Data-Gouv-ML/pcri-informations-sur-les-projets-laureats huggingface dataset:
Closing in on Runx3 and CXCL4 to open novel avenues for therapeutic intervention in systemic sclerosis (CIRCUMVENT)

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: Netherlands
Call:  (ERC-2011-StG_20101109, 2011)
Start date: 2012-08-01
End date: 2017-07-31
Duration (months): 60.0
Total project cost (EUR): 1500000.0
EU funding (EUR): 1500000.0
Participants: 1
Project status: CLOSED

Systemic sclerosis (SSc) is an autoimmune disease that culminates in excessive extra-cellular matrix deposition (fibrosis) in skin and internal organs. SSc is a severe disease in which fibrotic events lead to organ failure such as renal failure, deterioration of lung function and development of pulmonary arterial hypertension (PAH). Together, these disease hallmarks culminate in profound disability and premature death. Over the past three years several crucial observations by my group changed the landscape of our thinking about the ethiopathogenesis of this disease. First, plasmacytoid dendritic (pDCs) cells were found to be extremely frequent in the circulation of SSc patients (1000-fold) compared with healthy individuals. In addition, we observed that pDCs from SSc patients are largely dedicated to synthesize CXCL4 that was proven to be directly implicated in fibroblast biology and endothelial cell activation, two events recapitulating SSc. Finally, research aimed to decipher the underlying cause of this increased pDCs frequency led to the observation that Runx3, a transcription factor that controls the differentiation of DC subsets, was almost not expressed in pDC of SSc patients. Together, these observations led me to pose the “SSc immune postulate” in which the pathogenesis of SSc is explained by a multi-step process in which Runx3 and CXCL4 play a central role. The project CIRCUMVENT is designed to provide proof of concept for the role of CXCL4 and RUNX3 in SSc. For this aim we will exploit a unique set of patient material (cell subsets, protein and DNA bank), various recently developed in vitro techniques (siRNA for pDCs, viral over expression of CXCL4/RUNX3) and apply three recently optimised experimental models (CXCL4 subcutaneous pump model, DC specific RUNX3 KO and the SCID/NOD/rag2 KO mice). The project CIRCUMVENT aims to proof the direct role for Runx3 and CXCL4 that could provide the final step towards the development of novel therapeutic targets

Keywords: plasmacytoid dendritic cells,chemokines,transcription factors,systemic sclerosis
The mechanisms for lateral gene transfer in nature as reflected in prokaryote genomes (EVOLATERAL)

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,Germany
Call:  (ERC-2011-StG_20101109, 2011)
Start date: 2012-07-01
End date: 2018-06-30
Duration (months): 72.0
Total project cost (EUR): 1500000.0
EU funding (EUR): 1500000.0
Participants: 2
Project status: CLOSED

Lateral gene transfer (LGT) is the process by which prokaryotes acquire DNA across wide taxonomic boundaries and incorporate it into their genome. Accumulating evidence shows that LGT plays a major role in prokaryote evolution. The biological and evolutionary significance of lateral gene transfer has broad implications for our understanding of microbial biology, not only in terms of evolution, but also in terms of human health. Mechanisms of lateral gene transfer include: transformation, transduction, conjugation, and gene transfer agents. Each of these transfer mechanisms leaves distinct and recognizable molecular footprints in genome sequences. The molecular details of these footprints betray the workings of the corresponding mechanisms in nature, but their relative contributions to the evolution of sequenced genomes have so far not been investigated. By identifying these footprints one can specify and quantify the relative contribution of the different LGT mechanisms during prokaryote genome evolution and thereby uncover more of the biology underlying prokaryote evolution in nature. The goal of this proposal is to quantify those contributions and to bring forth a general computer-based model of prokaryote genome evolution that approximates the underlying evolutionary process far more realistically than phylogenetic trees alone possibly can. Here I propose to apply directed networks to the study of prokaryotic genome evolution in an evolutionary model that allows both for vertical inheritance and for lateral gene transfer events. With methods to identify gene donors, all recent LGTs can be described in a single directed network. This is a fundamentally new, biologically more realistic and evolutionarily more accurate, general computational model of prokaryote genome evolution. Such a model will substantially enrich our ability to understand the process of prokaryote evolution as it is recorded in genomic and metagenomic data.

