Data-Gouv-ML/pcri-informations-sur-les-projets-laureats huggingface dataset:
Polycomb/Trithorax: Functional EpiGenomics Integrators for Metabolic Disease (METABOLICPOLYCOMBICS)

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-2011-StG_20101109, 2011)
Start date: 2011-12-01
End date: 2016-11-30
Duration (months): 60.0
Total project cost (EUR): 1654430.36
EU funding (EUR): 1654430.36
Participants: 1
Project status: CLOSED

The last decade has seen an explosion of research into the epigenetic regulation of cell biology. Indeed, great efforts have been made to elucidate epigenetic regulation in stem cell biology, development, and within the plastic states of cancer. Current estimates place the prevalence of obesity in the range of 300 million to beyond 1 billion by the year 2030. As a critical risk factor for heart disease, diabetes and stroke, obesity currently represents one of the world’s chief economic and health care challenges. While studies have established a genetic framework for our current understanding of obesity, the contribution of several critical regulatory layers, in particular epigenetic regulation, remains poorly understood. We recently performed the first genome-wide RNAi screen for obesity regulators in the adult fly. Intriguingly, developmental regulators scored among the most enriched pathways (Pospisilik, Cell 2010). Systematic interrogation of the 500 candidate obesity genes by tissue-specific knockdown has now identified the Polycomb-Trithorax system (PcG-Trx) as the most enriched obesity-altering pathway. Here, we propose to translate these findings to the mammalian context through completion of three aims: i. generation and characterization of 8 PcG conditional knockout mouse lines, ii. dissection of the functional roles of PcG in adipose tissue differentiation, function and disease, and iii. building of a functionally interrogated unbiased epigenetic map of the PcG-system for murine and human obesity. To achieve these goals we will combine targeted mouse genetics, complex phenotyping and state-of-the-art integrative bioinformatics. Using this unique functional-genetics-to-epigenomics approach we will provide an unprecedented functionally validated genomics resource for obesity research worldwide, unravel an entire regulatory niveau in obesity, and if we are lucky, highlight novel therapeutic strategies for metabolic disease.

Keywords: metabolic disease,obesity,adipose tissue,epigenetics,conditional knockout mice,epigenomics,deep-sequencing,developmental reprogramming,adipogenesis,agouti mice,stochastic obesity
In vivo dynamics of antibody responses to lymph-borne viruses (IVM-VIRUS-NAB)

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: Italy
Call:  (ERC-2011-StG_20101109, 2011)
Start date: 2012-02-01
End date: 2017-06-30
Duration (months): 65.0
Total project cost (EUR): 1934200.0
EU funding (EUR): 1934200.0
Participants: 1
Project status: CLOSED

Objective. Our objective is to elucidate how neutralizing antibody (nAb) responses against live viruses are generated in vivo within lymph nodes (LNs). To this end we will make use of state-of-the-art imaging technology (i.e. multiphoton intravital microscopy [MP-IVM]), fluorescent replication-competent viruses and dedicated mouse models. Background/Rationale. nAbs are critical for virus control, prevention of re-infection and protection conferred by available vaccines. Thanks to the recent advent of MP-IVM, several cellular and molecular events by which LNs orchestrate humoral immune responses have been clarified. As none of these studies employed live viruses, further work is required to extend these results to a more relevant natural setting. Also, the mechanisms by which cytopathic viruses (e.g. rabies virus in humans and vesicular stomatitis virus [VSV] in mice) induce early high affinity nAb responses while non-cytopathic viruses (e.g. hepatitis C virus in humans and lymphocytic choriomeningitis virus [LCMV] in mice) fail to do so remain poorly understood. Our rationale is based on the notion that, by bringing together unique reagents and advanced technology, we can - at last - address these issues experimentally. Description of the project. The spatial and temporal constraints whereby virus-specific naïve B cells encounter viral antigen, interact with different LN cells and differentiate into plasma cells will be dynamically dissected in the various LN sub-compartments of mice infected with live cytopathic (VSV) and non-cytopathic (LCMV) viruses. Anticipated output. We will provide the first complete in vivo imaging survey of virus-specific B cell activation, from the first minutes of viral entry into LNs to the generation of high affinity nAb-secreting cells. We will also identify virus-induced mechanisms interfering with nAb responses. This new knowledge will provide insight into aspects of viral immunity that may lead to novel rational vaccine strategies.

