Project acronym 3D-BioMat
Project Deciphering biomineralization mechanisms through 3D explorations of mesoscale crystalline structure in calcareous biomaterials
Researcher (PI) VIRGINIE CHAMARD
Host Institution (HI) CENTRE NATIONAL DE LA RECHERCHE SCIENTIFIQUE CNRS
Country France
Call Details Consolidator Grant (CoG), PE3, ERC-2016-COG
Summary The fundamental 3D-BioMat project aims at providing a biomineralization model to explain the formation of microscopic calcareous single-crystals produced by living organisms. Although these crystals present a wide variety of shapes, associated to various organic materials, the observation of a nanoscale granular structure common to almost all calcareous crystallizing organisms, associated to an extended crystalline coherence, underlies a generic biomineralization and assembly process. A key to building realistic scenarios of biomineralization is to reveal the crystalline architecture, at the mesoscale, (i. e., over a few granules), which none of the existing nano-characterization tools is able to provide.
3D-BioMat is based on the recognized PI’s expertise in the field of synchrotron coherent x-ray diffraction microscopy. It will extend the PI’s disruptive pioneering microscopy formalism, towards an innovative high-throughput approach able at giving access to the 3D mesoscale image of the crystalline properties (crystal-line coherence, crystal plane tilts and strains) with the required flexibility, nanoscale resolution, and non-invasiveness.
This achievement will be used to timely reveal the generics of the mesoscale crystalline structure through the pioneering explorations of a vast variety of crystalline biominerals produced by the famous Pinctada mar-garitifera oyster shell, and thereby build a realistic biomineralization scenario.
The inferred biomineralization pathways, including both physico-chemical pathways and biological controls, will ultimately be validated by comparing the mesoscale structures produced by biomimetic samples with the biogenic ones. Beyond deciphering one of the most intriguing questions of material nanosciences, 3D-BioMat may contribute to new climate models, pave the way for new routes in material synthesis and supply answers to the pearl-culture calcification problems.
Summary
The fundamental 3D-BioMat project aims at providing a biomineralization model to explain the formation of microscopic calcareous single-crystals produced by living organisms. Although these crystals present a wide variety of shapes, associated to various organic materials, the observation of a nanoscale granular structure common to almost all calcareous crystallizing organisms, associated to an extended crystalline coherence, underlies a generic biomineralization and assembly process. A key to building realistic scenarios of biomineralization is to reveal the crystalline architecture, at the mesoscale, (i. e., over a few granules), which none of the existing nano-characterization tools is able to provide.
3D-BioMat is based on the recognized PI’s expertise in the field of synchrotron coherent x-ray diffraction microscopy. It will extend the PI’s disruptive pioneering microscopy formalism, towards an innovative high-throughput approach able at giving access to the 3D mesoscale image of the crystalline properties (crystal-line coherence, crystal plane tilts and strains) with the required flexibility, nanoscale resolution, and non-invasiveness.
This achievement will be used to timely reveal the generics of the mesoscale crystalline structure through the pioneering explorations of a vast variety of crystalline biominerals produced by the famous Pinctada mar-garitifera oyster shell, and thereby build a realistic biomineralization scenario.
The inferred biomineralization pathways, including both physico-chemical pathways and biological controls, will ultimately be validated by comparing the mesoscale structures produced by biomimetic samples with the biogenic ones. Beyond deciphering one of the most intriguing questions of material nanosciences, 3D-BioMat may contribute to new climate models, pave the way for new routes in material synthesis and supply answers to the pearl-culture calcification problems.
Max ERC Funding
1 966 429 €
Duration
Start date: 2017-03-01, End date: 2022-08-31
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
Country France
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 AbioEvo
Project Conditions for the emergence of evolution during abiogenesis
Researcher (PI) Philippe Nghe
Host Institution (HI) ECOLE SUPERIEURE DE PHYSIQUE ET DECHIMIE INDUSTRIELLES DE LA VILLE DEPARIS
Country France
Call Details Consolidator Grant (CoG), LS1, ERC-2020-COG
Summary Abiogenesis, the transition from non-living to living matter, is at the core of the origin of life question. However, the dynamical processes underlying abiogenesis remain unknown.
