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 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 AstroWireSyn
Project Wiring synaptic circuits with astroglial connexins: mechanisms, dynamics and impact for critical period plasticity
Researcher (PI) Nathalie Rouach
Host Institution (HI) COLLEGE DE FRANCE
Call Details Consolidator Grant (CoG), LS5, ERC-2015-CoG
Summary Brain information processing is commonly thought to be a neuronal performance. However recent data point to a key role of astrocytes in brain development, activity and pathology. Indeed astrocytes are now viewed as crucial elements of the brain circuitry that control synapse formation, maturation, activity and elimination. How do astrocytes exert such control is matter of intense research, as they are now known to participate in critical developmental periods as well as in psychiatric disorders involving synapse alterations. Thus unraveling how astrocytes control synaptic circuit formation and maturation is crucial, not only for our understanding of brain development, but also for identifying novel therapeutic targets.
We recently found that connexin 30 (Cx30), an astroglial gap junction subunit expressed postnatally, tunes synaptic activity via an unprecedented non-channel function setting the proximity of glial processes to synaptic clefts, essential for synaptic glutamate clearance efficacy. Our work not only reveals Cx30 as a key determinant of glial synapse coverage, but also extends the classical model of neuroglial interactions in which astrocytes are generally considered as extrasynaptic elements indirectly regulating neurotransmission. Yet the molecular mechanisms involved in such control, its dynamic regulation by activity and impact in a native developmental context are unknown. We will now address these important questions, focusing on the involvement of this novel astroglial function in wiring developing synaptic circuits.
Thus using a multidisciplinary approach we will investigate:
1) the molecular and cellular mechanisms underlying Cx30 regulation of synaptic function
2) the activity-dependent dynamics of Cx30 function at synapses
3) a role for Cx30 in wiring synaptic circuits during critical developmental periods
This ambitious project will provide essential knowledge on the molecular mechanisms underlying astroglial control of synaptic circuits.
Summary
Brain information processing is commonly thought to be a neuronal performance. However recent data point to a key role of astrocytes in brain development, activity and pathology. Indeed astrocytes are now viewed as crucial elements of the brain circuitry that control synapse formation, maturation, activity and elimination. How do astrocytes exert such control is matter of intense research, as they are now known to participate in critical developmental periods as well as in psychiatric disorders involving synapse alterations. Thus unraveling how astrocytes control synaptic circuit formation and maturation is crucial, not only for our understanding of brain development, but also for identifying novel therapeutic targets.
We recently found that connexin 30 (Cx30), an astroglial gap junction subunit expressed postnatally, tunes synaptic activity via an unprecedented non-channel function setting the proximity of glial processes to synaptic clefts, essential for synaptic glutamate clearance efficacy. Our work not only reveals Cx30 as a key determinant of glial synapse coverage, but also extends the classical model of neuroglial interactions in which astrocytes are generally considered as extrasynaptic elements indirectly regulating neurotransmission. Yet the molecular mechanisms involved in such control, its dynamic regulation by activity and impact in a native developmental context are unknown. We will now address these important questions, focusing on the involvement of this novel astroglial function in wiring developing synaptic circuits.
Thus using a multidisciplinary approach we will investigate:
1) the molecular and cellular mechanisms underlying Cx30 regulation of synaptic function
2) the activity-dependent dynamics of Cx30 function at synapses
3) a role for Cx30 in wiring synaptic circuits during critical developmental periods
This ambitious project will provide essential knowledge on the molecular mechanisms underlying astroglial control of synaptic circuits.
Max ERC Funding
2 000 000 €
Duration
Start date: 2016-10-01, End date: 2021-09-30
Project acronym BigFastData
Project Charting a New Horizon of Big and Fast Data Analysis through Integrated Algorithm Design
Researcher (PI) Yanlei DIAO
Host Institution (HI) ECOLE POLYTECHNIQUE
Call Details Consolidator Grant (CoG), PE6, ERC-2016-COG
Summary This proposal addresses a pressing need from emerging big data applications such as genomics and data center monitoring: besides the scale of processing, big data systems must also enable perpetual, low-latency processing for a broad set of analytical tasks, referred to as big and fast data analysis. Today’s technology falls severely short for such needs due to the lack of support of complex analytics with scale, low latency, and strong guarantees of user performance requirements. To bridge the gap, this proposal tackles a grand challenge: “How do we design an algorithmic foundation that enables the development of all necessary pillars of big and fast data analysis?” This proposal considers three pillars:
1) Parallelism: There is a fundamental tension between data parallelism (for scale) and pipeline parallelism (for low latency). We propose new approaches based on intelligent use of memory and workload properties to integrate both forms of parallelism.
2) Analytics: The literature lacks a large body of algorithms for critical order-related analytics to be run under data and pipeline parallelism. We propose new algorithmic frameworks to enable such analytics.
