Data-Gouv-ML/pcri-erc-participations-et-projets-laureats huggingface dataset:
Projet ERC : RobustSynapses (Horizon 2020, appel 2014, Consolidator grants)
Domaine scientifique : Life Science
Panel : Neuroscience and Disorders of the Nervous System
Entité participante : Vlaams Instituut voor Biotechnologie — Pays : Belgique — Rôle : PI
Acronyme de l'entité : VIB
Type d'entité : Recherche
Financement ERC de l'entité : 1999025.0 €

Neurodegeneration is characterized by misfolded proteins and dysfunctional synapses. Synapses are often located very far away from their cell bodies and they must therefore largely independently cope with the unfolded, dysfunctional proteins that form as a result of synaptic activity and stress. My hypothesis is that synaptic terminals have adopted specific mechanisms to maintain robustness over their long lives and that these may become disrupted in neurodegenerative diseases. Recent evidence indicates an intriguing relationship between several Parkinson disease genes, synaptic vesicle trafficking and autophagy, providing an excellent entry point to study key molecular mechanisms and interactions in synaptic membrane trafficking and synaptic autophagy. We will use novel genome editing methodologies enabling fast in vivo structure-function studies in fruit flies and we will use differentiated human neurons to assess the conservation of mechanisms across evolution. In a complementary approach I also propose to capitalize on innovative in vitro liposome-based proteome-wide screening methods as well as in vivo genetic screens in fruit flies to find novel membrane-associated machines that mediate synaptic autophagy with the ultimate aim to reveal how these mechanisms regulate the maintenance of synaptic health. Our work not only has the capacity to uncover novel aspects in the regulation of presynaptic autophagy and function, but it will also reveal mechanisms of synaptic dysfunction in models of neuronal demise and open new research lines on mechanisms of synaptic plasticity.
Projet ERC : NeuroFish (Horizon 2020, appel 2019, 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 : 1874863.0 €

Neurofilaments (NFs) are a highly dynamic cytoskeletal network, which exhibits essential functions in neurons and are key actors in neurodegeneration. NFs are not only a genetic cause of neuronal death in human, their abnormal aggregation is an early pathological hallmark in disease, and their genetic removal from axons has shown spectacular benefits in delaying disease onset, extending survival and restoring neurological functions in mouse models. In this project, I propose the concept that the defects in NF transport and degradation are the causes of neurodegeneration. I will tackle the live dynamic of these processes in health and disease in a meaningful in vivo context, using the zebrafish. Combining state-of-the-art and innovative live-imaging and proteomic methodologies in zebrafish, our program has three major goals. First, we will study the dynamic of NF transport along the axons and its spatial regulation by myelinating cells, with novel zebrafish lines expressing fluorescently labeled NFs. Second, we will decipher the mechanisms of NF degradation by generating a zebrafish line overexpressing gigaxonin, an E3 ligase adaptor we found to destroy the stable NF network, and by designing a new proteomic methodology in zebrafish. Finally, we will investigate NF dysfunctions and their pathological roles in disease, by generating models for neurodegenerative diseases carrying NF mutations and using the methodologies described above. I anticipate that interventions on NF dynamics will substantially reverse neurodegeneration, and proofs of concept will be obtained by overexpressing gigaxonin in our disease zebrafish models and through drug screening. Thus, this ERC project will generate forefront knowledge in the field of NFs and neurodegeneration and will provide a highly significant platform for therapeutic intervention on NFs, for the benefit of most neurodegenerative diseases.

