Data-Gouv-ML/pcri-informations-sur-les-projets-laureats huggingface dataset:
Ultrafast Imaging of the Heart Using Ultrasound: a breakthrough for early diagnosis of cardiac diseases (ULTRAECHOCARDIO)

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: France
Call:  (ERC-2012-StG_20111109, 2012)
Start date: 2013-02-01
End date: 2018-01-31
Duration (months): 60.0
Total project cost (EUR): 1417480.0
EU funding (EUR): 1417480.0
Participants: 1
Project status: CLOSED

Heart failure (HF) affects 14 million people in Europe, and this number is forecast to increase to 30 million by 2020. Early diagnosis of HF is essential for successfully addressing underlying causes. However, initial diagnosis is difficult in many situations so that HF is correctly diagnosed in only half of affected patients. Diastolic HF, for example, that accounts for more than 50% of all HF patients, is due to abnormal ventricular stiffness which remains very difficult to diagnose. The characterization of myocardial properties remains today a challenge and there is currently no imaging technique that can assess myocardial stiffness in clinical practice. In ULTRAECHOCARDIO, a novel ultrafast imaging approach is proposed not only to image myocardial stiffness but also myocardial electromechanical properties and blood flows with high sensitivity. Whereas conventional ultrasound scanners can achieve 100 images/s, ultrafast imaging can perform 100 times faster, up to 10,000 images/s. This ultrafast capability is a breakthrough in cardiac imaging that opens new possibilities, such as imaging tissue and blood motion with high temporal resolution, but also mechanical (shear waves) and electromechanical waves that remain undetectable with conventional techniques. New echocardiographic modalities will be developed based on a unique ultrafast imaging platform: (1) Shear Wave Imaging for quantitative evaluation of myocardial stiffness, (2) Electromechanical Wave Imaging for mapping of electrical activation in the heart and (3) Ultrafast Doppler Imaging for blood flow mapping with high sensitivity. These modalities will be validated on preclinical models with early modifications of myocardial stiffness and electrical disorders. Finally, the clinical impact will be evaluated on patients with diastolic HF, electrical disorder and coronary artery disease. This technology will provide new diagnostic information crucial for early diagnosis of HF and assessment of HF treatment.

Keywords: ultrasound,echocardiography,heart failure,myocardial stiffness,shear wave,viscoelasticity,electrical disorder,acoustic radiation force,ultrafast imaging,doppler imaging
A novel two-step model for neurodegeneration in Parkinson’s disease (2STEPPARKIN)

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: Switzerland
Call:  (ERC-2012-StG_20111109, 2012)
Start date: 2013-06-01
End date: 2018-08-31
Duration (months): 63.0
Total project cost (EUR): 1518960.0
EU funding (EUR): 1518960.0
Participants: 2
Project status: CLOSED

Parkinson’s disease (PD) is the second most common neurodegenerative disorder primarily caused by the progressive loss of dopaminergic (DA) neurons in the substantia nigra (SN). Despite the advances in gene discovery associated with PD, the knowledge of the PD pathogenesis is largely limited to the involvement of these genes in the generic cell death pathways, and why degeneration is specific to DA neurons and why the degeneration is progressive remain enigmatic. Broad goal of our work is therefore to elucidate the mechanisms underlying specific and progressive DA neuron degeneration in PD. Our new Drosophila model of PD ⎯Fer2 gene loss-of-function mutation⎯ is unusually well suited to address these questions. Fer2 mutants exhibit specific and progressive death of brain DA neurons as well as severe locomotor defects and short life span. Strikingly, the death of DA neuron is initiated in a small cluster of Fer2-expressing DA neurons and subsequently propagates to Fer2-negative DA neurons. We therefore propose a novel two-step model of the neurodegeneration in PD: primary cell death occurs in a specific subset of dopamindegic neurons that are genetically defined, and subsequently the failure of the neuronal connectivity triggers and propagates secondary cell death to remaining DA neurons. In this research, we will test this hypothesis and investigate the underlying molecular mechanisms. This will be the first study to examine circuit-dependency in DA neuron degeneration. Our approach will use a combination of non-biased genomic techniques and candidate-based screening, in addition to the powerful Drosophila genetic toolbox. Furthermore, to test this hypothesis beyond the Drosophila model, we will establish new mouse models of PD that exhibit progressive DA neuron degeneration. Outcome of this research will likely revolutionize the understanding of PD pathogenesis and open an avenue toward the discovery of effective therapy strategies against PD.

