Data-Gouv-ML/pcri-erc-participations-et-projets-laureats huggingface dataset:
Projet ERC : REPSUMODDT (Horizon 2020, appel 2015, Consolidator grants)
Domaine scientifique : Life Science
Panel : Molecules of Life: Biological Mechanisms, Structures and Functions
Entité participante : FIRC Institute of Molecular Oncology — Pays : Italie — Rôle : PI
Type d'entité : Recherche
Financement ERC de l'entité : 1991250.0 €

Accurate chromosomal DNA replication is of fundamental importance for cellular function, genome integrity and development. In response to replication perturbations, DNA damage response (DDR) and DNA damage tolerance (DDT) pathways become activated and are crucial for detection and tolerance of lesions, as well as for facilitating replication completion and supporting chromosome structural integrity. While important functions and key players of these regulatory processes have been outlined, much less is known about the choreography and mechanistic interplay between DDR and DDT during replication. Moreover, the principles by which they uniquely or commonly affect replication-associated chromosome integrity remain poorly understood. Here, we will use novel tools and a palette of ingenious genetic, molecular and proteomic based experimental strategies, to investigate the replication stress response triggered by diverse endogenous and exogenous cues, and to identify the underlying mechanisms. We will define the principles of local and temporal regulation of DDT in response to genotoxic stress, with a focus on the mechanisms of SUMO-regulated DNA metabolism processes. Additionally, we will investigate the topological DNA transitions triggered at intrinsically difficult to replicate genomic regions, stalled and terminal forks, with the aim of identifying key mechanisms and regulators of replication integrity at specific complex genomic regions or following specific types of replication stress. Finally, we will explore the relationship between DDT, replication fork architecture and sister chromatid cohesion in the context of DDR- and SUMO-orchestrated DNA transactions. We expect that these studies will reveal new aspects of how replication-associated DNA metabolism processes are inter-related and regulated, uniformly or at specific loci in the genome, and will break new ground in areas of replication mechanisms and chromosome integrity in general.

Mots-clés : dna replication,sumo,dna damage tolerance,sister chromatid cohesion,dna damage response
Projet ERC : MolStruKT (Horizon 2020, appel 2014, Starting grants)
Domaine scientifique : Life Science
Panel : Molecules of Life: Biological Mechanisms, Structures and Functions
Entité participante : Ludwig-Maximilians-Universität München — Pays : Allemagne — Rôle : PI
Acronyme de l'entité : LMU
Type d'entité : Enseignement supérieur ou secondaire
Financement ERC de l'entité : 1499932.0 €

Accurate chromosome segregation in eukaryotes requires the assembly of the macromolecular kinetochore complex at centromeres to attach chromosomes to the mitotic spindle. The kinetochore proteins are organized in stable subcomplexes that bind to dynamic microtubules and ensure fidelity of sister chromatid separation through feedback control. Characterizing the kinetochore structure will significantly advance our understanding of chromosome segregation and how defects in this process can lead to aneuploidy, which is associated with tumorigenesis. X-ray crystallography has provided detailed insights into the function of subcomplexes, however, a molecular analysis of the native kinetochore subunit architecture is still missing. I have recently combined chemical cross-linking with mass spectrometry (CXMS) which allows for the first time the topological analysis of native macromolecular protein structures by a comprehensive set of distance restraints. Applying this approach to kinetochores assembled on budding yeast minichromosomes I aim to elucidate the architecture of the native centromere-assembled kinetochore complex and analyze how tension sensing by the chromosomal passenger complex is integrated into the structure. Secondly, the systematic analyses of changes in phosphorylation levels and in protein stoichiometries of soluble and nucleosome-associated human kinetochore complexes will reveal how the tight temporal control of assembling a functional kinetochore in mitosis is achieved. Thirdly, I will investigate the architecture of the centromere-associated network of kinetochore proteins by CXMS to unveil its role in directing CENP-A replenishment at mitotic exit in order to maintain centromere identity through generations. The analysis of the native kinetochore structure in different functional states will provide fundamental mechanistic insights and help us to understand how this architecture confers fidelity to centromere propagation and chromosome segregation.

