Data-Gouv-ML/pcri-erc-participations-et-projets-laureats huggingface dataset:
Projet ERC : DPR-VAX (Horizon 2020, appel 2019, Proof of concept grants)
Domaine scientifique : Life Science
Panel : Neuroscience and Disorders of the Nervous System
Entité participante : German Center for Neurodegenerative Diseases — Pays : Allemagne — Rôle : PI
Acronyme de l'entité : DZNE
Type d'entité : Recherche
Financement ERC de l'entité : 150000.0 €

Neurodegenerative diseases are triggered by protein aggregation in the CNS, but developing therapies has been challenging. Since key disease mechanisms change during disease progression, halting further neuron loss has not been achieved and may not even improve the symptoms and survival. Causal therapy is most realistic for monogenic disease variants. About 10% of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) cases are caused by repeat expansion in the C9orf72 gene. We have shown that the expanded repeat is translated into multiple aggregating dipeptide repeat (DPR) proteins. Poly-GA, the most abundant DPR species, is a key driver of downstream pathology. A poly-GA vaccine reduces aggregates and almost completely prevents motor deficits in our mouse model. With additional validation and safety experiment we will generate a pharma-ready data package for rapid preclinical and clinical devel-opment of the vaccine as first-in-class drug for prevention of ALS and FTD in C9orf72 carriers. The parallel development of suitable biomarkers to show clearance of DPR aggregates in vivo will greatly accelerate clinical trials. Thus, we will optimize our published immunoassays to allow more sensitive detection of DPRs in patient CSF. Moreover, we will develop our patented DPR monoclonal antibodies into a PET tracer. The solid data package is complemented by internal and external expertise in business development and regulatory affairs to shape an attractive business proposition and create value. ERC-PoC funding will allow us to present the opportunity to potential partners in large pharmaceutical companies and reputable venture capitalists for licensing or spin-off generation. Another proven strategy in the rare disease space would be collaboration with patient organizations to fund initial clinical trials. Preventing fatal ALS and FTD using vaccination in C9orf72 mutation carriers would be cost-effective for society and a blessing for affected families.

Mots-clés : neurodegeneration,vaccination,prevention,protein aggregates,biomarker,pet imaging,immunopet
Projet ERC : CholAminCo (Horizon 2020, appel 2016, Starting grants)
Domaine scientifique : Life Science
Panel : Neuroscience and Disorders of the Nervous System
Entité participante : Hungarian Academy of Sciences — Pays : Hongrie — Rôle : PI
Acronyme de l'entité : MTA
Type d'entité : Recherche
Financement ERC de l'entité : 1499463.0 €

Neuromodulators such as acetylcholine and dopamine are able to rapidly reprogram neuronal information processing and dynamically change brain states. Degeneration or dysfunction of cholinergic and dopaminergic neurons can lead to neuropsychiatric conditions like schizophrenia and addiction or cognitive diseases such as Alzheimer’s. Neuromodulatory systems control overlapping cognitive processes and often have similar modes of action; therefore it is important to reveal cooperation and competition between different systems to understand their unique contributions to cognitive functions like learning, memory and attention. This is only possible by direct comparison, which necessitates monitoring multiple neuromodulatory systems under identical experimental conditions. Moreover, simultaneous recording of different neuromodulatory cell types goes beyond phenomenological description of similarities and differences by revealing the underlying correlation structure at the level of action potential timing. However, such data allowing direct comparison of neuromodulatory actions are still sparse. As a first step to bridge this gap, I propose to elucidate the unique versus complementary roles of two “classical” neuromodulatory systems, the cholinergic and dopaminergic projection system implicated in various cognitive functions including associative learning and plasticity. First, we will record optogenetically identified cholinergic and dopaminergic neurons simultaneously using chronic extracellular recording in mice undergoing classical and operant conditioning. Second, we will determine the postsynaptic impact of cholinergic and dopaminergic neurons by manipulating them both separately and simultaneously while recording consequential changes in cortical neuronal activity and learning behaviour. These experiments will reveal how major neuromodulatory systems interact to mediate similar or different aspects of the same cognitive functions.

