Data-Gouv-ML/pcri-informations-sur-les-projets-laureats huggingface dataset:
Hypothalamic Lipotoxicity and Endoplasmic Reticulum Stress: a New Pathophysiological Mechanism of Obesity (OBERSTRESS)

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: Spain
Call:  (ERC-2011-StG_20101109, 2011)
Start date: 2011-12-01
End date: 2017-05-31
Duration (months): 66.0
Total project cost (EUR): 1484000.0
EU funding (EUR): 1484000.0
Participants: 1
Project status: CLOSED

It is well established that metabolically relevant organs such as adipose tissue, pancreatic beta cells, liver and skeletal muscle develop endoplasmic reticulum (ER) stress under conditions of obesity induced lipotoxicity. Here, the applicant will investigate if/how the hypothalamus is affected by lipotoxicity and ER stress in the context of obesity * Scientific Hypotheses: 1. Obesity is associated with lipotoxicity and ER stress in the hypothalamus. 2. Hypothalamic ER stress may contribute to the development of obesity through dysregulation of the mechanisms controlling energy balance. 3. Based on our preliminary data, we hypothesize that CHOP, a mediator of ER stress, could be a key modulator of the association between obesity and ER dysfunction in the hypothalamus. * General Objective: to determine the relevance of hypothalamic lipotoxicity and ER stress for the development of obesity and whether targeting ER stress mechanisms is a successful therapeutic strategy to prevent or revert obesity and its metabolic complications. * Specific Objectives: 1. To determine whether obesity and the metabolic syndrome are associated with hypothalamic lipotoxicity, ER stress and whether these effects are hypothalamic nuclei specific 2. To determine whether primary hypothalamic ER stress is a cause of altered energy balance leading to obesity and metabolic complications 3. To determine whether in the context of obesity inhibition of ER stress in hypothalamus affects energy balance and obesity associated metabolic complications 4. To determine the role of CHOP on energy balance and obesity in specific hypothalamic neuronal populations This project is central to the applicant’s goal of understanding how the hypothalamus regulates energy balance under physiological and pathophysiological conditions, as an essential step towards identifying and developing novel molecular drug targets to tackle the problem of obesity and their metabolic complications.

Keywords: obesity,hypothalamus,er stress,lipids,lipotoxicity,energy balance,body weight
Cortical circuits of visual perception (PERCEPT)

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: Germany
Call:  (ERC-2011-StG_20101109, 2011)
Start date: 2012-01-01
End date: 2016-12-31
Duration (months): 60.0
Total project cost (EUR): 1299992.0
EU funding (EUR): 1299992.0
Participants: 1
Project status: CLOSED

Active perception relies on the concerted activity of populations of neurons in the cerebral cortex. These neuronal populations communicate via dense local and long-range connections, forming complex cortical circuits. While we are beginning to understand the elementary building blocks of such circuits during sensory processing, the circuit-level mechanisms by which top-down signals modulate sensory activity are largely unknown. The core of my proposal is to dissect the cortical circuits underlying top-down guided visual perception during active behaviour. The primary innovation of this proposal is to seek large-scale recordings from single neurons of identified type across all cortical layers in an actively behaving animal performing a well- controlled perceptual task. In Aim 1 we will develop novel paradigms to perform in the mouse visual perception experiments that achieve the ‘gold-standard’ in experimental control set by the behaving monkey. We will train mice in psychophysical tasks that offer exquisite control over the visual stimulus and the behavioural response, yield hundreds of trials per session, can be easily combined with recordings of neuronal activity and allow the manipulation of top-down factors. In Aim 2 we will conduct, for the first time, a detailed, circuit-level analysis of top-down modulations of sensory processing in visual cortex. Specifically, we will identify inhibitory interneurons in the neuronal population with optogenetic techniques and ask how behavioural relevance modulates activity for different cell types. This work will bring us closer to a functional explanation of active perception and will bridge the gap between two hitherto disconnected fields: it will open up questions of Cognitive Neuroscience for the field of Cellular Neuroscience.