Mots-clés : kinetochore,hybrid structural biology
Projet ERC : GlobalGoals (Horizon 2020, appel 2017, Advanced grants)
Domaine scientifique : Social Sciences and Humanities
Panel : Institutions, Governance and Legal Systems
Entité participante : Utrecht University — Pays : Pays-Bas — Rôle : PI
Type d'entité : Enseignement supérieur ou secondaire
Financement ERC de l'entité : 2493750.0 €

Achieving sustainable development worldwide remains probably the biggest political challenge of our time. In 2015, the international community adopted 17 'Sustainable Development Goals' with no less than 169 ‘targets’ as part of a global '2030 Agenda for Sustainable Development'. The ambition expressed in these goals is unprecedented. But can such goal-setting, as a new central approach in global governance, help resolve the pressing challenges of economic development, poverty eradication, social justice and global environmental protection? Nobody knows at this stage. While the United Nations and its member states place high hopes on this novel strategy, there is little scientific knowledge on whether such global goals can live up to exceedingly high expectations. Sustainability research has tended to focus on concrete institutions, actors and practices – not on aspirational goals that bring little in terms of normative specificity, stable regime formation or compliance mechanisms. How can ‘global governance through goals’ nonetheless be effective – and under which conditions? GLOBALGOALS will address this puzzle and break new ground in sustainability and global governance theories. It offers the first and most comprehensive data compilation, network mapping and comparative institutional analysis of the evolution, effectiveness and future prospects of 'global governance through goals' as a central novel steering mechanism in world politics. This 5–year study programme deploys a unique set of cutting-edge methodologies, including social network analysis and online surveys, to assess and explain the steering effects of nine Sustainable Development Goals through a detailed investigation of their institutional arrangements and actor networks, at international and national levels. GLOBALGOALS makes a crucial knowledge contribution to both the theory of global sustainability governance and the successful implementation of the 2030 Agenda for Sustainable Development.
Projet ERC : CCMI-ARDS (Horizon 2020, appel 2014, Proof of concept grants)
Entité participante : National University of Ireland — Pays : Irlande — Rôle : PI
Acronyme de l'entité : NUI
Type d'entité : Enseignement supérieur ou secondaire
Financement ERC de l'entité : 149101.0 €

Acute Respiratory Distress Syndrome (ARDS) is a devastating condition, which kills 40% of sufferers, resulting in hundreds of thousands of deaths worldwide annually. Despite decades of intensive research efforts, there are no clinical therapeutic strategies available for this catastrophic condition. In our ERC Starter Grant, HA-NFkB-VILI, we have shown Mesenchymal Stem Cells (MSCs) to be beneficial in several relevant preclinical ARDS models. However, for cell therapies to be successfully used in the clinic, they will need to be sourced allogeneically, culture passaged and cryofrozen for transport to the clinical site, where they can then thawed near the bedside and administered to the patient with ARDS. This project will therefore examine the potential of cryofrozen human MSCs, manufactured at the CCMI cell therapy facility at NUI Galway, in relevant models of ARDS. A demonstration that the cryofrozen CCMI-hMSC exhibit therapeutic potential would be a major step towards the clinical testing of these cells in patients with this devastating disease.

Mots-clés : ards,cryofrozen
Projet ERC : LIFT (Horizon 2020, appel 2018, Proof of concept grants)
Domaine scientifique : Life Science
Panel : Prevention, Diagnosis and Treatment of Human Diseases
Entité participante : Technion – Israel Institute of Technology — Pays : Israël — Rôle : PI
Type d'entité : Enseignement supérieur ou secondaire
Financement ERC de l'entité : 150000.0 €

