Data-Gouv-ML/pcri-erc-participations-et-projets-laureats huggingface dataset:
Projet ERC : bloodANDbone (Horizon 2020, appel 2017, Starting grants)
Domaine scientifique : Life Science
Panel : Biotechnology and Biosystems Engineering
Entité participante : Leibniz University Hannover — Pays : Allemagne — Rôle : PI
Type d'entité : Enseignement supérieur ou secondaire
Financement ERC de l'entité : 1355804.54 €

Blood and bone are closely intertwined. Their intrinsic regenerative capacities are disturbed in many hematological and musculoskeletal diseases. Re-establishing the regenerative potential is the key to cure these diseases by regenerative medicine. Multipotent stem cells of both tissues – hematopoietic stem cells (HSCs) for blood and mesenchymal stem/stromal (MSCs) for bone – are the basis for their regenerative capacity. While it is well established that HSCs are influenced by the bone marrow in their natural environment including MSCs and their progeny, surprisingly little attention has been paid to the reciprocal relationship. The hypothesis of the current proposal is that only when taking both tissues and their mutual crosstalk into account, we will be able to understand how the regenerative potential of blood and bone is impaired in disease and how it can be re-established with novel treatment strategies. For this purpose we need to understand the early events of disease onset and progression. Due to the limitations of such studies in human beings and animals, I propose to develop human in vitro models of healthy bone marrow, which can be induced to develop hematological and musculoskeletal diseases with high incidence, namely leukemia, multiple myeloma and bone metastasis. Previously my team and I developed a simplified bone marrow analog that bases on macroporous, cell-laden biomaterials with tunable physical, biochemical and biological properties. This versatility will enable us to create biomimetic human in vitro models of the human bone marrow in health and disease, which are ground-breaking in their applicability to investigate how the regenerative balance of bone marrow is maintained in health and disturbed in the different kinds of diseases – a prerequisite to develop novel regenerative treatments – as well as their scalability and thus suitability as in vitro test systems for screening of novel drugs or treatments.
Projet ERC : ZF_Blood (Horizon 2020, appel 2015, Starting grants)
Domaine scientifique : Life Science
Panel : Cellular, Developmental and Regenerative Biology
Entité participante : University of Cambridge — Pays : Royaume-Uni — Rôle : PI
Acronyme de l'entité : U. Cambridge
Type d'entité : Enseignement supérieur ou secondaire
Financement ERC de l'entité : 1500000.0 €

Blood stem cells need to both perpetuate themselves (self-renew) and differentiate into all mature blood cells to maintain blood formation throughout life. However, it is unclear how the underlying gene regulatory network maintains this population of self-renewing and differentiating stem cells, and how it accommodates the transition from a stem cell to a mature blood cell. Our current knowledge of transcriptomes of various blood cell types has mainly been advanced by population-level analysis. However, the population of seemingly homogenous blood cells may include many distinct cell types with substantially different transcriptomes and abilities to make diverse fate decisions. To overcome these limitations, I will use single-cell transcriptome sequencing of zebrafish blood cells. I will apply an integrative strategy, combining genetic perturbation with computational sequence and network analysis methods, to reconstruct the regulatory networks that maintain the dynamic balance between different blood cell types. This will be achieved by pursuing two main aims: 1) I will create a comprehensive atlas of single cell gene expression in adult zebrafish blood cells and computationally reconstruct the blood lineage tree. I will order cells according to their most likely developmental chronology and identify genes and gene regulatory networks that define distinct cell types. The completion of the first aim will be followed by a more ambitious long-term one that is based on: 2) The in-depth functional characterisation of a subset of novel key regulators of blood formation and identified cell types in vivo. To achieve this I will generate a number of loss-of-function and transgenic zebrafish lines. By sequencing thousands of single cells, this study is poised to go beyond traditional approaches in examining the complex relationships between the continuous spectra of blood cells, and will provide unprecedented insight into the regulation of blood cell formation.

