Data-Gouv-ML/pcri-erc-participations-et-projets-laureats huggingface dataset:
Projet ERC : evolSingleCellGRN (Horizon 2020, appel 2018, Starting grants)
Domaine scientifique : Life Science
Panel : Environmental Biology, Ecology and Evolution
Entité participante : Humboldt-Universität zu Berlin — Pays : Allemagne — Rôle : PI
Acronyme de l'entité : HU
Type d'entité : Enseignement supérieur ou secondaire
Financement ERC de l'entité : 1499900.0 €

Cell types in development arise from precise patterns of gene expression driven by differential usage of DNA regulatory elements. Mutations affecting these elements, or proteins binding them, are major contributors to disease and underlie the evolution of new morphologies. To better understand these elements and how they evolve, I introduce a set of single-cell RNA and ATAC-Seq sequencing technologies that: A) Identify tissue-specific regulatory elements and expression profiles by interrogating individual cells, B) Allow for a precise read-out of developmental responses to mutation and perturbation, including cell-fate re-specification, C) Lead to the development of a regulatory-information based concept of homology that will be used to understand developmental evolution. The research makes use of sea urchins. The well-annotated sea urchin regulatory network, a detailed understanding of inductive interactions in early development, and an active body of evolutionary research justify this choice. Using single-cell ATAC-Seq and a new method for resolving single-cell, nascent transcripts, I will build a detailed atlas of sea urchin development and use this atlas to understand how regulatory landscapes change during specification and how they evolve between closely related species. I will also investigate, at single-cell resolution, how larval skeletal cells are regenerated following the loss of a cell lineage that mirrors euechinoid evolution. To better understand the origins of cell types in sea urchins, I will characterize embryos of the cnidarian Nematostella, using shared regulatory sites to define cell types which I will compare to urchins and my previous work in Drosophila. The work will generate single-cell methods for non-traditional model systems and help to resolve the processes by which, and the paths along which, development evolves.

Mots-clés : single cell
Projet ERC : ABCvolume (Horizon 2020, appel 2014, Advanced grants)
Domaine scientifique : Life Science
Panel : Molecules of Life: Biological Mechanisms, Structures and Functions
Entité participante : University of Groningen — Pays : Pays-Bas — Rôle : PI
Acronyme de l'entité : RUG
Type d'entité : Enseignement supérieur ou secondaire
Financement ERC de l'entité : 2247230.68 €

Cell volume regulation is crucial for any living cell because changes in volume determine the metabolic activity through e.g. changes in ionic strength, pH, macromolecular crowding and membrane tension. These physical chemical parameters influence interaction rates and affinities of biomolecules, folding rates, and fold stabilities in vivo. Understanding of the underlying volume regulatory mechanisms has immediate application in biotechnology and health, yet these factors are generally ignored in systems analyses of cellular functions. My team has uncovered a number of mechanisms and insights of cell volume regulation. The next step forward is to elucidate how the components of a cell volume regulatory circuit work together and control the physicochemical conditions of the cell. I propose construction of a synthetic cell in which an osmoregulatory transporter and mechanosensitive channel form a minimal volume regulatory network. My group has developed the technology to reconstitute membrane proteins into lipid vesicles (synthetic cells). One of the challenges is to incorporate into the vesicles an efficient pathway for ATP production and maintain energy homeostasis while the load on the system varies. We aim to control the transmembrane flux of osmolytes, which requires elucidation of the molecular mechanism of gating of the osmoregulatory transporter. We will focus on the glycine betaine ABC importer, which is one of the most complex transporters known to date with ten distinct protein domains, transiently interacting with each other. The proposed synthetic metabolic circuit constitutes a fascinating out-of-equilibrium system, allowing us to understand cell volume regulatory mechanisms in a context and at a level of complexity minimally needed for life. Analysis of this circuit will address many outstanding questions and eventually allow us to design more sophisticated vesicular systems with applications, for example as compartmentalized reaction networks.

