Project acronym 3MC
Project 3D Model Catalysts to explore new routes to sustainable fuels
Researcher (PI) Petra Elisabeth De jongh
Host Institution (HI) UNIVERSITEIT UTRECHT
Call Details Consolidator Grant (CoG), PE4, ERC-2014-CoG
Summary Currently fuels, plastics, and drugs are predominantly manufactured from oil. A transition towards renewable resources critically depends on new catalysts, for instance to convert small molecules (such as solar or biomass derived hydrogen, carbon monoxide, water and carbon dioxide) into more complex ones (such as oxygenates, containing oxygen atoms in their structure). Catalyst development now often depends on trial and error rather than rational design, as the heterogeneity of these composite systems hampers detailed understanding of the role of each of the components.
I propose 3D model catalysts as a novel enabling tool to overcome this problem. Their well-defined nature allows unprecedented precision in the variation of structural parameters (morphology, spatial distribution) of the individual components, while at the same time they mimic real catalysts closely enough to allow testing under industrially relevant conditions. Using this approach I will address fundamental questions, such as:
* What are the mechanisms (structural, electronic, chemical) by which non-metal promoters influence the functionality of copper-based catalysts?
* Which nanoalloys can be formed, how does their composition influence the surface active sites and catalytic functionality under reaction conditions?
* Which size and interface effects occur, and how can we use them to tune the actitivity and selectivity towards desired products?
Our 3D model catalysts will be assembled from ordered mesoporous silica and carbon support materials and Cu-based promoted and bimetallic nanoparticles. The combination with high resolution characterization and testing under realistic conditions allows detailed insight into the role of the different components; critical for the rational design of novel catalysts for a future more sustainable production of chemicals and fuels from renewable resources.
Summary
Currently fuels, plastics, and drugs are predominantly manufactured from oil. A transition towards renewable resources critically depends on new catalysts, for instance to convert small molecules (such as solar or biomass derived hydrogen, carbon monoxide, water and carbon dioxide) into more complex ones (such as oxygenates, containing oxygen atoms in their structure). Catalyst development now often depends on trial and error rather than rational design, as the heterogeneity of these composite systems hampers detailed understanding of the role of each of the components.
I propose 3D model catalysts as a novel enabling tool to overcome this problem. Their well-defined nature allows unprecedented precision in the variation of structural parameters (morphology, spatial distribution) of the individual components, while at the same time they mimic real catalysts closely enough to allow testing under industrially relevant conditions. Using this approach I will address fundamental questions, such as:
* What are the mechanisms (structural, electronic, chemical) by which non-metal promoters influence the functionality of copper-based catalysts?
* Which nanoalloys can be formed, how does their composition influence the surface active sites and catalytic functionality under reaction conditions?
* Which size and interface effects occur, and how can we use them to tune the actitivity and selectivity towards desired products?
Our 3D model catalysts will be assembled from ordered mesoporous silica and carbon support materials and Cu-based promoted and bimetallic nanoparticles. The combination with high resolution characterization and testing under realistic conditions allows detailed insight into the role of the different components; critical for the rational design of novel catalysts for a future more sustainable production of chemicals and fuels from renewable resources.
