Data-Gouv-ML/pcri-informations-sur-les-projets-laureats huggingface dataset:
Next generation sequencing for detection of human primary immunodeficiency syndromes characterized by impaired cytotoxic lymphocyte function (SEQ-CYTOTOX)

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: Sweden
Call:  (ERC-2012-StG_20111109, 2012)
Start date: 2013-05-01
End date: 2018-04-30
Duration (months): 60.0
Total project cost (EUR): 1499996.0
EU funding (EUR): 1499996.0
Participants: 1
Project status: CLOSED

Human primary immunodeficiencies affecting cytotoxic lymphocyte function are associated with high morbidity and mortality. They often present as hyperinflammatory syndromes triggered by viral infections, hematological malignancies, or systemic autoimmunity. Although recent advances have provided molecular diagnoses for some of the most severe cases, only a handful of genes have been identified and disease in a majority of patients cannot be explained by current insights. My work has elucidated fundamental mechanisms of lymphocyte cytotoxicity. Furthermore, my group is leading international efforts in developing sensitive assays of human lymphocyte cytotoxicity. Some of our assays have been implemented for clinical diagnostics world-wide. Recently, we have also identified new, widespread mutations that explain many cases of fatal immunodeficiencies early in life. We now seek support for taking such studies to yet a higher level. The outlined interdisciplinary approach presented here aims at evaluating cytotoxic lymphocyte development and function in large numbers of patients, in addition to healthy individuals in a complementary approach, using state-of-the-art methodology. We will employ next-generation sequencing to identify novel genes associated with disease. The significance of putative mutations for lymphocyte cytotoxicity will be assessed using cutting-edge experimental platforms. Together, such genotype-immunotype studies promise to reveal novel genes associated with disease and further provide understanding of human genetic diversity. Thus, these studies can directly benefit patients through improved diagnosis, aiding targeted treatments, and offer new insights into human cytotoxic lymphocyte development and function with relevance to health. Insights will also pave the way for prospective, population-based molecular epidemiology studies required to more accurately assess the panorama of diseases associated with congenital defects in lymphocyte cytotoxicity.

Keywords: primary immunodeficiencies,natural killer cells,cytotoxic t cells
Neuro-vascular communication in the neural tube during development (NEUROVASCULAR LINK)

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-2012-StG_20111109, 2012)
Start date: 2012-12-01
End date: 2018-11-30
Duration (months): 72.0
Total project cost (EUR): 1498419.0
EU funding (EUR): 1498419.0
Participants: 1
Project status: CLOSED

Despite the critical importance of a precisely formed vascular network within the central nervous system (CNS), little is known about the molecular mechanisms that specifically control CNS vascularization. While other embryonic tissues undergo primary vascularization, the CNS becomes secondarily vascularized by sprouting angiogenesis from a previously formed vascular plexus. Angiogenesis within the CNS seems to require a different code of angiogenic signals compared to other organs, as surprisingly newly formed blood vessels avoid CNS regions where the pro-angiogenic factor VEGF is expressed. Still, angiogenesis within the developing neural tube (NT) follows a highly stereotypic pattern with blood vessels sprouting always at the same locations, following the same paths and avoiding specific regions. The goal of this project is to elucidate the cellular and molecular mechanisms that control this specialized two-step CNS vascularization. The originality and innovative character of this proposal relates to the hypothesis that in contrast to primary vascularization, which happens in response to conventional angiogenic signals, NT vascularization occurs by an orchestration of neuronal-derived signals, guiding vessels into the developing CNS, thereby assuring synchrony and adaptation to the specialized CNS tissue. Two research tracks are proposed: 1: Identification of the neuronal cell populations that communicate with blood vessels during NT vascularization 2: Identification and functional characterization of the molecular players controlling vascular patterning within the NT Both tracks are designed to follow a multidisciplinary approach combining cutting edge technology in in vitro cell and 3D tissue culture, time-lapse microscopy, transcriptomics, proteomics and mouse genetics. This project will provide fundamental knowledge on the mechanisms of CNS vascularization and open new research lines for understanding and treating developmental and traumatic CNS disorders

Keywords: angiogenesis,neuro-vascular communication,central nervous system vascularization
Protection against reactive oxygen species in neurodegeneration (PAROSIN)

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: United Kingdom
Call:  (ERC-2012-StG_20111109, 2012)
Start date: 2013-02-01
End date: 2018-05-31
Duration (months): 64.0
Total project cost (EUR): 1328956.0
EU funding (EUR): 1328956.0
Participants: 1
Project status: CLOSED