Mots-clés : membrane transport,cell volume regulation,membrane reconstitution,synthetic cell,abc transporter,osmoregulation,mechanosensitive channel,molecular sensor
Projet ERC : VOLSIGNAL (Horizon 2020, appel 2016, Advanced grants)
Domaine scientifique : Life Science
Panel : Physiology in Health, Disease and Ageing
Entité participante : Forschungsverbund Berlin — Pays : Allemagne — Rôle : PI
Acronyme de l'entité : FVB
Type d'entité : Recherche
Financement ERC de l'entité : 2499991.0 €

Cells must regulate their volume in response to changes in osmolarity and during cell division, migration, apoptosis, and transepithelial transport. Regulated membrane transport of ions and metabolites creates osmotic gradients that secondarily drive water across the membrane. Organic ‘osmolytes’ such as glutamate also serve in extracellular signalling and volume-regulatory ion transporters are often used for other purposes, putting volume regulation into the context of diverse organismal functions. Research on cell volume regulation stagnated because the identity of a key player, the Volume-Regulated Anion Channel VRAC, remained unknown. Very recently we identified LRRC8 heteromers as VRAC components and discovered that VRACs are a heterogeneous group of channels. Their remarkable ability to transport not only Cl-, but also signalling molecules or drugs, depends on their LRRC8 subunit composition. This breakthrough now allows us to search for functionally relevant interactors and to dissect the physiological roles of different VRACs using mouse models. Whereas disruption of Lrrc8a abolishes VRAC function, abrogating other Lrrc8 genes (in total five) will change its transport properties. Conditional KO mice will first focus on epithelia which faces large osmolarity changes, on the brain where VRAC-released signalling molecules are supposed to play important roles in physiology and pathology, and on VRAC’s assumed role in vesicle exocytosis. We expect to discover many surprising novel roles of VRACs. Emboldened by our identification of VRAC, we will use genome-wide siRNA screens to identify two other ‘missing’ ion channels, which have been known physiologically for many years and may have widespread roles in signalling and other physiological processes. Once identified, these channels will be studied at a structural, cellular and organismal level. These projects will break new ground in physiology, cell biology, signalling and pathology.

Mots-clés : ion channels,renal physiology,glia neuron interaction,metabolism,neurotransmitter release
Projet ERC : BIOMECANET (Horizon 2020, appel 2020, Synergy grants)
Entité participante : Max Planck Society — Pays : Allemagne — Rôle : CO-PI
Acronyme de l'entité : MPG
Type d'entité : Recherche
Financement ERC de l'entité : 3100000.0 €

Cellular and sub-cellular organisation at the micrometre length scale ultimately reflects the activity of molecular networks that harness chemical energy to perform precise mechanical work, create functional spatial gradients, and sustain timely temporal changes in molecular activities. In eukaryotic cell division, the biochemical oscillations of the cell cycle drive dramatic morphological changes of the cytoskeleton necessary for bi-orientation of chromosomes and for their subsequent delivery into two daughter cells. This mechanism is at the heart of biology, but it is poorly understood and hard to address because it involves out-of-equilibrium chemistry of many components and Brownian mechanics of the cytoskeleton. BIOMECANET’s extraordinarily ambitious goal is to unravel this interplay by re-engineering it in vitro and by modelling it in silico. To achieve this, BIOMECANET will mobilize an unrivalled catalogue of purified human proteins to reconstitute four fundamental and interlinked biochemical and mechanical protein networks: 1) the cell cycle oscillator with the spindle assembly checkpoint; 2) the metaphase spindle; 3) the chromosome bi-orientation machinery of kinetochores; and 4) the central spindle and its links with the actin cytoskeleton required for cell fission. Then, BIOMECANET will combine these reconstituted networks, integrating temporal control and mechanical forces to analyse the emergence of complex life-like biological function, thus elevating scale and scope of in vitro reconstitutions to an entirely new level. Crucial to the attainment of BIOMECANET’s long-term goals is the synergetic alliance of two biochemists having pioneered different types of biochemical reconstitutions in the complementary areas of cell cycle and chromosome biology (Musacchio) and the cytoskeleton (Surrey), and a theoretician having pioneered physically faithful modelling and simulation of intracellular systems (Nédélec).