Mots-clés : haematopoiesis,single cell rna seq,zebrafish
Projet ERC : VitruVius (Horizon 2020, appel 2015, Advanced grants)
Domaine scientifique : Life Science
Panel : Cellular, Developmental and Regenerative Biology
Entité participante : Centre national de la recherche scientifique — Pays : France — Rôle : Partner
Acronyme de l'entité : CNRS
Type d'entité : Recherche
Financement ERC de l'entité : 0.0 €

Body size is an intrinsic property of living organisms that is intimately linked to the developmental program to produce fit individuals with proper proportions. Final size is the result of both genetic determinants and sophisticated mechanisms adapting size to available resources. Classical regeneration and transplantation experiments have established that different body parts grow according to autonomous programs, challenging the concept of systemic and harmonious growth. Therefore, coordination mechanisms must ensure that all parts have reached appropriate final size before animals stop growing. The main objective of this program is to tackle the mechanisms ensuring growth coordination and size determination. To tackle these questions, we propose to bring together physiology, genetics, advanced imaging and modelling approaches in an unprecedented integrated project. We will develop these approaches on the Drosophila model where we gained expertise, and will develop the vertebrate model Ambystoma mexicanum (axolotl) well adapted for limb growth and regeneration studies. Three major aims will be addressed: 1- We will explore the mechanisms coupling the developmental clock with organ growth. 2- We will dissect the mechanisms allowing inter-organ growth coordination both in response to abnormal growth (injury/neoplasm) and in the course of normal development (control of developmental instability). 3- We will use our knowledge acquired on insect models to develop Ambystoma mexicanum (axolotl) as a vertebrate model for organ growth coordination. We believe this project brings together novel and complementary expertise that will contribute to broader understanding of the fascinating question of body growth and final size assessment.

Mots-clés : growth control,developmental timing,insulin,igf signaling,ecdysone signaling
Projet ERC : deFIBER (Horizon 2020, appel 2017, Starting grants)
Domaine scientifique : Life Science
Panel : Physiology in Health, Disease and Ageing
Entité participante : Erasmus MC — Pays : Pays-Bas — Rôle : PI
Type d'entité : Enseignement supérieur ou secondaire
Financement ERC de l'entité : 1498544.0 €

Bone marrow (BM) fibrosis is the continuous replacement of blood forming cells in the bone marrow by scar tissue, ultimately leading to failure of the body to produce blood cells. Primary myelofibrosis (PMF), an incurable blood cancer, is the prototypic example of the step-wise development of BM fibrosis. The specific mechanisms that cause BM fibrosis are not understood, in particular as the cells driving fibrosis have remained obscure. My recent findings demonstrate that Gli1+ cells are fibrosis-driving cells in PMF, that their frequency correlates with fibrosis severity in patients, and that their ablation ameliorates BM fibrosis. These results indicate that Gli1+ cells are the primary effector cells in BM fibrosis and that they represent a highly attractive therapeutic target. This puts me in a unique position to vastly expand our knowledge of the BM fibrosis pathogenesis, improve diagnostics, and discover new therapeutic strategies for this fatal disease. I will do this by: 1) dissecting the molecular and cellular mechanisms of the fibrotic transformation, 2) defining the stepwise disease evolution by genetic fate tracing and analysis of the previously unknown critical effector cells of BM fibrosis , 3) understanding early forms of BM fibrosis for improved diagnostics in patients, all with the ultimate aim to identify novel therapeutic targets to directly block the cellular and molecular changes occuring in BM fibrosis. I will apply state-of-the-art techniques, including genetic fate tracing experiments, conditional genetic knockout mouse models, tissue engineering of the bone marrow niche and in vivo and in vitro CRISPR/Cas9 gene editing, to unravel the complex molecular and cellular interaction between fibrosis-causing cells and the malignant hematopoietic cells. I will translate these findings into patient samples with the aim to improve the early diagnosis of the disease and to ultimately develop novel targeted therapies with curative intentions.