Acute Respiratory Distress Syndrome (ARDS) is an inflammatory lung condition caused e.g. by sepsis, pneumonia and head or chest injury, affecting annually 133,000 people in Europe and 255,000 in the US. ARDS is characterized by the depletion of the lungs’ inner liquid coating (pulmonary surfactant), which reduces surface tension forces and allows the lungs to expand. Patients span across all age groups and lay anesthetized in the intensive care unit with mortality rates at 40%. Although surfactant replacement therapy (SRT) is a life-saving procedure in newborn neonates, current administration methods to treat adults and even children remain inadequate. Endotracheal surfactant liquid instillations used in babies fail in larger lungs: liquid drains into pools, drowning these lung regions while leaving others untreated. Meanwhile, inhalation aerosols can only deliver small doses (<1ml/hr for nebulizers), far from the required ~100ml of surfactant. To overcome such hurdles, we advocate using liquid foam as a surfactant carrier to the lungs, i.e. LIquid Foam Therapy (LIFT). Foam is weakly affected by gravity, distributes homogeneously within lungs and in abundance. LIFT brings a paradigm shift in SRT, and more broadly, in the field of therapeutic pulmonary delivery. Our team bridges expertise in clinical ARDS treatment in neonates, pulmonary medicine, biomedical engineering and business. Together, we have demonstrated the feasibility of our patent pending technology, both in vitro in 3D printed and microfabricated airway models, and ex vivo in excised pig lungs using fluoroscopy. In this PoC, we will optimize the foam formulation, design and construct a delivery device, and run pre-clinical in vivo animal experiments. LIFT has the potential to extend far beyond ARDS treatment and be leveraged for other lung therapies, such as stem cell delivery directly to the lungs to treat Idiopathic Pulmonary Fibrosis (IPF) and Chronic Obstructive Pulmonary Disease (COPD).

Mots-clés : lungs,respiratory distress syndrome,pulmonary therapy,biomedical engineering,medical devices
Projet ERC : GvHDCure (Horizon 2020, appel 2015, Consolidator grants)
Domaine scientifique : Life Science
Panel : Prevention, Diagnosis and Treatment of Human Diseases
Entité participante : University of Freiburg — Pays : Allemagne — Rôle : PI
Type d'entité : Enseignement supérieur ou secondaire
Financement ERC de l'entité : 1987500.0 €

Acute graft-versus-host disease (GvHD) is the leading cause of the high mortality of patients having undergone allogeneic hematopoietic cell transplantation. A key event in the pathogenesis of GvHD is the injury and loss of epithelial cells in the intestinal tract. The overall goal of GvHDCure is to identify the pathophysiological mechanisms that initiate (1), propagate (2) and maintain (3) GvHD. (1) We found that one of the earliest events during GvHD initiation is infiltration of the intestines by neutrophils. By using transgenic neutrophil cell lines carrying selective gene defects, we will systematically evaluate molecules in neutrophils that are critical for their sensing and effector function during GvHD in combination with novel imaging methods to track bacterial translocation. (2) The molecular programs propagating inflammation-induced epithelial apoptosis, endoplasmic reticulum stress and the sensing of DAMPs in GvHD are not understood. We will isolate enterocytes from GvHD mice to develop a precise quantitative genomic and micro RNA (miR) fingerprint of their death. The connection between ER stress and enterocyte death will be validated in intestinal organoid culture systems and in vivo in an XBP-1 mRNA splicing reporter mouse. In addition, we will make use of our human tissue bank, allowing the efficient genetic screening and verification of regulatory molecular networks in the cells from GvHD patients. (3) Maintenance of GvHD relies on continuous immune cell activation. Based on our miR array and phospho-proteomics data set, we will selectively analyze the role of several miRs and kinases in neutrophils, dendritic cells, T cells and enterocytes for GvHD maintenance by using multiple Cre-lox mice and kinase inhibitors to manipulate GvHD. Via a combination of murine and human studies GvHDCure aims to directly develop individualized therapeutic strategies to interfere with GvHD at multiple levels to make allo-HCT more safe for patients with blood cancer.

