Project acronym 20SComplexity
Project An integrative approach to uncover the multilevel regulation of 20S proteasome degradation
Researcher (PI) Michal Sharon
Host Institution (HI) WEIZMANN INSTITUTE OF SCIENCE
Call Details Starting Grant (StG), LS1, ERC-2014-STG
Summary For many years, the ubiquitin-26S proteasome degradation pathway was considered the primary route for proteasomal degradation. However, it is now becoming clear that proteins can also be targeted for degradation by a ubiquitin-independent mechanism mediated by the core 20S proteasome itself. Although initially believed to be limited to rare exceptions, degradation by the 20S proteasome is now understood to have a wide range of substrates, many of which are key regulatory proteins. Despite its importance, little is known about the mechanisms that control 20S proteasomal degradation, unlike the extensive knowledge acquired over the years concerning degradation by the 26S proteasome. Our overall aim is to reveal the multiple regulatory levels that coordinate the 20S proteasome degradation route.
To achieve this goal we will carry out a comprehensive research program characterizing three distinct levels of 20S proteasome regulation:
Intra-molecular regulation- Revealing the intrinsic molecular switch that activates the latent 20S proteasome.
Inter-molecular regulation- Identifying novel proteins that bind the 20S proteasome to regulate its activity and characterizing their mechanism of function.
Cellular regulatory networks- Unraveling the cellular cues and multiple pathways that influence 20S proteasome activity using a novel systematic and unbiased screening approach.
Our experimental strategy involves the combination of biochemical approaches with native mass spectrometry, cross-linking and fluorescence measurements, complemented by cell biology analyses and high-throughput screening. Such a multidisciplinary approach, integrating in vitro and in vivo findings, will likely provide the much needed knowledge on the 20S proteasome degradation route. When completed, we anticipate that this work will be part of a new paradigm – no longer perceiving the 20S proteasome mediated degradation as a simple and passive event but rather a tightly regulated and coordinated process.
Summary
For many years, the ubiquitin-26S proteasome degradation pathway was considered the primary route for proteasomal degradation. However, it is now becoming clear that proteins can also be targeted for degradation by a ubiquitin-independent mechanism mediated by the core 20S proteasome itself. Although initially believed to be limited to rare exceptions, degradation by the 20S proteasome is now understood to have a wide range of substrates, many of which are key regulatory proteins. Despite its importance, little is known about the mechanisms that control 20S proteasomal degradation, unlike the extensive knowledge acquired over the years concerning degradation by the 26S proteasome. Our overall aim is to reveal the multiple regulatory levels that coordinate the 20S proteasome degradation route.
To achieve this goal we will carry out a comprehensive research program characterizing three distinct levels of 20S proteasome regulation:
Intra-molecular regulation- Revealing the intrinsic molecular switch that activates the latent 20S proteasome.
Inter-molecular regulation- Identifying novel proteins that bind the 20S proteasome to regulate its activity and characterizing their mechanism of function.
Cellular regulatory networks- Unraveling the cellular cues and multiple pathways that influence 20S proteasome activity using a novel systematic and unbiased screening approach.
Our experimental strategy involves the combination of biochemical approaches with native mass spectrometry, cross-linking and fluorescence measurements, complemented by cell biology analyses and high-throughput screening. Such a multidisciplinary approach, integrating in vitro and in vivo findings, will likely provide the much needed knowledge on the 20S proteasome degradation route. When completed, we anticipate that this work will be part of a new paradigm – no longer perceiving the 20S proteasome mediated degradation as a simple and passive event but rather a tightly regulated and coordinated process.
Max ERC Funding
1 500 000 €
Duration
Start date: 2015-04-01, End date: 2020-03-31
Project acronym 3D-CAP
Project 3D micro-supercapacitors for embedded electronics
Researcher (PI) David Sarinn PECH
Host Institution (HI) CENTRE NATIONAL DE LA RECHERCHE SCIENTIFIQUE CNRS
Call Details Consolidator Grant (CoG), PE7, ERC-2017-COG
Summary The realization of high-performance micro-supercapacitors is currently a big challenge but the ineluctable applications requiring such miniaturized energy storage devices are continuously emerging, from wearable electronic gadgets to wireless sensor networks. Although they store less energy than micro-batteries, micro-supercapacitors can be charged and discharged very rapidly and exhibit a quasi-unlimited lifetime. The global scientific research is consequently largely focused on the improvement of their capacitance and energetic performances. However, to date, they are still far from being able to power sensors or electronic components.
Here I propose a 3D paradigm shift of micro-supercapacitor design to ensure increased energy storage capacities. Hydrous ruthenium dioxide (RuO2) is a pseudocapacitive material for supercapacitor electrode well-known for its high capacitance. A thin-film of ruthenium will be deposited by atomic layer deposition (ALD), followed by an electrochemical oxidation process, onto a high-surface-area 3D current collector prepared via an ingenious dynamic template built with hydrogen bubbles. The structural features of these 3D architectures will be controllably tailored by the processing methodologies. These electrodes will be combined with an innovative electrolyte in solid form (a protic ionogel) able to operate over an extended cell voltage. In a parallel investigation, we will develop a fundamental understanding of electrochemical reactions occurring at the nanoscale with a FIB-patterned (Focused Ion Beam) RuO2 nano-supercapacitor. The resulting 3D micro-supercapacitors should display extremely high power, long lifetime and – for the first time – energy densities competing or even exceeding that of micro-batteries. As a key achievement, prototypes will be designed using a new concept based on a self-adaptative micro-supercapacitors matrix, which arranges itself according to the global amount of energy stored.
Summary
The realization of high-performance micro-supercapacitors is currently a big challenge but the ineluctable applications requiring such miniaturized energy storage devices are continuously emerging, from wearable electronic gadgets to wireless sensor networks. Although they store less energy than micro-batteries, micro-supercapacitors can be charged and discharged very rapidly and exhibit a quasi-unlimited lifetime. The global scientific research is consequently largely focused on the improvement of their capacitance and energetic performances. However, to date, they are still far from being able to power sensors or electronic components.
Here I propose a 3D paradigm shift of micro-supercapacitor design to ensure increased energy storage capacities. Hydrous ruthenium dioxide (RuO2) is a pseudocapacitive material for supercapacitor electrode well-known for its high capacitance. A thin-film of ruthenium will be deposited by atomic layer deposition (ALD), followed by an electrochemical oxidation process, onto a high-surface-area 3D current collector prepared via an ingenious dynamic template built with hydrogen bubbles. The structural features of these 3D architectures will be controllably tailored by the processing methodologies. These electrodes will be combined with an innovative electrolyte in solid form (a protic ionogel) able to operate over an extended cell voltage. In a parallel investigation, we will develop a fundamental understanding of electrochemical reactions occurring at the nanoscale with a FIB-patterned (Focused Ion Beam) RuO2 nano-supercapacitor. The resulting 3D micro-supercapacitors should display extremely high power, long lifetime and – for the first time – energy densities competing or even exceeding that of micro-batteries. As a key achievement, prototypes will be designed using a new concept based on a self-adaptative micro-supercapacitors matrix, which arranges itself according to the global amount of energy stored.
Max ERC Funding
1 673 438 €
Duration
Start date: 2018-04-01, End date: 2023-03-31
Project acronym 3DEpi
Project Transgenerational epigenetic inheritance of chromatin states : the role of Polycomb and 3D chromosome architecture
Researcher (PI) Giacomo CAVALLI
Host Institution (HI) CENTRE NATIONAL DE LA RECHERCHE SCIENTIFIQUE CNRS
Call Details Advanced Grant (AdG), LS2, ERC-2017-ADG
Summary Epigenetic inheritance entails transmission of phenotypic traits not encoded in the DNA sequence and, in the most extreme case, Transgenerational Epigenetic Inheritance (TEI) involves transmission of memory through multiple generations. Very little is known on the mechanisms governing TEI and this is the subject of the present proposal. By transiently enhancing long-range chromatin interactions, we recently established isogenic Drosophila epilines that carry stable alternative epialleles, defined by differential levels of the Polycomb-dependent H3K27me3 mark. Furthermore, we extended our paradigm to natural phenotypes. These are ideal systems to study the role of Polycomb group (PcG) proteins and other components in regulating nuclear organization and epigenetic inheritance of chromatin states. The present project conjugates genetics, epigenomics, imaging and molecular biology to reach three critical aims.
Aim 1: Analysis of the molecular mechanisms regulating Polycomb-mediated TEI. We will identify the DNA, protein and RNA components that trigger and maintain transgenerational chromatin inheritance as well as their mechanisms of action.