Max ERC Funding
1 999 625 €
Duration
Start date: 2015-09-01, End date: 2020-08-31
Project acronym A-FRO
Project Actively Frozen - contextual modulation of freezing and its neuronal basis
Researcher (PI) Marta de Aragão Pacheco Moita
Host Institution (HI) FUNDACAO D. ANNA SOMMER CHAMPALIMAUD E DR. CARLOS MONTEZ CHAMPALIMAUD
Call Details Consolidator Grant (CoG), LS5, ERC-2018-COG
Summary When faced with a threat, an animal must decide whether to freeze, reducing its chances of being noticed, or to flee to the safety of a refuge. Animals from fish to primates choose between these two alternatives when confronted by an attacking predator, a choice that largely depends on the context in which the threat occurs. Recent work has made strides identifying the pre-motor circuits, and their inputs, which control freezing behavior in rodents, but how contextual information is integrated to guide this choice is still far from understood. We recently found that fruit flies in response to visual looming stimuli, simulating a large object on collision course, make rapid freeze/flee choices that depend on the social and spatial environment, and the fly’s internal state. Further, identification of looming detector neurons was recently reported and we identified the descending command neurons, DNp09, responsible for freezing in the fly. Knowing the sensory input and descending output for looming-evoked freezing, two environmental factors that modulate its expression, and using a genetically tractable system affording the use of large sample sizes, places us in an unique position to understand how a information about a threat is integrated with cues from the environment to guide the choice of whether to freeze (our goal). To assess how social information impinges on the circuit for freezing, we will examine the sensory inputs and neuromodulators that mediate this process, mapping their connections to DNp09 neurons (Aim 1). We ask whether learning is required for the spatial modulation of freezing, which cues flies are using to discriminate different places and which brain circuits mediate this process (Aim 2). Finally, we will study how activity of DNp09 neurons drives freezing (Aim 3). This project will provide a comprehensive understanding of the mechanism of freezing and its modulation by the environment, from single neurons to behaviour.
Summary
When faced with a threat, an animal must decide whether to freeze, reducing its chances of being noticed, or to flee to the safety of a refuge. Animals from fish to primates choose between these two alternatives when confronted by an attacking predator, a choice that largely depends on the context in which the threat occurs. Recent work has made strides identifying the pre-motor circuits, and their inputs, which control freezing behavior in rodents, but how contextual information is integrated to guide this choice is still far from understood. We recently found that fruit flies in response to visual looming stimuli, simulating a large object on collision course, make rapid freeze/flee choices that depend on the social and spatial environment, and the fly’s internal state. Further, identification of looming detector neurons was recently reported and we identified the descending command neurons, DNp09, responsible for freezing in the fly. Knowing the sensory input and descending output for looming-evoked freezing, two environmental factors that modulate its expression, and using a genetically tractable system affording the use of large sample sizes, places us in an unique position to understand how a information about a threat is integrated with cues from the environment to guide the choice of whether to freeze (our goal). To assess how social information impinges on the circuit for freezing, we will examine the sensory inputs and neuromodulators that mediate this process, mapping their connections to DNp09 neurons (Aim 1). We ask whether learning is required for the spatial modulation of freezing, which cues flies are using to discriminate different places and which brain circuits mediate this process (Aim 2). Finally, we will study how activity of DNp09 neurons drives freezing (Aim 3). This project will provide a comprehensive understanding of the mechanism of freezing and its modulation by the environment, from single neurons to behaviour.
Max ERC Funding
1 969 750 €
Duration
Start date: 2019-02-01, End date: 2024-01-31
Project acronym Acclimatize
Project Hypothalamic mechanisms of thermal homeostasis and adaptation
Researcher (PI) Jan SIEMENS
Host Institution (HI) UNIVERSITATSKLINIKUM HEIDELBERG
Call Details Consolidator Grant (CoG), LS5, ERC-2017-COG
Summary Mammalian organisms possess the remarkable ability to maintain internal body temperature (Tcore) within a narrow range close to 37°C despite wide environmental temperature variations. The brain’s neural “thermostat” is made up by central circuits in the hypothalamic preoptic area (POA), which orchestrate peripheral thermoregulatory responses to maintain Tcore. Thermogenesis requires metabolic fuel, suggesting intricate connections between the thermoregulatory centre and hypothalamic circuits controlling energy balance. How the POA detects and integrates temperature and metabolic information to achieve thermal balance is largely unknown. A major question is whether this circuitry could be harnessed therapeutically to treat obesity.
We have recently identified the first known molecular temperature sensor in thermoregulatory neurons of the POA, transient receptor potential melastatin 2 (TRPM2), a thermo-sensitive ion channel. I aim to use TRPM2 as a molecular marker to gain access to and probe the function of thermoregulatory neurons in vivo. I propose a multidisciplinary approach, combining local, in vivo POA temperature stimulation with optogenetic circuit-mapping to uncover the molecular and cellular logic of the hypothalamic thermoregulatory centre and to assess its medical potential to counteract metabolic syndrome.
