Data-Gouv-ML/pcri-informations-sur-les-projets-laureats huggingface dataset:
The evolution of antibiotic resistance: integrating molecular mechanisms of resistance and evolutionary context (RESISTEVO)

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: 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): 1196639.0
EU funding (EUR): 1196639.0
Participants: 1
Project status: CLOSED

The evolution of antibiotic resistance poses an important threat to human health and welfare. Antibiotic resistance is accompanied by fitness costs that have been shown to play a key role in the spread of resistance. These costs are variable, but the underlying ecological and genetic causes of this variation remain obscure. Unfortunately, bacteria can adapt to the cost of resistance by compensatory mutations, and this permits resistance to be maintained in pathogen populations after antibiotics have been withdrawn from use. Resistance mutations vary in their potential for compensatory adaptation, but the causes of this variation remain unknown. In this project, we will determine how the molecular mechanisms of antibiotic resistance and the (i) ecological and (ii) genetic context in which resistance evolves interact to determine (a) the fitness costs associated with antibiotic resistance and (b) the potential and mechanisms for adaptation to the cost of resistance. Conceptually, we will approach this problem using an interdisciplinary approach that combines theory from population genetics and systems biology into the same evolutionary framework. To carry out this research program, we will use high-throughput experimental evolution of resistance to the broad-spectrum antibiotic rifampicin in bacteria from the genus Pseudomonas. This research approach will allow us to measure both the costs of resistance and the (i) rate and (ii) mechanisms of compensation for this cost at an unprecedented scale. The results of this research program will provide key insights into the underlying drivers of resistance emergence and persistence, and it may ultimately be possible to apply the insights from this research program to help combat resistance in pathogen populations. At a more conceptual level, this research will provide an important experimental test of the roles of chance, necessity, and historical contingency in shaping the rate and mechanisms of adaptation.

Keywords: experimental evolution,antibiotic resistance,compensatory adaptation,costs of resistance
Signaling and activation pathways of the NOD-like receptors Ipaf, Nlrp1b and Nlrp12 (SIGNLRACT)

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: Belgium
Call:  (ERC-2011-StG_20101109, 2011)
Start date: 2012-01-01
End date: 2016-12-31
Duration (months): 60.0
Total project cost (EUR): 1498266.99
EU funding (EUR): 1498266.99
Participants: 1
Project status: CLOSED

My overall aim is to define the role of NOD-like receptors (NLRs) in immunity and to understand the importance of their signaling networks in health and disease. NLR family members are thought to sense pathogens and endogenous alarmins in intracellular compartments to trigger innate immune responses. Recent progress was made in mapping the signaling pathways of the NLRs Nod1, Nod2 and Nlrp3, but the roles and signaling cascades of most other NLRs remain unclear. Indeed, the NLRs Ipaf and Nlrp1b assemble caspase-1-activating inflammasome complexes, but the molecular events leading to Ipaf and Nlrp1b activation remain enigmatic. Similarly, mutations in the NLR Nlrp12 are associated with auto-inflammation, but the precise molecular functions and signaling networks of this NLR require further study. To increase our understanding of the role and signaling pathways of Ipaf, Nlrp1b and Nlrp12, my first aim is to define the subcellular localization and co-regulated genes of these NLRs in naive and activated immune cells. In the second aim, I will define and validate the interactomes of Nlrp1b, Ipaf and Nlrp12 in immune cells from Ipaf, Nlrp1b and Nlrp12 mutant mice. In my third aim, these results will be used to map the activation mechanisms of the Nlrp1b and Ipaf inflammasomes in macrophages intoxicated with anthrax lethal toxin or infected with Salmonella, respectively; and to define the role of Nlrp12 and its interaction partners in innate immune signaling. To approach these aims, I will combine enabling proteomics approaches such as the proprietary mass spectrometry-based COFRADIC technology and interactome technologies such as MAPPIT with detailed biochemical and cell biological studies in NLR knockout cells and mice. Given the importance of NLRs in infection and autoimmunity, characterization of the activation and signaling pathways of Nlrp1b, Ipaf and Nlrp12 is likely to have far-reaching implications for our understanding of host defense and the immune response.