Mots-clés : neuromodulatory systems,dopamine,acetylcholine,rodent cognition,learning,optogenetics,electrophysiology,computational modelling
Projet ERC : AxoMyoGlia (Horizon 2020, appel 2020, Starting grants)
Domaine scientifique : Life Science
Panel : Neuroscience and Disorders of the Nervous System
Entité participante : Leipzig University — Pays : Allemagne — Rôle : PI
Type d'entité : Enseignement supérieur ou secondaire
Financement ERC de l'entité : 1492175.0 €

Neuromuscular disorders belong to the most common but least treatable neurological conditions and are caused by defects in cell types that together build the neuromuscular unit – motoneurons and their axons, glial cells and myocytes. Clinically, neuromuscular diseases share an impairment of motor function and the intimate functional relationship of involved cell types suggests overlapping pathological mechanisms. As our current understanding is largely confined to locally isolated processes, the present AxoMyoGlia proposal will undertake the ambitious approach to elucidate the spatial dimensions of the molecular interplay among the key cellular players of the neuromuscular unit. By taking demyelinating peripheral neuropathies as a powerful model system, I aim at unravelling basic principles of how local glial impairment propagates malfunction within the neuromuscular unit, including potential remote axon and muscle feedback mechanisms. To this end, I will employ neuropathic mouse models and generate a holistic transcriptional cellular interactome of the diseased neuromuscular unit at single cell resolution level. With milli- to nanometer imaging precision, this interactome will be extended to the first visualization of the spatial relation between glial and axonal dysfunction along the entire longitudinal dimension of the nerve. In order to untangle local and distant causes from consequences, I will develop an innovative mouse model that will offer the unprecedented option to specifically induce and examine the global consequences of locally restricted glial neuropathy at any position in the neuromuscular system. With its pioneering multimodal approach to converge different areas of neuromuscular research, AxoMyoGlia aims at uncovering general pathological mechanisms at the interface of basic neuroscience and applied neurology - that will be highly relevant for therapeutic advance in neuromuscular diseases and related disorders of the central nervous system.

Mots-clés : peripheral nervous system,neuropathy,schwann cell,axon glia interaction,myelin,demyelinating diseases,charcot marie tooth diseases,neuromuscular unit
Projet ERC : makingtheretina (Horizon 2020, appel 2018, Consolidator grants)
Domaine scientifique : Life Science
Panel : Neuroscience and Disorders of the Nervous System
Entité participante : Calouste Gulbenkian Foundation — Pays : Portugal — Rôle : PI
Type d'entité : Recherche
Financement ERC de l'entité : 1923750.0 €

Neuronal lamination is a hallmark of many diverse brain areas where it is important for efficient circuit formation and neuronal wiring. Despite this significance, the cellular and tissue scale principles that ensure successful and robust lamination are not fully understood. In particular, how cell-tissue interactions and biomechanics influence neuronal lamination is only scarcely explored. To fill this gap, we will use the vertebrate retina with its five neuronal cell types arranged in a highly ordered pattern to investigate the emergence of neuronal lamination. We will initially use the zebrafish system and employ long term light sheet imaging to reveal the migration behaviour of the different retinal neurons. Based on this, transcriptomics approaches will enable the dissection of cellular pathways and extracellular cues involved in neuronal migration and overall lamination. To dissect how biomechanics influence lamination, we will use Brillouin microscopy to explore the influence of changing tissue stiffness on lamination and test the role of differential adhesion. These combined results will be the basis to expand studies to the human system and ex vivo human organoids to generate insights into human retinal development. To date, systematic studies investigating molecular pathways in combination with biophysical parameters to understand brain formation across model systems are rare. Due to our previous expertise, we are in an excellent position to perform such interdisciplinary, integrative and interspecies approach. This will unveil common denominators of retinal neuronal lamination in zebrafish, humans and human organoids and thereby reveal the similarities of retinal development in different species and how developmental programs compare in vivo versus ex vivo. In addition, while this proposal focuses on neural lamination in the retina, findings will also inspire future cross-disciplinary studies investigating neuronal lamination in other parts of the brain.
Projet ERC : NEUROPHAGY (Horizon 2020, appel 2016, Starting grants)
Domaine scientifique : Life Science
Panel : Neuroscience and Disorders of the Nervous System
Entité participante : Foundation for Research and Technology Hellas — Pays : Grèce — Rôle : Partner
Acronyme de l'entité : FORTH;ΙΤΕ
Type d'entité : Recherche
Financement ERC de l'entité : 568442.81 €

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 : ULTRARESOLUTION (Horizon 2020, appel 2020, Synergy grants)
Entité participante : Universitätsmedizin Göttingen — Pays : Allemagne — Rôle : CO-PI
Acronyme de l'entité : UMG
Type d'entité : Enseignement supérieur ou secondaire
Financement ERC de l'entité : 3078736.0 €

