variation, individual-specific variation and that which varies between cases and controls. We will explore whether there are T2D-specific patterns of methylation that are distinct from those in lean or obese normoglycemic subjects using bisulfite-whole genome sequencing. Overall, we will identify genome-wide methylation patterns that are cell and tissue-specific and disease-specific for five main tissues important in T2D. Together, genetics and epigenetics will complement each other to give a deeper understanding of both insulin deficiency and resistance.

Keywords: whole exome sequencing monogenic diabetes next generation sequencing
Parasponia to Crack Evolution of Rhizobium Symbiosis (PARAEVOLUTION)

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: Netherlands
Call:  (ERC-2011-ADG_20110310, 2011)
Start date: 2012-05-01
End date: 2018-04-30
Duration (months): 72.0
Total project cost (EUR): 2498950.8
EU funding (EUR): 2498950.8
Participants: 1
Project status: CLOSED

Mutualism is wide spread in nature and significantly impacts ecosystems. However, the principles governing its evolution have proved elusive. The rhizobium-legume symbiosis is one of the most sophisticated mutualistic interactions, as it results in the formation of a novel organ, the root nodule, where rhizobium is hosted intracellularly as nitrogen fixing ‘organelles’. These are named symbiosomes and produce ammonia from air. The rhizobium legume symbiosis evolved shortly after the rise of the legume family; 60 million years ago. However, by convergent evolution it also evolved more recent in the non-legume Parasponia. Ever since the discovery of Parasponia as the only non-legume that independently evolved the nodule symbiosis with rhizobium, it has intrigued the scientific community. It has been clear that this ‘bridging species’ will provide insight in how this unique symbiosis could arise during evolution. Further, it can teach us how to transfer this important agricultural trait to non-legume crops. However, it is first now that we can fully exploit the potential of this unique genus. Major insight in molecular mechanisms underlying the rhizobium legume symbiosis has been obtained by studying model legumes. This has made the rhizobium legume symbiosis one of the best understood mutualistic interactions. This insight can now be exploited to determine the evolutionary trajectory of the Parasponia rhizobium symbiosis, and to identify the genetic constraints of this interaction. Further, the revolution brought about by so-called next generation sequence technologies has made it now possible to cost efficiently sequence genomes of plant species with key positions in rhizobium nodule evolution. The overall objective of this project is to identify the evolutionary trajectory underlying rhizobium nodule evolution by using Parasponia. To validate the findings I will copy this evolutionary trajectory in Trema; the non-nodulating sister genus of Parasponia.

Keywords: rhizobium root nodule evolution
A Bayesian Framework for Cellular Structural Biology (BAYCELLS)

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: France
Call:  (ERC-2011-ADG_20110310, 2011)
Start date: 2012-05-01
End date: 2017-04-30
Duration (months): 60.0
Total project cost (EUR): 2130212.0
EU funding (EUR): 2130212.0
Participants: 1
Project status: CLOSED

The functioning of a single cell or organism is governed by the laws of chemistry and physics. The bridge from biology to chemistry and physics is provided by structural biology: to understand the functioning of a cell, it is necessary to know the atomic structure of macromolecular assemblies, which may contain hundreds of components. To characterise the structures of the increasingly large and often flexible complexes, high resolution structure determination (as was possible for example for the ribosome) will likely stay the exception, and multiple sources of structural data at multiple resolutions are employed. Integrating these data into one consistent picture poses particular difficulties, since data are much more sparse than in high resolution methods, and the data sets from heterogeneous sources are of highly different and unknown quality and may be mutually inconsistent, and that data are in general averaged over large ensembles and long times. Molecular modelling, a crucial element of any structure determination, plays an even more important role in these multi-scale and multi-technique approaches, not only to obtain structures from the data, but also to evaluate their reliability. This proposal is to develop a consistent framework for this highly complex data integration problem, principally based on Bayesian probability theory. Appropriate models for the major types data types used in hybrid approaches will be developed, as well as representations to include structural knowledge for the components of the complexes, at multiple scales. The new methods will be applied to a series of problems with increasing complexity, going from the determination of protein complexes with high resolution information, over low resolution structures based on protein-protein interaction data such as the nuclear pore, to the genome organisation in the nucleus.

Keywords: integrative structural biology,data integration