Mots-clés : fibrosis,hematology,myeloproliferative neoplasms,hematopoeitic stem cells
Projet ERC : HARMONIC (Horizon 2020, appel 2018, Starting grants)
Domaine scientifique : Physical Sciences and Engineering
Panel : Computer science and informatics
Entité participante : Technion – Israel Institute of Technology — Pays : Israël — Rôle : PI
Type d'entité : Enseignement supérieur ou secondaire
Financement ERC de l'entité : 1473750.0 €

Boolean function analysis is a topic of research at the heart of theoretical computer science. It studies functions on n input bits (for example, functions computed by Boolean circuits) from a spectral perspective, by treating them as real-valued functions on the group Z_2^n, and using techniques from Fourier and functional analysis. Boolean function analysis has been applied to a wide variety of areas within theoretical computer science, including hardness of approximation, learning theory, coding theory, and quantum complexity theory. Despite its immense usefulness, Boolean function analysis has limited scope, since it is only appropriate for studying functions on {0,1}^n (a domain known as the Boolean hypercube). Discrete harmonic analysis is the study of functions on domains possessing richer algebraic structure such as the symmetric group (the group of all permutations), using techniques from representation theory and Sperner theory. The considerable success of Boolean function analysis suggests that discrete harmonic analysis could likewise play a central role in theoretical computer science. The goal of this proposal is to systematically develop discrete harmonic analysis on a broad variety of domains, with an eye toward applications in several areas of theoretical computer science. We will generalize classical results of Boolean function analysis beyond the Boolean hypercube, to domains such as finite groups, association schemes (a generalization of finite groups), the quantum analog of the Boolean hypercube, and high-dimensional expanders (high-dimensional analogs of expander graphs). Potential applications include a quantum PCP theorem and two outstanding open questions in hardness of approximation: the Unique Games Conjecture and the Sliding Scale Conjecture. Beyond these concrete applications, we expect that the fundamental results we prove will have many other applications that are hard to predict in advance.

Mots-clés : computational complexity
Projet ERC : ALS-Networks (Horizon 2020, appel 2015, Consolidator grants)
Domaine scientifique : Life Science
Panel : Neuroscience and Disorders of the Nervous System
Entité participante : Institut national de la santé et de la recherche médicale — Pays : France — Rôle : PI
Acronyme de l'entité : Inserm
Type d'entité : Recherche
Financement ERC de l'entité : 2000000.0 €

Brain and spinal cord diseases affect 38% of the European population and cost over 800 billion € annually; representing by far the largest health challenge. ALS is a prevalent neurological disease caused by motor neuron death with an invariably fatal outcome. I contributed to ALS research with the groundbreaking discovery of TDP-43 mutations, functionally characterized these mutations in the first vertebrate model and demonstrated a genetic interaction with another major ALS gene FUS. Emerging evidence indicates that four major causative factors in ALS, C9orf72, TDP-43, FUS & SQSTM1, genetically interact and could function in common cellular mechanisms. Here, I will develop zebrafish transgenic lines for all four genes, using state of the art genomic editing tools to combine simultaneous gene knockout and expression of the mutant alleles. Using these innovative disease models I will study the functional interactions amongst these four genes and their converging effect on key ALS pathogenic mechanisms: autophagy degradation, stress granule formation and RNA regulation. These studies will permit to pinpoint the molecular cascades that underlie ALS-related neurodegeneration. We will further expand the current ALS network by proposing and validating novel genetic interactors, which will be further screened for disease-causing variants and as pathological markers in patient samples. The power of zebrafish as a vertebrate model amenable to high-content phenotype-based screens will enable discovery of bioactive compounds that are neuroprotective in multiple animal models of disease. This project will increase the fundamental understanding of the relevance of C9orf72, TDP-43, FUS and SQSTM1 by developing animal models to characterize common pathophysiological mechanisms. Furthermore, I will uncover novel genetic, disease-related and pharmacological modifiers to extend the ALS network that will facilitate development of therapeutic strategies for neurodegenerative disorders

Mots-clés : molecular and cellular neuroscience,human and functional genetics,genomic engineering,physiological analysis,zebrafish transgenesis,chemical screening analysis
Projet ERC : BRAINCOMPATH (Horizon 2020, appel 2014, Advanced grants)
Domaine scientifique : Life Science
Panel : Neuroscience and Disorders of the Nervous System
Entité participante : University of Zurich — Pays : Suisse — Rôle : PI
Acronyme de l'entité : UZH
Type d'entité : Enseignement supérieur ou secondaire
Financement ERC de l'entité : 2498915.0 €