Neurons contain hundreds of specialized proteins, whose topology reflects activity, plasticity and disease. Present imaging techniques are unable to present this topology accurately, since even the best super-resolution tools are limited to at least 20-30 nm, many times the size of individual proteins (~3-7 nm). To solve this problem, our ground-breaking objective is to develop reliable ultra-resolution imaging, with true molecular resolution of 1-5 nm. We will combine optics-based super-resolution with a recent innovation, pioneered by our team – physical expansion of the samples. Our efforts will be aided by several imaging tools we have generated, from super-resolution modalities to nano-affinity probes, which, thanks to their power and ease-of-use, are already employed by hundreds of research groups. We will apply ultra-resolution to reveal the functional organization of key components of the synapse, in health and disease. We will also develop protocols for brain pathology samples, for future use in medical diagnostics. Finally, we will establish simple protocols that will enable the application of ultra-resolution in every biomedical laboratory. Our multidisciplinary group, composed of a synapse physiologist (Rizzoli), a single-molecule imaging chemist (Sauer), and a physics and bio-engineering specialist (Boyden), is optimally placed to address this challenge. All PIs are also super-resolution specialists, with extensive expertise in stimulated emission depletion (STED), direct stochastic optical reconstruction microscopy (dSTORM) and expansion microscopy (ExM), respectively. The vast expertise required by this project implies that none of our groups could pursue it alone, and that no other groups, world-wide, could attempt it. Its successful implementation will provide: 1) imaging technology far beyond the state-of-the-art, which will prove transformative in many branches of biology; 2) solutions to multiple questions on synaptic and brain function.

Mots-clés : synapse,neuron,imaging,synuclein,resolution,super resolution,expansion microscopy,sted,storm
Projet ERC : ULTRARESOLUTION (Horizon 2020, appel 2020, Synergy grants)
Entité participante : University of Würzburg — Pays : Allemagne — Rôle : PI
Type d'entité : Enseignement supérieur ou secondaire
Financement ERC de l'entité : 4376485.0 €

Neurons contain hundreds of specialized proteins, whose topology reflects activity, plasticity and disease. Present imaging techniques are unable to present this topology accurately, since even the best super-resolution tools are limited to at least 20-30 nm, many times the size of individual proteins (~3-7 nm). To solve this problem, our ground-breaking objective is to develop reliable ultra-resolution imaging, with true molecular resolution of 1-5 nm. We will combine optics-based super-resolution with a recent innovation, pioneered by our team – physical expansion of the samples. Our efforts will be aided by several imaging tools we have generated, from super-resolution modalities to nano-affinity probes, which, thanks to their power and ease-of-use, are already employed by hundreds of research groups. We will apply ultra-resolution to reveal the functional organization of key components of the synapse, in health and disease. We will also develop protocols for brain pathology samples, for future use in medical diagnostics. Finally, we will establish simple protocols that will enable the application of ultra-resolution in every biomedical laboratory. Our multidisciplinary group, composed of a synapse physiologist (Rizzoli), a single-molecule imaging chemist (Sauer), and a physics and bio-engineering specialist (Boyden), is optimally placed to address this challenge. All PIs are also super-resolution specialists, with extensive expertise in stimulated emission depletion (STED), direct stochastic optical reconstruction microscopy (dSTORM) and expansion microscopy (ExM), respectively. The vast expertise required by this project implies that none of our groups could pursue it alone, and that no other groups, world-wide, could attempt it. Its successful implementation will provide: 1) imaging technology far beyond the state-of-the-art, which will prove transformative in many branches of biology; 2) solutions to multiple questions on synaptic and brain function.

Mots-clés : synapse,neuron,imaging,synuclein,resolution,super resolution,expansion microscopy,sted,storm
Projet ERC : ULTRARESOLUTION (Horizon 2020, appel 2020, Synergy grants)
Entité participante : Massachusetts Institute of Technology — Pays : Etats-Unis — Rôle : PI
Acronyme de l'entité : MIT
Type d'entité : Enseignement supérieur ou secondaire
Financement ERC de l'entité : 3645000.0 €

Neurons contain hundreds of specialized proteins, whose topology reflects activity, plasticity and disease. Present imaging techniques are unable to present this topology accurately, since even the best super-resolution tools are limited to at least 20-30 nm, many times the size of individual proteins (~3-7 nm). To solve this problem, our ground-breaking objective is to develop reliable ultra-resolution imaging, with true molecular resolution of 1-5 nm. We will combine optics-based super-resolution with a recent innovation, pioneered by our team – physical expansion of the samples. Our efforts will be aided by several imaging tools we have generated, from super-resolution modalities to nano-affinity probes, which, thanks to their power and ease-of-use, are already employed by hundreds of research groups. We will apply ultra-resolution to reveal the functional organization of key components of the synapse, in health and disease. We will also develop protocols for brain pathology samples, for future use in medical diagnostics. Finally, we will establish simple protocols that will enable the application of ultra-resolution in every biomedical laboratory. Our multidisciplinary group, composed of a synapse physiologist (Rizzoli), a single-molecule imaging chemist (Sauer), and a physics and bio-engineering specialist (Boyden), is optimally placed to address this challenge. All PIs are also super-resolution specialists, with extensive expertise in stimulated emission depletion (STED), direct stochastic optical reconstruction microscopy (dSTORM) and expansion microscopy (ExM), respectively. The vast expertise required by this project implies that none of our groups could pursue it alone, and that no other groups, world-wide, could attempt it. Its successful implementation will provide: 1) imaging technology far beyond the state-of-the-art, which will prove transformative in many branches of biology; 2) solutions to multiple questions on synaptic and brain function.