Oxidative stress (OS) is implicated in the pathogenesis of some of the most devastating neurological diseases. Therefore, identification of pathways that counteract oxidative damage may lead to therapeutic strategies applicable to a wide range of disorders. I have recently identified the importance of the mitochondrial oxidation resistance 1 (Oxr1) gene for neuronal survival; loss of Oxr1 causes neurodegeneration in mice, whereas over-expression in vitro is able to confer protection against OS. Deregulation of this protein is also observed in human ALS and additional mouse models of in neurodegeneration. Despite the apparent high level of conservation of Oxr1-related proteins, virtually nothing is known about their function in vivo. This proposal will establish an independent research programme to understand the role of Oxr1 and related proteins as part of novel pathways that provide protection against both OS and neurodegeneration. Preliminary data I have generated has identified proteins that interact with Oxr1 in neurons; significantly, a number of these binding partners are mutated in neurodegenerative disease. Therefore, using a combination of mutational and biochemical analysis the relationship of these interactions to neuronal cell death will be investigated . Studies will also focus on the role of Oxr1 in mitochondria, examining the significance of this localisation to the control of the OS response. This will be complemented by in vivo studies in the mouse to to determine whether the loss or disruption of Oxr1-related proteins is critical for CNS function. Using the latest techniques in molecular genetics and in vivo modelling this project has major translational opportunities and will provide an excellent opportunity to answer one of the key questions in neurodegenerative research.

Keywords: oxidative stress,neurodegeneration
Functional redundancy of bacterial communities in the laboratory and in the wild (REDUNDANCY)

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-2012-StG_20111109, 2012)
Start date: 2013-02-01
End date: 2018-01-31
Duration (months): 60.0
Total project cost (EUR): 1484258.0
EU funding (EUR): 1484258.0
Participants: 1
Project status: CLOSED

Understanding how species mediate ecosystem processes, such as energy and nutrient fluxes, is among the foremost challenges in ecology. Bacterial communities are pivotal for the functioning of the world’s ecosystems. Although there have been great advances in describing the biodiversity of bacteria, little effort has been directed at understanding how differences in bacterial communities translate into differences in ecosystem functioning. The proposed research will develop a comprehensive framework to determine how bacterial species affect functioning while in complex mixtures of species. Once this baseline is obtained, it is possible to ask detailed questions about the ‘functional ecology’ of bacterial communities. Foremost among these is whether ecological processes (species sorting) are more important than evolutionary processes (adaptation) in establishing species roles in ecosystems. The research has implications for the fundamental understanding how ecological communities operate.

Keywords: biodiversity and ecosystem functioning,microcosm experiments
Mechanical Understanding of Membrane Fission in Endocytosis and Cytokinesis (MEMFIS)

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: Switzerland
Call:  (ERC-2012-StG_20111109, 2012)
Start date: 2013-01-01
End date: 2017-12-31
Duration (months): 60.0
Total project cost (EUR): 1374882.0
EU funding (EUR): 1374882.0
Participants: 1
Project status: CLOSED

The envelope of living cell is a lipid membrane. It is rather difficult to break, to ensure cell survival when under mechanical stress. However, in many events of cell life, the membrane needs to be broken in a controlled manner. It is the case in Endocytosis, when membrane carriers budding from the plasma membrane need to be separated from the plasma membrane, in order to uptake external components needed for the cell life. This reaction is called fission. It is also the case at the final step of cell division, cytokinesis, when the connecting membrane bridge between the two daughter cells is broken in a process called abscission. Even if fission and abscission machineries have been identified and are different, the reaction by which they break membranes should be the same, but is still unknown. By using membrane physics concepts and tools, we will investigate the mechanics of these two fission machineries. As they have different dynamics (tens of seconds for fission, tens of minutes for abscission), different scales (tens of nanometers for fission, microns for abscission) and different topology (fission machinery works from outside the neck, abscission machinery works from inside the neck), we will: 1-explain how each machinery breaks membranes, 2-find essential parameters that control all membrane fission reactions. We will thus draw a mechanical framework to then understand the role of keyfactors in all membrane fission reactions of cells.

Keywords: lipid membrane/molecular motors/dynamin/endocytosis/cell division/cytokinesis/abscission/escrt-iii/giant liposomes/biomimetics/membrane physics
Angiogenesis-metabolism crosstalk in vascular homeostasis and disease (ANGIOMET)

Framework: FP7 — Ideas
Programme: European Research Council
Theme: European research council
Destination: Starting grants
Action type: Support for frontier research (ERC)
Panel: Physiology, Pathophysiology and Endocrinology
Countries involved: Germany
Call:  (ERC-2012-StG_20111109, 2012)
Start date: 2012-09-01
End date: 2017-08-31
Duration (months): 60.0
Total project cost (EUR): 1487920.0
EU funding (EUR): 1487920.0
Participants: 1
Project status: CLOSED

