Data-Gouv-ML/pcri-informations-sur-les-projets-laureats huggingface dataset:
Mitochondrial crosstalk signalling in the regulation of ageing (MITOSIGAGE)

Framework: FP7 — Ideas
Programme: European Research Council
Theme: European research council
Destination: Starting grants
Action type: Support for frontier research (ERC)
Panel: ERC Starting Grant Interdisciplinary Panel
Countries involved: Spain
Call:  (ERC-2011-StG_20101109, 2011)
Start date: 2012-06-01
End date: 2018-05-31
Duration (months): 72.0
Total project cost (EUR): 1424640.0
EU funding (EUR): 1424640.0
Participants: 1
Project status: CLOSED

Mitochondrial defects are associated with aging and age-related pathology, but the molecular mechanisms regulating mitochondrial function during ageing are poorly understood. The most relevant genetic pathway regulating ageing is the insulin/IGF-1 signalling (IIS) pathway. The mitochondrial prohibitin (PHB) complex influences cellular metabolism and mitochondrial biogenesis, affecting ageing in opposite ways in wild-type animals and IIS-defective C. elegans mutants. The aim of the proposed research programme is to shed light on the intricate communication between mitochondria and cell-signalling networks in the regulation of ageing. Our specific objectives are: 1-Elucidate the cellular signalling pathways involved in the metabolic responses to mitochondrial dysfunction upon PHB depletion in wild type animals and IIS-defective mutants, using genome-wide RNAi screens, 2-Conduct a comprehensive metabolic profiling of wild type and IIS mutants in the presence and absence of prohibitins and 3-Identify genetic suppressors of prohibitins by performing forward genetic suppressor screens. As an ultimate goal, genes discovered in C. elegans will be tested in vertebrate assays for a conserved role in ageing. We will implement an interdisciplinary approach that combines the genetic power of C. elegans with state-of-the-art metabolomic approaches as well as automated sorting and optical imaging technologies to monitor fat content and mitochondrial biogenesis, in a genome-wide scale, in vivo. The fine-tuning of cellular metabolism, by integration of diverse signalling inputs is the molecular basis of longevity. This project represents a truly integrative and innovative approach to identify cellular signalling pathways involved in mediating lifespan-extending metabolism adjustments, and what these metabolic adjustments entail. These studies will provide fundamental insights to understand the ageing process and to combat ageing-related diseases.

Keywords: mitochondria,insulin signalling,lifespan,metabolism,metabolomics,c. elegans,genome-wide rnai screens,reverse genetics,forward genetics.
How does the X chromosome regulate DNA methylation in pluripotent stem cells? (XXDNAM)

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: United Kingdom
Call:  (ERC-2011-StG_20101109, 2011)
Start date: 2011-10-01
End date: 2017-03-31
Duration (months): 66.0
Total project cost (EUR): 1497710.0
EU funding (EUR): 1497710.0
Participants: 1
Project status: CLOSED

Epigenetic processes regulate gene transcription states during cellular differentiation, playing key roles in the maintenance of pluripotency and differentiation. Epigenetic alterations are common in diseases such as in cancer and cognitive disorders. Understanding the mechanisms by which epigenetic states are inherited and propagated is of fundamental importance, and will help in the development of biomarkers for screening as well identification of targets for disease treatment. DNA methylation remains the best-characterized epigenetic process. XX pluripotent stem cells (Embryonic Stem (ES) and induced Pluripotent Stem (iPS) cells) display genome-wide hypomethylation relative to XY stem cells but the mechanisms are unknown. This proposal will elucidate the pathways responsible. Irradiation Microcell-Mediated Chromosome Transfer (XMMCT) will be used to identify the critical region(s) of the X chromosome involved. In parallel and as an alternative approach, candidate X-linked genes will be over-expressed in XY ES cells to identify the factors responsible for global hypomethylation. Further insight will be provided using protein interaction screens using epitope-tagged versions of all active Dnmts as well as the known regulators URHF1 and Dnmt3L in XX and XY ES cells. The role of XX-induced hypomethylation in cellular reprogramming will be investigated by using different cell types from Oct4-GFP transgenic mice to examine whether iPS efficiency is affected by cells with a greater propensity to lose DNA methylation. Together these aims will elucidate the signals necessary to maintain global genomic DNA methylation. Aberrant loss is an important hallmark and contributor of disease that could be used for disease diagnosis and treatment. It could also be exploited to help improve the efficiency of cellular reprogramming for regenerative medicine.