The AbioEvo project aims to test the hypothesis that RNA-catalysed RNA recombination, if coupled with template-based mechanisms, provides a gradual route for the emergence of evolution by natural selection, starting from collective autocatalysis, toward template-based replication. Indeed, recombination allows both self-reproduction and shuffling of other sequences, thus, once combined with templating, provides the basic ingredients of reproduction, heredity and variation required for Darwinian evolution.
The project decomposes the problem into five steps: (WP1) the study of molecular-level mechanisms to generate and stabilize novel sequences by recombination and templating; (WP2) collective dynamics integrating these mechanisms into the properties of reproduction with heredity, variation, and selection, in order to establish proof-of-concepts of evolutionary modes; (WP3) viability thresholds of recombination-based replicators from increasingly random substrates; (WP4) conditions for open-ended evolution toward template-based replication; (WP5) experimentally informed theoretical estimates of the probability of the proposed evolutionary transitions.
The project would provide first demonstrations of evolution by natural selection in a purely chemical system, gradual and experimentally accessible paths from oligomers to template-based replication, and a method to evaluate prebiotic plausibility from sequence-to-function relationships, kinetics and evolutionary dynamics.
Summary
Abiogenesis, the transition from non-living to living matter, is at the core of the origin of life question. However, the dynamical processes underlying abiogenesis remain unknown.
The AbioEvo project aims to test the hypothesis that RNA-catalysed RNA recombination, if coupled with template-based mechanisms, provides a gradual route for the emergence of evolution by natural selection, starting from collective autocatalysis, toward template-based replication. Indeed, recombination allows both self-reproduction and shuffling of other sequences, thus, once combined with templating, provides the basic ingredients of reproduction, heredity and variation required for Darwinian evolution.
The project decomposes the problem into five steps: (WP1) the study of molecular-level mechanisms to generate and stabilize novel sequences by recombination and templating; (WP2) collective dynamics integrating these mechanisms into the properties of reproduction with heredity, variation, and selection, in order to establish proof-of-concepts of evolutionary modes; (WP3) viability thresholds of recombination-based replicators from increasingly random substrates; (WP4) conditions for open-ended evolution toward template-based replication; (WP5) experimentally informed theoretical estimates of the probability of the proposed evolutionary transitions.
The project would provide first demonstrations of evolution by natural selection in a purely chemical system, gradual and experimentally accessible paths from oligomers to template-based replication, and a method to evaluate prebiotic plausibility from sequence-to-function relationships, kinetics and evolutionary dynamics.
Max ERC Funding
2 000 000 €
Duration
Start date: 2021-06-01, End date: 2026-05-31
Project acronym ADDITIVES
Project Exposure to ‘cocktails’ of food additives and chronic disease risk
Researcher (PI) Mathilde Touvier
Host Institution (HI) INSTITUT NATIONAL DE LA SANTE ET DE LA RECHERCHE MEDICALE
Country France
Call Details Consolidator Grant (CoG), LS7, ERC-2019-COG
Summary Today, our daily diet typically contains dozens of food additives (e.g. colours, emulsifiers, sweeteners: ~350 substances allowed on the EU market). Safety assessment is performed by health agencies to protect consumers against potential adverse effects of each additive, yet such an assessment is only based on current available evidence, i.e., for most additives, only in-vitro/in-vivo toxicological studies and exposure simulations. Meanwhile, the long-term health impact of additives intake and any potential ‘cocktail’ effects remain largely unknown and have become a source of serious concern. Growing evidence link the consumption of ultra-processed foods, containing numerous additives, to adverse health outcomes, in particular our recent results on cancer (Fiolet BMJ 2018). While most additives allowed in the EU are likely to be neutral for health and some may even be beneficial, recent animal and cell-based studies have suggested detrimental effects of several such compounds. In humans, data is lacking. No epidemiological study has ever assessed individual-level exposure to a wide range of food additives and its association with health, hampered by unsuited traditional dietary assessment tools facing the high additive content variability across commercial brands. Hence, a major breakthrough will come from the novel and unique tools I developed with my team, notably within the NutriNet-Santé cohort (n=164,000), collecting precise and repeated data on foods and beverages usually consumed, including names and brands of industrial products. With this unique resource, I propose a project at the forefront of international research to provide answers to a question of major importance for public health. Built as a combination of epidemiological studies and in-vitro/in-vivo experiments, this project will shed light on individual exposure to food additive 'cocktails' in relation to obesity, cancer, cardiovascular diseases and mortality, while depicting underlying mechanisms.