Mots-clés : graft versus host disease,allogeneic hematopoietic stem cell transplantation
Projet ERC : De-StunHeartAttacks (Horizon 2020, appel 2020, Starting grants)
Domaine scientifique : Life Science
Panel : Prevention, Diagnosis and Treatment of Human Diseases
Entité participante : University of Gothenburg — Pays : Suède — Rôle : PI
Type d'entité : Enseignement supérieur ou secondaire
Financement ERC de l'entité : 1500000.0 €

Acute ischemic heart failure (AIHF) after ST-elevation myocardial infarction (STEMI) is a common and life-threatening condition for which the prognosis has not improved over the past decade, and for which no effective treatment option exists. Women, who have been underrepresented in most STEMI studies are more likely than men to develop AIHF after STEMI. My research aims to shift focus from traditional treatment targets (increased cardiac work and maintenance of blood pressure) to manipulation of myocardial stunning, the physiological phenomenon in which viable myocardium suddenly lose its function (becomes ‘stunned’) when exposed to a stressor (e.g. ischemia). Specifically, I aim to: 1) compare how stunning and propensity for AIHF affect prognosis for women vs. men with STEMI – using causal mediation analysis applied to a unique nationwide STEMI cohort (around 40,000 patients); 2) prospectively compare the rate of stunning resolution in STEMI patients with vs. without microvascular obstruction, in patients with STEMI vs. patients with takotsubo (another form of myocardial stunning with more favorable prognosis), and for women with STEMI vs. men with STEMI; 3) conduct a nationwide multicenter randomized registry trial to determine if adenosine, which has anti-inflammatory, vasodilatory and cytoprotective effects, improves resolution of myocardial stunning and clinical outcomes in STEMI; and 4) determine if pre-existing takotsubo-like stunning is protective in experimental AIHF. If my main hypothesis is correct, my this project could change the way researchers and clinicians approach the pathophysiology and treatment in STEMI. Irrespective of whether my main hypothesis is correct, my research proposal is designed to provide important insight into the pathophysiology and prognosis of myocardial stunning in STEMI, with a clear sex perspective that can help mitigate the sex gap in the level of evidence supporting the use and benefit of current treatments for STEMI.

Mots-clés : st elevation myocardial infarction  stemi,acute ischemic heart failure  aihf,myocardial stunning,mediation analysis,registry randomized clinical trial  rrct,adenosine
Projet ERC : IL7RsignaTHER (Horizon 2020, appel 2019, Proof of concept grants)
Domaine scientifique : Life Science
Panel : Physiology in Health, Disease and Ageing
Entité participante : University of Lisbon — Pays : Portugal — Rôle : PI
Type d'entité : Recherche
Financement ERC de l'entité : 150000.0 €

Acute lymphoblastic leukemia (ALL), a highly aggressive hematological cancer, is the most frequent childhood malignancy and the second most common acute leukemia in adults. The use of risk-adjusted multi-agent intensive chemotherapy has led to a remarkable improvement in treatment outcome of pediatric cases, with more than 80% of children with ALL being alive and disease-free at 5 years. However, a significant number of relapses still occur, whose prognosis is dismal, and the intensive regimens used are often associated with long-term, severe complications. In adults, the scenario is considerably worse: only 30–40% of the cases achieve long-term remission. Therefore, there is an obvious unmet need, and a major challenge, to develop novel, more efficient therapeutic strategies that specifically target the leukemic cells, minimize the detrimental side effects associated with conventional therapies and improve overall treatment outcome. Based on exciting and robust preliminary data from our ERC Consolidator Grant IL7sigNETure (CoG-648455), we now propose to explore the dependence of ALL cells on IL-7/IL-7R-mediated signaling and the broad expression of IL-7R on the surface of ALL cells to develop and commercialize novel monoclonal antibody-based biopharmaceuticals that we will generate targeting the IL-7/IL-7R axis for treatment of this malignancy. Our innovative therapeutic strategies have significant market potential that extends beyond ALL. Other possible indications include other lymphoid malignancies (Hodgkin's lymphoma, peripheral T-cell lymphoma, chronic lymphocytic leukemia), solid cancers with ectopic expression of IL-7R (including melanoma, breast, lung, bladder and colorectal cancer, or glioblastoma), and autoimmune and chronic inflammatory diseases (diabetes, multiple sclerosis, rheumatoid arthritis, inflammatory bowel disease) in which the IL-7/IL-7R axis plays a pathological role.