Keywords: dna methylation,chromatin,functional gene mapping,protein interaction,transgenesis
Genetic and epigenetic determinants of allele-specific gene expression in the human Major Histocompatibility Complex (REGVARMHC)

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: United Kingdom
Call:  (ERC-2011-StG_20101109, 2011)
Start date: 2012-01-01
End date: 2016-12-31
Duration (months): 60.0
Total project cost (EUR): 1496899.0
EU funding (EUR): 1496899.0
Participants: 1
Project status: CLOSED

The overall aim of this proposal is to understand how individual genetic and epigenetic variation in the Major Histocompatibility Complex (MHC) on chromosome 6p21 may determine susceptibility to autoimmune, infectious and inflammatory disease. The human MHC is a paradigm for genomics, showing remarkable polymorphism and striking association with disease, but causal genetic variants remain largely unresolved. The identification of specific disease risk variants is particularly challenging in the MHC due to the extent of genetic diversity now recognised, the complexity of coinheritance between genetic markers and the difficulty of resolving specific regulatory variants modulating gene expression. We have previously established the importance of allele-specific gene expression in the MHC at specific loci including the TNF, HSP70 and HLA-DRB1 genes. We now propose a comprehensive global analysis for the MHC addressing the following specific objectives: (1) to define allele-specific transcription across the classical MHC for disease associated haplotypes in specific peripheral blood cells using RNA sequencing; (2) to compliment this by identifying allelic differences in gene regulation at the level of chromatin structure and histone modifications; (3) to resolve DNA sequence variants associated with differences in MHC gene expression by quantitative trait mapping in healthy volunteers; (4) to investigate the extent and consequences of allele-specific DNA methylation in the MHC; (5) to functionally characterise specific gene loci showing evidence of allele-specific gene expression in the context of reported disease associations. The proposal is scientifically ambitious, using cutting edge genomic technologies to address in innovative ways a major roadblock in this field of scientific research. The work is of significant translational importance as we apply genomic medicine to improve care for the individual patient and advance our understanding of disease pathogenesis.

Keywords: allele-specific gene expression chromatin genetic variation disease association autoimmunity
Cellular pathways determining growth and human brain size (HUMGENSIZE)

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: United Kingdom
Call:  (ERC-2011-StG_20101109, 2011)
Start date: 2012-11-01
End date: 2018-07-31
Duration (months): 69.0
Total project cost (EUR): 1499666.1
EU funding (EUR): 1499666.1
Participants: 1
Project status: CLOSED

The greatest differences between mammals are size. As well, the large evolutionary expansion of the cerebral cortex is a defining feature humans. Despite this, much remains to be learnt about the developmental and evolutionary factors controlling organ and organism size. This is in marked contrast to the exquisite detail in which developmental patterning has been defined in model organisms. The identification of genes for human disorders of extreme growth failure (microcephalic primordial dwarfism) provides a means to gain new insights into the regulation of human brain and body size. I have identified eight genes regulating cerebral cortex volume and organism size, all of which encode fundamental components of cell machinery regulating cell division. This proposal aims to ascertain the genes causing the other 85% of primordial dwarfism, and define their cellular and developmental functions. The central hypothesis for the proposed work is that such primordial dwarfism and microcephaly genes are components of common cellular pathway(s) relevant to organ and organism growth. I propose to pursue complementary approaches involving human disease gene identification, cell biology studies, and model organisms, to address this hypothesis and further define the pathogenesis of these conditions. These cross-disciplinary studies will contribute to our understanding of vertebrate growth regulation and help us understand how the human brain evolved. They may provide insights into neural stem cell division relevant to brain repair. Finally and not least, regulation of DNA replication, centrosome function and DNA damage response signalling are key cellular processes perturbed in many important human diseases, from developmental disorders to cancer.

Keywords: growth,cell division,dna replication,centrosomes,human disease
Dissecting the gene regulatory mechanisms that generate serotonergic neurons and their link to mental disorders (SEROTONINANDDISEASE)

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: Spain
Call:  (ERC-2011-StG_20101109, 2011)
Start date: 2012-12-01
End date: 2018-11-30
Duration (months): 72.0
Total project cost (EUR): 1931621.0
EU funding (EUR): 1931621.0
Participants: 1
Project status: CLOSED