Keywords: evolutionary microbiology,genomics,phylogenomics,networks
Role of Professional and Non-professional Antigen Presenting Cells In Autoimmunity and Cancer (PROSPECT)

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): 1492754.4
EU funding (EUR): 1492754.4
Participants: 1
Project status: CLOSED

Immunological tolerance to self is essential in the prevention of autoimmune disease. Although central tolerance is remarkably efficient, potentially autoaggressive T cells can reach the periphery. Peripheral mechanisms of tolerance induction are therefore required to protect peripheral tissues from autoimmune attack. The two main types of dendritic cells (DC) are conventional DC (cDC) and plasmacytoid DC (pDC), both derived from the hematopoietic lineage. The prevailing model for peripheral tolerance involves the cross-presentation of tissue antigens (Ag) by quiescent cDC. The exposure of cDC to selected inflammatory stimuli can change the outcome of the immune response from tolerance to immunity. In contrast to cDC, pDC were initially believed to be involved in innate immune responses via the secretion of type I interferons following viral or bacterial infections. However, recent findings demonstrate that like cDC, pDC are also implicated in adaptive immune responses. This proposal will allow the intricate in vivo analysis of the impact on immune responses following the selective loss of Ag presentation function by pDC. These models involving cDC and/or pDC limit however the presentation of particular Ags to the lymph nodes draining the tissues in which the Ag is expressed. An alternative mechanism, involving non-hematopoietic lymph node stromal cells, has recently emerged. In this mechanism, the lymph node stromal cells express various tissue self-Ag and could thus contribute to peripheral T cell tolerance. This grant application will investigate whether non-hematopoietic stromal cells can present tissue self-Ag in inflammatory situations in vivo, and whether it has a impact on T cell responses during the development of diseases. Overall, we will investigate the respective contribution of hematopoietic and non-hematopoietic cellular compartments in the maintenance of peripheral T cell tolerance and prevention from disease.

Keywords: antigen presentation,dendritic cell,t cell,lymph node stroma,autoimmunity,cancer,peripheral t cell tolerance
Evolution of Alzheimer’s Disease: From dynamics of single synapses to memory loss (ABATSYNAPSE)

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: Israel
Call:  (ERC-2011-StG_20101109, 2011)
Start date: 2011-12-01
End date: 2017-09-30
Duration (months): 70.0
Total project cost (EUR): 2000000.0
EU funding (EUR): 2000000.0
Participants: 1
Project status: CLOSED

A persistent challenge in unravelling mechanisms that regulate memory function is how to bridge the gap between inter-molecular dynamics of single proteins, activity of individual synapses and emerging properties of neuronal circuits. The prototype condition of disintegrating neuronal circuits is Alzheimer’s Disease (AD). Since the early time of Alois Alzheimer at the turn of the 20th century, scientists have been searching for a molecular entity that is in the roots of the cognitive deficits. Although diverse lines of evidence suggest that the amyloid-beta peptide (Abeta) plays a central role in synaptic dysfunctions of AD, several key questions remain unresolved. First, endogenous Abeta peptides are secreted by neurons throughout life, but their physiological functions are largely unknown. Second, experience-dependent physiological mechanisms that initiate the changes in Abeta composition in sporadic, the most frequent form of AD, are unidentified. And finally, molecular mechanisms that trigger Abeta-induced synaptic failure and memory decline remain elusive. To target these questions, I propose to develop an integrative approach to correlate structure and function at the level of single synapses in hippocampal circuits. State-of-the-art techniques will enable the simultaneous real-time visualization of inter-molecular dynamics within signalling complexes and functional synaptic modifications. Utilizing FRET spectroscopy, high-resolution optical imaging, electrophysiology, molecular biology and biochemistry we will determine the casual relationship between ongoing neuronal activity, temporo-spatial dynamics and molecular composition of Abeta, structural rearrangements within the Abeta signalling complexes and plasticity of single synapses and whole networks. The proposed research will elucidate fundamental principles of neuronal circuits function and identify critical steps that initiate primary synaptic dysfunctions at the very early stages of sporadic AD.