Aim 2: Role of 3D genome organization in the regulation of TEI. We will analyze the developmental dynamics of TEI-inducing long-range chromatin interactions, identify chromatin components mediating 3D chromatin contacts and characterize their function in the TEI process.
Aim 3: Identification of a broader role of TEI during development. TEI might reflect a normal role of PcG components in the transmission of parental chromatin onto the next embryonic generation. We will explore this possibility by establishing other TEI paradigms and by relating TEI to the normal PcG function in these systems and in normal development.
This research program will unravel the biological significance and the molecular underpinnings of TEI and lead the way towards establishing this area of research into a consolidated scientific discipline.
Summary
Epigenetic inheritance entails transmission of phenotypic traits not encoded in the DNA sequence and, in the most extreme case, Transgenerational Epigenetic Inheritance (TEI) involves transmission of memory through multiple generations. Very little is known on the mechanisms governing TEI and this is the subject of the present proposal. By transiently enhancing long-range chromatin interactions, we recently established isogenic Drosophila epilines that carry stable alternative epialleles, defined by differential levels of the Polycomb-dependent H3K27me3 mark. Furthermore, we extended our paradigm to natural phenotypes. These are ideal systems to study the role of Polycomb group (PcG) proteins and other components in regulating nuclear organization and epigenetic inheritance of chromatin states. The present project conjugates genetics, epigenomics, imaging and molecular biology to reach three critical aims.
Aim 1: Analysis of the molecular mechanisms regulating Polycomb-mediated TEI. We will identify the DNA, protein and RNA components that trigger and maintain transgenerational chromatin inheritance as well as their mechanisms of action.
Aim 2: Role of 3D genome organization in the regulation of TEI. We will analyze the developmental dynamics of TEI-inducing long-range chromatin interactions, identify chromatin components mediating 3D chromatin contacts and characterize their function in the TEI process.
Aim 3: Identification of a broader role of TEI during development. TEI might reflect a normal role of PcG components in the transmission of parental chromatin onto the next embryonic generation. We will explore this possibility by establishing other TEI paradigms and by relating TEI to the normal PcG function in these systems and in normal development.
This research program will unravel the biological significance and the molecular underpinnings of TEI and lead the way towards establishing this area of research into a consolidated scientific discipline.
Max ERC Funding
2 500 000 €
Duration
Start date: 2018-11-01, End date: 2023-10-31
Project acronym 4D-GenEx
Project Spatio-temporal Organization and Expression of the Genome
Researcher (PI) Antoine COULON
Host Institution (HI) CENTRE NATIONAL DE LA RECHERCHE SCIENTIFIQUE CNRS
Call Details Starting Grant (StG), LS2, ERC-2017-STG
Summary This project investigates the two-way relationship between spatio-temporal genome organization and coordinated gene regulation, through an approach at the interface between physics, computer science and biology.
In the nucleus, preferred positions are observed from chromosomes to single genes, in relation to normal and pathological cellular states. Evidence indicates a complex spatio-temporal coupling between co-regulated genes: e.g. certain genes cluster spatially when responding to similar factors and transcriptional noise patterns suggest domain-wide mechanisms. Yet, no individual experiment allows probing transcriptional coordination in 4 dimensions (FISH, live locus tracking, Hi-C...). Interpreting such data also critically requires theory (stochastic processes, statistical physics…). A lack of appropriate experimental/analytical approaches is impairing our understanding of the 4D genome.
Our proposal combines cutting-edge single-molecule imaging, signal-theory data analysis and physical modeling to study how genes coordinate in space and time in a single nucleus. Our objectives are to understand (a) competition/recycling of shared resources between genes within subnuclear compartments, (b) how enhancers communicate with genes domain-wide, and (c) the role of local conformational dynamics and supercoiling in gene co-regulation. Our organizing hypothesis is that, by acting on their microenvironment, genes shape their co-expression with other genes.
Building upon my expertise, we will use dual-color MS2/PP7 RNA labeling to visualize for the first time transcription and motion of pairs of hormone-responsive genes in real time. With our innovative signal analysis tools, we will extract spatio-temporal signatures of underlying processes, which we will investigate with stochastic modeling and validate through experimental perturbations. We expect to uncover how the functional organization of the linear genome relates to its physical properties and dynamics in 4D.
Summary
This project investigates the two-way relationship between spatio-temporal genome organization and coordinated gene regulation, through an approach at the interface between physics, computer science and biology.
In the nucleus, preferred positions are observed from chromosomes to single genes, in relation to normal and pathological cellular states. Evidence indicates a complex spatio-temporal coupling between co-regulated genes: e.g. certain genes cluster spatially when responding to similar factors and transcriptional noise patterns suggest domain-wide mechanisms. Yet, no individual experiment allows probing transcriptional coordination in 4 dimensions (FISH, live locus tracking, Hi-C...). Interpreting such data also critically requires theory (stochastic processes, statistical physics…). A lack of appropriate experimental/analytical approaches is impairing our understanding of the 4D genome.
Our proposal combines cutting-edge single-molecule imaging, signal-theory data analysis and physical modeling to study how genes coordinate in space and time in a single nucleus. Our objectives are to understand (a) competition/recycling of shared resources between genes within subnuclear compartments, (b) how enhancers communicate with genes domain-wide, and (c) the role of local conformational dynamics and supercoiling in gene co-regulation. Our organizing hypothesis is that, by acting on their microenvironment, genes shape their co-expression with other genes.
Building upon my expertise, we will use dual-color MS2/PP7 RNA labeling to visualize for the first time transcription and motion of pairs of hormone-responsive genes in real time. With our innovative signal analysis tools, we will extract spatio-temporal signatures of underlying processes, which we will investigate with stochastic modeling and validate through experimental perturbations. We expect to uncover how the functional organization of the linear genome relates to its physical properties and dynamics in 4D.
Max ERC Funding
1 499 750 €
Duration
Start date: 2018-04-01, End date: 2023-03-31
Project acronym AArteMIS
Project Aneurysmal Arterial Mechanics: Into the Structure
Researcher (PI) Pierre Joseph Badel
Host Institution (HI) ASSOCIATION POUR LA RECHERCHE ET LE DEVELOPPEMENT DES METHODES ET PROCESSUS INDUSTRIELS
Call Details Starting Grant (StG), PE8, ERC-2014-STG
Summary The rupture of an Aortic Aneurysm (AA), which is often lethal, is a mechanical phenomenon that occurs when the wall stress state exceeds the local strength of the tissue. Our current understanding of arterial rupture mechanisms is poor, and the physics taking place at the microscopic scale in these collagenous structures remains an open area of research. Understanding, modelling, and quantifying the micro-mechanisms which drive the mechanical response of such tissue and locally trigger rupture represents the most challenging and promising pathway towards predictive diagnosis and personalized care of AA.
The PI's group was recently able to detect, in advance, at the macro-scale, rupture-prone areas in bulging arterial tissues. The next step is to get into the details of the arterial microstructure to elucidate the underlying mechanisms.
Through the achievements of AArteMIS, the local mechanical state of the fibrous microstructure of the tissue, especially close to its rupture state, will be quantitatively analyzed from multi-photon confocal microscopy and numerically reconstructed to establish quantitative micro-scale rupture criteria. AArteMIS will also address developing micro-macro models which are based on the collected quantitative data.
The entire project will be completed through collaboration with medical doctors and engineers, experts in all required fields for the success of AArteMIS.
AArteMIS is expected to open longed-for pathways for research in soft tissue mechanobiology which focuses on cell environment and to enable essential clinical applications for the quantitative assessment of AA rupture risk. It will significantly contribute to understanding fatal vascular events and improving cardiovascular treatments. It will provide a tremendous source of data and inspiration for subsequent applications and research by answering the most fundamental questions on AA rupture behaviour enabling ground-breaking clinical changes to take place.
Summary
The rupture of an Aortic Aneurysm (AA), which is often lethal, is a mechanical phenomenon that occurs when the wall stress state exceeds the local strength of the tissue. Our current understanding of arterial rupture mechanisms is poor, and the physics taking place at the microscopic scale in these collagenous structures remains an open area of research. Understanding, modelling, and quantifying the micro-mechanisms which drive the mechanical response of such tissue and locally trigger rupture represents the most challenging and promising pathway towards predictive diagnosis and personalized care of AA.
The PI's group was recently able to detect, in advance, at the macro-scale, rupture-prone areas in bulging arterial tissues. The next step is to get into the details of the arterial microstructure to elucidate the underlying mechanisms.
Through the achievements of AArteMIS, the local mechanical state of the fibrous microstructure of the tissue, especially close to its rupture state, will be quantitatively analyzed from multi-photon confocal microscopy and numerically reconstructed to establish quantitative micro-scale rupture criteria. AArteMIS will also address developing micro-macro models which are based on the collected quantitative data.