Mots-clés : neurofilaments,zebrafish,charcot marie tooth type 2 diseases,cmt2
Projet ERC : INTERACT (Horizon 2020, appel 2018, Starting grants)
Domaine scientifique : Physical Sciences and Engineering
Panel : Systems and communication engineering
Entité participante : University of Twente — Pays : Pays-Bas — Rôle : PI
Type d'entité : Enseignement supérieur ou secondaire
Financement ERC de l'entité : 1500000.0 €

Neurological injuries such as stroke leave millions of people disabled worldwide every year. For these individuals motor recovery is often suboptimal. The impact of current neurorehabilitation machines is hampered by limited knowledge of their physical interaction with the human. As we move, our body adapts positively to optimal stimuli; motor improvement after stoke is promoted via physical training with an appropriate afferent input to the nervous system and mechanical loads to muscles. Loss of appropriate stimuli leads to motor dysfunction. Motor recovery requires positive neuromuscular adaptations to be steered over time. If neuro-modulative and orthotic machines could be controlled to generate optimal stimuli to the neuromuscular system, a new era in neurorehabilitation would begin. This project creates multi-scale models of human-machine interaction for radically new closed-loop control paradigms. We will combine biosignal recording and numerical modeling to decode the cellular activity of motor neurons in the spinal cord with resulting musculoskeletal forces at a resolution not considered before. This will enable breakthroughs for tracking the spinal-musculoskeletal system across spatiotemporal scales: short-to-long term adaptation from cellular to organ scales. We will use these concepts to design new machine control schemes. With a focus on spinal cord electrical stimulation and mechatronic exosuits, we will demonstrate how motor dysfunction is repaired by inducing optimal changes in neuromuscular targets. The innovative aspect is that of gaining control of the stimuli that govern neuromuscular function over time. This will enable machines to co-adapt with the body; an achievement that will disrupt the development of man-machine interfaces from neuroprostheses, to robotic limbs, to exosuits. INTERACT will answer fundamental questions in movement neuromechanics via novel principles of human-machine interaction with broad impact on bioengineering and robotics

Mots-clés : emg driven musculoskeletal modelling,movement neuromechanics,muscle actuated simulation,myoelectric powered orthosis,neurorehabilitation technologies
Projet ERC : OrganellenanoComp (Horizon 2020, appel 2019, Advanced grants)
Domaine scientifique : Life Science
Panel : Neuroscience and Disorders of the Nervous System
Entité participante : Centre national de la recherche scientifique — Pays : France — Rôle : PI
Acronyme de l'entité : CNRS
Type d'entité : Recherche
Financement ERC de l'entité : 2374698.0 €

Neuronal and glial physiology in nanodomains remains poorly understood due to the spatio-temporal limitation of direct unperturbed in vivo measurements. Yet, it is the scale of voltage regulation, ionic, proteins and molecular trafficking, metabolism control and local signal transduction. The goal of this proposal is to determine how the flow of ions and molecules is regulated in the cytoplasm in relation with organelles, such as the endoplasmic reticulum and mitochondria in various physiological conditions such as steady-state, induction of plastic changes or ionic depletion. The approach is based on mathematical modeling, large data analysis, simulation methods, and developing the associated fast and efficient algorithms. We developed in the past 15 years computational tools such as molecular modeling, stochastic simulations and data analysis at a molecular level to study various signals such as voltage recordings or super-resolution microscopy single particle trajectories (SPTs). However, these theoretical approaches are not sufficient today to face the novel data revolution coming from SPTs, but also voltage dyes, voltage recorded by nanopipettes, or photoconversion in nanocompartments. The aim of the project is to develop physical models of molecular diffusion and electro-diffusion. These models will be applied to reconstruct and interpret the local transport, which is not homogeneous because molecules or receptors could aggregate in some specific nano-regions. We will explore the mechanisms underlying this heterogeneity. Second, we will apply these modeling and numerical simulations to analyze data about flux regulation inside the cytoplasm but also in organelles, such as the ER and mitochondria.Third, we analyze calcium fluorescent data (photoactivation, local uncaging) to study how calcium is exchanged in nanodomains during synaptic transmission in dendrites and dendritic spines.
Projet ERC : MultiScaleNeurovasc (Horizon 2020, appel 2014, Starting grants)
Domaine scientifique : Life Science
Panel : Neuroscience and Disorders of the Nervous System
Entité participante : Tel Aviv University — Pays : Israël — Rôle : PI
Acronyme de l'entité : TAU
Type d'entité : Enseignement supérieur ou secondaire
Financement ERC de l'entité : 1500000.0 €