Keywords: synaptic trasmission,synaptic plasticity,amyoid-beta,presynaptic function,hippocampal neurons,alzheimer's disease,functional imaging,fret.
Viral frontiers – species barriers of hepatitis C virus replication (VIRAFRONT)

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: 2012-02-01
End date: 2017-01-31
Duration (months): 60.0
Total project cost (EUR): 1444515.59
EU funding (EUR): 1444515.59
Participants: 1
Project status: CLOSED

RNA viruses are responsible for important acute, chronic as well as emerging human infections. While some of these viruses – like for instance the hepatitis C virus (HCV) – are highly species-specific, others (e.g. Dengue Virus) infect different host species. These latter viruses cause zoonotic infections, i.e. infections of animal hosts that are transmitted to humans by unintentional contact. Why some RNA viruses are highly species-specific, whereas others have a broad species-tropism is poorly understood. Moreover, host-derived control mechanisms that prevent viruses to transmit across species barriers and viral evasion and adaptation strategies are only beginning to emerge. While climatic changes, augmented population density and mobility increase the risk for human exposure to novel RNA viruses, therapeutics preventing disease in humans or precluding transmission are lacking. In some cases, small animal models for drug discovery, vaccine research and pathogenesis studies are not available. The objective of the proposal is to define all factors that prevent HCV propagation in mouse liver cells. The inability of HCV to propagate in non-human cells may be due to lack or genetic incompatibility of essential viral replication co-factors and/or due to antiviral restriction mechanisms effectively suppressing viral replication in non-human host cells. Taking this into account, both rationale and unbiased genetic screening systems will be employed to derive a comprehensive profile of all factors relevant to the species barrier for HCV infection of mouse cells. Moreover, viral adaptation and evasion strategies to overcome these barriers will be explored. These pioneer studies will prepare the ground for development of urgently needed HCV small animal models and provide valuable insights into the mechanisms of pathogen control at species barriers. This should promote future development of strategies which prevent zoonotic transmission of emerging RNA viruses to humans.

Keywords: tropism
Rapid reliable volume status and ventricular function assessment by non-specialist staff using innovative imaging in clinical practice (SURESCAN)

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: United Kingdom
Call:  (ERC-2011-StG_20101109, 2011)
Start date: 2012-01-01
End date: 2017-12-31
Duration (months): 72.0
Total project cost (EUR): 1537288.64
EU funding (EUR): 1537288.64
Participants: 1
Project status: CLOSED

Many urgent medical settings require immediate assessment of intravascular volume status to initiate treatment and non-invasive monitoring of progressive changes in volume. Other diagnostic medical scenarios require urgent identification of impairment of ventricular function, to select appropriate initial treatment. With standard approaches, accessing this information quantitatively requires expert cardiological involvement, which introduces potentially harmful delay and unnecessary cost. My research is a high-risk leap in the opposite direction to the obvious avenue. Instead of using increasingly difficult measurements to study an increasingly narrow range of specifically cardiac conditions, I will harness physiological knowledge with technological advances, to develop and validate devices that a novice can reliably use with little training, to make limited but reliable and clinically useful quantitative measurements. Specifically, I aim to: • develop unique tools that support health care professionals with minimal training, to reliably acquire a limited set of echo measurements in patients • experimentally verify the ability of novices to thereby track changes in volume status • experimentally verify the ability of novices to detect abnormalities in ventricular function The immediate impact of this research will be the development, and evaluation by clinical physiological experiments, of a system that guides a novice operator to obtain good images, and helps them to detect ventricular dysfunction and disorders of fluid status. There will be numerous auxiliary benefits of this work. One will be the support tools for trainee echocardiographers/cardiologists who could get automatic, personalised guidance in improving image positioning in the early months of their work, making it easier to train these individuals who are in very short supply. Secondly, clinical practices and trials can use these tools to express image quality of echo measurements.

Keywords: emergency medicine clinical medicine intrascular volume status
The Cellular Basis of Multicellular Pattern Formation (CELLPATTERN)

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: Netherlands
Call:  (ERC-2011-StG_20101109, 2011)
Start date: 2011-10-01
End date: 2016-09-30
Duration (months): 60.0
Total project cost (EUR): 1499070.15
EU funding (EUR): 1499070.15
Participants: 1
Project status: CLOSED

The formation of plant organs (leaves, roots, flowers) depends on the activity of stem cells (SC), located in stem cell niches (meristems) together with adjoining organizer cells (OC) that prevent SC differentiation. Despite their importance, SC and OC have been poorly described at molecular and cellular level and mechanisms for their coordinated specification are only partially understood. We study the specification of the very first SC and OC for the root in the early Arabidopsis embryo where cell divisions are almost invariant and, in the absence of cell motility, highly predictable. Previously we have established a central role for the transcription factor MONOPTEROS (MP) in OC specification and we have recently found that MP also controls SC specification. Hence, MP offers a unique entry point into studying the genomic and cellular reprogramming that underlies coordinated SC and OC specification. Our recent identification of MP target genes has shown that its function in SC specification is cell-autonomous, while MP-dependent OC specification involves a mobile transcription factor. In recent years we have developed a set of resources to systematically study embryonic root meristem initiation, and are now in a unique position to answer the following questions in this ERC project: 1. What transcriptional reprogramming underlies the first specification of SC and OC in the plant embryo? 2. What cellular changes follow from transcriptional reprogramming and mediate elongation and asymmetric division of SC and OC? 3. What is the mechanism of directional protein transport that ensures spatiotemporal coordination between SC and OC? The project will provide genome-wide insight in the cellular reprogramming underlying the coordinated formation of a multicellular structure. Finally, this work will shed light on mechanisms of stem cell and stem cell niche formation.