Acclimation is a beneficial adaptive process that fortifies thermal responses upon environmental temperature challenges. Thermoregulatory neuron plasticity is thought to mediate acclimation. Conversely, maladaptive thermoregulatory changes affect obesity. The cell-type-specific neuronal plasticity mechanisms underlying these changes within the POA, however, are unknown.
Using ex-vivo slice electrophysiology and in vivo imaging, I propose to characterize acclimation- and obesity-induced plasticity of thermoregulatory neurons. Ultimately, I aim to manipulate thermoregulatory neuron plasticity to test its potential counter-balancing effect on obesity.
Summary
Mammalian organisms possess the remarkable ability to maintain internal body temperature (Tcore) within a narrow range close to 37°C despite wide environmental temperature variations. The brain’s neural “thermostat” is made up by central circuits in the hypothalamic preoptic area (POA), which orchestrate peripheral thermoregulatory responses to maintain Tcore. Thermogenesis requires metabolic fuel, suggesting intricate connections between the thermoregulatory centre and hypothalamic circuits controlling energy balance. How the POA detects and integrates temperature and metabolic information to achieve thermal balance is largely unknown. A major question is whether this circuitry could be harnessed therapeutically to treat obesity.
We have recently identified the first known molecular temperature sensor in thermoregulatory neurons of the POA, transient receptor potential melastatin 2 (TRPM2), a thermo-sensitive ion channel. I aim to use TRPM2 as a molecular marker to gain access to and probe the function of thermoregulatory neurons in vivo. I propose a multidisciplinary approach, combining local, in vivo POA temperature stimulation with optogenetic circuit-mapping to uncover the molecular and cellular logic of the hypothalamic thermoregulatory centre and to assess its medical potential to counteract metabolic syndrome.
Acclimation is a beneficial adaptive process that fortifies thermal responses upon environmental temperature challenges. Thermoregulatory neuron plasticity is thought to mediate acclimation. Conversely, maladaptive thermoregulatory changes affect obesity. The cell-type-specific neuronal plasticity mechanisms underlying these changes within the POA, however, are unknown.
Using ex-vivo slice electrophysiology and in vivo imaging, I propose to characterize acclimation- and obesity-induced plasticity of thermoregulatory neurons. Ultimately, I aim to manipulate thermoregulatory neuron plasticity to test its potential counter-balancing effect on obesity.
Max ERC Funding
1 902 500 €
Duration
Start date: 2018-09-01, End date: 2023-08-31
Project acronym ACoolTouch
Project Neural mechanisms of multisensory perceptual binding
Researcher (PI) James Francis Alexander Poulet
Host Institution (HI) MAX DELBRUECK CENTRUM FUER MOLEKULARE MEDIZIN IN DER HELMHOLTZ-GEMEINSCHAFT (MDC)
Call Details Consolidator Grant (CoG), LS5, ERC-2015-CoG
Summary Sensory perception involves the discrimination and binding of multiple modalities of sensory input. This is especially evident in the somatosensory system where different modalities of sensory input, including thermal and mechanosensory, are combined to generate a unified percept. The neural mechanisms of multisensory binding are unknown, in part because sensory perception is typically studied within a single modality in a single brain region. I propose a multi-level approach to investigate thermo-tactile processing in the mouse forepaw system from the primary sensory afferent neurons to thalamo-cortical circuits and behaviour.
The mouse forepaw system is the ideal system to investigate multisensory binding as the sensory afferent neurons are well investigated, cell type-specific lines are available, in vivo optogenetic manipulation is possible both in sensory afferent neurons and central circuits and we have developed high-resolution somatosensory perception behaviours. We have previously shown that mouse primary somatosensory forepaw cortical neurons respond to both tactile and thermal stimuli and are required for non-noxious cooling perception. With multimodal neurons how, then, is it possible to both discriminate and bind thermal and tactile stimuli?