Keywords: mouse,psychophysics,primary visual cortex,population activity,optogenetics,multielectrode recordings,contrast responses,laminar analysis,inhibition,interneurons,top-down modulation
Emergent Active Mechanical Behaviour of the Actomyosin Cell Cortex (ACTMECH)

Framework: FP7 — Ideas
Programme: European Research Council
Theme: European research council
Destination: Starting grants
Action type: Support for frontier research (ERC)
Panel: Cellular and Developmental Biology
Countries involved: Germany,Germany
Call:  (ERC-2011-StG_20101109, 2011)
Start date: 2011-12-01
End date: 2017-08-31
Duration (months): 69.0
Total project cost (EUR): 1500000.0
EU funding (EUR): 1500000.0
Participants: 2
Project status: CLOSED

The cell cortex is a highly dynamic layer of crosslinked actin filaments and myosin molecular motors beneath the cell membrane. It plays a central role in large scale rearrangements that occur inside cells. Many molecular mechanisms contribute to cortex structure and dynamics. However, cell scale physical properties of the cortex are difficult to grasp. This is problematic because for large scale rearrangements inside a cell, such as coherent flow of the cell cortex, it is the cell scale emergent properties that are important for the realization of such events. I will investigate how the actomyosin cytoskeleton behaves at a coarse grained and cellular scale, and will study how this emergent active behaviour is influenced by molecular mechanisms. We will study the cell cortex in the one cell stage C. elegans embryo, which undergoes large scale cortical flow during polarization and cytokinesis. We will combine theory and experiment. We will characterize cortex structure and dynamics with biophysical techniques such as cortical laser ablation and quantitative photobleaching experiments. We will develop and employ novel theoretical approaches to describe the cell scale mechanical behaviour in terms of an active complex fluid. We will utilize genetic approaches to understand how these emergent mechanical properties are influenced by molecular activities. A central goal is to arrive at a coarse grained description of the cortex that can predict future dynamic behaviour from the past structure, which is conceptually similar to how weather forecasting is accomplished. To date, systematic approaches to link molecular scale physical mechanisms to those on cellular scales are missing. This work will open new opportunities for cell biological and cell biophysical research, by providing a methodological approach for bridging scales, for studying emergent and large-scale active mechanical behaviours and linking them to molecular mechanisms.

Keywords: actomyosin,cortex,mechanics,hydrodynamic approach
Detection and interpretation of de novo mutations and structural genomic variations in mental retardation (DENOVO)

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: Netherlands
Call:  (ERC-2011-StG_20101109, 2011)
Start date: 2012-02-01
End date: 2017-01-31
Duration (months): 60.0
Total project cost (EUR): 1499154.0
EU funding (EUR): 1499154.0
Participants: 1
Project status: CLOSED

Mental retardation, like most common neurodevelopmental and psychiatric diseases, shows a strong genetic component, but these underlying genetic causes remain largely unknown. For a long time it was hypothesized that these kind of common diseases are mainly caused by common inherited genetic variants with reduced penetrance. In contrast to this common variant-common disease hypothesis, I here hypothesize that a large proportion of this so-called “missing heritability” for conditions such as mental retardation, schizophrenia, and autism lies in de novo genetic variation that is rapidly eliminated from the population because individuals with such diseases have severely compromised fecundity. My previous work using microarrays has already demonstrated de novo genomic copy number variations in mental retardation and in schizophrenia. However, microarrays do not allow us to capture the most common form of de novo mutations, those occurring at the nucleotide level. Technological innovations now for the first time allow us to comprehensively study the entire genome of an individual for genomic variations at all levels. In this project I will explore the de novo mutation hypothesis in whole exome and whole genome sequence data from patients with mental retardation. I will optimize and apply whole genome sequencing strategies using patient-parent trios, both in rare mental retardation syndromes as well as common forms of mental retardation. Guidelines for pathogenicity will be established by computational studies aimed at unraveling genotype-phenotype correlations in these family-based genome sequence type datasets. This project will contribute significantly to resolving the genetic causes of reproductively lethal disorders such as mental retardation, provide critical knowledge on the frequency and consequences of de novo mutations in our genome and help to establish medical genome sequencing as a routine diagnostic approach.

Keywords: mental retardation,learning disability,next generation sequencing
Membrane-triggered actin polymerisation: molecular mechanisms and morphogenesis (MEMBRANESACTIN)

Framework: FP7 — Ideas
Programme: European Research Council
Theme: European research council
Destination: Starting grants
Action type: Support for frontier research (ERC)
Panel: Cellular and Developmental Biology
Countries involved: United Kingdom
Call:  (ERC-2011-StG_20101109, 2011)
Start date: 2012-01-01
End date: 2018-12-31
Duration (months): 84.0
Total project cost (EUR): 1938322.2
EU funding (EUR): 1938322.2
Participants: 1
Project status: CLOSED