3) Optimization: To run analytics, today's big data systems are best effort only. We transform such systems into a principled optimization framework that suits the new characteristics of big data infrastructure and adapts to meet user performance requirements.
The scale and complexity of the proposed algorithm design makes this project high-risk, at the same time, high-gain: it will lay a solid foundation for big and fast data analysis, enabling a new integrated parallel processing paradigm, algorithms for critical order-related analytics, and a principled optimizer with strong performance guarantees. It will also broadly enable accelerated information discovery in emerging domains such as genomics, as well as economic benefits of early, well-informed decisions and reduced user payments.
Summary
This proposal addresses a pressing need from emerging big data applications such as genomics and data center monitoring: besides the scale of processing, big data systems must also enable perpetual, low-latency processing for a broad set of analytical tasks, referred to as big and fast data analysis. Today’s technology falls severely short for such needs due to the lack of support of complex analytics with scale, low latency, and strong guarantees of user performance requirements. To bridge the gap, this proposal tackles a grand challenge: “How do we design an algorithmic foundation that enables the development of all necessary pillars of big and fast data analysis?” This proposal considers three pillars:
1) Parallelism: There is a fundamental tension between data parallelism (for scale) and pipeline parallelism (for low latency). We propose new approaches based on intelligent use of memory and workload properties to integrate both forms of parallelism.
2) Analytics: The literature lacks a large body of algorithms for critical order-related analytics to be run under data and pipeline parallelism. We propose new algorithmic frameworks to enable such analytics.
3) Optimization: To run analytics, today's big data systems are best effort only. We transform such systems into a principled optimization framework that suits the new characteristics of big data infrastructure and adapts to meet user performance requirements.
The scale and complexity of the proposed algorithm design makes this project high-risk, at the same time, high-gain: it will lay a solid foundation for big and fast data analysis, enabling a new integrated parallel processing paradigm, algorithms for critical order-related analytics, and a principled optimizer with strong performance guarantees. It will also broadly enable accelerated information discovery in emerging domains such as genomics, as well as economic benefits of early, well-informed decisions and reduced user payments.
Max ERC Funding
2 472 752 €
Duration
Start date: 2017-09-01, End date: 2022-08-31
Project acronym BITCRUMBS
Project Towards a Reliable and Automated Analysis of Compromised Systems
Researcher (PI) Davide BALZAROTTI
Host Institution (HI) EURECOM
Call Details Consolidator Grant (CoG), PE6, ERC-2017-COG
Summary "The vast majority of research in computer security is dedicated to the design of detection, protection, and prevention solutions. While these techniques play a critical role to increase the security and privacy of our digital infrastructure, it is enough to look at the news to understand that it is not a matter of ""if"" a computer system will be compromised, but only a matter of ""when"". It is a well known fact that there is no 100% secure system, and that there is no practical way to prevent attackers with enough resources from breaking into sensitive targets. Therefore, it is extremely important to develop automated techniques to timely and precisely analyze computer security incidents and compromised systems. Unfortunately, the area of incident response received very little research attention, and it is still largely considered an art more than a science because of its lack of a proper theoretical and scientific background.
The objective of BITCRUMBS is to rethink the Incident Response (IR) field from its foundations by proposing a more scientific and comprehensive approach to the analysis of compromised systems. BITCRUMBS will achieve this goal in three steps: (1) by introducing a new systematic approach to precisely measure the effectiveness and accuracy of IR techniques and their resilience to evasion and forgery; (2) by designing and implementing new automated techniques to cope with advanced threats and the analysis of IoT devices; and (3) by proposing a novel forensics-by-design development methodology and a set of guidelines for the design of future systems and software.
To provide the right context for these new techniques and show the impact of the project in different fields and scenarios, BITCRUMBS plans to address its objectives using real case studies borrowed from two different
domains: traditional computer software, and embedded systems.
"
Summary
"The vast majority of research in computer security is dedicated to the design of detection, protection, and prevention solutions. While these techniques play a critical role to increase the security and privacy of our digital infrastructure, it is enough to look at the news to understand that it is not a matter of ""if"" a computer system will be compromised, but only a matter of ""when"". It is a well known fact that there is no 100% secure system, and that there is no practical way to prevent attackers with enough resources from breaking into sensitive targets. Therefore, it is extremely important to develop automated techniques to timely and precisely analyze computer security incidents and compromised systems. Unfortunately, the area of incident response received very little research attention, and it is still largely considered an art more than a science because of its lack of a proper theoretical and scientific background.
The objective of BITCRUMBS is to rethink the Incident Response (IR) field from its foundations by proposing a more scientific and comprehensive approach to the analysis of compromised systems. BITCRUMBS will achieve this goal in three steps: (1) by introducing a new systematic approach to precisely measure the effectiveness and accuracy of IR techniques and their resilience to evasion and forgery; (2) by designing and implementing new automated techniques to cope with advanced threats and the analysis of IoT devices; and (3) by proposing a novel forensics-by-design development methodology and a set of guidelines for the design of future systems and software.