Mots-clés : cancer,leukemia,t all,il 7r,targeted therapies,novel antibody based biopharmaceuticals
Projet ERC : MAMLE (Horizon 2020, appel 2016, Starting grants)
Domaine scientifique : Life Science
Panel : Physiology in Health, Disease and Ageing
Entité participante : Weizmann Institute of Science — Pays : Israël — Rôle : PI
Type d'entité : Enseignement supérieur ou secondaire
Financement ERC de l'entité : 1750000.0 €

Acute myeloid leukemia (AML) is one of the most deadly cancers. Currently, we do not fully understand how and why AML starts or why it tends to relapse after treatment. Recent discoveries by the applicant and others have identified preleukemic stem and progenitor cells (preL-HSPCs) as the root of AML evolution. Many healthy elderly individuals carry the preleukemic mutations in their preL-HSPCs and yet, do not develop AML. It is also becoming clearer that leukemia evolution is spanning over many years but most research is focused on the late stages of the disease. Population genetics tools are specifically suited for the study of historical evolution however such tools are not well developed in the field of somatic evolution. This proposal will integrate population genetics, stem cell and leukemia biology in order to unravel human leukemia evolution from the very early preleukemic phase to relapse. Novel single cell population genetics tools will be used to describe the naive clonal structure of the human hematopoietic system in both health and disease. A unique cohort of half a million Europeans, who have been followed for years, will be used to understand why only a small fraction of the individuals carrying preleukemic mutations develop AML. Novel genetic analysis will be developed to study the clonal structure of blood cells, years before AML was diagnosed. A large cohort (N=100) of AML patients were collected serially over a year and will be collected until relapse. Detailed molecular and population genetics of this cohort will aid in understanding the mechanism of AML relapse and in developing novel molecular methodologies, that will allow early relapse diagnosis. AML like many other malignancies is diagnosed late in its evolutionary path. In this proposal the evolution of AML before diagnosis and before it relapses will be studied by novel population genetic tools so that the vision of early diagnosis and treatment will become reality.

Mots-clés : early cancer evolution,acute myeloid leukemia,clonal hematopoeisis
Projet ERC : TREAT-NPM1-AML (Horizon 2020, appel 2016, Advanced grants)
Domaine scientifique : Life Science
Panel : Prevention, Diagnosis and Treatment of Human Diseases
Entité participante : University of Perugia — Pays : Italie — Rôle : PI
Type d'entité : Enseignement supérieur ou secondaire
Financement ERC de l'entité : 2745836.0 €

Acute myeloid leukemia (AML) is the most common acute leukemia in adults accounting for approximately 15,000 new cases/year in Europe and 20,000 new cases/year in US. Currently, 40-50% of AML patients (age 18-60 years) and only 5-10% of older patients (who are usually more frequently affected by the disease) can be cured using conventional chemotherapy +/- allogeneic hematopoietic stem cell transplantation. Thus, AML still remains an urgent medical need which calls for new forms of molecular targeted therapies (similarly to those available for acute promyelocytic leukemia). The P.I. previously discovered the nucleophosmin (NPM1) mutations, the most common genetic lesion in AML (about one-third of cases) and gave fundamental contributions in the translation of this seminal discovery into the clinic (improved classification of myeloid neoplasms according to WHO, genetic-based risk- stratification of AML patients, monitoring of minimal residual disease and first demonstration of the anti-leukemic activity of actinomycin D). The present research proposal is focused on improving therapy of NPM1-mutated AML. Specifically, it is aimed to: i) identify novel chemical tools interfering with NPM1 functions by interacting with the N-terminal portion of the protein (objective 1); ii) conduct a clinical trial (AML-PG02; Eudract 2014-003490-41) with actinomycin D in older untreated and/or unfit patients with NPM1-mutated AML and to better understand in vitro and in mice models the mechanisms of action of this drug, used alone or in combination with other agents (objective 2); iii) develop compound mouse models aimed to investigate how NPM1 mutations cooperate with FLT3-ITD or DNMT3A mutations in promoting AML with the goal to better understand the characteristics of relapsed cases and to design new therapeutic strategies (objectives 3 and 4): and iv) generate a murine model for testing the feasibility of “in situ” vaccination in AML, especially in NPM1-mutated AML (objective 5).

Mots-clés : acute myeloid leukemia,npm1,gene mutations,target therapy,immunotherapy,preclinical,models