Neuronal computations in the brain require a high metabolic budget yet the brain has extremely limited resources; calling for an on-demand, robust supply system to deliver nutrients to active regions. In most cases, neuronal activity results in an increase in blood flow to the active area, a phenomenon called functional hyperaemia. This coupling between neuronal and vascular activtuy underpins the mechanism enabling fMRI to map neuronal activity based on vascular dynamics; further, malfunction of the cellular players involved in coupling is now considered to play a key role in otherwise classically defined neurodegenerative diseases. We lack a concise description of the inner workings of this mechanism and a thorough quantitative description of the neuro-gila-vascular interface; issues that are best addressed by an investigation into the cellular mechanisms, the temporal dynamics and multi-scale spatial organization governing neurovascular coupling. My long-term goal is to provide a unified theory to encapsulate our knowledge on neurovascular coupling. Here, I hypothesize that functional hyperaemia results from the constant integration of vasoactive cues with region-dependent coupling emerging from different neuro-glia-vascular microcircuits, nuances in afferent wiring into vascular contractile elements and/or neuronal activity patterns. I will test this hypothesis with a multi-faceted correlative approach combining: two-photon awake imaging of cellular and vascular dynamics to obtain physiological data unaffected by anaesthetics; super-resolution structural imaging of intact volumes to map the fine details of micro-circuit structure; array-tomography to map in situ the neurovascular signalling machinery and novel optogenic tools to manipulate several of its specific components. I expect to offer a revolutionary mechanistic insight into one of the most basic and fundamental physiological processes behind the structure and function of the brain.

Mots-clés : layer dependent neurovascular coupling,two photon awake imaging,interneurons,pericytes,astrocytes,micro circuit,array tomography,large scale mapping,optical cleared tissue,function structure
Projet ERC : NEUROPHAGY (Horizon 2020, appel 2016, Starting grants)
Domaine scientifique : Life Science
Panel : Neuroscience and Disorders of the Nervous System
Entité participante : University of Lausanne — Pays : Suisse — Rôle : PI
Acronyme de l'entité : UNIL
Type d'entité : Enseignement supérieur ou secondaire
Financement ERC de l'entité : 925307.19 €

Neuronal metabolism is emerging as an essential regulator of brain function and its deregulation is a common denominator in neurological disorders entailing intellectual disability and synapse dys-morphogenesis. The autophagy-lysosome system is the major catabolic pathway dedicated to the recycling not only of protein aggregates but also lipids, nucleic acids, polysaccharides and defective or superfluous organelles, among others. Appreciation of the role of autophagic pathways in the healthy and diseased brain continues to expand, as accumulating evidence indicates that proper regulation of autophagy is indispensable for neuronal integrity. At the cellular level, several lines of evidence implicate autophagy in the regulation of synaptic plasticity. However, the synapse-specific substrates of autophagy remain elusive. Similarly, the synaptic defects arising from autophagy impairment have never been thus far systematically addressed, yet they translate into severe behavioural deficiencies, such as compromised memory and cognition, pertinent to disorders of intellectual disability. The present proposal aims to determine how autophagy regulates synaptic plasticity and how its deregulation contributes to synaptic defects. In particular, the objectives aim to: 1) Monitor and characterize the presence of the autophagic machinery in pre- and post-synaptic sites. 2) Identify autophagic substrates residing in synapses and whose turnover via autophagy determines synaptic plasticity. 3) Characterize the synaptic defects and ensuing behavioural deficits arising from impaired autophagy in the hippocampus. 4) Use C. elegans as a model system to address the evolutionary conservation of the synaptic role of autophagy and perform forward genetic screens to reveal novel regulators of autophagy in synapses.