I propose 3 objectives to address this question. We will first, perform functional mapping of the thermal and tactile pathways to cortex; second, investigate the neural mechanisms of thermo-tactile discrimination in behaving mice; and third, compare neural processing during two thermo-tactile binding tasks, the first using passively applied stimuli, and the second, active manipulation of thermal objects.
At each stage we will perform cell type-specific neural recordings and causal optogenetic manipulations in awake and behaving mice. Our multi-level approach will provide a comprehensive investigation into how the brain performs multisensory perceptual binding: a fundamental yet unsolved problem in neuroscience.
Summary
Sensory perception involves the discrimination and binding of multiple modalities of sensory input. This is especially evident in the somatosensory system where different modalities of sensory input, including thermal and mechanosensory, are combined to generate a unified percept. The neural mechanisms of multisensory binding are unknown, in part because sensory perception is typically studied within a single modality in a single brain region. I propose a multi-level approach to investigate thermo-tactile processing in the mouse forepaw system from the primary sensory afferent neurons to thalamo-cortical circuits and behaviour.
The mouse forepaw system is the ideal system to investigate multisensory binding as the sensory afferent neurons are well investigated, cell type-specific lines are available, in vivo optogenetic manipulation is possible both in sensory afferent neurons and central circuits and we have developed high-resolution somatosensory perception behaviours. We have previously shown that mouse primary somatosensory forepaw cortical neurons respond to both tactile and thermal stimuli and are required for non-noxious cooling perception. With multimodal neurons how, then, is it possible to both discriminate and bind thermal and tactile stimuli?
I propose 3 objectives to address this question. We will first, perform functional mapping of the thermal and tactile pathways to cortex; second, investigate the neural mechanisms of thermo-tactile discrimination in behaving mice; and third, compare neural processing during two thermo-tactile binding tasks, the first using passively applied stimuli, and the second, active manipulation of thermal objects.
At each stage we will perform cell type-specific neural recordings and causal optogenetic manipulations in awake and behaving mice. Our multi-level approach will provide a comprehensive investigation into how the brain performs multisensory perceptual binding: a fundamental yet unsolved problem in neuroscience.
Max ERC Funding
1 999 877 €
Duration
Start date: 2016-09-01, End date: 2021-08-31
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
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 ALZSYN
Project Imaging synaptic contributors to dementia
Researcher (PI) Tara Spires-Jones
Host Institution (HI) THE UNIVERSITY OF EDINBURGH
Call Details Consolidator Grant (CoG), LS5, ERC-2015-CoG
Summary Alzheimer's disease, the most common cause of dementia in older people, is a devastating condition that is becoming a public health crisis as our population ages. Despite great progress recently in Alzheimer’s disease research, we have no disease modifying drugs and a decade with a 99.6% failure rate of clinical trials attempting to treat the disease. This project aims to develop relevant therapeutic targets to restore brain function in Alzheimer’s disease by integrating human and model studies of synapses. It is widely accepted in the field that alterations in amyloid beta initiate the disease process. However the cascade leading from changes in amyloid to widespread tau pathology and neurodegeneration remain unclear. Synapse loss is the strongest pathological correlate of dementia in Alzheimer’s, and mounting evidence suggests that synapse degeneration plays a key role in causing cognitive decline. Here I propose to test the hypothesis that the amyloid cascade begins at the synapse leading to tau pathology, synapse dysfunction and loss, and ultimately neural circuit collapse causing cognitive impairment. The team will use cutting-edge multiphoton and array tomography imaging techniques to test mechanisms downstream of amyloid beta at synapses, and determine whether intervening in the cascade allows recovery of synapse structure and function. Importantly, I will combine studies in robust models of familial Alzheimer’s disease with studies in postmortem human brain to confirm relevance of our mechanistic studies to human disease. Finally, human stem cell derived neurons will be used to test mechanisms and potential therapeutics in neurons expressing the human proteome. Together, these experiments are ground-breaking since they have the potential to further our understanding of how synapses are lost in Alzheimer’s disease and to identify targets for effective therapeutic intervention, which is a critical unmet need in today’s health care system.