The entire project will be completed through collaboration with medical doctors and engineers, experts in all required fields for the success of AArteMIS.
AArteMIS is expected to open longed-for pathways for research in soft tissue mechanobiology which focuses on cell environment and to enable essential clinical applications for the quantitative assessment of AA rupture risk. It will significantly contribute to understanding fatal vascular events and improving cardiovascular treatments. It will provide a tremendous source of data and inspiration for subsequent applications and research by answering the most fundamental questions on AA rupture behaviour enabling ground-breaking clinical changes to take place.
Max ERC Funding
1 499 783 €
Duration
Start date: 2015-04-01, End date: 2020-03-31
Project acronym AbCURE_COPD
Project Antibody mediated clearance of senescent cells for treatment of COPD
Researcher (PI) Valery KRIZHANOVSKY
Host Institution (HI) WEIZMANN INSTITUTE OF SCIENCE
Call Details Proof of Concept (PoC), ERC-2017-PoC
Summary Chronic Obstructive Pulmonary Disease (COPD) is a group of chronic diseases characterized by airflow limitations in the lung. COPD is a critical international health problem. It is estimated to affect up to 600 million people worldwide and by 2020 it will become the third most frequent cause of death. In Europe alone, COPD affects up to 10% of people (i.e. more people than breast cancer and diabetes) and it takes the life of around 300,000 Europeans each year. Up to date, COPD has no cure as current treatments fail to halt the long-term decline in lung function. They are only able to delay its progression. Those treatments however, are associated with a variety of side effects some of which can be acute and even life threatening. Thus, COPD remains a disease with a significant unmet medical need.
In this project (acronymed AbCURE_COPD) we intend to carry out a set of necessary activities for the evaluation of a potentially groundbreaking approach for treating COPD. Our approach is focusing on antibody-mediated clearance of senescent cells which accumulate in tissues with age and contribute to multiple age-related diseases, including COPD. The goal of the PoC project is two-fold. (1) The first goal is to establish the technical feasibility of our idea by testing the effect of senescence-specific antibodies on COPD development and progression by implementing COPD mouse model we developed. (2) The second goal is to establish the business feasibility of our revolutionary approach by taking the necessary steps towards its commercialization, focusing on the creation of strategic alliances with key private sector companies. We firmly believe that with our approach we can significantly extend the health span and improve the quality of life of COPD patients. Equally important, our approach will pave the way for the development of novel treatment strategies applicable to other age-related diseases, such as osteoarthritis, cardiovascular, and neurodegenerative diseases.
Summary
Chronic Obstructive Pulmonary Disease (COPD) is a group of chronic diseases characterized by airflow limitations in the lung. COPD is a critical international health problem. It is estimated to affect up to 600 million people worldwide and by 2020 it will become the third most frequent cause of death. In Europe alone, COPD affects up to 10% of people (i.e. more people than breast cancer and diabetes) and it takes the life of around 300,000 Europeans each year. Up to date, COPD has no cure as current treatments fail to halt the long-term decline in lung function. They are only able to delay its progression. Those treatments however, are associated with a variety of side effects some of which can be acute and even life threatening. Thus, COPD remains a disease with a significant unmet medical need.
In this project (acronymed AbCURE_COPD) we intend to carry out a set of necessary activities for the evaluation of a potentially groundbreaking approach for treating COPD. Our approach is focusing on antibody-mediated clearance of senescent cells which accumulate in tissues with age and contribute to multiple age-related diseases, including COPD. The goal of the PoC project is two-fold. (1) The first goal is to establish the technical feasibility of our idea by testing the effect of senescence-specific antibodies on COPD development and progression by implementing COPD mouse model we developed. (2) The second goal is to establish the business feasibility of our revolutionary approach by taking the necessary steps towards its commercialization, focusing on the creation of strategic alliances with key private sector companies. We firmly believe that with our approach we can significantly extend the health span and improve the quality of life of COPD patients. Equally important, our approach will pave the way for the development of novel treatment strategies applicable to other age-related diseases, such as osteoarthritis, cardiovascular, and neurodegenerative diseases.
Max ERC Funding
150 000 €
Duration
Start date: 2018-11-01, End date: 2020-04-30
Project acronym ABIOS
Project ABIOtic Synthesis of RNA: an investigation on how life started before biology existed
Researcher (PI) Guillaume STIRNEMANN
Host Institution (HI) CENTRE NATIONAL DE LA RECHERCHE SCIENTIFIQUE CNRS
Call Details Starting Grant (StG), PE4, ERC-2017-STG
Summary The emergence of life is one of the most fascinating and yet largely unsolved questions in the natural sciences, and thus a significant challenge for scientists from many disciplines. There is growing evidence that ribonucleic acid (RNA) polymers, which are capable of genetic information storage and self-catalysis, were involved in the early forms of life. But despite recent progress, RNA synthesis without biological machineries is very challenging. The current project aims at understanding how to synthesize RNA in abiotic conditions. I will solve problems associated with three critical aspects of RNA formation that I will rationalize at a molecular level: (i) accumulation of precursors, (ii) formation of a chemical bond between RNA monomers, and (iii) tolerance for alternative backbone sugars or linkages. Because I will study problems ranging from the formation of chemical bonds up to the stability of large biopolymers, I propose an original computational multi-scale approach combining techniques that range from quantum calculations to large-scale all-atom simulations, employed together with efficient enhanced-sampling algorithms, forcefield improvement, cutting-edge analysis methods and model development.
My objectives are the following:
1 • To explain why the poorly-understood thermally-driven process of thermophoresis can contribute to the accumulation of dilute precursors.
2 • To understand why linking RNA monomers with phosphoester bonds is so difficult, to understand the molecular mechanism of possible catalysts and to suggest key improvements.
3 • To rationalize the molecular basis for RNA tolerance for alternative backbone sugars or linkages that have probably been incorporated in abiotic conditions.
This unique in-silico laboratory setup should significantly impact our comprehension of life’s origin by overcoming major obstacles to RNA abiotic formation, and in addition will reveal significant orthogonal outcomes for (bio)technological applications.
Summary
The emergence of life is one of the most fascinating and yet largely unsolved questions in the natural sciences, and thus a significant challenge for scientists from many disciplines. There is growing evidence that ribonucleic acid (RNA) polymers, which are capable of genetic information storage and self-catalysis, were involved in the early forms of life. But despite recent progress, RNA synthesis without biological machineries is very challenging. The current project aims at understanding how to synthesize RNA in abiotic conditions. I will solve problems associated with three critical aspects of RNA formation that I will rationalize at a molecular level: (i) accumulation of precursors, (ii) formation of a chemical bond between RNA monomers, and (iii) tolerance for alternative backbone sugars or linkages. Because I will study problems ranging from the formation of chemical bonds up to the stability of large biopolymers, I propose an original computational multi-scale approach combining techniques that range from quantum calculations to large-scale all-atom simulations, employed together with efficient enhanced-sampling algorithms, forcefield improvement, cutting-edge analysis methods and model development.
My objectives are the following:
1 • To explain why the poorly-understood thermally-driven process of thermophoresis can contribute to the accumulation of dilute precursors.
2 • To understand why linking RNA monomers with phosphoester bonds is so difficult, to understand the molecular mechanism of possible catalysts and to suggest key improvements.
3 • To rationalize the molecular basis for RNA tolerance for alternative backbone sugars or linkages that have probably been incorporated in abiotic conditions.
This unique in-silico laboratory setup should significantly impact our comprehension of life’s origin by overcoming major obstacles to RNA abiotic formation, and in addition will reveal significant orthogonal outcomes for (bio)technological applications.
Max ERC Funding
1 497 031 €
Duration
Start date: 2018-02-01, End date: 2023-01-31
Project acronym ACTINIT
Project Brain-behavior forecasting: The causal determinants of spontaneous self-initiated action in the study of volition and the development of asynchronous brain-computer interfaces.