Changes in cell shape, movement and vesicle traffic all require remodelling of the actin cytoskeleton. While the actin filament remains chemically the same, the filaments are assembled differently for different functions, e.g. long, bundled, parallel filaments in filopodia and short meshworks in endocytosis. The membrane appears to function as an organising surface where proteins come together to form multiprotein complexes to generate distinct actin structures. The proposed research is aimed at understanding the roles contributed by the membrane and the identities of the signalling and effector proteins that form distinct actin structures. I have formulated in vitro reconstitution systems, using artificial membranes and extracts, that mimic the formation of two uses of actin: filopodia and endocytosis. I propose to use these reconstitution systems to identify proteins important for actin polymerisation during filopodia formation and endocytosis and then investigate their functions in vivo in Xenopus embryos. The first objective is to use biochemical fractionation to identify actin filament elongation factors to understand how filopodial length and rate of growth are regulated in cells during morphogenesis, with the ultimate goal of finding a minimal set of proteins that can make a filopodium. My second objective is to elucidate the molecular pathway that dictates how phosphoinositides and membrane curvature stimulate actin polymerisation during endocytosis, find how different actin regulators contribute to trafficking pathways in vivo, and the contribution of these endocytic pathways to early development. Solving the molecular basis of how the membrane-cytosol interface signals to actin polymerisation will reveal how changes in cellular organisation are orchestrated to achieve cell shape and movement during morphogenesis.

Keywords: filopodia actin endocytosis xenopus membrane phosphoinositide
Inflammatory signals emerging from the endoplasmic reticulum (ERINFLAMMATION)

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-2011-StG_20101109, 2011)
Start date: 2012-01-01
End date: 2016-12-31
Duration (months): 60.0
Total project cost (EUR): 1498076.0
EU funding (EUR): 1498076.0
Participants: 1
Project status: CLOSED

The endoplasmic reticulum (ER) serves many general functions, including the facilitation of protein folding and the transport of synthesized proteins, but it also has an important and more specialized role in sensing cellular stress. ER-stress identifies a group of signals that induce a transcriptional program enabling cells to survive protein overload and injury in the ER. This highly coordinated response involves three parallel signaling branches localized at the ER, namely IRE1, ATF6 and PERK. New findings suggest that these signaling pathways may regulate cellular processes independently of the ER-stress response. We have previously shown that some innate immune receptors such as Toll-like receptors specifically activate the IRE1 signaling pathway to enhance cytokine production. However, this is an emerging field of research and little is known on the specific nature of ER-signaling pathways and their function in regulating pathways in absence of a classical ER-stress response. The longterm goals of this proposal are to elucidate the molecular mechanisms and pathways emerging from the ER and regulating innate immune responses, and to address the physiological role of specific ER-signaling pathways in inflammation. Three complementary research sub-projects were designed. The first sub-project will identify and characterize compounds and conditions that trigger specific ER-signaling pathways. The second sub-project focuses on the biochemical characterization of signaling pathways emerging from the ER-associated kinases IRE1 and PERK. The third sub-project is aimed at investigating mechanisms by which ER-signaling pathways affect innate immune and inflammatory responses. The knowledge gained from this study will provide a better understanding of the mechanisms by which the ER and the cytosol interact to orchestrate physiological responses that help the organism to cope with infections and pathogenic insults.

Keywords: inflammation endoplasmic reticulum danger signals
Evolution and Transfer of Antibiotic Resistance (EVOTAR)

Framework: FP7 — Cooperation
Programme: Health
Destination: Translating research for human health
Action type: Collaborative project
Countries involved: Netherlands,Spain,Sweden,Denmark,Netherlands,Denmark,France,Spain,United Kingdom,Italy,Netherlands,Spain
Call:  (FP7-HEALTH-2011-single-stage, 2011)
Start date: 2011-10-01
End date: 2015-09-30
Duration (months): 48.0
Total project cost (EUR): 16044083.62
EU funding (EUR): 11997391.97
Participants: 18
Project status: CLOSED

Antibiotics are essential therapeutics in the treatment of bacterial infections. However, the indiscriminate use of antibiotics has led to the emergence of antibiotic resistant bacteria that pose a major threat to human health as options for treating infections by these bacteria have become limited. The evolution, emergence and spread of antibiotic resistance genes are still only poorly understood and expanding our knowledge on these aspects will provide novel leads to combat the emergence of antibiotic resistance. The EvoTAR consortium gathers a multi-disciplinary group of leading European researchers in the fields of antibiotic resistance, microbial genomics and mathematical modelling. In addition, three research-intensive SMEs participate in EvoTAR, two of which are involved in the development of novel approaches to minimize the emergence and spread of antibiotic resistance. The purpose of EvoTAR is to increase the understanding of the evolution and spread of antibiotic resistance in human pathogens. EvoTAR will characterise the human reservoir of antibiotic resistance genes (“the resistome”) by investigating the dynamics and evolution of the interaction between resistant and non-resistant bacteria from the human microbiome and the interrelations of the human resistome with non-human reservoirs of resistance genes. Novel methods will be used to quantify resistance transfer under controlled conditions in gene exchange communities. Mathematical modelling will be applied to predict gene flow between different reservoirs and to predict future resistance trends. Novel in vitro and in vivo models will allow the study of the efficacy of novel therapeutics aimed at reducing selection and spread of antibiotic resistance. The EvoTAR project will generate novel insights into the evolution and spread of antibiotic resistance genes and thereby create opportunities for the development of novel interventions to curb the rising tide of antibiotic resistance in human pathogens.