Keywords: intravital microscopy,b cells,virus,lymph nodes
Treatment of Adrenal Insufficiency in neonates- Development of a Hydrocortisone Preparation for the treatment of Adrenal Insufficiency in neonatesand infants. (TAIN)

Framework: FP7 — Cooperation
Programme: Health
Destination: Other Actions across the Health Theme
Action type: Collaborative project
Countries involved: United Kingdom,United Kingdom,Germany,United Kingdom,United Kingdom,Switzerland,Germany
Call:  (FP7-HEALTH-2011-single-stage, 2011)
Start date: 2011-12-01
End date: 2016-11-30
Duration (months): 60.0
Total project cost (EUR): 5512693.6
EU funding (EUR): 4197147.2
Participants: 8
Project status: CLOSED

The aim of TAIN is to develop a neonatal formulation of hydrocortisone, a drug included in the EMA priority list that needs specific evaluation in the age range 0 – 2 years (neonates & infants). Hydrocortisone is an essential glucocorticoid hormone used as replacement therapy for the treatment of congenital and acquired adrenal insufficiency as well playing an important therapeutic role in oncology in infants, specifically brain tumours and leukaemia’s. TAIN involves European leaders in neonatology, paediatric pharmacology, methodology and SMEs that will establish links with ethical bodies and regulatory authorities. The programme will perform in silico experiments and evaluate formulations for neonates. The phase 3 clinical trial comparing the neonatal hydrocortisone versus current (unlicensed) therapy will be optimized using age-appropriate state-of-the-art methods adapted to neonates (including in silico experiments and pharmacokinetics) to validate the components of a Paediatric Investigation Plan. It will be performed by neonatologists trained in paediatric pharmacology and clinical research in line with guidelines on Good Clinical Practice. All the ethical issues will be considered, including pain and distress, blood sampling (number and volume) and informed consent. Parent information sheets and consent form will be submitted to patient and parents’ associations for approval. TAIN will include short term safety studies and Phase 3 clinical studies in neonates and infants. Results will be reported in order to allow a PUMA application to be submitted and to improve neonatal and infant care. Therefore, TAIN will validate the appropriate use of hydrocortisone in neonates and infants which will be of direct benefit to children, their families and health professionals. TAIN will strengthen paediatric drug evaluation across Europe and build up a network of units with experience in clinical research that will be used for additional drug evaluation in neonates.

Keywords: paediatrics,hydrocortisone,ema priority list,puma,pip,clinical trial,neonates,infants,pharmacokinetics
Decoding the ubiquitin code (UBICODE)

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: Netherlands
Call:  (ERC-2011-StG_20101109, 2011)
Start date: 2011-11-01
End date: 2016-10-31
Duration (months): 60.0
Total project cost (EUR): 1498240.0
EU funding (EUR): 1498240.0
Participants: 2
Project status: CLOSED

Ubiquitin (Ub) is a 76 amino acid protein that is commonly found in isopeptide linkage to a lysine residue of a target protein. This post-translational modification controls most cellular processes, including DNA repair, trafficking and protein degradation. Ubiquitin conjugation onto any of its 7 own lysine residues or onto its N-terminus results in a large number of differently linked polymers; the shape, charge and size of which determine how they interact with ubiquitin binding domains (UBDs). Binding to proteins containing such domains triggers further events that determine the fate of a Ub-tagged substrate in subsequent biochemical events in a Ub chain topology dependent manner. Malfunction of these signal transduction events contributes to the pathology of human disease. Although all Ub linkages are found in cells and all likely have specific functions, only few of them have been intensively studied so far as most linkages cannot be generated biochemically. This project will investigate how Ub linkages are recognized by UBDs to transduce cellular signals in a chain specific manner, including all linkages with all their possible topoisomers. This information will then be used to generate pharmacological modulators aimed at interfering with specific UBD-mediated signal transduction events.

Keywords: ubiquitin deubiquitinating enzyme drug development
Heterotypic Cell Interactions in Hepatitis induced Liver Cancer (LIVERMIRCOENV)

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: Israel
Call:  (ERC-2011-StG_20101109, 2011)
Start date: 2011-10-01
End date: 2017-09-30
Duration (months): 72.0
Total project cost (EUR): 1499940.0
EU funding (EUR): 1499940.0
Participants: 1
Project status: CLOSED