Researcher (PI) Aaron Schurger
Host Institution (HI) INSTITUT NATIONAL DE LA SANTE ET DE LA RECHERCHE MEDICALE
Call Details Starting Grant (StG), LS5, ERC-2014-STG
Summary "How are actions initiated by the human brain when there is no external sensory cue or other immediate imperative? How do subtle ongoing interactions within the brain and between the brain, body, and sensory context influence the spontaneous initiation of action? How should we approach the problem of trying to identify the neural events that cause spontaneous voluntary action? Much is understood about how the brain decides between competing alternatives, leading to different behavioral responses. But far less is known about how the brain decides "when" to perform an action, or "whether" to perform an action in the first place, especially in a context where there is no sensory cue to act such as during foraging. This project seeks to open a new chapter in the study of spontaneous voluntary action building on a novel hypothesis recently introduced by the applicant (Schurger et al, PNAS 2012) concerning the role of ongoing neural activity in action initiation. We introduce brain-behavior forecasting, the converse of movement-locked averaging, as an approach to identifying the neurodynamic states that commit the motor system to performing an action "now", and will apply it in the context of information foraging. Spontaneous action remains a profound mystery in the brain basis of behavior, in humans and other animals, and is also central to the problem of asynchronous intention-detection in brain-computer interfaces (BCIs). A BCI must not only interpret what the user intends, but also must detect "when" the user intends to act, and not respond otherwise. This remains the biggest challenge in the development of high-performance BCIs, whether invasive or non-invasive. This project will take a systematic and collaborative approach to the study of spontaneous self-initiated action, incorporating computational modeling, neuroimaging, and machine learning techniques towards a deeper understanding of voluntary behavior and the robust asynchronous detection of decisions-to-act."
Summary
"How are actions initiated by the human brain when there is no external sensory cue or other immediate imperative? How do subtle ongoing interactions within the brain and between the brain, body, and sensory context influence the spontaneous initiation of action? How should we approach the problem of trying to identify the neural events that cause spontaneous voluntary action? Much is understood about how the brain decides between competing alternatives, leading to different behavioral responses. But far less is known about how the brain decides "when" to perform an action, or "whether" to perform an action in the first place, especially in a context where there is no sensory cue to act such as during foraging. This project seeks to open a new chapter in the study of spontaneous voluntary action building on a novel hypothesis recently introduced by the applicant (Schurger et al, PNAS 2012) concerning the role of ongoing neural activity in action initiation. We introduce brain-behavior forecasting, the converse of movement-locked averaging, as an approach to identifying the neurodynamic states that commit the motor system to performing an action "now", and will apply it in the context of information foraging. Spontaneous action remains a profound mystery in the brain basis of behavior, in humans and other animals, and is also central to the problem of asynchronous intention-detection in brain-computer interfaces (BCIs). A BCI must not only interpret what the user intends, but also must detect "when" the user intends to act, and not respond otherwise. This remains the biggest challenge in the development of high-performance BCIs, whether invasive or non-invasive. This project will take a systematic and collaborative approach to the study of spontaneous self-initiated action, incorporating computational modeling, neuroimaging, and machine learning techniques towards a deeper understanding of voluntary behavior and the robust asynchronous detection of decisions-to-act."
Max ERC Funding
1 338 130 €
Duration
Start date: 2015-10-01, End date: 2020-09-30
Project acronym ADIPOR
Project Molecular and structural pharmacology of adiponectin receptor: towards innovative treatments of obesity-related diseases.
Researcher (PI) Sebastien Jean Antoine Granier
Host Institution (HI) INSTITUT NATIONAL DE LA SANTE ET DE LA RECHERCHE MEDICALE
Call Details Consolidator Grant (CoG), LS7, ERC-2014-CoG
Summary The human kind is witnessing an escalation of obesity-related health problems such as cardiovascular diseases and type 2 diabetes. A recent groundbreaking study revealed adiponectin receptors (ADIPOR) as key targets for treating such obesity-related diseases. Indeed, the modulation of this integral membrane protein by small molecules agonists ameliorates diabetes and prolongs lifespan of genetically obese rodent model. Despite these exciting results and the importance of ADIPOR in human physiology, there is a complete lack of knowledge of ADIPOR mechanisms of action and pharmacology. This is mainly due to the challenges associated with the characterization of membrane protein structure and function. To fill this gap of knowledge and based on my extensive experience in membrane protein biology, I propose here to characterize the the proximal signaling pathways associated with ADIPOR activation as well as the molecular and structural mechanisms of ADIPOR activation. We will develop an innovative integrated strategy combining state-of-the-art molecular and structural pharmacology approaches including 1) molecular analyses of ADIPOR network of interaction using resonance energy transfer measurement in living cells and a proteomic analysis and 2) structural analyses of ADIPOR and signaling complexes using biophysics and X-ray crystallography. Our data will have a major impact on drug discovery for treating obesity-related diseases as it will enable the application of structure-based drug design and in silico screening for the molecular control of ADIPOR activity. The proposed high-risk endeavor of obtaining structural data on these atypical membrane signaling complexes is a new direction both for my career and for the field of adiponectin biology; the exceptionally high gain from these studies fully justifies the risks; the feasibility of this project is supported by my recent success in membrane protein pharmacology, biochemistry, biophysics and crystallography.
Summary
The human kind is witnessing an escalation of obesity-related health problems such as cardiovascular diseases and type 2 diabetes. A recent groundbreaking study revealed adiponectin receptors (ADIPOR) as key targets for treating such obesity-related diseases. Indeed, the modulation of this integral membrane protein by small molecules agonists ameliorates diabetes and prolongs lifespan of genetically obese rodent model. Despite these exciting results and the importance of ADIPOR in human physiology, there is a complete lack of knowledge of ADIPOR mechanisms of action and pharmacology. This is mainly due to the challenges associated with the characterization of membrane protein structure and function. To fill this gap of knowledge and based on my extensive experience in membrane protein biology, I propose here to characterize the the proximal signaling pathways associated with ADIPOR activation as well as the molecular and structural mechanisms of ADIPOR activation. We will develop an innovative integrated strategy combining state-of-the-art molecular and structural pharmacology approaches including 1) molecular analyses of ADIPOR network of interaction using resonance energy transfer measurement in living cells and a proteomic analysis and 2) structural analyses of ADIPOR and signaling complexes using biophysics and X-ray crystallography. Our data will have a major impact on drug discovery for treating obesity-related diseases as it will enable the application of structure-based drug design and in silico screening for the molecular control of ADIPOR activity. The proposed high-risk endeavor of obtaining structural data on these atypical membrane signaling complexes is a new direction both for my career and for the field of adiponectin biology; the exceptionally high gain from these studies fully justifies the risks; the feasibility of this project is supported by my recent success in membrane protein pharmacology, biochemistry, biophysics and crystallography.
Max ERC Funding
1 989 518 €
Duration
Start date: 2015-07-01, End date: 2020-06-30
Project acronym AEROFLEX
Project AEROelastic instabilities and control of FLEXible Structures
Researcher (PI) Olivier Pierre MARQUET
Host Institution (HI) OFFICE NATIONAL D'ETUDES ET DE RECHERCHES AEROSPATIALES
Call Details Starting Grant (StG), PE8, ERC-2014-STG
Summary Aeroelastic instabilities are at the origin of large deformations of structures and are limiting the capacities of products in various industrial branches such as aeronautics, marine industry, or wind electricity production. If suppressing aeroelastic instabilities is an ultimate goal, a paradigm shift in the technological development is to take advantage of these instabilities to achieve others objectives, as reducing the drag of these flexible structures. The ground-breaking challenges addressed in this project are to design fundamentally new theoretical methodologies for (i) describing mathematically aeroelastic instabilities, (ii) suppressing them and (iii) using them to reduce mean drag of structures at a low energetic cost. To that aim, two types of aeroelastic phenomena will be specifically studied: the flutter, which arises as a result of an unstable coupling instability between two stable dynamics, that of the structures and that the flow, and vortex-induced vibrations which appear when the fluid dynamics is unstable. An aeroelastic global stability analysis will be first developed and applied to problems of increasing complexity, starting from two-dimensional free-vibrating rigid structures and progressing towards three-dimensional free-deforming elastic structures. The control of these aeroelastic instabilities will be then addressed with two different objectives: their suppression or their use for flow control. A theoretical passive control methodology will be established for suppressing linear aeroelastic instabilities, and extended to high Reynolds number flows and experimental configurations. New perturbation methods for solving strongly nonlinear problems and adjoint-based control algorithm will allow to use these aeroelastic instabilities for drag reduction. This project will allow innovative control solutions to emerge, not only in flutter or vortex-induced vibrations problems, but also in a much broader class of fluid-structure problems.
Summary
Aeroelastic instabilities are at the origin of large deformations of structures and are limiting the capacities of products in various industrial branches such as aeronautics, marine industry, or wind electricity production. If suppressing aeroelastic instabilities is an ultimate goal, a paradigm shift in the technological development is to take advantage of these instabilities to achieve others objectives, as reducing the drag of these flexible structures. The ground-breaking challenges addressed in this project are to design fundamentally new theoretical methodologies for (i) describing mathematically aeroelastic instabilities, (ii) suppressing them and (iii) using them to reduce mean drag of structures at a low energetic cost. To that aim, two types of aeroelastic phenomena will be specifically studied: the flutter, which arises as a result of an unstable coupling instability between two stable dynamics, that of the structures and that the flow, and vortex-induced vibrations which appear when the fluid dynamics is unstable. An aeroelastic global stability analysis will be first developed and applied to problems of increasing complexity, starting from two-dimensional free-vibrating rigid structures and progressing towards three-dimensional free-deforming elastic structures. The control of these aeroelastic instabilities will be then addressed with two different objectives: their suppression or their use for flow control. A theoretical passive control methodology will be established for suppressing linear aeroelastic instabilities, and extended to high Reynolds number flows and experimental configurations. New perturbation methods for solving strongly nonlinear problems and adjoint-based control algorithm will allow to use these aeroelastic instabilities for drag reduction. This project will allow innovative control solutions to emerge, not only in flutter or vortex-induced vibrations problems, but also in a much broader class of fluid-structure problems.