Mots-clés : cell cycle,mitotic spindle,cytoskeleton,self organization,cell division,spindle architecture,mechanical network,biochemical network,active network,molecular motors,computer simulation,microtubules,in vitro reconstitution,kinetochore,fluorescence microscopy,force spectroscopy,droplet microfluidics,biochemical reconstitution,modelling,simulation,theory,central spindle,anaphase,metaphase,origami
Projet ERC : BIOMECANET (Horizon 2020, appel 2020, Synergy grants)
Entité participante : Centre for Genomic Regulation — Pays : Espagne — Rôle : PI
Acronyme de l'entité : CRG;CRG-CERCA
Type d'entité : Recherche
Financement ERC de l'entité : 4581608.0 €

Cellular and sub-cellular organisation at the micrometre length scale ultimately reflects the activity of molecular networks that harness chemical energy to perform precise mechanical work, create functional spatial gradients, and sustain timely temporal changes in molecular activities. In eukaryotic cell division, the biochemical oscillations of the cell cycle drive dramatic morphological changes of the cytoskeleton necessary for bi-orientation of chromosomes and for their subsequent delivery into two daughter cells. This mechanism is at the heart of biology, but it is poorly understood and hard to address because it involves out-of-equilibrium chemistry of many components and Brownian mechanics of the cytoskeleton. BIOMECANET’s extraordinarily ambitious goal is to unravel this interplay by re-engineering it in vitro and by modelling it in silico. To achieve this, BIOMECANET will mobilize an unrivalled catalogue of purified human proteins to reconstitute four fundamental and interlinked biochemical and mechanical protein networks: 1) the cell cycle oscillator with the spindle assembly checkpoint; 2) the metaphase spindle; 3) the chromosome bi-orientation machinery of kinetochores; and 4) the central spindle and its links with the actin cytoskeleton required for cell fission. Then, BIOMECANET will combine these reconstituted networks, integrating temporal control and mechanical forces to analyse the emergence of complex life-like biological function, thus elevating scale and scope of in vitro reconstitutions to an entirely new level. Crucial to the attainment of BIOMECANET’s long-term goals is the synergetic alliance of two biochemists having pioneered different types of biochemical reconstitutions in the complementary areas of cell cycle and chromosome biology (Musacchio) and the cytoskeleton (Surrey), and a theoretician having pioneered physically faithful modelling and simulation of intracellular systems (Nédélec).

Mots-clés : cell cycle,mitotic spindle,cytoskeleton,self organization,cell division,spindle architecture,mechanical network,biochemical network,active network,molecular motors,computer simulation,microtubules,in vitro reconstitution,kinetochore,fluorescence microscopy,force spectroscopy,droplet microfluidics,biochemical reconstitution,modelling,simulation,theory,central spindle,anaphase,metaphase,origami
Projet ERC : ORISPECIFICATION (Horizon 2020, appel 2017, Starting grants)
Domaine scientifique : Life Science
Panel : Molecules of Life: Biological Mechanisms, Structures and Functions
Entité participante : Friedrich Miescher Institute — Pays : Suisse — Rôle : PI
Acronyme de l'entité : FMI
Type d'entité : Recherche
Financement ERC de l'entité : 1500000.0 €

Cellular life depends on the timely and accurate duplication of chromosomal DNA through semi-conservative replication to sustain genomic integrity and organismal viability. In all domains of life, DNA replication relies on dedicated initiator proteins that recognize and bind specific genomic sites, termed replication origins, to facilitate the loading of ring-shaped replicative helicases onto DNA. While origin recognition by initiators is determined by specific DNA sequences in prokaryotes and in the eukaryote S. cerevisiae, origin specification in higher eukaryotes instead appears to rely on chromatin context and DNA structure. Yet, how initiators help specify replication origins at the molecular level and how their binding sites are established in higher eukaryotes remain foremost and long-standing questions in the field. This research proposal focuses on uncovering the molecular and structural principles for chromosomal binding site selection by the eukaryotic initiator, the origin recognition complex (ORC), in metazoan systems. Employing integrated biochemical, structural, and cell-based approaches, we aim to 1) elucidate how ORC binds DNA and how DNA structural elements contribute to this interaction, 2) determine how nucleosomes are recognized by ORC, and 3) identify auxiliary binding partners of ORC and establish how they contribute to origin specification. The outcomes of our proposed efforts will have far-reaching implications for multiple scientific fields by defining mechanistic links between chromatin architecture and DNA replication initiation, and they will set the foundation to understand at the molecular level how the replication initiation program is altered during cell differentiation and development. Our studies also have significant biomedical relevance, as failure to precisely replicate chromosomal DNA leads to genetic instability, which in turn underpins many human diseases, including cancer and certain developmental disorders.