Summary
Today, our daily diet typically contains dozens of food additives (e.g. colours, emulsifiers, sweeteners: ~350 substances allowed on the EU market). Safety assessment is performed by health agencies to protect consumers against potential adverse effects of each additive, yet such an assessment is only based on current available evidence, i.e., for most additives, only in-vitro/in-vivo toxicological studies and exposure simulations. Meanwhile, the long-term health impact of additives intake and any potential ‘cocktail’ effects remain largely unknown and have become a source of serious concern. Growing evidence link the consumption of ultra-processed foods, containing numerous additives, to adverse health outcomes, in particular our recent results on cancer (Fiolet BMJ 2018). While most additives allowed in the EU are likely to be neutral for health and some may even be beneficial, recent animal and cell-based studies have suggested detrimental effects of several such compounds. In humans, data is lacking. No epidemiological study has ever assessed individual-level exposure to a wide range of food additives and its association with health, hampered by unsuited traditional dietary assessment tools facing the high additive content variability across commercial brands. Hence, a major breakthrough will come from the novel and unique tools I developed with my team, notably within the NutriNet-Santé cohort (n=164,000), collecting precise and repeated data on foods and beverages usually consumed, including names and brands of industrial products. With this unique resource, I propose a project at the forefront of international research to provide answers to a question of major importance for public health. Built as a combination of epidemiological studies and in-vitro/in-vivo experiments, this project will shed light on individual exposure to food additive 'cocktails' in relation to obesity, cancer, cardiovascular diseases and mortality, while depicting underlying mechanisms.
Max ERC Funding
2 000 000 €
Duration
Start date: 2020-05-01, End date: 2025-04-30
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
Country France
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: 2020-12-31
Project acronym AdOC
Project Advance Optical Clocks
Researcher (PI) Sebastien Andre Marcel Bize
Host Institution (HI) CENTRE NATIONAL DE LA RECHERCHE SCIENTIFIQUE CNRS
Country France
Call Details Consolidator Grant (CoG), PE2, ERC-2013-CoG
Summary "The proposed research program has three main objectives. The first and second objectives are to seek extreme precisions in optical atomic spectroscopy and optical clocks, and to use this quest as a mean of exploration in atomic physics. The third objective is to explore new possibilities that stem from extreme precision. These goals will be pursued via three complementary activities: #1: Search for extreme precisions with an Hg optical lattice clock. #2: Explore and exploit the rich Hg system, which is essentially unexplored in the cold and ultra-cold regime. #3: Identify new applications of clocks with extreme precision to Earth science. Clocks can measure directly the gravitational potential via Einstein’s gravitational redshift, leading to the idea of “clock-based geodesy”.
The 2 first activities are experimental and build on an existing setup, where we demonstrated the feasibility of an Hg optical lattice clock. Hg is chosen for its potential to surpass competing systems. We will investigate the unexplored physics of the Hg clock. This includes interactions between Hg atoms, lattice-induced light shifts, and sensitivity to external fields which are specific to the atomic species. Beyond, we will explore the fundamental limits of the optical lattice scheme. We will exploit other remarkable features of Hg associated to the high atomic number and the diversity of stable isotopes. These features enable tests of fundamental physical laws, ultra-precise measurements of isotope shifts, measurement of collisional properties toward evaporative cooling and quantum gases of Hg, investigation of forbidden transitions promising for measuring the nuclear anapole moment of Hg.
The third activity is theoretical and is aimed at initiating collaborations with experts in modelling Earth gravity. With this expertise, we will identify the most promising and realistic approaches for clocks and emerging remote comparison methods to contribute to geodesy, hydrology, oceanography, etc."