Keywords: evolution,transfer,antibiotic resistance,dynamics of the human microbiota,reservoirs of resistance,mathematical modelling,novel interventions,metagenomics,human pathogens
Sensory Integration in the Striatal Microcircuit (SENSTRIATUM)

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: Sweden
Call:  (ERC-2011-StG_20101109, 2011)
Start date: 2012-02-01
End date: 2017-01-31
Duration (months): 60.0
Total project cost (EUR): 1494445.0
EU funding (EUR): 1494445.0
Participants: 1
Project status: CLOSED

Motor behaviour requires the meaningful integration of a multitude of sensory information. The basal ganglia are essential for such sensory-motor processing and underlie motor planning, performance, and learning. The striatum is the input layer of the basal ganglia, acting as a “hub” that receives synaptic inputs from different brain regions, interacting primarily with the GABAergic striatal microcircuit. Sensory excitatory inputs to striatum arise from the thalamus and neocortex, targeting striatal projection neurons and interneurons. Previous work in basal ganglia focused mainly on their role in motor and reward related functions, but the functional role of striatum in sensory processing is largely unknown. In this study I will elucidate the principles of sensory processing performed at the striatal microcircuit. In particular, I aim to answer these fundamental questions: - How do striatal neurons integrate sensory input? How is sensory input from different sensory modalities integrated in the striatum? How are ipsi- and contralateral inputs integrated? - What are the respective roles of cortical and thalamic sensory inputs in striatal function? - How is the intra-striatal microcircuitry organized to support sensory integration? To address these questions I will use a combination of electrophysiological, optical, and anatomical methods, including: - In vivo whole-cell recordings from striatal neurons during visual and tactile stimulation. - Multi-neuron whole-cell recordings in corticostriatal and thalamostriatal slices. - Optical manipulation of identified neuronal subpopulations in slice and in vivo. The proposed study will provide a new understanding of sensory processing at the level of basal ganglia and may provide insights regarding basal ganglia dysfunction.

Keywords: striatum,basal ganglia,patch clamp,in vivo,sensorimotor
Determination of specific components from “stromal PDAC signature” involved in PDAC Associated Neural Remodeling (PANR) and their use as clinical tool-box. (STARGET-IN-PANR)

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-2011-StG_20101109, 2011)
Start date: 2011-12-01
End date: 2016-11-30
Duration (months): 60.0
Total project cost (EUR): 952686.0
EU funding (EUR): 952686.0
Participants: 1
Project status: CLOSED

Pancreatic ductal adenocarcinoma (PDAC) is the most intractable of human malignancies. Survival rate at 5 years is very low (less than 5%). Patients are most of the time diagnosed while the disease has already spread out and benefits from surgical resection is often cut off due to local recurrence and lack of efficient chemotherapy. Indeed, it is urgent to develop new tools to be used by clinicians in order to propose better management of the disease. This project is based on two specific characteristics of PDAC. First, the existence of a prominent tumor stroma compartment (desmoplasia) consisting of non-neoplastic myofibroblastic pancreatic stellate cells, vascular, nerve and immune cells surrounded by immense quantities of ECM, from far exceeding that found in most other tumor types. Second, the very specific and almost unique PDAC associated neural compartment remodeling (PANR) correlated with the intense neuropathic pain observed in this disease. PANR consists in a modification of nerve fiber structure/density and presence of tumoral cell within nerve fibers, a phenomenon called peri-neural invasion which is highly correlated to local recurrence of primary PDAC tumor. We and others hypothesized that, by dialoguing with cancer cells, non-tumoral stromal cells impact on PDAC tumor biology by modeling the own tumoral structure and fostering the tumor development. Regarding this concept we suppose that the intra-tumoral micro-environment has an active and efficient role on the neural compartment remodeling, its associated pain and local recurrence. By integrating preliminary and ongoing results from transcriptomic and proteomic analysis of human PDAC and endogenous mice model developing PDAC, as well as multiples cell lines co-culture studies, we aim to determine this “stromal PDAC signature” and its specific components involved in the PANR. Such improvement could permit to unravel novel diagnostic, prognostic, and therapeutic options for this deadly malignancy.

Keywords: pancreatic ductal adenocarcinoma,micro-environment,peri-neural invasion