The link between inflammation and cancer is now established, yet the underlying molecular mechanisms are unresolved. As tumors progress, they modulate inflammatory cells towards a pro-tumorigenic phenotype. We have shown that inflammatory cells reciprocate by sculpting the parenchymal epithelial cells. I hypothesize that these reciprocal interactions lie at the heart of the link between inflammation and cancer. Hepatocellular carcinoma (HCC), one of the deadliest tumors, is a prototype of inflammation induced cancer. My team will employ a twofold strategy to analyze the changes occuring in inflammatory cells before and after tumors emerge, based on preliminary findings showing that changes in inflammatory cells precede tumorigenesis. First, we will perform comprehensive mapping of the changing inflammatory microenvironment in a mouse model of inflammation induced HCC. We will employ genetic manipulation strategies, coupled to cell isolation techniques to delineate the molecular cues that mediate these changes and then will analyze the functional role of key mediators of these processes in HCC. Microfluidics approaches will give us a highthroughput quantitative view of these heterotypic interactions. The same approaches will be harnessed to identify the interactions that form the liver stem cell niche which dramatically expands in states of chronic inflammation. Second, drawing on our finding that a recurring tumor amplicon drives HCC progression by modulating the microenvironment, we will work towards identifying additional similar amplicons to define additional key effectors of the microenvironment. Of special importance, heterotypic cell interactions that play key roles in both cancer initiation and progression, present ideal therapeutic targets, which are easily accessible and less amenable to mutational selection. Furthermore, the results of our experiments could also have far reaching implications in other inflammatory states and different types of cancer.

Keywords: hepatitis,chronic inflammation,tumor promotion,tumor microenvironment,premalignant phase,tumor prevention,hepatocellular carcinoma
Health consequences of noise exposure from road traffic (QUIET)

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: Denmark,Denmark
Call:  (ERC-2011-StG_20101109, 2011)
Start date: 2012-03-01
End date: 2017-02-28
Duration (months): 60.0
Total project cost (EUR): 1334890.0
EU funding (EUR): 1334890.0
Participants: 2
Project status: CLOSED

There is growing public concern about adverse effects of traffic noise on health, as research has found that traffic noise increases the risk for cardiovascular diseases. Noise is thought to act as a stressor and disturbs sleep. Though this potentially could increase the risk for other major diseases, noise effects on other than the cardiovascular diseases are virtually unexplored. The main objective of this project is to investigate if long-term exposure to road traffic noise is detrimental to various health outcomes in susceptible groups, i.e. children and elderly. Outcomes in children include low birth weight, infections and cognitive performance, and in elderly outcomes include diabetes, cancer, cancer survival, health-related quality of life and health behaviour. The basis of this proposal is two unique Danish cohorts of, respectively, 57,053 elderly and 101,042 children (a national birth cohort). Historic and present residential addresses for all cohort members will be obtained through linkage with the nationwide Central Population Registry, and exposure to road traffic noise and air pollution will be calculated by validated models at all addresses. The health outcomes will be obtained from cohort interviews/questionnaires or found through linkage with unique, nationwide, population-based health registers, such as the Danish National Hospital Registry, the Diabetes Registry and the Cancer Registry. Data will be analysed using a number of statistical analyses depending on design and the character of the endpoint variable. All analyses will be adjusted for potential confounders such as air pollution, smoking and education. Within the EU, 30% of the population lives at locations where the 55dB WHO noise limit is exceeded. Knowledge of harmful effects of noise is, however, limited. The results of the proposed research have a high potential to influence the content and time schedule of noise action plans in the EU member states.

Keywords: road traffic noise modeling exposure cohort study cognitive performance health-related quality of life diabetes birth weight cancer cancer survival infections reproduction stress biomarker
Structural Biology of Mitochondrial Outer Membrane Proteins (MOMP)

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: Switzerland
Call:  (ERC-2011-StG_20101109, 2011)
Start date: 2011-12-01
End date: 2016-11-30
Duration (months): 60.0
Total project cost (EUR): 1997190.0
EU funding (EUR): 1997190.0
Participants: 1
Project status: CLOSED

To elucidate the biological role of the mitochondrial outer membrane (MOM), I propose to determine structures and functions of integral MOM protein complexes at atomic resolution, involving the three proteins VDAC, Bax and Sam. These are key elements of vital cellular functions: the regulation of bioenergetics, mitochondrial biogenesis, apoptosis and cancer. Our results will give new insights into the biology of eukaryotes and will open up new avenues for pharmaceutical applications. My research group will pursue the following objectives: A. Determination of the structures of the VDAC–NADH, the VDAC–cholesterol, and the VDAC–hexokinase complexes. These structures will provide the molecular basis for metabolism regulation by the voltage-dependent anion channel VDAC and for its role in the “Warburg effect”, a crucial step of cancerogenesis of most cancers. B. Determination of the structure and insertion mechanism of the Bax transmembrane-pore and its formation and inhibition by drug candidates. The formation of the Bax pore in the MOM is the final, deadly step in mitochondrial apoptosis and the structure will thus elucidate a key regulatory element of multicellular organisms. C. Determination of the structure and function of the sorting and assembly machinery (Sam), including its core protein, the beta-barrel protein Sam50, and its interactions with substrates. These results will explain the insertion of membrane proteins during the biogenesis of the MOM, an essential for eukaryotic life. Structure determinations of membrane proteins are still major technical challenges and so far, with VDAC, only a single structure of an integral MOM protein is known, determined by the present author and colleagues. While bringing groundbreaking biological insights, our research will further extend the methodological approaches for membrane protein structure determination by nuclear magnetic resonance (NMR) spectroscopy to a new level.