Max ERC Funding
1 377 290 €
Duration
Start date: 2015-07-01, End date: 2020-06-30
Project acronym ALKAGE
Project Algebraic and Kähler geometry
Researcher (PI) Jean-Pierre, Raymond, Philippe Demailly
Host Institution (HI) UNIVERSITE GRENOBLE ALPES
Call Details Advanced Grant (AdG), PE1, ERC-2014-ADG
Summary The purpose of this project is to study basic questions in algebraic and Kähler geometry. It is well known that the structure of projective or Kähler manifolds is governed by positivity or negativity properties of the curvature tensor. However, many fundamental problems are still wide open. Since the mid 1980's, I have developed a large number of key concepts and results that have led to important progress in transcendental algebraic geometry. Let me mention the discovery of holomorphic Morse inequalities, systematic applications of L² estimates with singular hermitian metrics, and a much improved understanding of Monge-Ampère equations and of singularities of plurisuharmonic functions. My first goal will be to investigate the Green-Griffiths-Lang conjecture asserting that an entire curve drawn in a variety of general type is algebraically degenerate. The subject is intimately related to important questions concerning Diophantine equations, especially higher dimensional generalizations of Faltings' theorem - the so-called Vojta program. One can rely here on a breakthrough I made in 2010, showing that all such entire curves must satisfy algebraic differential equations. A second closely related area of research of this project is the analysis of the structure of projective or compact Kähler manifolds. It can be seen as a generalization of the classification theory of surfaces by Kodaira, and of the more recent results for dimension 3 (Kawamata, Kollár, Mori, Shokurov, ...) to other dimensions. My plan is to combine powerful recent results obtained on the duality of positive cohomology cones with an analysis of the instability of the tangent bundle, i.e. of the Harder-Narasimhan filtration. On these ground-breaking questions, I intend to go much further and to enhance my national and international collaborations. These subjects already attract many young researchers and postdocs throughout the world, and the grant could be used to create even stronger interactions.
Summary
The purpose of this project is to study basic questions in algebraic and Kähler geometry. It is well known that the structure of projective or Kähler manifolds is governed by positivity or negativity properties of the curvature tensor. However, many fundamental problems are still wide open. Since the mid 1980's, I have developed a large number of key concepts and results that have led to important progress in transcendental algebraic geometry. Let me mention the discovery of holomorphic Morse inequalities, systematic applications of L² estimates with singular hermitian metrics, and a much improved understanding of Monge-Ampère equations and of singularities of plurisuharmonic functions. My first goal will be to investigate the Green-Griffiths-Lang conjecture asserting that an entire curve drawn in a variety of general type is algebraically degenerate. The subject is intimately related to important questions concerning Diophantine equations, especially higher dimensional generalizations of Faltings' theorem - the so-called Vojta program. One can rely here on a breakthrough I made in 2010, showing that all such entire curves must satisfy algebraic differential equations. A second closely related area of research of this project is the analysis of the structure of projective or compact Kähler manifolds. It can be seen as a generalization of the classification theory of surfaces by Kodaira, and of the more recent results for dimension 3 (Kawamata, Kollár, Mori, Shokurov, ...) to other dimensions. My plan is to combine powerful recent results obtained on the duality of positive cohomology cones with an analysis of the instability of the tangent bundle, i.e. of the Harder-Narasimhan filtration. On these ground-breaking questions, I intend to go much further and to enhance my national and international collaborations. These subjects already attract many young researchers and postdocs throughout the world, and the grant could be used to create even stronger interactions.
Max ERC Funding
1 809 345 €
Duration
Start date: 2015-09-01, End date: 2020-08-31
Project acronym AlmaCrypt
Project Algorithmic and Mathematical Cryptology
Researcher (PI) Antoine Joux
Host Institution (HI) SORBONNE UNIVERSITE
Call Details Advanced Grant (AdG), PE6, ERC-2014-ADG
Summary Cryptology is a foundation of information security in the digital world. Today's internet is protected by a form of cryptography based on complexity theoretic hardness assumptions. Ideally, they should be strong to ensure security and versatile to offer a wide range of functionalities and allow efficient implementations. However, these assumptions are largely untested and internet security could be built on sand.
The main ambition of Almacrypt is to remedy this issue by challenging the assumptions through an advanced algorithmic analysis.
In particular, this proposal questions the two pillars of public-key encryption: factoring and discrete logarithms. Recently, the PI contributed to show that in some cases, the discrete logarithm problem is considerably weaker than previously assumed. A main objective is to ponder the security of other cases of the discrete logarithm problem, including elliptic curves, and of factoring. We will study the generalization of the recent techniques and search for new algorithmic options with comparable or better efficiency.
We will also study hardness assumptions based on codes and subset-sum, two candidates for post-quantum cryptography. We will consider the applicability of recent algorithmic and mathematical techniques to the resolution of the corresponding putative hard problems, refine the analysis of the algorithms and design new algorithm tools.
Cryptology is not limited to the above assumptions: other hard problems have been proposed to aim at post-quantum security and/or to offer extra functionalities. Should the security of these other assumptions become critical, they would be added to Almacrypt's scope. They could also serve to demonstrate other applications of our algorithmic progress.
In addition to its scientific goal, Almacrypt also aims at seeding a strengthened research community dedicated to algorithmic and mathematical cryptology.
--
Summary
Cryptology is a foundation of information security in the digital world. Today's internet is protected by a form of cryptography based on complexity theoretic hardness assumptions. Ideally, they should be strong to ensure security and versatile to offer a wide range of functionalities and allow efficient implementations. However, these assumptions are largely untested and internet security could be built on sand.
The main ambition of Almacrypt is to remedy this issue by challenging the assumptions through an advanced algorithmic analysis.
In particular, this proposal questions the two pillars of public-key encryption: factoring and discrete logarithms. Recently, the PI contributed to show that in some cases, the discrete logarithm problem is considerably weaker than previously assumed. A main objective is to ponder the security of other cases of the discrete logarithm problem, including elliptic curves, and of factoring. We will study the generalization of the recent techniques and search for new algorithmic options with comparable or better efficiency.
We will also study hardness assumptions based on codes and subset-sum, two candidates for post-quantum cryptography. We will consider the applicability of recent algorithmic and mathematical techniques to the resolution of the corresponding putative hard problems, refine the analysis of the algorithms and design new algorithm tools.
Cryptology is not limited to the above assumptions: other hard problems have been proposed to aim at post-quantum security and/or to offer extra functionalities. Should the security of these other assumptions become critical, they would be added to Almacrypt's scope. They could also serve to demonstrate other applications of our algorithmic progress.
In addition to its scientific goal, Almacrypt also aims at seeding a strengthened research community dedicated to algorithmic and mathematical cryptology.
--
Max ERC Funding
2 403 125 €
Duration
Start date: 2016-01-01, End date: 2021-12-31
Project acronym AltCheM
Project In vivo functional screens to decipher mechanisms of stochastically- and mutationally-induced chemoresistance in Acute Myeloid Leukemia
Researcher (PI) Alexandre PUISSANT
Host Institution (HI) INSTITUT NATIONAL DE LA SANTE ET DE LA RECHERCHE MEDICALE
Call Details Starting Grant (StG), LS4, ERC-2017-STG
Summary Acute Myeloid Leukemia (AML), the most common leukemia diagnosed in adults, represents the paradigm of resistance to front-line therapies in hematology. Indeed, AML is so genetically complex that only few targeted therapies are currently tested in this disease and chemotherapy remains the only standard treatment for AML since the past four decades. Despite an initial sustained remission achieved by chemotherapeutic agents, almost all patients relapse with a chemoresistant minimal residual disease (MRD). The goal of my proposal is to characterize the still poorly understood biological mechanisms underlying persistence and emergence of MRD.
MRD is the consequence of the re-expansion of leukemia-initiating cells that are intrinsically more resistant to chemotherapy. This cell fraction may be stochastically more prone to survive front-line therapy regardless of their mutational status (the stochastic model), or genetically predetermined to resist by virtue of a collection of chemoprotective mutations (the mutational model).