Keywords: nod-like receptors,inflammasomes,caspases
Genetic variation in the susceptibility of Drosophila to infection (DROSOPHILAINFECTION)

Framework: FP7 — Ideas
Programme: European Research Council
Theme: European research council
Destination: Starting grants
Action type: Support for frontier research (ERC)
Panel: Evolutionary, population and environmental biology
Countries involved: United Kingdom
Call:  (ERC-2011-StG_20101109, 2011)
Start date: 2011-11-01
End date: 2017-10-31
Duration (months): 72.0
Total project cost (EUR): 1498072.0
EU funding (EUR): 1498072.0
Participants: 1
Project status: CLOSED

Insects vary in their susceptibility to viral infection, and this variation affects disease transmission by vectors and the survival of beneficial insects. Identifying the genes that cause this variation will provide insights into both the molecular interactions between insects and their parasites, and the processes that maintain this variation in populations. We propose to do this in Drosophila, where genome-wide association studies are now possible thanks to the publication of large numbers of genome sequences. Furthermore, new techniques allow the sequence of Drosophila genes to be precisely altered, which will allow the exact molecular changes affecting resistance to be confirmed experimentally. Using these powerful techniques, we will first identify genes that affect resistance to a diverse panel of different viruses, which will allow us to understand the molecular and cellular basis of how resistance to different groups of viruses evolves in nature. Next, we will repeat this analysis using different isolates of the same virus, to identify the molecular basis of the ‘specific’ resistance commonly observed in invertebrates, where different host genotypes are resistant to different parasite genotypes. Once we have identified the polymorphisms that affect resistance, we can then use these results to examine the evolutionary processes that maintain this variation in populations: are alleles that increase resistance costly, how has natural selection acted on the polymorphisms, and is there more variation if the virus has naturally coevolved with Drosophila than if the virus was isolated from another insect. Finally, by hybridising D. melanogaster to D. simulans, we will extend these experiments to identify genes that cause species to differ in resistance, which will reveal the molecular basis of how resistance evolves over millions of years and how viruses adapt to their hosts.

Keywords: drosophila,virus,coevolution
Receptor signalling mediating malaria parasite motility (PARAMOTSIG)

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: Germany
Call:  (ERC-2011-StG_20101109, 2011)
Start date: 2012-04-01
End date: 2017-03-31
Duration (months): 60.0
Total project cost (EUR): 1453800.0
EU funding (EUR): 1453800.0
Participants: 1
Project status: CLOSED

Plasmodium sporozoites are the motile forms of the malaria parasite injected into the host by a mosquito. Sporozoite motility is essential for tissue penetration as well as host cell invasion and thus pathogenesis suggesting that blocking motility could potentially add a new way in controlling malaria. It is dependent on a parasite specific myosin, a highly divergent actin and plasma membrane proteins, adhesins that link the substrate to the actomyosin motor. We want to understand the molecular and biophysical basis that underlies the motility of sporozoites to eventually be able to block it. Consequently, we developed methods that allow a systematic probing of key variables important in motility in order to reveal the basic mechanisms of sporozoite locomotion and to screen for small molecules that inhibit motility. Using these assays, we made a number of groundbreaking observations on the cellular and molecular level that gave new insights into the mechanisms of sporozoite adhesion and motility. For example, the dynamic, actin-dependent turnover of adhesion sites was found to be a key factor in sporozoite motility. It is our ultimate goal to understand sporozoite motility to a degree that we can provide a comprehensive dynamic model of sporozoite movement. With the current proposal we aim at unravelling the initial molecular events leading to sporozoite motility focussing on three different adhesins that are known or suspected to be involved in motility. We hypothesize that outside-in signalling leading to actin rearrangements originates from the formation of homo- or heterodimers between these adhesins. Additionally we suggest that inside-out signalling contributes to modulation of adhesion strengths mediated by these adhesins. To test these hypotheses we will generate recombinant parasites that lack two adhesins or express fluorescently tagged adhesin fusions, chimeric or mutant adhesins and investigate these with our recently developed toolbox of novel assays.

Keywords: imaging,biopyhsics
Macro domain proteins in the cellular stress response and links to human disease (MACDOPRO)

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: United Kingdom,United Kingdom
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: 2
Project status: CLOSED