Summary
Alzheimer's disease, the most common cause of dementia in older people, is a devastating condition that is becoming a public health crisis as our population ages. Despite great progress recently in Alzheimer’s disease research, we have no disease modifying drugs and a decade with a 99.6% failure rate of clinical trials attempting to treat the disease. This project aims to develop relevant therapeutic targets to restore brain function in Alzheimer’s disease by integrating human and model studies of synapses. It is widely accepted in the field that alterations in amyloid beta initiate the disease process. However the cascade leading from changes in amyloid to widespread tau pathology and neurodegeneration remain unclear. Synapse loss is the strongest pathological correlate of dementia in Alzheimer’s, and mounting evidence suggests that synapse degeneration plays a key role in causing cognitive decline. Here I propose to test the hypothesis that the amyloid cascade begins at the synapse leading to tau pathology, synapse dysfunction and loss, and ultimately neural circuit collapse causing cognitive impairment. The team will use cutting-edge multiphoton and array tomography imaging techniques to test mechanisms downstream of amyloid beta at synapses, and determine whether intervening in the cascade allows recovery of synapse structure and function. Importantly, I will combine studies in robust models of familial Alzheimer’s disease with studies in postmortem human brain to confirm relevance of our mechanistic studies to human disease. Finally, human stem cell derived neurons will be used to test mechanisms and potential therapeutics in neurons expressing the human proteome. Together, these experiments are ground-breaking since they have the potential to further our understanding of how synapses are lost in Alzheimer’s disease and to identify targets for effective therapeutic intervention, which is a critical unmet need in today’s health care system.
Max ERC Funding
2 000 000 €
Duration
Start date: 2016-11-01, End date: 2021-10-31
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
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 AMSEL
Project Atomic Force Microscopy for Molecular Structure Elucidation
Researcher (PI) Leo Gross
Host Institution (HI) IBM RESEARCH GMBH
Call Details Consolidator Grant (CoG), PE4, ERC-2015-CoG
Summary Molecular structure elucidation is of great importance in synthetic chemistry, pharmacy, life sciences, energy and environmental sciences, and technology applications. To date structure elucidation by atomic force microscopy (AFM) has been demonstrated for a few, small and mainly planar molecules. In this project high-risk, high-impact scientific questions will be solved using structure elucidation with the AFM employing a novel tool and novel methodologies.
A combined low-temperature scanning tunneling microscope/atomic force microscope (LT-STM/AFM) with high throughput and in situ electrospray deposition method will be developed. Chemical resolution will be achieved by novel measurement techniques, in particular the usage of different and novel tip functionalizations and combination with Kelvin probe force microscopy. Elements will be identified using substructure recognition provided by a database that will be erected and by refined theory and simulations.
The developed tools and techniques will be applied to molecules of increasing fragility, complexity, size, and three-dimensionality. In particular samples that are challenging to characterize with conventional methods will be studied. Complex molecular mixtures will be investigated molecule-by-molecule taking advantage of the single-molecule sensitivity. The absolute stereochemistry of molecules will be determined, resolving molecules with multiple stereocenters. The operation of single molecular machines as nanocars and molecular gears will be investigated. Reactive intermediates generated with atomic manipulation will be characterized and their on-surface reactivity will be studied by AFM.
Summary
Molecular structure elucidation is of great importance in synthetic chemistry, pharmacy, life sciences, energy and environmental sciences, and technology applications. To date structure elucidation by atomic force microscopy (AFM) has been demonstrated for a few, small and mainly planar molecules. In this project high-risk, high-impact scientific questions will be solved using structure elucidation with the AFM employing a novel tool and novel methodologies.
A combined low-temperature scanning tunneling microscope/atomic force microscope (LT-STM/AFM) with high throughput and in situ electrospray deposition method will be developed. Chemical resolution will be achieved by novel measurement techniques, in particular the usage of different and novel tip functionalizations and combination with Kelvin probe force microscopy. Elements will be identified using substructure recognition provided by a database that will be erected and by refined theory and simulations.