Mental disorders constitute a human an economic burden for developed countries. Many mental disorders are linked to serotonin dysfunction, but the exact mechanism underlying these disorders is not well understood. Serotonin Related Mental Disorders (SRMD) are multigenic, making the identification of these mechanisms a difficult task. Understanding the molecular mechanisms that generate serotonergic neurons will provide us with the tools to identify mutations that could predispose to SRMD. In this grant we will use a multidisciplinary approach to dissect the transcriptional mechanisms that generate serotonergic neurons and use this knowledge to identify genetic links to SRMD. Serotonergic neurons are very ancient in evolution and enzymes and transporters responsible for the production of serotonin (serotonin pathway genes) are very well conserved in all metazoans. We would take advantage of this evolutionary conservation and use the genetic amenability of C. elegans to dissect the genetic mechanisms responsible for the generation of the serotonergic neurons. We will apply the lessons learned from C. elegans to unravel analogous mechanisms regulating mouse serotonergic differentiation. Our preliminary results show that the serotonergic pathway genes are co-regulated by the same factors and that this mechanism is evolutionary conserved. We will identify the cis-acting sequences (serotonergic motif) and trans-acting factors responsible for the activation of the serotonergic features, both in worms and mice. Finally, we will apply our knowledge on serotonergic differentiation to identify genetic association to SRMDs. Mutations in the serotonergic motif could lead to defects on the expression of the serotonergic genes, resulting in a dysfunctional serotonergic neuron. We will build a database of all human serotonergic motifs and look for mutations in these sites in SRMD patients. In summary, this grant will give us the tools to better understand and treat SRMD.

Keywords: terminal fate,serotonin,regulatory logic,transcription factor,terminal selector,mental disorders
Asian Regional Capacity Development for Research on Social Determinants of Health (ARCADE RSDH)

Framework: FP7 — Cooperation
Programme: Health
Destination: Optimising the delivery of healthcare to European citizens
Action type: Coordination and support actions
Countries involved: Sweden,China,India,United Kingdom,Finland,Oman,Viet Nam,South Africa
Call:  (FP7-HEALTH-2011-single-stage, 2011)
Start date: 2011-12-01
End date: 2015-11-30
Duration (months): 48.0
Total project cost (EUR): 2201583.9
EU funding (EUR): 1996595.0
Participants: 14
Project status: CLOSED

This project will add new research training capacity at low and middle-income countries (LMICs) in Asia, for promoting research on social determinants of health (RSDH). The focus is doctoral and post doctoral training, institutional strengthening for education, financial and administrative research management, and LMICs-based network building. Novel capacity building approaches will reduce brain drain, be more climate friendly and encourage gender equity with LMICs-based training. Internet mounted downloadable modules in related disciplines, like epidemiology, anthropology, economic methods, etc., will support excellent interdisciplinary courses. Addressing social determinants of health and tackling health inequity are research intensive, incremental improvement to measurement and understanding, implementation and evaluation. Therefore LMICs need to grow their own capacity to strengthen RSDH: interdisciplinary, rigorous and relevant. ARCADE-RSDH will support evidence informed decision making by producing a stream of well-trained young RSDH scientists, the next generation of health system leaders and researchers in LMICs. Activities will be aimed at individuals, institutions and the network. Tongji Medical College of HUST (TJMC, China), CBCI Society of Medical Education (SJNAHS, India) and Public Health Foundation of India (PHFI, India) are strong Asian Universities with RSDH focus. They will act as hubs in a network including TJMC, SJNAHS, PHFI, Beijing Normal University (BNU, China), Zhejiang University (ZJU, China), Indian Institute of Health Management Research (IIHMR, India), Ruxmaniben Deepchand Gardi Medical College (UCTH, India) and initially Sultan Qaboos University (SQU, Oman), Hanoi Medical University (HMU, Vietnam), working with strong European RSDH institutions (Karolinska Institutet KI, Sussex University Institutet for Development Studies IDS and University of Tampere UTA). This region-wide approach will draw skills, resources and students to a new LMICs-based RSDH capacity development network.

Keywords: research capacity development,low and middle income countries,asia,social determinants of health,health equity,network
New magnetic resonance techniques to determine the dynamic structure of mitochondrial outer membrane proteins and their complexes (DYNAMOM)

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,Germany
Call:  (ERC-2011-StG_20101109, 2011)
Start date: 2011-11-01
End date: 2017-10-31
Duration (months): 72.0
Total project cost (EUR): 1496200.0
EU funding (EUR): 1496200.0
Participants: 2
Project status: CLOSED

Membrane proteins are coded by about 30% of the genes in the human genome and are primary targets for the action of drugs. I propose an interdisciplinary approach that will provide insight into the dynamic structure of membrane proteins of the outer mitochondrial membrane at unprecedented detail with respect to spatial resolution and time scale separation. Analysis of the dynamics and structure of membrane proteins is one of the biggest challenges in structural biology. I propose several new techniques mainly for solution NMR spectroscopy but also for solid-state NMR and electron paramagnetic resonance that go far beyond the state of art and enrich the sparse information from each of the individual techniques. The integration of complementary experimental information together with molecular dynamics simulations will push the description of the dynamic structure of membrane proteins to a new level. This new level is characterized by the possibility to determine structural ensembles of higher structural complexity and by access to dynamic time scales ranging from picoseconds to milliseconds. The characterization of motion is expected to establish the essential link between structure and function. The chosen outer mitochondrial membrane proteins are linked to several human pathologies that cannot be treated because structural and dynamic information at atomic resolution is missing. I expect that the novel insight into the dynamic structure of mitochondrial proteins will be critical to lay the basis for the development of novel, selective and improved therapies for cancer and age-related neurodegeneration.
Progression factors in melanoma leading to novel therapeutic targets (PROMINENT)