Keywords: translational research,drosophila model,mouse model,parkinson's disease
New biomarkers for Alzheimer’s & Parkinson’s diseases - key tools for early diagnosis and drug development (BIOFINDER)

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: Sweden
Call:  (ERC-2012-StG_20111109, 2012)
Start date: 2013-06-01
End date: 2018-05-31
Duration (months): 60.0
Total project cost (EUR): 1500000.0
EU funding (EUR): 1500000.0
Participants: 1
Project status: CLOSED

Alzheimer’s disease (AD) and Parkinson’s disease (PD) are common in elderly and the prevalence of these is increasing. AD and PD have distinct pathogenesis, which precede the overt clinical symptoms by 10-15 years, opening a window for early diagnosis and treatment. New disease-modifying therapies are likely to be most efficient if initiated before the patients exhibit overt symptoms, making biomarkers for early diagnosis crucial for future clinical trials. Validated biomarkers would speed up initiation of treatment, avoid unnecessary investigations, and reduce patient insecurity. AIMS: (1) identify and validate accurate and cost-effective blood-based biomarkers for early identification of those at high risk to develop AD and PD, (2) develop algorithms using advanced imaging and cerebrospinal fluid biomarkers for earlier more accurate diagnoses, and (3) better understand the underlying pathology and early progression of AD and PD, aiming at finding new relevant drug targets. We will assess well-characterized and clinically relevant populations of patients and healthy elderly. We will use population- and clinic-based cohorts and follow them prospectively for 4 year. Participants will undergo neurocognitive evaluation, provide blood and cerebrospinal fluid, and have brain imaging using advanced MRI protocols and a newly developed PET-tracer visualizing brain amyloid. Sample will be analyzed with quantitative mass spectrometry and high sensitivity immunoassays. New biomarkers and brain imaging techniques will aid early diagnosis and facilitate the development of disease-modifying therapies, since treatment can start earlier in the disease process. New methods to quantify relevant drug targets, such as oligomers of β-amyloid and α-synuclein, will be vital when selecting drug candidates for large-scale clinical trials. By improving both diagnosis and therapies the social and economic burden of dementia might be reduced by expanding the period of healthy and active aging

Keywords: biomarkers,early diagnosis,dementia,alzheimer's disease,parkinson's disease,mild cognitive impairment,cerebrospinal fluid,plasma,positron emission tomography,magnetic resonance imaging
Signal integration of stomatal stress responses (STORM)

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-2012-StG_20111109, 2012)
Start date: 2012-12-01
End date: 2017-11-30
Duration (months): 60.0
Total project cost (EUR): 1494559.0
EU funding (EUR): 1494559.0
Participants: 1
Project status: CLOSED

Stomata are pores in the leaf epidermis allowing CO2 uptake essential for photosynthesis, but make plants vulnerable to water loss and pathogen invasion. Plants have therefore mechanisms to close stomata in response to microbes, which, however, must be balanced with the regulation of stomatal movements for photosynthesis and abiotic-stress parameters. The pathways and integration of diverse signals leading to stomatal closure still remain elusive, and how stomatal apertures are regulated to control pathogen invasion is a major biological question. My long-term objective is to understand how stomatal aperture is controlled in biotic stresses, how this interacts with abiotic stresses, and how membrane trafficking, an unexplored mechanism of stomatal movements, contributes to stomatal closure. The rationale behind this research relates to a novel high throughput imaging method monitoring the dynamics of stomatal behaviors, and exciting preliminary data that suggest specific and overlapping functions of some of the underlying genes regulating stomatal closure as well as a role for membrane trafficking stomatal movement. The overall aim of this proposal is to identify the molecular components of stomatal immunity and the genetic networks of stomata control. In order to achieve this, the specific objectives contained in this proposal are to understand: 1. What are the molecular components of pathogen-induced stomatal closure? 2. How does pathogen-induced stomatal closure interact with abiotic stresses? 3. How does membrane trafficking contribute to stomatal closure? I will investigate these questions using a combination of cell biology advanced imaging, genetic approaches and computational modelling that will allow me to dissect the significance and specificity of biotic and abiotic-stress induced stomatal closure and membrane trafficking in this context. This will pioneer new avenues from which to investigate and understand a plant’s interaction with its environment.