The developed tools and techniques will be applied to molecules of increasing fragility, complexity, size, and three-dimensionality. In particular samples that are challenging to characterize with conventional methods will be studied. Complex molecular mixtures will be investigated molecule-by-molecule taking advantage of the single-molecule sensitivity. The absolute stereochemistry of molecules will be determined, resolving molecules with multiple stereocenters. The operation of single molecular machines as nanocars and molecular gears will be investigated. Reactive intermediates generated with atomic manipulation will be characterized and their on-surface reactivity will be studied by AFM.
Max ERC Funding
2 000 000 €
Duration
Start date: 2016-06-01, End date: 2021-05-31
Project acronym ARTTOUCH
Project Generating artificial touch: from the contribution of single tactile afferents to the encoding of complex percepts, and their implications for clinical innovation
Researcher (PI) Rochelle ACKERLEY
Host Institution (HI) CENTRE NATIONAL DE LA RECHERCHE SCIENTIFIQUE CNRS
Call Details Consolidator Grant (CoG), LS5, ERC-2017-COG
Summary Somatosensation encompass a wide range of processes, from feeling touch to temperature, as well as experiencing pleasure and pain. When afferent inputs are degraded or removed, such as in neuropathies or amputation, exploring the world becomes extremely difficult. Chronic pain is a major health issue that greatly diminishes quality of life and is one of the most disabling and costly conditions in Europe. The loss of a body part is common due to accidents, tumours, or peripheral diseases, and it has instantaneous effects on somatosensory functioning. Treating such disorders entails detailed knowledge about how somatosensory signals are encoded. Understanding these processes will enable the restoration of healthy function, such as providing real-time, naturalistic feedback in prostheses. To date, no prosthesis currently provides long-term sensory feedback, yet accomplishing this will lead to great quality of life improvements. The present proposal aims to uncover how basic tactile processes are encoded and represented centrally, as well as how more complex somatosensation is generated (e.g. wetness, pleasantness). Novel investigations will be conducted in humans to probe these mechanisms, including peripheral in vivo recording (microneurography) and neural stimulation, combined with advanced brain imaging and behavioural experiments. Preliminary work has shown the feasibility of the approach, where it is possible to visualise the activation of single mechanoreceptive afferents in the human brain. The multi-disciplinary approach unites detailed, high-resolution, functional investigations with actual sensations generated. The results will elucidate how basic and complex somatosensory processes are encoded, providing insights into the recovery of such signals. The knowledge gained aims to provide pain-free, efficient diagnostic capabilities for detecting and quantifying a range of somatosensory disorders, as well as identifying new potential therapeutic targets.
Summary
Somatosensation encompass a wide range of processes, from feeling touch to temperature, as well as experiencing pleasure and pain. When afferent inputs are degraded or removed, such as in neuropathies or amputation, exploring the world becomes extremely difficult. Chronic pain is a major health issue that greatly diminishes quality of life and is one of the most disabling and costly conditions in Europe. The loss of a body part is common due to accidents, tumours, or peripheral diseases, and it has instantaneous effects on somatosensory functioning. Treating such disorders entails detailed knowledge about how somatosensory signals are encoded. Understanding these processes will enable the restoration of healthy function, such as providing real-time, naturalistic feedback in prostheses. To date, no prosthesis currently provides long-term sensory feedback, yet accomplishing this will lead to great quality of life improvements. The present proposal aims to uncover how basic tactile processes are encoded and represented centrally, as well as how more complex somatosensation is generated (e.g. wetness, pleasantness). Novel investigations will be conducted in humans to probe these mechanisms, including peripheral in vivo recording (microneurography) and neural stimulation, combined with advanced brain imaging and behavioural experiments. Preliminary work has shown the feasibility of the approach, where it is possible to visualise the activation of single mechanoreceptive afferents in the human brain. The multi-disciplinary approach unites detailed, high-resolution, functional investigations with actual sensations generated. The results will elucidate how basic and complex somatosensory processes are encoded, providing insights into the recovery of such signals. The knowledge gained aims to provide pain-free, efficient diagnostic capabilities for detecting and quantifying a range of somatosensory disorders, as well as identifying new potential therapeutic targets.