Mots-clés : dna replication initiation,origin licensing,origin recognition complex
Projet ERC : pArg_deg_signal (Horizon 2020, appel 2015, Advanced grants)
Domaine scientifique : Life Science
Panel : Molecules of Life: Biological Mechanisms, Structures and Functions
Entité participante : Research Institute of Molecular Pathology — Pays : Autriche — Rôle : PI
Acronyme de l'entité : IMP
Type d'entité : Organismes privés (hors enseignement)
Financement ERC de l'entité : 2499299.0 €

Cellular proteins are prone to misfolding and aggregation, particularly under harsh environmental conditions. To counteract this danger, all organisms from bacteria to humans evolved sophisticated protein quality control networks. The mechanisms employed in them tend to represent some of the most exciting biochemistry occurring in living cells. In Gram-positive bacteria, the key factors combating protein damage include a specialized protein kinase phosphorylating arginine residues (McsB), the central housekeeping protease (ClpP), as well as a AAA chaperone targeting aggregated proteins (ClpC). We find this quality-control system, organized around a distinct protein phospho mark (phosphoarginine, pArg), a fascinating model to investigate novel principles of dealing with proteotoxic stress. Using an integrative approach, we will delineate the precise role of protein arginine phosphorylation in the bacterial stress response. We will first analyze how this unique modification influences the stability and function of targeted proteins in vitro and in vivo. We are particularly interested in the possibility of pArg serving as a bacterial, ubiquitin-like degradation signal. We will then address the mechanism and regulation of the protein arginine kinase McsB. This analysis will uncover the specificity of the pArg tagging system. Additionally, these studies will reveal enzymatic innovations connected with the pArg chemistry that, due to the dependence of bacterial virulence on McsB, are of pharmaceutical interest. To address the further processing of pArg-modified proteins, we will perform an in-depth structural characterization of ClpC and related AAA disaggregases. A better understanding of the mechanism and regulation of these HSP100 molecular machines is also highly relevant to uncover general principles of how cells deal with toxic protein aggregates and, in parallel, keep control over their potentially dangerous shredding devices.
Projet ERC : DHARMA (Horizon 2020, appel 2018, Synergy grants)
Entité participante : University of Naples - L'Orientale — Pays : Italie — Rôle : PI
Type d'entité : Enseignement supérieur ou secondaire
Financement ERC de l'entité : 425228.0 €

Censuses report over a billion “Hindus” in the world today. But what is “Hinduism”? In answer, many accounts describe the doctrinal evolutions of various quite different currents of thought. To try to reply using material and social evidence is difficult because so many vital primary sources for institutional history remain inaccessible. What were the material foundations of the constellation of religious movements today classed as “Hindu”? How have different forms of religious agency shaped the institutional and religious landscape of a large sweep of Asia? How did such “Hindu” traditions, associated primarily with the ideas and practices of ascetics questing for liberation, become institutionally rooted? And what were the repercussions of the widespread patronage of pious foundations? Three types of sources will be examined: inscriptions, manuscripts, archaeological remains. Inscriptions are crucial because most of our historical knowledge of early South and Southeast Asia is based on epigraphy. We will explore, mine and diffuse these sources with the tools of digital humanities (rich mark-up of proper-names, technical terms, geodata, etc.). In order to contextualise epigraphy, unpublished prescriptive texts and new archaeological data will be adduced. Our goal is to identify and to map regional and interregional patterns of patronage. The actors are varied: “lettrés”, holy men and priestly intermediaries, as well as their patrons, often grandees of the state; but also cenobitic communities with their statutes, their libraries, their educational activities, and their incipient bureaucracy. Through a comparative approach (concentrating on “Hinduism”, but also considering the so-called “heretic” religions Buddhism and Jainism), and in a broad range of regional contexts, we shall attempt to uncover with unprecedented historical depth the complex interplay of religion, state and society in a formative period, the “Śaiva Age”, between the 6th and 13th centuries.