Keywords: plant stomata,stomatal movements,membrane trafficking
Autophagy as a cancer treatment (CANCERPHAGY)

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-2012-StG_20111109, 2012)
Start date: 2012-10-01
End date: 2018-09-30
Duration (months): 72.0
Total project cost (EUR): 1453219.0
EU funding (EUR): 1453219.0
Participants: 1
Project status: CLOSED

Cancer is one of the most prevalent human killer diseases. Autophagy, a lysosome-mediated process that degrades cellular components and damaged organelles, has recently emerged as an important player in cancer. Indeed, autophagy inhibition promotes cancer initiation through generation of genomic instability and inflammation, whereas in contrast, autophagy activation is often required to sustain growth of advanced solid tumours in a nutrient-deprived hypoxic environment. Recent findings firmly demonstrate that modulating autophagy can potentially be exploited to suppress tumours and to avoid resistance in anti-cancer therapy. However, the interplay between cancer and autophagy is complex, and further in-depth investigation is urgently required. Therefore I propose to use the well-described cancer models in Drosophila, together with the autophagy mutants that I have developed, firstly to test how an autophagy-proficient/deficient host environment alters growth and dissemination of allografted tumours. Secondly, I will examine how modulation of autophagy within the tumour can impact on its growth. In order to alter independently tumour induction with autophagy inhibition/activation, I will make use of the two inducible expression systems currently only available for Drosophila. These experiments will be accompanied by detailed analysis of mitochondrial status, as well as protein damage and DNA lesions, which will shed light on the intricate mechanisms whereby autophagy affects cancer and will help indicate optimal time points for further analysis of the tumours by in-depth transcriptional, proteomic and metabolomic profiling. Collectively, this project proposal is designed to rapidly test various hypotheses for cancer prevention and treatment, to provide valuable insights for further validation in higher organisms, and to identify new potential drug targets for cancer research.

Keywords: autophagy cancer tumour drosophila melanogaster dna damage protein damage mutation mitochondria transcriptomic metabolomic proteomic metastasis anti-cancer therapy environment stress allograft
Biochemical reconstitution of DNA repair reactions on physiological chromatin substrates (DNA-REPAIR-CHROMATIN)

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
Call:  (ERC-2012-StG_20111109, 2012)
Start date: 2013-01-01
End date: 2018-12-31
Duration (months): 72.0
Total project cost (EUR): 1747823.0
EU funding (EUR): 1747823.0
Participants: 1
Project status: CLOSED

For cells and organisms to survive and propagate, they must accurately pass on their genetic information to the next generation. Errors in this process may arise from spontaneous mistakes in normal cellular metabolism, or from exposure to external agents, such as chemical mutagens and radiation. To protect themselves from the consequences of DNA damage, cells have evolved a vast array of pathways DNA repair mechanisms, each optimised for the resolution of a particular problem. One method of DNA repair, called homologous recombination (HR), involves using intact undamaged DNA sequences as a template to repair the damaged copy. HR is used extensively in meiotic cells to repair DNA breaks that are purposely created by the cell. In this context, HR is not just a repair mechanism, but also a method to drive interaction and genetic exchange between maternally and paternally inherited chromosomes, creating haploid genomes which are chimeras of the parental genetic information. Thus, the study of DNA repair and recombination informs our understanding of mechanisms that maintain genome stability, but which also generate genetic diversity, topics that are as critical to the survival of an individual cell as they are for the evolution and survival of an entire ecosystem. In recent decades a great deal has been learned of the genetic and biochemical control of the DNA repair and recombination mechanism. In general we infer gene function from what happens (or doesn’t happen) when we mutate a pathway of interest, and use biochemistry to test function using surrogate, simplified in vitro assays. Here, to bridge the divide between these classic approaches, I propose to develop biochemical methods using intact chromatin prepared from living cells. I believe that integrating chromatin biochemistry, with cell biology and genome-wide analysis will enable a new mode of scientific investigation, detailing how molecular reactions occur on biologically-relevant chromosomal substrates.

Keywords: meiosis,biochemistry,dna repair,next-generation sequencing
Impact of virus infection on the host proteome (IVIP)

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-2012-StG_20111109, 2012)
Start date: 2012-11-01
End date: 2017-10-31
Duration (months): 60.0
Total project cost (EUR): 1498896.0
EU funding (EUR): 1498896.0
Participants: 2
Project status: CLOSED

Pathogens exploit cellular resources for their own benefit and their propagation. Co-evolution of viruses and their hosts led to the establishment of very specific interactions between both partners. The balance between both, the viral attack and the cellular defense mechanisms, dictates the outcome of an infection, either leading to a cure, to disease or life-long co-existence. Efforts from many laboratories have focused on virus-host interactions, mostly by testing isolated protein-protein interactions or by employing transcriptome analysis. Although this undoubtedly has been highly valuable to our knowledge on virus-host interactions, it is also clear that most virus-host interactions do not occur on transcriptome level and neither involve single protein-protein interactions. Here I propose to systematically test the impact of virus infection on the host proteome (iViP) by using the newest generation of mass spectrometry-based discovery tools combined with infection biology. iViP divides in three interconnected parts that individually and collectively warrant success: Part I evaluates changes in the abundance of the proteins after virus infection and correlates this to mRNA levels, determined by RNA sequencing. Part II identifies proteome-wide post-translational modifications that would be indicative for an involvement in infection biology. Part III dissects the role of virus stimulated/altered proteins in the antiviral protein-protein interaction network. Lastly, identified proteins will be validated in a two –step procedure involving a large-scale validation strategy and further focusing on few selected interactors. A comprehensive coherent data set describing and functionally explaining the cellular changes after encounter of a variety of viral pathogens on a proteome level would complement or even succeed currently available data sets and become invaluable to basic and translational research of the future.