I have already generated in mice, by consecutive rounds of chemotherapy, a stochastic MLL-AF9-driven chemoresistance model that I examined by RNA-sequencing. I will pursue the comprehensive cell autonomous and cell non-autonomous characterization of this chemoresistant AML disease using whole-exome and ChIP-sequencing.
To establish a mutationally-induced chemoresistant mouse model, I will conduct an innovative in vivo screen using pooled mutant open reading frame and shRNA libraries in order to predict which combinations of mutations, among those already known in AML, actively promote chemoresistance.
Finally, by combining genomic profiling and in vivo shRNA screening experiments, I will decipher the molecular mechanisms and identify the functional effectors of these two modes of resistance. Ultimately, I will then be able to firmly establish the fundamental relevance of the stochastic and/or the mutational model of chemoresistance for MRD genesis.
Summary
Acute Myeloid Leukemia (AML), the most common leukemia diagnosed in adults, represents the paradigm of resistance to front-line therapies in hematology. Indeed, AML is so genetically complex that only few targeted therapies are currently tested in this disease and chemotherapy remains the only standard treatment for AML since the past four decades. Despite an initial sustained remission achieved by chemotherapeutic agents, almost all patients relapse with a chemoresistant minimal residual disease (MRD). The goal of my proposal is to characterize the still poorly understood biological mechanisms underlying persistence and emergence of MRD.
MRD is the consequence of the re-expansion of leukemia-initiating cells that are intrinsically more resistant to chemotherapy. This cell fraction may be stochastically more prone to survive front-line therapy regardless of their mutational status (the stochastic model), or genetically predetermined to resist by virtue of a collection of chemoprotective mutations (the mutational model).
I have already generated in mice, by consecutive rounds of chemotherapy, a stochastic MLL-AF9-driven chemoresistance model that I examined by RNA-sequencing. I will pursue the comprehensive cell autonomous and cell non-autonomous characterization of this chemoresistant AML disease using whole-exome and ChIP-sequencing.
To establish a mutationally-induced chemoresistant mouse model, I will conduct an innovative in vivo screen using pooled mutant open reading frame and shRNA libraries in order to predict which combinations of mutations, among those already known in AML, actively promote chemoresistance.
Finally, by combining genomic profiling and in vivo shRNA screening experiments, I will decipher the molecular mechanisms and identify the functional effectors of these two modes of resistance. Ultimately, I will then be able to firmly establish the fundamental relevance of the stochastic and/or the mutational model of chemoresistance for MRD genesis.
Max ERC Funding
1 500 000 €
Duration
Start date: 2018-03-01, End date: 2023-02-28
Project acronym aLzINK
Project Alzheimer's disease and Zinc: the missing link ?
Researcher (PI) Christelle Sandrine Florence HUREAU-SABATER
Host Institution (HI) CENTRE NATIONAL DE LA RECHERCHE SCIENTIFIQUE CNRS
Call Details Starting Grant (StG), PE5, ERC-2014-STG
Summary Alzheimer's disease (AD) is one of the most serious diseases mankind is now facing as its social and economical impacts are increasing fastly. AD is very complex and the amyloid-β (Aβ) peptide as well as metallic ions (mainly copper and zinc) have been linked to its aetiology. While the deleterious impact of Cu is widely acknowledged, intervention of Zn is certain but still needs to be figured out.
The main objective of the present proposal, which is strongly anchored in the bio-inorganic chemistry field at interface with spectroscopy and biochemistry, is to design, synthesize and study new drug candidates (ligands L) capable of (i) targeting Cu(II) bound to Aβ within the synaptic cleft, where Zn is co-localized and ultimately to develop Zn-driven Cu(II) removal from Aβ and (ii) disrupting the aberrant Cu(II)-Aβ interactions involved in ROS production and Aβ aggregation, two deleterious events in AD. The drug candidates will thus have high Cu(II) over Zn selectively to preserve the crucial physiological role of Zn in the neurotransmission process. Zn is always underestimated (if not completely neglected) in current therapeutic approaches targeting Cu(II) despite the known interference of Zn with Cu(II) binding.
To reach this objective, it is absolutely necessary to first understand the metal ions trafficking issues in presence of Aβ alone at a molecular level (i.e. without the drug candidates).This includes: (i) determination of Zn binding site to Aβ, impact on Aβ aggregation and cell toxicity, (ii) determination of the mutual influence of Zn and Cu to their coordination to Aβ, impact on Aβ aggregation, ROS production and cell toxicity.
Methods used will span from organic synthesis to studies of neuronal model cells, with a major contribution of a wide panel of spectroscopic techniques including NMR, EPR, mass spectrometry, fluorescence, UV-Vis, circular-dichroism, X-ray absorption spectroscopy...
Summary
Alzheimer's disease (AD) is one of the most serious diseases mankind is now facing as its social and economical impacts are increasing fastly. AD is very complex and the amyloid-β (Aβ) peptide as well as metallic ions (mainly copper and zinc) have been linked to its aetiology. While the deleterious impact of Cu is widely acknowledged, intervention of Zn is certain but still needs to be figured out.
The main objective of the present proposal, which is strongly anchored in the bio-inorganic chemistry field at interface with spectroscopy and biochemistry, is to design, synthesize and study new drug candidates (ligands L) capable of (i) targeting Cu(II) bound to Aβ within the synaptic cleft, where Zn is co-localized and ultimately to develop Zn-driven Cu(II) removal from Aβ and (ii) disrupting the aberrant Cu(II)-Aβ interactions involved in ROS production and Aβ aggregation, two deleterious events in AD. The drug candidates will thus have high Cu(II) over Zn selectively to preserve the crucial physiological role of Zn in the neurotransmission process. Zn is always underestimated (if not completely neglected) in current therapeutic approaches targeting Cu(II) despite the known interference of Zn with Cu(II) binding.
To reach this objective, it is absolutely necessary to first understand the metal ions trafficking issues in presence of Aβ alone at a molecular level (i.e. without the drug candidates).This includes: (i) determination of Zn binding site to Aβ, impact on Aβ aggregation and cell toxicity, (ii) determination of the mutual influence of Zn and Cu to their coordination to Aβ, impact on Aβ aggregation, ROS production and cell toxicity.
Methods used will span from organic synthesis to studies of neuronal model cells, with a major contribution of a wide panel of spectroscopic techniques including NMR, EPR, mass spectrometry, fluorescence, UV-Vis, circular-dichroism, X-ray absorption spectroscopy...
Max ERC Funding
1 499 948 €
Duration
Start date: 2015-03-01, End date: 2020-02-29
Project acronym AMPERE
Project Accounting for Metallicity, Polarization of the Electrolyte, and Redox reactions in computational Electrochemistry
Researcher (PI) Mathieu Eric Salanne
Host Institution (HI) SORBONNE UNIVERSITE
Call Details Consolidator Grant (CoG), PE4, ERC-2017-COG
Summary Applied electrochemistry plays a key role in many technologies, such as batteries, fuel cells, supercapacitors or solar cells. It is therefore at the core of many research programs all over the world. Yet, fundamental electrochemical investigations remain scarce. In particular, electrochemistry is among the fields for which the gap between theory and experiment is the largest. From the computational point of view, there is no molecular dynamics (MD) software devoted to the simulation of electrochemical systems while other fields such as biochemistry (GROMACS) or material science (LAMMPS) have dedicated tools. This is due to the difficulty of accounting for complex effects arising from (i) the degree of metallicity of the electrode (i.e. from semimetals to perfect conductors), (ii) the mutual polarization occurring at the electrode/electrolyte interface and (iii) the redox reactivity through explicit electron transfers. Current understanding therefore relies on standard theories that derive from an inaccurate molecular-scale picture. My objective is to fill this gap by introducing a whole set of new methods for simulating electrochemical systems. They will be provided to the computational electrochemistry community as a cutting-edge MD software adapted to supercomputers. First applications will aim at the discovery of new electrolytes for energy storage. Here I will focus on (1) ‘‘water-in-salts’’ to understand why these revolutionary liquids enable much higher voltage than conventional solutions (2) redox reactions inside a nanoporous electrode to support the development of future capacitive energy storage devices. These selected applications are timely and rely on collaborations with leading experimental partners. The results are expected to shed an unprecedented light on the importance of polarization effects on the structure and the reactivity of electrode/electrolyte interfaces, establishing MD as a prominent tool for solving complex electrochemistry problems.