Blood vessels pervade all tissues in the body to supply nutrients and oxygen. Aberrant vessel growth and function are hallmarks of cancer and cardiovascular diseases and they contribute to disease pathogenesis. Antiangiogenic therapeutics have reached the clinic, but limited efficacy and resistance raise unresolved challenges. The current limitations of angiogenic medicine call for a more integrated understanding of the angiogenic process that focuses not only on the instigators of vessel branching but also on mechanisms that sustain vessel growth. Recent insights into fundamental aspects of cell growth move metabolism into spotlight and establish how proliferating cells reprogram their metabolism to provide energy and building blocks for cell replication. During angiogenesis, endothelial cells (ECs) also convert between growth states: although mostly quiescent in adult tissues, ECs divide and migrate rapidly upon angiogenic stimulation. To allow growth of new vessel branches, ECs therefore need to adjust their metabolism to increase energy production and biosynthetic activity. However, the molecular mechanisms that coordinate EC metabolism with angiogenic signalling are not known to date. In this proposal, we put forth the hypothesis that metabolic regulation is a key component of the endothelial angiogenic machinery that is required to sustain vessel growth. Thus, this proposal aims (I) to define transcriptional circuits that link EC growth with metabolism, (II) to explore the regulation of these transcriptional networks by lysine acetylation, a nutrient-regulated protein modification with key functions in metabolism, and (III) to assess the role of sirtuin deacetylases for sensing endothelial energetics during vascular growth. Understanding the principles of angiogenesis-metabolism crosstalk will not only yield novel insights into the basic mechanisms of vessel formation but will also provide unprecedented opportunities for future drug development.

Keywords: angiogenesis,endothelial cells,acetylation,sirtuins,transcription factors
Genome-wide identification of factors controlling the telomere damage response and telomere-driven genomic instability. (TELOMERES)

Framework: FP7 — Ideas
Programme: European Research Council
Theme: European research council
Destination: Starting grants
Action type: Support for frontier research (ERC)
Panel: Molecular and Structural Biology and Biochemistry
Countries involved: Netherlands
Call:  (ERC-2012-StG_20111109, 2012)
Start date: 2012-10-01
End date: 2017-09-30
Duration (months): 60.0
Total project cost (EUR): 1496400.0
EU funding (EUR): 1496400.0
Participants: 1
Project status: CLOSED

Telomeres are specialized nucleoprotein complexes that protect chromosome ends against recognition as DNA breaks. In somatic cells telomeres shorten every cell division, eventually compromising telomere function. This leads to activation of a DNA damage response that induces irreversible growth arrest or cell death and serves to suppress tumorigenesis by preventing outgrowth of incipient cancer cells. Furthermore, by limiting replicative potential, telomere dysfunction contributes to aging. However, deprotected chromosome ends are also subject to DNA repair activities that lead to chromosome end-to-end fusions. Upon cell division these fusions give rise to genomic instability through breakage-fusion-bridge cycles generating complex, unbalanced chromosome rearrangements. Cells with such instable genomes are highly prone to develop into cancer. The mechanisms underlying the telomere damage response and telomere-driven genomic instability are poorly understood. To increase our understanding of the cellular consequences of telomere dysfunction we will perform genome-wide functional genetic screens to identify factors with important roles in the telomere damage response and telomere-driven genomic instability. We will mechanistically study these genes for their role in the cellular response to telomere dysfunction. In addition, we will address if these factors act uniquely at telomeres or also affect the response to DNA lesions. Due to their unbiased nature these screens represent a unique opportunity to obtain highly novel and potentially unsuspected insights in the events following telomere deprotection. This work will lead to significantly increased mechanistic understanding of how dysfunctional telomeres affect genome stability, cancer development and aging, but might also lead to new insights in responses to DNA damage in general. Furthermore our research findings will facilitate development of new therapeutic strategies for inhibiting cancer and aging.

Keywords: telomere damage,genomic instability,rnai screens,dna repair
Therapies for inborn errors of metabolism (IEMTX)

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: Italy
Call:  (ERC-2012-StG_20111109, 2012)
Start date: 2012-11-01
End date: 2018-10-31
Duration (months): 72.0
Total project cost (EUR): 1491520.0
EU funding (EUR): 1491520.0
Participants: 1
Project status: CLOSED