Summary
"The proposed research program has three main objectives. The first and second objectives are to seek extreme precisions in optical atomic spectroscopy and optical clocks, and to use this quest as a mean of exploration in atomic physics. The third objective is to explore new possibilities that stem from extreme precision. These goals will be pursued via three complementary activities: #1: Search for extreme precisions with an Hg optical lattice clock. #2: Explore and exploit the rich Hg system, which is essentially unexplored in the cold and ultra-cold regime. #3: Identify new applications of clocks with extreme precision to Earth science. Clocks can measure directly the gravitational potential via Einstein’s gravitational redshift, leading to the idea of “clock-based geodesy”.
The 2 first activities are experimental and build on an existing setup, where we demonstrated the feasibility of an Hg optical lattice clock. Hg is chosen for its potential to surpass competing systems. We will investigate the unexplored physics of the Hg clock. This includes interactions between Hg atoms, lattice-induced light shifts, and sensitivity to external fields which are specific to the atomic species. Beyond, we will explore the fundamental limits of the optical lattice scheme. We will exploit other remarkable features of Hg associated to the high atomic number and the diversity of stable isotopes. These features enable tests of fundamental physical laws, ultra-precise measurements of isotope shifts, measurement of collisional properties toward evaporative cooling and quantum gases of Hg, investigation of forbidden transitions promising for measuring the nuclear anapole moment of Hg.
The third activity is theoretical and is aimed at initiating collaborations with experts in modelling Earth gravity. With this expertise, we will identify the most promising and realistic approaches for clocks and emerging remote comparison methods to contribute to geodesy, hydrology, oceanography, etc."
Max ERC Funding
1 946 432 €
Duration
Start date: 2014-04-01, End date: 2019-03-31
Project acronym ALFA
Project Shaping a European Scientific Scene : Alfonsine Astronomy
Researcher (PI) Matthieu Husson
Host Institution (HI) CENTRE NATIONAL DE LA RECHERCHE SCIENTIFIQUE CNRS
Country France
Call Details Consolidator Grant (CoG), SH6, ERC-2016-COG
Summary Alfonsine astronomy is arguably among the first European scientific achievements. It shaped a scene for actors like Regiomontanus or Copernicus. There is however little detailed historical analysis encompassing its development in its full breadth. ALFA addresses this issue by studying tables, instruments, mathematical and theoretical texts in a methodologically innovative way relying on approaches from the history of manuscript cultures, history of mathematics, and history of astronomy.
ALFA integrates these approaches not only to benefit from different perspectives but also to build new questions from their interactions. For instance the analysis of mathematical practices in astral sciences manuscripts induces new ways to analyse the documents and to think about astronomical questions.
Relying on these approaches the main objectives of ALFA are thus to:
- Retrace the development of the corpus of Alfonsine texts from its origin in the second half of the 13th century to the end of the 15th century by following, on the manuscript level, the milieus fostering it;
- Analyse the Alfonsine astronomers’ practices, their relations to mathematics, to the natural world, to proofs and justification, their intellectual context and audiences;
- Build a meaningful narrative showing how astronomers in different milieus with diverse practices shaped, also from Arabic materials, an original scientific scene in Europe.
ALFA will shed new light on the intellectual history of the late medieval period as a whole and produce a better understanding of its relations to related scientific periods in Europe and beyond. It will also produce methodological breakthroughs impacting the ways history of knowledge is practiced outside the field of ancient and medieval sciences. Efforts will be devoted to bring these results not only to the relevant scholarly communities but also to a wider audience as a resource in the public debates around science, knowledge and culture.
Summary
Alfonsine astronomy is arguably among the first European scientific achievements. It shaped a scene for actors like Regiomontanus or Copernicus. There is however little detailed historical analysis encompassing its development in its full breadth. ALFA addresses this issue by studying tables, instruments, mathematical and theoretical texts in a methodologically innovative way relying on approaches from the history of manuscript cultures, history of mathematics, and history of astronomy.
ALFA integrates these approaches not only to benefit from different perspectives but also to build new questions from their interactions. For instance the analysis of mathematical practices in astral sciences manuscripts induces new ways to analyse the documents and to think about astronomical questions.