Brain computations rely on proper signal flow through the complex network of connected brain regions. Despite a wealth of anatomical and functional data – from microscopic to macroscopic scale – we still poorly understand the principles of how signal flow is routed through neuronal networks to generate appropriate behavior. Brain dynamics on the 'mesoscopic' scale, the intermediate level where local microcircuits communicate via axonal pathways, has remained a particular blind spot of research as it has been difficult to access under in vivo conditions. Here, I propose to tackle the mesoscopic level of brain dynamics both experimentally and theoretically, adopting a fresh perspective centered on neuronal pathway dynamics. Experimentally, we will utilize and further advance state-of-the-art genetic and optical techniques to create a toolbox for measuring and manipulating signal flow in pathway networks across a broad range of temporal scales. In particular, we will improve fiber-optic based methods for probing the activity of either individual or multiple neuronal pathways with high specificity. Using these tools we will set out to reveal mesoscopic brain dynamics across relevant cortical and subcortical regions in awake, behaving mice. Specifically, we will investigate sensorimotor learning for a reward-based texture discrimination task and rapid sensorimotor control during skilled locomotion. Moreover, by combining fiber-optic methods with two-photon microscopy and fMRI, respectively, we will start linking the meso-level to the micro- and macro-levels. Throughout the project, experiments will be complemented by computational approaches to analyse data, model pathway dynamics, and conceptualize a formal theory of mesoscopic dynamics. This project may transform the field by bridging the hierarchical brain levels and opening significant new avenues to assess physiological as well as pathological signal flow in the brain.

Mots-clés : neocortex,thalamus,neuron,calcium indicator,imaging,in vivo,sensorimotor,optical fiber,two photon,fmri,axonal pathway,mesoscopic
Projet ERC : Ctrl-BBB (Horizon 2020, appel 2019, Consolidator grants)
Domaine scientifique : Life Science
Panel : Physiology in Health, Disease and Ageing
Entité participante : Université Libre de Bruxelles — Pays : Belgique — Rôle : PI
Acronyme de l'entité : ULB
Type d'entité : Enseignement supérieur ou secondaire
Financement ERC de l'entité : 2286542.5 €

Brain endothelial cells (ECs) are endowed with a set of molecular and metabolic adaptations that stringently orchestrate the molecular and cellular transit between the brain and the circulatory system. These adaptations constitute the blood-brain barrier (BBB) and are pivotal to brain homeostasis and protection. Accordingly, BBB dysfunction is a unifying hallmark of many cerebrovascular diseases, including stroke, multiple sclerosis and neurodegeneration. Healing the BBB to treat to the brain is therefore emerging as a powerful therapeutic avenue for a spectrum of human CNS disorders. In addition, through its neuroprotective function, the BBB represents the main obstacle for CNS drug delivery. There is consequently an urgent need to identify methods to control BBB in health and disease. Of pivotal importance, BBB is not genetically hardwired, but instead results from ongoing neurovascular communications taking place between the ECs and the other components of the neurovascular unit. Shedding light on these communications, and raising our understanding to the mechanistic level will undoubtedly yield transformative therapeutic strategies for human brain disorders. A key obstacle in the study of BBB permeability resides in its complex regulation across cells and tissues. This complexity cannot be recapitulated in cell culture experiments. Our laboratory has recently identified and validated the transparent zebrafish as ideally suited to facilitate these studies, by empowering non-invasive genetic analyses of BBB function under normoxia. Together with a conserved BBB genetic instruction program, the zebrafish cerebrovasculature qualifies as a an alternative “miniature BBB model” where neurovascular communication can be studied at an unprecedented pace. Ctrl-BBB will pioneer synergistic approaches between the zebrafish and the mouse model, to bring BBB research in the era of highly parallel genetic approaches and BBB-focused therapeutic strategies for brain disorders.