We discovered that phenylbutyrate, prevents both in vitro and in vivo the inactivation by phosphorylation of the branched chain ketoacid dehydrogenase complex (BCKDC) and pyruvate dehydrogenase complex (PDHC). We show that phenylbutyrate is effective for treatment of maple syrup urine disease (MSUD) due to deficiency of branched chain ketoacid dehydrogenase complex (BCKDC), and has potential for therapy of deficiency of pyruvate dehydrogenase complex (PDHC). We propose to investigate phenylbutyrate for PDHC deficiency in a zebrafish model and in PDHC-deficient patients. We have recently developed a systems biology tool for prediction of drug mode of action starting from their gene expression profiles. This tool has a significant potential for drug discovery and repositioning. Through this approach, we found several FDA-approved drugs sharing with phenylbutyrate a similar mode of action. We propose to investigate the efficacy of these drugs for increasing the enzymatic activity of both BCKDC and PDHC and their therapeutic potential. While useful for proof-of-concept studies animal models are not suited to predict patient response to drugs which depends upon multiple factors including type of mutation and affected enzyme subunit. We propose to develop PDHC deficient neurons and MSUD hepatocytes from induced pluripotent stem cells (iPSCs) derived from patients’ fibroblasts. Drug response in these disease-relevant cell types will better predict clinical response of patients. Human iPSCs will be generated through a novel system based on high cloning capacity, non-integrating helper-dependent adenoviral (HDAd) vector expressing a combination of reprogramming factors. We will investigate altered metabolic pathways in PDHC deficient neurons and MSUD hepatocytes to search for effective drugs by an innovative systems biology approach. In summary, the results of the proposed study have the potential to provide novel and effective treatments for MSUD and PDHC deficiency.

Keywords: inborn errors of metabolism,small molecule therapy,pyruvate dehydrogenase complex,maple syrup urine disease
Towards sustainable global food safety collaboration (COLLAB4SAFETY)

Framework: FP7 — Cooperation
Programme: Food, Agriculture and Fisheries, and Biotechnology
Destination: Fork to farm: Food (including seafood), health and well being
Action type: Coordination and support actions
Countries involved: Netherlands,United Kingdom,France,Portugal,Russian Federation,United Kingdom,Poland,China,Brazil
Call:  (FP7-KBBE-2012-6-singlestage, 2012)
Start date: 2012-08-01
End date: 2016-07-31
Duration (months): 48.0
Total project cost (EUR): 1168960.0
EU funding (EUR): 999990.0
Participants: 10
Project status: CLOSED

Guaranteeing the long term availability of safe foods is a global concern that has initiated a large number of activities, including research, policy development and implementation, legislation and training. Extensive information is generated about food safety, but it is fragmented, and not internationally disseminated. The Collab4Safety consortium will establish a global network on food safety with the aim of developing a sustainable coordination platform for exchange of food safety information about research findings, capacity building and policies and facilitate the control and mitigation of existing and emerging food risks. Tried and tested methods will be used to identify problems and gaps in knowledge, resulting in generation of outputs valuable to research managers and interested stakeholders globally. Establishing a permanent structure will contribute to the development of trust between key players and institutions, which is needed to create an international forum for exchange of information and opinions on matters pertaining to food safety in the food and feed chain

Keywords: food safety,coordination,collaboration,research,legislation and policies,global network
Clonal evolution in acute leukemia: from molecular and functional profiling towards therapeutic intervention (CEVAL)

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: 2013-04-01
End date: 2019-03-31
Duration (months): 72.0
Total project cost (EUR): 1497028.0
EU funding (EUR): 1497028.0
Participants: 1
Project status: CLOSED

Clonal evolution represents a driving force for cancer cells and a major challenge for therapy. There is a long-standing knowledge that clonal diversification and selection allows cancer cells to pass through distinct steps of transformation. More recently has emerged the concept that "more malignant" leukemia subclones can persist after treatment leading to relapse. My research is focused on two diseases which represent privileged models to study clonal evolution: Fanconi anemia (FA), which is a genetic condition predisposing to acute leukemia, and T-cell acute lymphoblastic leukemia (T-ALL), an aggressive leukemia which frequently relapses. The goal of this project is to decipher the crucial molecular and cellular events that drive gain of malignancy and to design new strategies to follow up and treat the patients. Specifically, we aim to: 1. Identify the key pathways involved in leukemia progression at two major steps: from pre-leukemia to overt leukemia (in FA), and from primary diagnosis to relapse (in T-ALL). This aim will use high-throughput molecular profiling and functional characterization of longitudinal samples from patients. 2. Model leukemia progression in vivo to functionally validate these pathways. We have developed read-outs based on gene silencing in human primary cells from patients followed by leukemia monitoring in immunodeficient mice. 3. Define new strategies to prevent the transition towards acute leukemia in pre-leukemic states in FA patients. We will develop new markers for transformation that should help in monitoring therapeutic intervention. 4. Test drugs in pre-clinical models to target critical pathways of relapsed ALL. We will use xenografted T-ALL which recapitulates leukemia progression. Completion of this innovative transversal project should markedly improve the knowledge on tumor progression and lead to new strategies to prevent, early detect and/or treat relapse, with the final objective to cure more patients.

Keywords: clonal evolution