The macrodomain is a ubiquitous protein module known to bind to ADP-ribose derivatives, which diverged through evolution to support protein functions involved in DNA repair and the maintenance of genomic stability, transcriptional regulation, cell signaling, telomere dynamics, necrosis and apoptosis. Derivatives of ADP-ribose are synthesized by NAD+-dependent protein modification enzymes poly(ADP-ribose) polymerases (PARPs) and NAD+-dependent protein deacetylases (sirtuins). PARPs attracted enormous attention over the past several years, when it was demonstrated that permeable PARP inhibitors are highly effective against hereditary breast and ovarian cancers, as well as against acute cardiovascular conditions such as myocardial infarction and stroke. Given the apparent impact and prevalence of these diseases, there has been a rapidly growing interest in the search for alternative targets operating in PARP-dependent pathways that can be explored in therapy. However, these efforts have been hampered by our lack of knowledge about the mechanistic basis of cellular processes regulated by PARPs. In the first two sections of this proposal we will focus on the characterization of the two human macrodomain proteins poly(ADP-ribose) glycohydrolase (PARG) and the chromatin remodeler ALC1 (Amplified in Liver Cancer) that act as mediators of PARP-dependent signalling and have been implicated in human disease. Furthermore, in the third section we will study the sirtuin-linked macrodomain proteins found exclusively in fungal and bacterial pathogens and analyze their importance virulence. Collectively, the aims of this proposal are to define the molecular mechanisms governing the ADP-ribosylation-dependent signalling pathways mediated by several macrodomain proteins that are implicated in human disease. We feel that these studies can make a significant contribution to human health by providing the ground-work for the development of novel drugs that will ultimately provide cures.

Keywords: poly(adp-ribosyl)ation
Single Heart beat MApping of myocardial Performance, Activation, and Scar by ultrasound (HEARTMAPAS)

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: Belgium
Call:  (ERC-2011-StG_20101109, 2011)
Start date: 2012-02-01
End date: 2018-01-31
Duration (months): 72.0
Total project cost (EUR): 1602401.0
EU funding (EUR): 1602401.0
Participants: 1
Project status: CLOSED

Heart failure affects about 2% of the European population with an annual mortality rate of 10%. Cardiac Resynchronization Therapy (CRT) has been proven to reduce morbidity and mortality and has become a recommended treatment. Optimal lead placement for CRT not only requires exact anatomically mapped information on the mechanical activation sequence to be corrected but also tissue viability and performance maps. Unfortunately, to date, no imaging technique allows building such maps non-invasively in a single examination in CRT patients. In this project, a new ultrasound imaging approach is proposed that will not only allow mapping all of these characteristics in a single examination but that will actually do this in a single heart beat. Hereto, real-time segmentation of the left ventricle will be used to limit the data acquisition to the spatial regions that contain myocardium. In this way unnecessary spatial sampling can be avoided which combined with new beam forming strategies will allow imaging the entire left ventricle at frame rates above 1000Hz. This very high temporal resolution will be used to accurately measure the onset of local deformation of the left ventricle in order to construct a mechanical activation map. Subsequently, cardiac motion estimates will be used to track anatomical regions throughout the cardiac cycle in order to construct a temporally averaged backscatter intensity map. As scar tissue is known to be more reflective than normal myocardium, this should allow mapping of scar. Finally, the automatic segmentation process will allow to locally measure wall thickness and curvature from which the mechanical load distribution within the ventricle can be derived. This, combined with estimates of regional myocardial deformation will produce a map of myocardial performance. The proposed system will thus provide important new diagnostic and therapeutic information and will therefore allow better CRT planning for the individual heart failure patient.

Keywords: ultrasound imaging,cardiac,heart failure,3d imaging,cardiac resynchronization therapy
Small RNA-directed control of the plant and animal innate immune responses (SILENCING & IMMUNITY)

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: France
Call:  (ERC-2011-StG_20101109, 2011)
Start date: 2011-12-01
End date: 2017-11-30
Duration (months): 72.0
Total project cost (EUR): 1499955.4
EU funding (EUR): 1499955.4
Participants: 1
Project status: CLOSED

The innate immune response is the first line of defence against pathogens, which is initiated by the detection of pathogen-derived signatures referred to as Pathogen-Associated Molecular Patterns (PAMPs). Plants and animals sense PAMPs and in turn differentially regulate a large set of immune response genes, among which microRNAs (miRNAs) were recently identified. In the model plant Arabidopsis thaliana, dozens of miRNAs are PAMP-responsive, among them we found that a conserved miRNA contributes to antibacterial resistance. More recently, we have reported a major role of the Arabidopsis miRNA pathway in antibacterial defence and, as a corollary, have identified a series of bacterial-derived suppressors of the miRNA pathway. This pioneering work represents an important contribution to the understanding of virulence strategies employed by pathogenic bacteria and suggests that analogous strategies may also be used by human pathogenic bacteria. In the proposed project, we will first aim to investigate the extent to which an RNA silencing suppression strategy employed by a phytopathogenic bacterial effector is also used by effectors from human pathogenic bacteria. We will additionally aim to generate a comprehensive view of small RNA repertoires produced in the course of bacterial infection using both a human and a plant pathogenic bacteria. The second aspect of our proposal is directed toward a better understanding of the influence of PAMPs and bacterial effectors on Arabidopsis transcriptional gene silencing (TGS), a pathway that silences transposable elements and repeats through the establishment and maintenance of cytosine DNA methylation. Finally, we will aim to identify and characterize bacterial effectors that interfere with TGS. Overall, these studies should reveal completely novel bacterial virulence strategies and contribute to a better understanding of the mechanisms underlying post-transriptional- and transcriptional- gene silencing in different organisms.