Mots-clés : blood brain barrier,vascular biology,neurovascular biology,zebrafish
Projet ERC : ENSEMBLE (Horizon 2020, appel 2020, Synergy grants)
Entité participante : Centre national de la recherche scientifique — Pays : France — Rôle : CO-PI
Acronyme de l'entité : CNRS
Type d'entité : Recherche
Financement ERC de l'entité : 5085310.0 €

Brain research has made tremendous progress over the last few decades in nearly all areas of investigation with the exception of one: the extracellular space (ECS). It is however a key compartment defined as the web-like space between brain cells, filled with a myriad of molecules that enable brain functions and homeostasis. How molecules navigate in the ECS is a very important, yet unsolved, challenge that precludes conceptual advance in brain science and innovation in therapeutics (e.g. immunotherapy). The lack of knowledge is mainly due to the absence of dedicated investigation strategies for such a complex and finely structured biological entity. Our ground-breaking project (ENSEMBLE) will shed light on the conceptual and methodological roadblocks that have prevented us from understanding the fine architecture of the ECS and how molecules navigate within it throughout the brain. We posit that molecular diffusion in the ECS is locally regulated by the properties of the ECS, which is essential for brain functions. Four world-class scientists, L. Groc (molecular neuroscience, CNRS), E. Bezard (systems neuroscience, INSERM), L. Cognet (optics & nanoscience, CNRS), and U.V. Nägerl (neurophotonics, Univ. Bordeaux), team up to develop and apply unconventional investigation approaches, based on original nano-imaging strategies (super-resolution microscopy and carbon nanotube/nanoparticle tracking), to the in vivo brain. Yet, to consider and achieve such an experimental and multidisciplinary tour de force a side-by-side and daily interactive effort is necessary. Thanks to our complementary expertise and geographical proximity, ENSEMBLE will provide a unique opportunity to unveil in vivo the structure and functions of this crucial brain compartment and will offer a new theoretical and experimental framework to manipulate molecule navigation. The ENSEMBLE project will also cross-fertilize the fields of nanoscience, optical imaging, organ pathophysiology and immunotherapy.

Mots-clés : brain,extracellular space,superresolution microscopy,single molecule imaging,single nanoparticle tracking,immunoglobulin,neuronal communication
Projet ERC : METROMOD (Horizon 2020, appel 2016, Consolidator grants)
Domaine scientifique : Social Sciences and Humanities
Panel : Cultures and cultural production
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 : 1928400.0 €

Breaking new ground, METROMOD proposes a rewriting of modern art history as a history of global interconnections, spurred by migration movements and rooted in cities. Revising the historiography of modern art, which still continues to be dominated by the hegemonic and normative narratives of (Western) European Modernism and ignores the significance of exile movements, METROMOD conceptualizes art history as a result of interrelations and negotiations in global contact zones, unstable flows, transformations and crises. In its analysis, METROMOD focuses on the first half of the 20th century. During this era the modern movement emerged as a paradigm in art and architecture, and rapid urbanization took place globally; thousands of persecuted European modern artists fled their homes, re-establishing their practices in metropolises across the world. Reflecting both the geographical extent of these exile movements and their local urban impact METROMOD examines 6 key migrant destinations—the global cities of London, New York, Buenos Aires, Istanbul, Shanghai and Bombay (now Mumbai)—following three main objectives: to explore transformations in urban topographies, identifying artistic contact zones and places of transcultural art production; to investigate networks of exiled and local artists as well as collaborative projects and exhibitions; and to analyse art publications and discourse generated in centres of exile. Digital mapping will locate sites of artistic migration in the cities and demonstrate linkages between transforming metropolises and flows of people and objects around the world. The conceptual triangle of modernism, migration and the metropolis forms the foundation of an innovative comparative, interdisciplinary methodology. As well as impacting art history, METROMOD will provide a historical perspective from which today’s mass migration movements can be better understood.

Mots-clés : migration and exile history,cultural transfer,urban studies,history of modernism,transfer of ideas and knowledge,historiography,20th century,jewish studies