Mots-clés : metabolism,dendritic spines,forward genetic screens
Projet ERC : SPLICECODE (Horizon 2020, appel 2015, Advanced grants)
Domaine scientifique : Life Science
Panel : Neuroscience and Disorders of the Nervous System
Entité participante : University of Basel — Pays : Suisse — Rôle : PI
Type d'entité : Enseignement supérieur ou secondaire
Financement ERC de l'entité : 2496460.0 €

Neuronal networks represent an impressive example of highly organized complex systems. Sperry postulated that selective neuronal connectivity is achieved by chemoaffinity labels. Several such labels for axon guidance and topographic mapping have been defined. However, until recently, molecules that direct the recognition of synaptic partners and functional specification of synapses have remained obscure. Chemoaffinity tags are envisioned to provide a recognition code that would encompass the recognition of self versus non-self, recognition of sister cells, and recognition of appropriate and inappropriate synaptic partners. Key parameters that determine the function of recognition systems are the diversity (number of independently recognizable tags), the repertoires of recognition tags in a cell population, and the contribution of tags to selective interactions. The finite number of protein-coding genes in the human genome severely limits the genetic resources that can be employed for generating molecular diversity. In this project we will test the hypothesis that alternative splicing is a central mechanism for the amplification of molecular diversity in recognition tags and their role in synaptic specificity. We will implement novel mass-spectrometry and sequencing methods to define molecular diversity of a highly diversified receptor family in mice. We will unravel the logic of receptor repertoires across cell populations and test the importance of cell type-specific alternative splicing programs for synaptic specificity. The focus of this project on cell-type specific alternative splicing advances a new dimension in neuronal transcriptomics. Discoveries and technical innovations made in this work should be applicable to molecular studies of recognition events in any system. Finally, human genetic studies link mutations in the gene families explored here to autism. Thus, insights from this work will facilitate analysis of the pathophysiology of this disorder.

Mots-clés : cell biological mechanism,synapse formation,cell adhesion,recognition
Projet ERC : 3DPartForm (Horizon 2020, appel 2019, Starting grants)
Domaine scientifique : Physical Sciences and Engineering
Panel : Products and processes engineering
Entité participante : Otto-von-Guericke University Magdeburg — Pays : Allemagne — Rôle : PI
Acronyme de l'entité : OvGU
Type d'entité : Enseignement supérieur ou secondaire
Financement ERC de l'entité : 311786.94 €

New polymer materials are necessary to match the demand for highly integrated, multifunctional, responsive systems for sensing, information processing, soft robotics or multi-parametric implants. Both established material design concepts based on lithography, and emerging engineering efforts based on additive manufacturing (AM) are currently not able to fully address the need for topologically complex, multifunctional and stimuli-responsive polymer materials. This proposal aims at establishing a radically new approach for polymer material design, rethinking AM on both material and process level. Here, functionality will be already embedded at the building block level to emerge into larger scales. The exact methodology relies on polymer microparticles as a novel material basis with arbitrary geometry, function, mechanics and responsiveness. These microparticulate formulations will serve as predefined, voxel-like building blocks in AM yielding hierarchical assemblies with spatially defined voxel position and programmable, adaptive properties, which clearly go beyond existing functional material classes. With that, 3DPartForm will address the current lack of additive manufacturing providing multifunctional, stimuli-responsive materials, in which not only strongly different, but most importantly functional building blocks with intrinsic time axis will be processed into true 4D-polymer multimaterials. Products emerging from this approach will reach a previously unknown level of system integration, where optical transparency, electric and thermal conductivity as well as diffusivity and mechanical rigidity will become spatiotemporally tunable at single-voxel level. Coupled sensing and actuation operations will be realized by processing, transforming and manipulating single or combined input stimuli within these materials in the focus of 3DPartform, and platforms for biomimetics and cell-free biotechnology will be implemented as a long-term goal.