Keywords: rna silencing,innate immunity,epigenetics,bacterial effectors
Sensory and cognitive ecology of species interactions in bat communities (INTERBAT)

Framework: FP7 — Ideas
Programme: European Research Council
Theme: European research council
Destination: Starting grants
Action type: Support for frontier research (ERC)
Panel: Evolutionary, population and environmental biology
Countries involved: Germany
Call:  (ERC-2011-StG_20101109, 2011)
Start date: 2012-01-01
End date: 2014-02-28
Duration (months): 26.0
Total project cost (EUR): 405672.0
EU funding (EUR): 405672.0
Participants: 1
Project status: CLOSED

There are two fundamental questions on the interaction of animal species that intrigue me: 1) What ‘knowledge’ do animals have of the behaviour and the ecology of other animal species (heterospecific recognition hypothesis)? 2) Do differences in sensory ability play a role in mediating resource partitioning between coexisting, potentially competing animal species (sensory niche partitioning hypothesis)? The central aim of the proposed project is to tackle these questions where species interactions really happens: out in the field (years 3-5). The model system will be a European community of bat species. Bats are an ideal model system, because they largely live in an acoustic world. Echolocation calls of heterospecific bats and acoustic prey cues can be experimentally manipulated and presented in field playback experiments. The central commitment of this project is to study animal behaviour using an experimental and hypothesis driven approach. To reconcile aim and commitment, I want to develop (year 1-2) automated experimental stations (AES) that can be deployed in the field. These stations will autonomously interact with wild animals, run individualized experiments and gather high-quality data for hypothesis testing. A key element will be a loudspeaker array that for the first time can realistically simulate moving sound sources (echolocating bats or prey insects) in the field. The proposal thus strives to answer ecological and evolutionary questions at a new level by developing and employing new technical apparatus, which will remain available for future applications beyond this project. The project will be hosted by the Max Planck Institute for Ornithology in Seewiesen, Germany, where I will benefit from a world-class, stimulating research environment. Field work will be conducted in Bulgaria in cooperation with Bulgarian colleagues and students.

Keywords: sensory ecology,cognitive ecology,bats,insects,bioacoustics,signaling,competition,predator-prey interaction,playback experiments,field experiments
Development of tumor penetrating peptides for glioma targeting (GLIOMADDS)

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: Estonia
Call:  (ERC-2011-StG_20101109, 2011)
Start date: 2012-01-01
End date: 2016-12-31
Duration (months): 60.0
Total project cost (EUR): 1499931.0
EU funding (EUR): 1499931.0
Participants: 1
Project status: CLOSED

This application addresses a major problem in therapy of solid tumors: poor penetration of anti-cancer drugs into tumor tissue and to infiltrating tumor cells. Recently, we have identified tumor penetrating peptides (TPP) that trigger specific penetration of co-administered un-conjugated drugs deep into tumor and increase their therapeutic index. Current TPP target angiogenic tumor vessels and may not be suitable for targeting slow-growing tumors and invasive tumor cells. TPP are composed of functional modules (tumor recruitment motif, cryptic tissue penetrating C-end Rule element, and a protease cleavage site), which can be rearranged to yield peptides of novel specificities. Our goal is to develop TPP platform for delivery of co-administered drugs to the deadliest brain tumor – glioblastoma (GBM). High-grade glioma is a target that is particularly evasive and well-suited for tissue penetrative drug delivery. We will develop glioma-specific TPP (gTPP) by combination of in vivo and ex vivo phage display of constrained peptide libraries on state-of-the-art glioma animal models. These gTPP will be able to penetrate gliomas (and potentially other tumors) independent of their angiogenic status, and to deliver drugs to infiltrating malignant cells far from the bulk glioma lesion. We will characterize, validate, and optimize the gTPP platform for enhanced glioma delivery of co-injected drugs. These studies will provide the preclinical data needed to advance the gTPP combination therapy of glioma to GLP toxicology and subsequent IND filing.

Keywords: targeted drug delivery,peptide,angiogenesis,glioma,cytotoxic drug,tissue penetration