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: United Kingdom
Call:  (ERC-2011-StG_20101109, 2011)
Start date: 2012-02-01
End date: 2017-01-31
Duration (months): 60.0
Total project cost (EUR): 1498500.0
EU funding (EUR): 1498500.0
Participants: 1
Project status: CLOSED

Presently, there is little hope of cure for patients with metastatic melanoma. Greater insight into the molecular and cellular biology of melanoma and the immune response mounted against it is required to indicate new therapeutic approaches. We have created zebrafish models for analyzing melanoma initiation and progression. Using whole genome transcriptome profiling, we have identified a number of genes that are induced during malignant progression. Moreover, we have established an efficient method for assessing the ability of a given gene to promote melanoma progression in its natural setting. Having analysed the ontologies of our malignancy-associated gene set, we propose screening multiple exemplars from various functional categories, including classes of gene function not previously validated as therapeutic targets. We also propose using recombinant zinc-finger nucleases to delete candidate progression-inducing genes and determine their impact on melanoma progression. Experiments performed in cultured human melanoma cells will demonstrate conserved action. Recent collaborative work shows that melanoma cells, even when present as small clones, interact with neutrophils and macrophages, which appear to play both immunosurveillance and tumour-promoting roles. Likewise, CD4+ T cells play dual roles in shaping the immune response to melanoma. We have access to a macrophage-specific driver line and are in the process of developing a CD4+ T-cell specific driver line. Using these tools and other reagents, we propose to perform detailed analyses of neoplastic-melanocye–immune-cell interactions during malignant progression. Moreover, by driving expression of immunomodulatory factors, we shall follow the impact on progression of melanocyte neoplasms of manipulating the differentiation of these two leukocyte lineages. Pursuing these objectives will move us beyond the current boundaries of knowledge and lead to the discovery of novel therapeutic targets.

Keywords: melanoma,zebrafish,malignant progression,metastasis,immune response
Overcoming the challenge of large gene transfer for the therapy of inherited retinal diseases (RETGENTX)

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: Italy
Call:  (ERC-2011-StG_20101109, 2011)
Start date: 2012-01-01
End date: 2016-12-31
Duration (months): 60.0
Total project cost (EUR): 1500000.0
EU funding (EUR): 1500000.0
Participants: 1
Project status: CLOSED

Inherited retinal diseases (IRDs) cause blindness in over 200,000 individuals in Europe. The majority are due to mutations in genes expressed in photoreceptors (PR) in the retina. We have recently demonstrated the safety and efficacy of gene therapy for IRDs in patients with Leber congenital amaurosis (LCA). One of the major limitations to extend this clinical success to other blinding conditions is that many are caused by mutations in genes with large coding sequences that exceed the cargo capacity of the most efficient gene transfer vector for PR, the adeno-associated virus (AAV). Conversely, vectors for large gene delivery like lentiviral (LV) or high-capacity adenoviral (HC-Ad) vectors have poor PR tropism. This project aims at overcoming the challenge of large gene delivery to the retina. We propose to either expand AAV cargo capacity or to identify/modify LV and HD-Ad vectors with improved PR transduction ability. We plan to expand AAV cargo capacity by either producing AAV vectors from single plasmid containing large genes or by generating 2-split AAV vectors each containing one of 2 halves of a large gene which is reconstituted upon AAV intermolecular concatemerization in the nucleus of target cells. In parallel, we will screen a series of existing LV pseudotypes and Ad serotypes for their ability to transduce PR. Alternatively, we propose to modify the Ad capsid or LV envelope using epitopes identified by in vivo biopanning that bind to PR and. We will compare the efficiency of the three vector platforms to transduce murine and porcine PR. The platform with highest PR transduction efficiency will then be used to correct the retinal phenotype of murine models of common severe IRDs due to mutations in large genes. Overcoming the challenge of large gene transfer will allow to cure photoreceptor-specific diseases which are currently untreatable and will provide important therapeutic tools for those diseases targeting tissues other than the retina.

Keywords: viral vectors,retinal degeneration,large genes