Mots-clés : south asia,southeast asia,religion,sanskrit,tamil,kannada,telugu,old javanese,khmer,indology,epigraphy,archaeology,state,society,patronage,indianisation,digital humanities
Projet ERC : DHARMA (Horizon 2020, appel 2018, 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 : 2557325.25 €

Censuses report over a billion “Hindus” in the world today. But what is “Hinduism”? In answer, many accounts describe the doctrinal evolutions of various quite different currents of thought. To try to reply using material and social evidence is difficult because so many vital primary sources for institutional history remain inaccessible. What were the material foundations of the constellation of religious movements today classed as “Hindu”? How have different forms of religious agency shaped the institutional and religious landscape of a large sweep of Asia? How did such “Hindu” traditions, associated primarily with the ideas and practices of ascetics questing for liberation, become institutionally rooted? And what were the repercussions of the widespread patronage of pious foundations? Three types of sources will be examined: inscriptions, manuscripts, archaeological remains. Inscriptions are crucial because most of our historical knowledge of early South and Southeast Asia is based on epigraphy. We will explore, mine and diffuse these sources with the tools of digital humanities (rich mark-up of proper-names, technical terms, geodata, etc.). In order to contextualise epigraphy, unpublished prescriptive texts and new archaeological data will be adduced. Our goal is to identify and to map regional and interregional patterns of patronage. The actors are varied: “lettrés”, holy men and priestly intermediaries, as well as their patrons, often grandees of the state; but also cenobitic communities with their statutes, their libraries, their educational activities, and their incipient bureaucracy. Through a comparative approach (concentrating on “Hinduism”, but also considering the so-called “heretic” religions Buddhism and Jainism), and in a broad range of regional contexts, we shall attempt to uncover with unprecedented historical depth the complex interplay of religion, state and society in a formative period, the “Śaiva Age”, between the 6th and 13th centuries.

Mots-clés : south asia,southeast asia,religion,sanskrit,tamil,kannada,telugu,old javanese,khmer,indology,epigraphy,archaeology,state,society,patronage,indianisation,digital humanities
Projet ERC : V-EPC (Horizon 2020, appel 2016, Advanced grants)
Domaine scientifique : Life Science
Panel : Physiology in Health, Disease and Ageing
Entité participante : FIRC Institute of Molecular Oncology — Pays : Italie — Rôle : PI
Type d'entité : Recherche
Financement ERC de l'entité : 2451250.0 €

Cerebral cavernous malformations (CCM) is a disease characterized by focal capillary-venous cavernomas located in the central nervous system. These malformations are fragile and bleed leading to seizures, paralysis and cerebral hemorrhages. The familial form of CCM is due to loss of function mutations of anyone of three genes called Ccm1, Ccm 2 and Ccm 3. Open skull surgery is the only possible therapy since effective medical treatments are still missing. In mouse models of CCM and human patients’ specimens, endothelial cells (ECs) lining the cavernomas co-express endothelial, mesenchymal and stem cell markers. These features combined to high cell proliferation are reminiscent of tumor initiating cells. In preliminary work, we isolated a rare population of highly proliferative ECs (V-EPC) intermingled with the normal vascular endothelium in vivo and co-expressing endothelial and stem cell markers. Our working hypothesis is that CCM originates from the clonal expansion of these V-EPCs that are more sensitive than mature endothelium to inactivation of Ccm genes. This possibility is supported by the observation that V-EPCs present a comparable gene expression profile and selective markers than the ECs lining CCM cavernomas. The project is divided in three related objectives: 1) To define the nature and functions of V-EPCs in normal vessels; 2) to test the capacity of V-EPCs to trigger the formation of CCM by undergoing clonal expansion in vivo; 3) to test whether targeting V-EPCs or inducing V-EPC maturation by pharmacological tools reduce or prevent the formation of CCM. If successful this work will introduce novel concepts in vascular biology such as: 1) the presence of resident V-EPCs that are differentially sensitive than mature endothelium to the same genetic mutation and angiogenic stimuli; 2) the identification of specific signaling pathways in V-EPC that explain their high proliferative potential; 3) the identification of V-EPC as therapeutic targets for CCM.