Relying on these approaches the main objectives of ALFA are thus to:
- Retrace the development of the corpus of Alfonsine texts from its origin in the second half of the 13th century to the end of the 15th century by following, on the manuscript level, the milieus fostering it;
- Analyse the Alfonsine astronomers’ practices, their relations to mathematics, to the natural world, to proofs and justification, their intellectual context and audiences;
- Build a meaningful narrative showing how astronomers in different milieus with diverse practices shaped, also from Arabic materials, an original scientific scene in Europe.
ALFA will shed new light on the intellectual history of the late medieval period as a whole and produce a better understanding of its relations to related scientific periods in Europe and beyond. It will also produce methodological breakthroughs impacting the ways history of knowledge is practiced outside the field of ancient and medieval sciences. Efforts will be devoted to bring these results not only to the relevant scholarly communities but also to a wider audience as a resource in the public debates around science, knowledge and culture.
Max ERC Funding
1 871 250 €
Duration
Start date: 2017-09-01, End date: 2022-08-31
Project acronym ALS-Networks
Project Defining functional networks of genetic causes for ALS and related neurodegenerative disorders
Researcher (PI) Edor Kabashi
Host Institution (HI) INSTITUT NATIONAL DE LA SANTE ET DE LA RECHERCHE MEDICALE
Country France
Call Details Consolidator Grant (CoG), LS5, ERC-2015-CoG
Summary Brain and spinal cord diseases affect 38% of the European population and cost over 800 billion € annually; representing by far the largest health challenge. ALS is a prevalent neurological disease caused by motor neuron death with an invariably fatal outcome. I contributed to ALS research with the groundbreaking discovery of TDP-43 mutations, functionally characterized these mutations in the first vertebrate model and demonstrated a genetic interaction with another major ALS gene FUS. Emerging evidence indicates that four major causative factors in ALS, C9orf72, TDP-43, FUS & SQSTM1, genetically interact and could function in common cellular mechanisms. Here, I will develop zebrafish transgenic lines for all four genes, using state of the art genomic editing tools to combine simultaneous gene knockout and expression of the mutant alleles. Using these innovative disease models I will study the functional interactions amongst these four genes and their converging effect on key ALS pathogenic mechanisms: autophagy degradation, stress granule formation and RNA regulation. These studies will permit to pinpoint the molecular cascades that underlie ALS-related neurodegeneration. We will further expand the current ALS network by proposing and validating novel genetic interactors, which will be further screened for disease-causing variants and as pathological markers in patient samples. The power of zebrafish as a vertebrate model amenable to high-content phenotype-based screens will enable discovery of bioactive compounds that are neuroprotective in multiple animal models of disease. This project will increase the fundamental understanding of the relevance of C9orf72, TDP-43, FUS and SQSTM1 by developing animal models to characterize common pathophysiological mechanisms. Furthermore, I will uncover novel genetic, disease-related and pharmacological modifiers to extend the ALS network that will facilitate development of therapeutic strategies for neurodegenerative disorders
Summary
Brain and spinal cord diseases affect 38% of the European population and cost over 800 billion € annually; representing by far the largest health challenge. ALS is a prevalent neurological disease caused by motor neuron death with an invariably fatal outcome. I contributed to ALS research with the groundbreaking discovery of TDP-43 mutations, functionally characterized these mutations in the first vertebrate model and demonstrated a genetic interaction with another major ALS gene FUS. Emerging evidence indicates that four major causative factors in ALS, C9orf72, TDP-43, FUS & SQSTM1, genetically interact and could function in common cellular mechanisms. Here, I will develop zebrafish transgenic lines for all four genes, using state of the art genomic editing tools to combine simultaneous gene knockout and expression of the mutant alleles. Using these innovative disease models I will study the functional interactions amongst these four genes and their converging effect on key ALS pathogenic mechanisms: autophagy degradation, stress granule formation and RNA regulation. These studies will permit to pinpoint the molecular cascades that underlie ALS-related neurodegeneration. We will further expand the current ALS network by proposing and validating novel genetic interactors, which will be further screened for disease-causing variants and as pathological markers in patient samples. The power of zebrafish as a vertebrate model amenable to high-content phenotype-based screens will enable discovery of bioactive compounds that are neuroprotective in multiple animal models of disease. This project will increase the fundamental understanding of the relevance of C9orf72, TDP-43, FUS and SQSTM1 by developing animal models to characterize common pathophysiological mechanisms. Furthermore, I will uncover novel genetic, disease-related and pharmacological modifiers to extend the ALS network that will facilitate development of therapeutic strategies for neurodegenerative disorders