Mots-clés : synapse,neuron,imaging,synuclein,resolution,super resolution,expansion microscopy,sted,storm
Projet ERC : Neuro-UTR (Horizon 2020, appel 2018, Starting grants)
Domaine scientifique : Life Science
Panel : Cellular, Developmental and Regenerative Biology
Entité participante : Max Planck Society — Pays : Allemagne — Rôle : PI
Acronyme de l'entité : MPG
Type d'entité : Recherche
Financement ERC de l'entité : 1497500.0 €

Neurons employ cell-specific gene regulatory mechanisms. One particularly striking process is the recently discovered, drastic lengthening of the 3’ untranslated region (3’ UTR) of hundreds of genes, which occurs in neurons from flies to humans. The function of the resulting ultra-long 3’ UTRs is unknown. RNA deregulation plays a central role in neurological diseases; to understand underlying causes, it is essential to study regulatory processes and define the function of these novel 3’ UTRs. In Drosophila, the neuronal RNA-binding protein ELAV is the main effector of nervous system specific 3’ UTR extension. ELAV’s association with the promoter region of its target genes is required for synthesis of alternative, ultra-long 3’ UTRs. The mechanistic framework of this novel and exciting link between transcription initiation and alternative 3’ end processing is not understood yet. We hypothesise that mRNAs carrying ultra-long 3’ UTRs create an important communication avenue between transcription regulation and synaptic function. In this proposal, we will study the regulation of ELAV-mediated 3’ UTR extension in a Drosophila model. First, we will provide mechanistic insight into the co-transcriptional processes that give rise to ultra-long 3’ UTRs. Employing genomics, proteomics and biochemistry, we will study the recruitment of ELAV at gene promoters and to nascent mRNA. Second, we will follow the journey of extended mRNAs from their site of synthesis to their destination using imaging, proteomics, and functional genetics. Finally, based on our unpublished results that 3’ UTR plasticity impacts neuronal function, we will analyse the role of ultra-long 3’ UTRs in memory, aging and disease. Our study will integrate the molecular mechanisms that govern biogenesis and function of ultra-long 3’ UTRs, from nucleus to synapse, in an animal model. The results of this research will create a major impact on our understanding of neuronal gene regulation in health and disease.

Mots-clés : 3  utr,nervous system,mrna regulation,rna processing,neurogenesis,aging,synapse,rna granule
Projet ERC : EngineeringBAP (Horizon 2020, appel 2018, Consolidator grants)
Domaine scientifique : Life Science
Panel : Neuroscience and Disorders of the Nervous System
Entité participante : Board of the Swiss Federal Institutes of Technology — Pays : Suisse — Rôle : PI
Acronyme de l'entité : ETH Zurich
Type d'entité : Enseignement supérieur ou secondaire
Financement ERC de l'entité : 1998984.0 €

Neuropsychiatric and neurological disorders are complex dysfunctions of neuronal circuits. Their treatment has been limited by the lack of non-invasive methods for measuring the underlying circuit dysfunctions, and for direct and localized modifications of these circuits. We propose minimally invasive technologies for measuring brain activity and functional connectivity patterns, and for manipulating them directly in vivo to correct the abnormal behavioural phenotypes (in rodents with potential scalability to non-human primates and humans). First, we present a proof-of-principle study on mutant zebrafish, in which we correct whole-brain level abnormal activity patterns and behaviours by using large-scale single-neuron resolution measurements, and by simultaneously modulating multiple sub-networks via neuromodulator cocktails. Next, we present strong preliminary data in rodents and our plan: (1) For manipulating brain circuits in rodents/primates noninvasively, we will develop technologies that can deliver receptive-specific neuromodulators to spatially precise brain targets without opening/damaging the blood brain barrier. These methods will employ engineered ultrasound pulses and drug carrying microparticles we designed. (2) For reading out the brain circuits in rodents/primates, we will develop flexible low-power neuromorphic μECoG circuits that can detect single neuron signals from superficial cortical layers of many cortical areas simultaneously. (3) Finally, these novel technologies will be comprehensively evaluated on a mouse model of obsessive compulsivity and anxiety using a battery of behavioural tasks to reverse the pathological symptoms (beyond what is achievable by existing approaches). This project constitutes a major step towards the development and testing of minimallyinvasive and high-precision technologies for manipulating brain activity patterns, which can impact both our understanding of the brain and treatment of intractable brain disorders.