Keywords: pattern formation,auxin,cell-cell communication
HOST FACTORS THAT FACILITATE AND RESTRICT HIV-1 REPLICATION (HIV HOST FACTORS)

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: 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: 1
Project status: CLOSED

The efficient replication and spread of the Human Immunodeficiency Virus type 1 (HIV-1), the causative agent of the AIDS pandemic, requires that it parasitize an array of cellular proteins, many of which are unknown or uncharacterized, to facilitate its replication. In addition the virus must also defeat or subvert the human immune defences arrayed against it. Some of these immune defences, the innate retroviral restriction factors, have the capacity not only to directly interfere with the replication of the virus, but potentially to relay the information of its presence to activate a wider immune response – so called innate immune ‘sensing’. Molecular characterization of these processes for in vitro and in vivo replication of HIV-1 are essential for our understanding of the pathogenesis of HIV/AIDS. Additionally, it will provide strategies for the development of novel therapeutics for HIV treatment, and also potentially provide new paradigms that are applicable to other pathogenic mammalian viruses. To fill these gaps in our understanding this application seeks 5 years of ERC Starter Grant funding to explore two major research aims. Firstly we propose to characterize the interactions of retroviral restriction factors with the wider systemic immune response focusing on Tetherin/CD317/BST2 as a model system. In particular we will build on preliminary data suggesting that Tetherin can act as a general “pattern recognition molecule” for sensing assembling enveloped viruses by: A) transducing a proinflammatory signal and B) targeting nascent viral particles for antigen processing and presentation. Secondly we will apply novel genetic methods based on a haploid human cell line to identify, isolate and characterize human proteins that are required for early post-entry events in HIV replication or the function of the viral accessory protein Vpu.

Keywords: tetherin/cd317,vpu,restriction factor,pattern recognition,nf-kb,interferon,antigen presentation,cellular cofactors,haploid cell genetic screen
Exploitation of actinomycetes genomics using synthetic and system biology approaches (EXPLOGEN)

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-2011-StG_20101109, 2011)
Start date: 2012-01-01
End date: 2016-12-31
Duration (months): 60.0
Total project cost (EUR): 1484016.0
EU funding (EUR): 1484016.0
Participants: 1
Project status: CLOSED

Actinomycetes produce a wealth of important natural products, which play a pivotal role in modern drug-based therapy of various diseases. Recent whole-genome sequencing projects have revealed that the number of biosynthetic gene clusters significantly outnumbers the natural products produced by actinomycetes under laboratory conditions. Only a minority of biosynthetic gene clusters are expressed under known laboratory conditions. The major challenge in the field now is to exploit this untapped reservoir of potentially active and useful compounds. Using synthetic and system biology approaches we will access these so far unavailable natural products. The overall strategy of the EXPLOGEN project will be implemented through the activities of four different work packages. WP1. Synthetic biobricks. Construction of different synthetic biobricks, which can be mixed and matched to build the synthetic devices and systems in actinomycetes. Generation of streptomyces strains with minimized genomes. WP2. Systems biology. The metabolic reconstruction of Streptomyces albus and S. lividans and its simulation in order to deliver gene targets for knockouts and overexpression experiments. Predicted mutants should accumulate main precursors of natural products, particularly polyketides. WP3. Regulatory network identification. Using systematic in vivo transposon mutagenesis combined with GFP-based flow cytometry assay and gusA based screening, we will identify gene networks responsible for the regulation and “silencing” of natural product biosynthesis. WP4. Metabolic engineering of the hosts. Generation of S. albus and S. lividans hosts accumulating main precursors for the heterologous production of natural products. Heterologous expression of the aranciamycin, phenalinolactone, and two "cryptic" biosynthetic gene clusters in the developed hosts. The outcome of this project will be a new platform for the production of novel natural products including valuable pharmaceuticals.

Keywords: heterologous expression of the biosynthetic gene clusters