Max ERC Funding
1 223 639 €
Duration
Start date: 2019-01-01, End date: 2023-12-31
Project acronym ASSIMILES
Project Advanced Spectroscopy and Spectrometry for Imaging Metabolism using Isotopically-Labeled Endogenous Substrates
Researcher (PI) Arnaud Comment
Host Institution (HI) THE CHANCELLOR MASTERS AND SCHOLARS OF THE UNIVERSITY OF CAMBRIDGE
Call Details Consolidator Grant (CoG), PE4, ERC-2015-CoG
Summary A technological revolution is currently taking place making it possible to noninvasively study metabolism in mammals (incl. humans) in vivo with unprecedented temporal and spatial resolution. Central to these developments is the phenomenon of hyperpolarization, which transiently enhances the magnetic resonance (MR) signals so much that real-time metabolic imaging and spectroscopy becomes possible. The first clinical translation of hyperpolarization MR technology has recently been demonstrated with prostate cancer patients.
I have played an active role in these exciting developments, through design and construction of hyperpolarization MR setups that are defining the cutting-edge for in vivo preclinical metabolic studies. However, important obstacles still exist for the technology to fulfill its enormous potential.
With this highly interdisciplinary proposal, I will overcome the principal drawbacks of current hyperpolarization technology, namely: 1) A limited time window for hyperpolarized MR detection; 2) The conventional use of potentially toxic polarizing agents; 3) The necessity to use supra-physiological doses of metabolic substrates to reach detectable MR signal
I will develop a novel hyperpolarization instrument making use of photoexcited compounds as polarizing agents to produce hyperpolarized solutions containing exclusively endogenous compounds. It will become possible to deliver hyperpolarized solutions in a quasi-continuous manner, permitting infusion of physiological doses and greatly increasing sensitivity. I will also use a complementary isotope imaging technique, the so-called CryoNanoSIMS (developed at my institution over the last year), which can image isotopic distributions in frozen tissue sections and reveal the localization of injected substrates and their metabolites with subcellular spatial resolution. Case studies will include liver and brain cancer mouse models. This work is pioneering and will create a new frontier in molecular imaging.
Summary
A technological revolution is currently taking place making it possible to noninvasively study metabolism in mammals (incl. humans) in vivo with unprecedented temporal and spatial resolution. Central to these developments is the phenomenon of hyperpolarization, which transiently enhances the magnetic resonance (MR) signals so much that real-time metabolic imaging and spectroscopy becomes possible. The first clinical translation of hyperpolarization MR technology has recently been demonstrated with prostate cancer patients.
I have played an active role in these exciting developments, through design and construction of hyperpolarization MR setups that are defining the cutting-edge for in vivo preclinical metabolic studies. However, important obstacles still exist for the technology to fulfill its enormous potential.
With this highly interdisciplinary proposal, I will overcome the principal drawbacks of current hyperpolarization technology, namely: 1) A limited time window for hyperpolarized MR detection; 2) The conventional use of potentially toxic polarizing agents; 3) The necessity to use supra-physiological doses of metabolic substrates to reach detectable MR signal
I will develop a novel hyperpolarization instrument making use of photoexcited compounds as polarizing agents to produce hyperpolarized solutions containing exclusively endogenous compounds. It will become possible to deliver hyperpolarized solutions in a quasi-continuous manner, permitting infusion of physiological doses and greatly increasing sensitivity. I will also use a complementary isotope imaging technique, the so-called CryoNanoSIMS (developed at my institution over the last year), which can image isotopic distributions in frozen tissue sections and reveal the localization of injected substrates and their metabolites with subcellular spatial resolution. Case studies will include liver and brain cancer mouse models. This work is pioneering and will create a new frontier in molecular imaging.
Max ERC Funding
2 199 146 €
Duration
Start date: 2016-09-01, End date: 2021-08-31