Summary
Applied electrochemistry plays a key role in many technologies, such as batteries, fuel cells, supercapacitors or solar cells. It is therefore at the core of many research programs all over the world. Yet, fundamental electrochemical investigations remain scarce. In particular, electrochemistry is among the fields for which the gap between theory and experiment is the largest. From the computational point of view, there is no molecular dynamics (MD) software devoted to the simulation of electrochemical systems while other fields such as biochemistry (GROMACS) or material science (LAMMPS) have dedicated tools. This is due to the difficulty of accounting for complex effects arising from (i) the degree of metallicity of the electrode (i.e. from semimetals to perfect conductors), (ii) the mutual polarization occurring at the electrode/electrolyte interface and (iii) the redox reactivity through explicit electron transfers. Current understanding therefore relies on standard theories that derive from an inaccurate molecular-scale picture. My objective is to fill this gap by introducing a whole set of new methods for simulating electrochemical systems. They will be provided to the computational electrochemistry community as a cutting-edge MD software adapted to supercomputers. First applications will aim at the discovery of new electrolytes for energy storage. Here I will focus on (1) ‘‘water-in-salts’’ to understand why these revolutionary liquids enable much higher voltage than conventional solutions (2) redox reactions inside a nanoporous electrode to support the development of future capacitive energy storage devices. These selected applications are timely and rely on collaborations with leading experimental partners. The results are expected to shed an unprecedented light on the importance of polarization effects on the structure and the reactivity of electrode/electrolyte interfaces, establishing MD as a prominent tool for solving complex electrochemistry problems.
Max ERC Funding
1 588 769 €
Duration
Start date: 2018-04-01, End date: 2023-03-31
Project acronym ANADEL
Project Analysis of Geometrical Effects on Dispersive Equations
Researcher (PI) Danela Oana IVANOVICI
Host Institution (HI) CENTRE NATIONAL DE LA RECHERCHE SCIENTIFIQUE CNRS
Call Details Starting Grant (StG), PE1, ERC-2017-STG
Summary We are concerned with localization properties of solutions to hyperbolic PDEs, especially problems with a geometric component: how do boundaries and heterogeneous media influence spreading and concentration of solutions. While our first focus is on wave and Schrödinger equations on manifolds with boundary, strong connections exist with phase space localization for (clusters of) eigenfunctions, which are of independent interest. Motivations come from nonlinear dispersive models (in physically relevant settings), properties of eigenfunctions in quantum chaos (related to both physics of optic fiber design as well as number theoretic questions), or harmonic analysis on manifolds.
Waves propagation in real life physics occur in media which are neither homogeneous or spatially infinity. The birth of radar/sonar technologies (and the raise of computed tomography) greatly motivated numerous developments in microlocal analysis and the linear theory. Only recently toy nonlinear models have been studied on a curved background, sometimes compact or rough. Understanding how to extend such tools, dealing with wave dispersion or focusing, will allow us to significantly progress in our mathematical understanding of physically relevant models. There, boundaries appear naturally and most earlier developments related to propagation of singularities in this context have limited scope with respect to crucial dispersive effects. Despite great progress over the last decade, driven by the study of quasilinear equations, our knowledge is still very limited. Going beyond this recent activity requires new tools whose development is at the heart of this proposal, including good approximate solutions (parametrices) going over arbitrarily large numbers of caustics, sharp pointwise bounds on Green functions, development of efficient wave packets methods, quantitative refinements of propagation of singularities (with direct applications in control theory), only to name a few important ones.
Summary
We are concerned with localization properties of solutions to hyperbolic PDEs, especially problems with a geometric component: how do boundaries and heterogeneous media influence spreading and concentration of solutions. While our first focus is on wave and Schrödinger equations on manifolds with boundary, strong connections exist with phase space localization for (clusters of) eigenfunctions, which are of independent interest. Motivations come from nonlinear dispersive models (in physically relevant settings), properties of eigenfunctions in quantum chaos (related to both physics of optic fiber design as well as number theoretic questions), or harmonic analysis on manifolds.
Waves propagation in real life physics occur in media which are neither homogeneous or spatially infinity. The birth of radar/sonar technologies (and the raise of computed tomography) greatly motivated numerous developments in microlocal analysis and the linear theory. Only recently toy nonlinear models have been studied on a curved background, sometimes compact or rough. Understanding how to extend such tools, dealing with wave dispersion or focusing, will allow us to significantly progress in our mathematical understanding of physically relevant models. There, boundaries appear naturally and most earlier developments related to propagation of singularities in this context have limited scope with respect to crucial dispersive effects. Despite great progress over the last decade, driven by the study of quasilinear equations, our knowledge is still very limited. Going beyond this recent activity requires new tools whose development is at the heart of this proposal, including good approximate solutions (parametrices) going over arbitrarily large numbers of caustics, sharp pointwise bounds on Green functions, development of efficient wave packets methods, quantitative refinements of propagation of singularities (with direct applications in control theory), only to name a few important ones.
Max ERC Funding
1 293 763 €
Duration
Start date: 2018-02-01, End date: 2023-01-31
Project acronym ANT
Project Automata in Number Theory
Researcher (PI) Boris Adamczewski
Host Institution (HI) CENTRE NATIONAL DE LA RECHERCHE SCIENTIFIQUE CNRS
Call Details Consolidator Grant (CoG), PE1, ERC-2014-CoG
Summary Finite automata are fundamental objects in Computer Science, of great importance on one hand for theoretical aspects (formal language theory, decidability, complexity) and on the other for practical applications (parsing). In number theory, finite automata are mainly used as simple devices for generating sequences of symbols over a finite set (e.g., digital representations of real numbers), and for recognizing some sets of integers or more generally of finitely generated abelian groups or monoids. One of the main features of these automatic structures comes from the fact that they are highly ordered without necessarily being trivial (i.e., periodic). With their rich fractal nature, they lie somewhere between order and chaos, even if, in most respects, their rigidity prevails. Over the last few years, several ground-breaking results have lead to a great renewed interest in the study of automatic structures in arithmetics.
A primary objective of the ANT project is to exploit this opportunity by developing new directions and interactions between automata and number theory. In this proposal, we outline three lines of research concerning fundamental number theoretical problems that have baffled mathematicians for decades. They include the study of integer base expansions of classical constants, of arithmetical linear differential equations and their link with enumerative combinatorics, and of arithmetics in positive characteristic. At first glance, these topics may seem unrelated, but, surprisingly enough, the theory of finite automata will serve as a natural guideline. We stress that this new point of view on classical questions is a key part of our methodology: we aim at creating a powerful synergy between the different approaches we propose to develop, placing automata theory and related methods at the heart of the subject. This project provides a unique opportunity to create the first international team focusing on these different problems as a whole.
Summary
Finite automata are fundamental objects in Computer Science, of great importance on one hand for theoretical aspects (formal language theory, decidability, complexity) and on the other for practical applications (parsing). In number theory, finite automata are mainly used as simple devices for generating sequences of symbols over a finite set (e.g., digital representations of real numbers), and for recognizing some sets of integers or more generally of finitely generated abelian groups or monoids. One of the main features of these automatic structures comes from the fact that they are highly ordered without necessarily being trivial (i.e., periodic). With their rich fractal nature, they lie somewhere between order and chaos, even if, in most respects, their rigidity prevails. Over the last few years, several ground-breaking results have lead to a great renewed interest in the study of automatic structures in arithmetics.
A primary objective of the ANT project is to exploit this opportunity by developing new directions and interactions between automata and number theory. In this proposal, we outline three lines of research concerning fundamental number theoretical problems that have baffled mathematicians for decades. They include the study of integer base expansions of classical constants, of arithmetical linear differential equations and their link with enumerative combinatorics, and of arithmetics in positive characteristic. At first glance, these topics may seem unrelated, but, surprisingly enough, the theory of finite automata will serve as a natural guideline. We stress that this new point of view on classical questions is a key part of our methodology: we aim at creating a powerful synergy between the different approaches we propose to develop, placing automata theory and related methods at the heart of the subject. This project provides a unique opportunity to create the first international team focusing on these different problems as a whole.
Max ERC Funding
1 438 745 €
Duration
Start date: 2015-10-01, End date: 2020-09-30
Project acronym aNtHESIS
Project Novel heart regeneration strategies
Researcher (PI) Eldad Tzahor
Host Institution (HI) WEIZMANN INSTITUTE OF SCIENCE
Call Details Proof of Concept (PoC), PC1, ERC-2014-PoC
Summary Heart disease and particularly myocardial infarction, i.e. heart attack, is the leading cause of death in the Western world today. The diminished regenerative potential of the heart begins shortly after birth, when most CardioMyocytes (CMs) cease to proliferate and make a transition from hyperplastic to hypertrophic growth. The Tzahor lab has been intensively exploring novel molecules, compounds as well as the molecular mechanisms that facilitate CM cell division in the adult heart of mammals as a strategy for eliciting heart regeneration. These efforts, had led to the identification of novel compounds which significantly increased the proliferation of adult CMs. Drawing upon these findings, the aim of the aNtHESIS project is two-fold. First, to (i) validate the pre-clinical application of our two novel compounds by conducting comprehensive in-vitro and in-vivo tests in mice as well as by carrying out experiments using human CMs. The second aim is (ii) to establish the business feasibility of our cardiac regenerative therapy concept by taking the necessary steps towards the commercialization of our novel compounds, focusing on the creation of strategic alliances with key private sector companies.