Mots-clés : microfluidics,polymer gels,4d materials,additive manufacturing,hierarchical assembly,stimuli responsiveness
Projet ERC : ExtremeQuantum (Horizon 2020, appel 2015, Consolidator grants)
Domaine scientifique : Physical Sciences and Engineering
Panel : Condensed matter physics
Entité participante : University of Warwick — Pays : Royaume-Uni — Rôle : PI
Type d'entité : Enseignement supérieur ou secondaire
Financement ERC de l'entité : 1840513.0 €

New states of matter offer an unparalleled testing ground for studying fundamental physics, particularly interacting quantum systems. The EXTREMEQUANTUM project will significantly advance our knowledge of these states by using extreme conditions of magnetic field and pressure to enable a continuous, clean and reversible tuning of quantum interactions, thereby shedding light on the building blocks of exotic magnetism and unconventional superconductivity. By developing the materials and methodology to achieve this, we will push our understanding of quantum systems beyond current limitations and open a route for exploiting the untapped potential of these materials to underpin future technology in fields as diverse as electrical power networks, quantum computation and healthcare. EXTREMEQUANTUM takes as its starting point recent theoretical and experimental discoveries in the area of quantum materials and will capitalize on a novel measurement technique developed in my research group over the past few years. By utilizing both atomic and molecular substitution, the project will focus on a series of materials that are on the verge of a phase instability. Ultra-high fields and applied pressure will push these systems through the critical region where the state of matter changes and inherently quantum effects dominate. Electronic, magnetic and structural properties will be measured as the tipping point is breached and the resulting data compared with predictions of theoretical models. The results will provide answers to questions of deep concern to modern physics, such how quantum fluctuations, topology and disorder can be used to create states of matter with novel and functional properties.

Mots-clés : functional properties of materials,molecular materials,high magnetic fields,extreme conditions,symmetry and topology in condensed matter physics,low dimensional magnetism
Projet ERC : TROJAN (Horizon 2020, appel 2020, Proof of concept grants)
Domaine scientifique : Life Science
Panel : Biotechnology and Biosystems Engineering
Entité participante : Warsaw University of Life Sciences — Pays : Pologne — Rôle : PI
Acronyme de l'entité : SGGW
Type d'entité : Enseignement supérieur ou secondaire
Financement ERC de l'entité : 150000.0 €

New therapeutic approaches have led to significant improvements in cancer treatment, but none have been able to overcome the limited efficacy of solid tumor treatment due to poor tumor delivery and the presence of hypoxic tumor cells. Macrophages represent a promising vesicle to deliver cancer therapeutics to solid tumors as they are continuously recruited into the tumor mass, even the most hypoxic regions. Our pioneering research demonstrated that macrophages are able to take up ferritins loaded with anti-cancer drugs, creating Macrophage-Drug Conjugates (MDCs), and transfer these to cancer cells and kill them, a phenomenon we named TRAIN. In my ongoing ERC STARTING GRANT PROJECT ‘MCHAP’, we have proven that MDCs can be used as a ‘Trojan horse’ to efficiently deliver drugs directly to the cancer cells via TRAIN. Now we aim to turn the MDC technology into a COMMERCIAL and SOCIAL VALUE PROPOSITION by confirming our findings in a PDX model, which is crucial to raise interest of and establish a co-development (or licensing) deal with big pharma’s to realize commercialization and clinical uptake of our IP-protected MDC technology. During the ERC PoC project, we determine the optimal efficacy of MDC delivery, examine the concentration of the drug delivered to the tumor and other organs, validate the efficacy of MDC delivery in PDX mice after MDC treatment,and optimize our business case. This project will thus provide PROOF OF CONCEPT for the efficacy and pharmacokinetics of, and establish the viability, feasibility, commercialization and overall direction for our innovative MDC technology. This project will substantially contribute to bring our MDC technology to the market and in clinical practice, where our MDC technology has the promising potential to improve prognosis of cancer patients, improve the performance of anti-cancer drugs, and reduce healthcare costs. THE NEW, INNOVATIVE MDC TECHNOLOGY CAN THUS REALIZE SIGNIFICANT BENEFITS FOR OUR SOCIETY AND OUR ECONOMY.

Mots-clés : drug delivery platform,targeted drug delivery,macrophage drug conjugates  mdcs,transfer of,iron binding proteins  train,macrophages,ferritins,advanced solid tumors