Keywords: host-pathogen interactions cellular responses to viral infections antiviral immunity
Bacterial effector secretion: Function and Architecture of the Type 3 Secretion System (FUTURE T3SS)

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-2012-StG_20111109, 2012)
Start date: 2013-01-01
End date: 2017-12-31
Duration (months): 60.0
Total project cost (EUR): 1488240.0
EU funding (EUR): 1488240.0
Participants: 2
Project status: CLOSED

Bacterial pathogens secrete effector proteins to manipulate host cells during infection. In Gram-negative bacteria the conserved type 3 secretion system (T3SS) delivers effector proteins to the host cell in a spatiotemporal manner. Although major T3SS constituting components were identified the function of this macromolecular complex remains elusive which is why the transport mechanism is not understood yet. Here, I present my research proposal of the functional and structural analysis of the T3SS with respect to the effector transport dynamics. The proposal is divided in three sections addressing the T3SS architecture, the cytosolic mechanism preceding effector molecule release and the molecular mechanisms of secretion regulation. Research focus of the first section is on the 3-dimensional structural analysis of isolated T3SS. The proposed studies should help detecting structural features related to the effector transport. A combination of electron microscopy (EM) and mass spectrometry is proposed to analyze the structure and surface properties of the transport channel together with bound effector molecule. I am also planning localization of bound lipids as well as to detect lipid induced structural changes in the T3SS by EM. Characterization of cytosolic processes, preceding the translocation is the focus of the second section. Effector molecule targeting, insertion into the T3SS channel and the chaperone function will be studied using a combination of biochemical and biophysical techniques.Finally, I propose experiments to analyze the T3SS regulation. Here, the research focus is on host signal reception and downstream posttranslational modifications inside bacteria as well as on conformational dynamics of the T3SS needle tip complex. The overall goal of the proposed work is to understand the molecular mechanisms of the T3SS. I believe these studies will impact both the understanding of bacterial pathogenesis as well as the transmembrane transport of proteins.

Keywords: protein transport,t3ss,gram-negative bacteria,macromolecular complex,shigella,salmonella
Function and production of secondary metabolites (PROSECMET)

Framework: FP7 — Ideas
Programme: European Research Council
Theme: European research council
Destination: Starting grants
Action type: Support for frontier research (ERC)
Panel: Applied life sciences and biotechnology
Countries involved: Germany
Call:  (ERC-2012-StG_20111109, 2012)
Start date: 2013-03-01
End date: 2018-02-28
Duration (months): 60.0
Total project cost (EUR): 1754700.0
EU funding (EUR): 1754700.0
Participants: 1
Project status: CLOSED

Secondary metabolites (SMs) of bacterial origin play a pivotal role in modern therapy of various diseases. Whole-genome sequencing projects have revealed that all SM producing organisms have the capacity to produce many more compounds than reported from the respective strains. Despite their importance and their broad use in medicine, we hardly know anything about (i) the natural function of these important compounds, (ii) the underlying regulatory networks, and (iii) how to increase the number and yield of SMs produced by a single organism. PROSECMET will address all these issues through the activities in four different work packages. As model organisms Photorhabdus and Xenorhabdus bacteria will be used that live in symbiosis with nematodes and together with them form an entomopathogenic complex. WP1-Identification of SM targets. Derivatives of SMs will be synthesized allowing the identification of their molecular targets in bacteria, nematodes, insects and/or food competitors using methods of chemical biology. WP2-Regulatory networks. External factors that activate SM production and if and how SMs act as internal signals in the producer will be identified (eg. by flow cytometry) with specific strains carrying SM biosynthesis gene promoters or promoter libraries fused to genes encoding different reporters (fluorescent proteins, resistance genes). WP3-Increasing chemical diversity. Factors identified in WP2 will be applied to at least 100 different Photorhabdus and Xenorhabdus isolates in order to increase the number and the yield of SMs produced by them. Additionally, the genome of selected isolates will be sequenced in order to exchange the promoters responsible for SM biosynthesis leading to the production of additional compounds WP4-Optimization of SM production. Using either regulatory elements identified in WP2 or artificially designed regulators, cell growth will be coupled to SM production, thus enabling the systematic construction of SM overproducers.

Keywords: natural product,chemical biology,target identification,product optimisation,regulatory network identification