Summary
Heart disease and particularly myocardial infarction, i.e. heart attack, is the leading cause of death in the Western world today. The diminished regenerative potential of the heart begins shortly after birth, when most CardioMyocytes (CMs) cease to proliferate and make a transition from hyperplastic to hypertrophic growth. The Tzahor lab has been intensively exploring novel molecules, compounds as well as the molecular mechanisms that facilitate CM cell division in the adult heart of mammals as a strategy for eliciting heart regeneration. These efforts, had led to the identification of novel compounds which significantly increased the proliferation of adult CMs. Drawing upon these findings, the aim of the aNtHESIS project is two-fold. First, to (i) validate the pre-clinical application of our two novel compounds by conducting comprehensive in-vitro and in-vivo tests in mice as well as by carrying out experiments using human CMs. The second aim is (ii) to establish the business feasibility of our cardiac regenerative therapy concept by taking the necessary steps towards the commercialization of our novel compounds, focusing on the creation of strategic alliances with key private sector companies.
Max ERC Funding
150 000 €
Duration
Start date: 2016-01-01, End date: 2017-06-30
Project acronym ANTIViR
Project Molecular mechanisms of interferon-induced antiviral restriction and signalling
Researcher (PI) Caroline GOUJON
Host Institution (HI) INSTITUT NATIONAL DE LA SANTE ET DE LA RECHERCHE MEDICALE
Call Details Starting Grant (StG), LS6, ERC-2017-STG
Summary Interferons (IFNs), which are signalling proteins produced by infected cells, are the first line of defence against viral infections. IFNs induce, in infected and neighbouring cells, the expression of hundreds of IFN-stimulated genes (ISGs). The ISGs in turn induce in cells a potent antiviral state, capable of preventing replication of most viruses, including Human Immunodeficiency Virus type 1 (HIV-1) and influenza A virus (FLUAV). Identifying the antiviral ISGs and understanding their mechanisms of action is therefore crucial to progress in the fight against viruses.
ISGs playing a role in the antiviral state have been identified, such as human MX1, a well-known antiviral factor able to restrict numerous viruses including FLUAV, and MX2, an HIV-1 inhibitor. Both proteins bind to viral components but their detailed mechanisms of action, as well as the consequences of restriction on the activation of the innate immune system, remain unclear. Moreover, our preliminary work shows that additional anti-HIV-1 and anti-FLUAV ISGs remain to identify.
In this context, this proposal seeks an ERC StG funding to explore 3 major aims: 1) unravelling the mechanisms of antiviral action of MX proteins, by taking advantage of their similar structure and engineered chimeric proteins, and by using functional genetic screens to identify their cofactors; 2) investigating the consequences of incoming virus recognition by MX proteins on innate immune signalling, by altering their expression in target cells and measuring the cell response in terms of gene induction and cytokine production; 3) identifying and characterizing new ISGs able to inhibit viral replication with a combination of powerful approaches, including a whole-genome CRISPR/Cas9 knock-out screen.
Overall, this proposal will provide a better understanding of the molecular mechanisms involved in the antiviral effect of IFN, and may guide future efforts to identify novel therapeutic targets against major pathogenic viruses.
Summary
Interferons (IFNs), which are signalling proteins produced by infected cells, are the first line of defence against viral infections. IFNs induce, in infected and neighbouring cells, the expression of hundreds of IFN-stimulated genes (ISGs). The ISGs in turn induce in cells a potent antiviral state, capable of preventing replication of most viruses, including Human Immunodeficiency Virus type 1 (HIV-1) and influenza A virus (FLUAV). Identifying the antiviral ISGs and understanding their mechanisms of action is therefore crucial to progress in the fight against viruses.
ISGs playing a role in the antiviral state have been identified, such as human MX1, a well-known antiviral factor able to restrict numerous viruses including FLUAV, and MX2, an HIV-1 inhibitor. Both proteins bind to viral components but their detailed mechanisms of action, as well as the consequences of restriction on the activation of the innate immune system, remain unclear. Moreover, our preliminary work shows that additional anti-HIV-1 and anti-FLUAV ISGs remain to identify.
In this context, this proposal seeks an ERC StG funding to explore 3 major aims: 1) unravelling the mechanisms of antiviral action of MX proteins, by taking advantage of their similar structure and engineered chimeric proteins, and by using functional genetic screens to identify their cofactors; 2) investigating the consequences of incoming virus recognition by MX proteins on innate immune signalling, by altering their expression in target cells and measuring the cell response in terms of gene induction and cytokine production; 3) identifying and characterizing new ISGs able to inhibit viral replication with a combination of powerful approaches, including a whole-genome CRISPR/Cas9 knock-out screen.
Overall, this proposal will provide a better understanding of the molecular mechanisms involved in the antiviral effect of IFN, and may guide future efforts to identify novel therapeutic targets against major pathogenic viruses.
Max ERC Funding
1 499 794 €
Duration
Start date: 2017-12-01, End date: 2022-11-30
Project acronym ANTSolve
Project A multi-scale perspective into collective problem solving in ants
Researcher (PI) Ofer Feinerman
Host Institution (HI) WEIZMANN INSTITUTE OF SCIENCE
Call Details Consolidator Grant (CoG), LS8, ERC-2017-COG
Summary Cognition improves an animal’s ability to tune its responses to environmental conditions. In group living animals, communication works to form a collective cognition that expands the group’s abilities beyond those of individuals. Despite much research, to date, there is little understanding of how collective cognition emerges within biological ensembles. A major obstacle towards such an understanding is the rarity of comprehensive multi-scale empirical data of these complex systems.
We have demonstrated cooperative load transport by ants to be an ideal system to study the emergence of cognition. Similar to other complex cognitive systems, the ants employ high levels of emergence to achieve efficient problem solving over a large range of scenarios. Unique to this system, is its extreme amenability to experimental measurement and manipulation where internal conflicts map to forces, abstract decision making is reflected in direction changes, and future planning manifested in pheromone trails. This allows for an unprecedentedly detailed, multi-scale empirical description of the moment-to-moment unfolding of sophisticated cognitive processes.
This proposal is aimed at materializing this potential to the full. We will examine the ants’ problem solving capabilities under a variety of environmental challenges. We will expose the underpinning rules on the different organizational scales, the flow of information between them, and their relative contributions to collective performance. This will allow for empirical comparisons between the ‘group’ and the ‘sum of its parts’ from which we will quantify the level of emergence in this system. Using the language of information, we will map the boundaries of this group’s collective cognition and relate them to the range of habitable environmental niches. Moreover, we will generalize these insights to formulate a new paradigm of emergence in biological groups opening new horizons in the study of cognitive processes in general.
Summary
Cognition improves an animal’s ability to tune its responses to environmental conditions. In group living animals, communication works to form a collective cognition that expands the group’s abilities beyond those of individuals. Despite much research, to date, there is little understanding of how collective cognition emerges within biological ensembles. A major obstacle towards such an understanding is the rarity of comprehensive multi-scale empirical data of these complex systems.
We have demonstrated cooperative load transport by ants to be an ideal system to study the emergence of cognition. Similar to other complex cognitive systems, the ants employ high levels of emergence to achieve efficient problem solving over a large range of scenarios. Unique to this system, is its extreme amenability to experimental measurement and manipulation where internal conflicts map to forces, abstract decision making is reflected in direction changes, and future planning manifested in pheromone trails. This allows for an unprecedentedly detailed, multi-scale empirical description of the moment-to-moment unfolding of sophisticated cognitive processes.
This proposal is aimed at materializing this potential to the full. We will examine the ants’ problem solving capabilities under a variety of environmental challenges. We will expose the underpinning rules on the different organizational scales, the flow of information between them, and their relative contributions to collective performance. This will allow for empirical comparisons between the ‘group’ and the ‘sum of its parts’ from which we will quantify the level of emergence in this system. Using the language of information, we will map the boundaries of this group’s collective cognition and relate them to the range of habitable environmental niches. Moreover, we will generalize these insights to formulate a new paradigm of emergence in biological groups opening new horizons in the study of cognitive processes in general.
Max ERC Funding
2 000 000 €
Duration
Start date: 2018-06-01, End date: 2023-05-31