Max ERC Funding
2 000 000 €
Duration
Start date: 2017-04-01, End date: 2022-03-31
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
Country France
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 ANGI
Project Adaptive significance of Non Genetic Inheritance
Researcher (PI) Benoit Francois Pujol
Host Institution (HI) CENTRE NATIONAL DE LA RECHERCHE SCIENTIFIQUE CNRS
Country France
Call Details Consolidator Grant (CoG), LS8, ERC-2015-CoG
Summary Our ability to predict adaptation and the response of populations to selection is limited. Solving this issue is a fundamental challenge of evolutionary ecology with implications for applied sciences such as conservation, and agronomy. Non genetic inheritance (NGI; e.g., ecological niche transmission) is suspected to play a foremost role in adaptive evolution but such hypothesis remains untested. Using quantitative genetics in wild plant populations, experimental evolution, and epigenetics, we will assess the role of NGI in the adaptive response to selection of plant populations. The ANGI project will follow the subsequent research program: (1) Using long-term survey data, we will measure natural selection in wild populations of Antirrhinum majus within its heterogeneous array of micro-habitats. We will calculate the fitness gain provided by multiple traits and stem elongation to plants growing in bushes where they compete for light. Stem elongation is known to depend on epigenetic variation. (2) Using a statistical approach that we developed, we will estimate the quantitative genetic and non genetic heritability of traits. (3) We will identify phenotypic changes caused by fitness that are based on genetic variation and NGI and assess their respective roles in adaptive evolution. (4) In controlled conditions, we will artificially select for increased stem elongation in clonal lineages, thereby excluding DNA variation. We will quantify the non genetic response to selection and test for a quantitative epigenetic signature of selection. (5) We will build on our results to generate an inclusive theory of genetic and non genetic natural selection. ANGI builds on a confirmed expertise in selection experiments, quantitative genetics and NGI. In addition, the availability of survey data provides a solid foundation for the achievement of this project. Our ambition is to shed light on original mechanisms underlying adaptation that are an alternative to genetic selection.
Summary
Our ability to predict adaptation and the response of populations to selection is limited. Solving this issue is a fundamental challenge of evolutionary ecology with implications for applied sciences such as conservation, and agronomy. Non genetic inheritance (NGI; e.g., ecological niche transmission) is suspected to play a foremost role in adaptive evolution but such hypothesis remains untested. Using quantitative genetics in wild plant populations, experimental evolution, and epigenetics, we will assess the role of NGI in the adaptive response to selection of plant populations. The ANGI project will follow the subsequent research program: (1) Using long-term survey data, we will measure natural selection in wild populations of Antirrhinum majus within its heterogeneous array of micro-habitats. We will calculate the fitness gain provided by multiple traits and stem elongation to plants growing in bushes where they compete for light. Stem elongation is known to depend on epigenetic variation. (2) Using a statistical approach that we developed, we will estimate the quantitative genetic and non genetic heritability of traits. (3) We will identify phenotypic changes caused by fitness that are based on genetic variation and NGI and assess their respective roles in adaptive evolution. (4) In controlled conditions, we will artificially select for increased stem elongation in clonal lineages, thereby excluding DNA variation. We will quantify the non genetic response to selection and test for a quantitative epigenetic signature of selection. (5) We will build on our results to generate an inclusive theory of genetic and non genetic natural selection. ANGI builds on a confirmed expertise in selection experiments, quantitative genetics and NGI. In addition, the availability of survey data provides a solid foundation for the achievement of this project. Our ambition is to shed light on original mechanisms underlying adaptation that are an alternative to genetic selection.
Max ERC Funding
1 999 970 €
Duration
Start date: 2016-03-01, End date: 2022-02-28