Keywords: membrane proteins,mitochondria
How to Replicate Chromatin - Maturation, Timing Control and Stress-Induced Aberrations (CHROMATINREPLICATION)

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: Denmark
Call:  (ERC-2011-StG_20101109, 2011)
Start date: 2011-11-01
End date: 2017-04-30
Duration (months): 66.0
Total project cost (EUR): 1692736.8
EU funding (EUR): 1692736.8
Participants: 1
Project status: CLOSED

Inheritance of DNA sequence and its proper organization into chromatin is fundamental for eukaryotic life. The challenge of propagating genetic and epigenetic information is met in S phase and entails genome-wide disruption and restoration of chromatin coupled to faithful copying of DNA. How specific chromatin structures are restored on new DNA and transmitted through mitotic cell division remains a fundamental question in biology central to understand cell fate and identity. Chromatin restoration on new DNA involves a complex set of events including nucleosome assembly and remodelling, restoration of marks on DNA and histones, deposition of histone variants and establishment of higher order chromosomal structures including sister-chromatid cohesion. To dissect these fundamental processes and their coordination in time and space with DNA replication, we have developed a novel technology termed nascent chromatin capture (NCC) that provides unique possibility for biochemical and proteomic analysis of chromatin replication in human cells. I propose to apply this innovative cutting-edge technique for a comprehensive characterization of chromatin restoration during DNA replication and to reveal how replication timing and genotoxic stress impact on final chromatin state. This highly topical project brings together the fields of chromatin biology, DNA replication, epigenetics and genome stability and we expect to make groundbreaking discoveries that will improve our understanding of human development, somatic cell reprogramming and complex diseases like cancer. The proposed research will 1) identify and characterize novel mechanisms in chromatin restoration and 2) address molecularly how replication timing and genotoxic insults influence chromatin maturation and final chromatin state.

Keywords: chromatin biology,genetic stability,epigenetic stability,cancer,dna replication,histone marks,replication stress,repair,chromosomal organization,replication timing,chromatin assembly
Chromatin and transcription in ES cells: from single cells to genome wide views (EXPRES)

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: Israel
Call:  (ERC-2011-StG_20101109, 2011)
Start date: 2011-12-01
End date: 2016-11-30
Duration (months): 60.0
Total project cost (EUR): 1500000.0
EU funding (EUR): 1500000.0
Participants: 1
Project status: CLOSED

How embryonic stem cells (ESCs) maintain their dual capacity to self-renew and to differentiate into all cell types is one of the fundamental questions in biology. Although this question remains largely open, there is growing evidence suggesting that chromatin plasticity is a fundamental hallmark of ESCs, providing their necessary flexibility. Previously we found that ESCs possess a relatively open chromatin conformation, giving rise to permissive transcriptional program. Here I propose to investigate the mechanisms that support chromatin plasticity and pluripotency in ESCs. Using a simple biochemical assay which I developed (DCAP: Differential Chromatin Associated Proteins), based on micrococcal nuclease (MNase) digestion combined with multi-dimensional protein identification technology (MudPIT), I seek to identify ESC-specific chromatin proteins. Selected proteins will be knocked-down (or out) and their ESC function will be evaluated. In addition, I will conduct a hypothesis-driven research using mutant ESCs and epigenetic-related drugs to search for potential mechanisms, (i.e. histone modifications, DNA methylation), that may support chromatin plasticity in ESCs. Based on our intriguing preliminary data, I will also focus on the link between the nuclear lamina and ESC plasticity. Thirdly, we will analyze non-polyadenylated transcription using genome-wide tiling arrays and RNA-seq. We will design custom microarrays containing the identified sequences, which will allow us to reveal, using ChIP-chip experiments, the mechanistic regulation of the non-polyadenylated transcripts. Finally, we will knockout, using zinc-finger nuclease technology, selected highly conserved candidates in search of their function. Understanding chromatin regulation, plasticity and function will enable one to intelligently manipulate ESCs to transition between the pluripotent, multipotent and unipotent states and to expedite their use in the clinic.

Keywords: embryonic stem cells,chromatin,chromatin plasticity,transcription,pluripotency