To provide the right context for these new techniques and show the impact of the project in different fields and scenarios, BITCRUMBS plans to address its objectives using real case studies borrowed from two different
domains: traditional computer software, and embedded systems.
"
Max ERC Funding
1 991 504 €
Duration
Start date: 2018-04-01, End date: 2023-03-31
Project acronym Brain3.0
Project Invasive cognitive brain computer interfaces to enhance and restore attention: proof of concept and underlying cortical mechanisms.
Researcher (PI) Suliann Benhamed-Daghighi-Ardekani
Host Institution (HI) CENTRE NATIONAL DE LA RECHERCHE SCIENTIFIQUE CNRS
Call Details Consolidator Grant (CoG), LS5, ERC-2015-CoG
Summary The present project focuses on a barely scratched aspect of invasive cognitive brain-computer interfaces (cBCIs), i.e. closed-loop invasive cBCIs to augment and restore attentional functions. Its aim is to achieve an efficient enhanced cognition protocol both in the healthy brain and in the damaged brain and to study the local and global plasticity mechanisms underlying these effects. The project relies on the unique methodological combination of multi-electrode multisite intracortical recordings and functional magnetic resonance imaging, in association with reversible cortical lesions and intracortical microstimulations, in an experimental model allowing to approach the attentional human function and its dysfunctions to the best. Our goal is to achieve:
1. A closed-loop invasive cBCI for augmented attention, by providing the subjects with a feedback on their cortical spatial and feature attention information content as estimated from real-time population decoding procedures, using reinforcement learning, to have them improve this cognitive content, and as a result, improve their overt attentional behavioural performance.
2. A closed-loop invasive cBCI for restored attention, by inducing a controlled attentional loss thanks to reversible cortical lesions targeted to key functionally-identified cortical regions and using the closed-loop cBCI to restore attentional performance.
3. An invasive cBCI for stimulated attentional functions. We will identify the neuronal population changes leading to a voluntary enhancement of attentional functions as quantified in aim 1 and inject these changes, using complex patterns of microstimulations, mimicking spikes, to enhance or restore attention, in the absence of any active control by the subjects.
This project will contribute to the development of novel therapeutical applications to restore acute or chronic severe attentional deficits and to provide an in depth understanding of the neural bases underlying closed-loop cBCIs.
Summary
The present project focuses on a barely scratched aspect of invasive cognitive brain-computer interfaces (cBCIs), i.e. closed-loop invasive cBCIs to augment and restore attentional functions. Its aim is to achieve an efficient enhanced cognition protocol both in the healthy brain and in the damaged brain and to study the local and global plasticity mechanisms underlying these effects. The project relies on the unique methodological combination of multi-electrode multisite intracortical recordings and functional magnetic resonance imaging, in association with reversible cortical lesions and intracortical microstimulations, in an experimental model allowing to approach the attentional human function and its dysfunctions to the best. Our goal is to achieve:
1. A closed-loop invasive cBCI for augmented attention, by providing the subjects with a feedback on their cortical spatial and feature attention information content as estimated from real-time population decoding procedures, using reinforcement learning, to have them improve this cognitive content, and as a result, improve their overt attentional behavioural performance.
2. A closed-loop invasive cBCI for restored attention, by inducing a controlled attentional loss thanks to reversible cortical lesions targeted to key functionally-identified cortical regions and using the closed-loop cBCI to restore attentional performance.
3. An invasive cBCI for stimulated attentional functions. We will identify the neuronal population changes leading to a voluntary enhancement of attentional functions as quantified in aim 1 and inject these changes, using complex patterns of microstimulations, mimicking spikes, to enhance or restore attention, in the absence of any active control by the subjects.
This project will contribute to the development of novel therapeutical applications to restore acute or chronic severe attentional deficits and to provide an in depth understanding of the neural bases underlying closed-loop cBCIs.
Max ERC Funding
1 997 748 €
Duration
Start date: 2016-10-01, End date: 2021-09-30
Project acronym BRAINSTRUCT
Project Building up a brain: understanding how neural stem cell fate and regulation controls nervous tissue architecture
Researcher (PI) Jean Livet
Host Institution (HI) SORBONNE UNIVERSITE
Call Details Consolidator Grant (CoG), LS5, ERC-2014-CoG
Summary The brain is an extraordinary complex assembly of neuronal and glial cells that underpins cognitive functions. How adequate numbers of these cells are generated by neural stem cells in embryonic and early postnatal development and how they distribute and interconnect within brain tissue is still debated. In particular, the potentialities of individual neural stem cells, their potential heterogeneity and the mechanisms regulating their function are still poorly characterized in situ; likewise, the clonal architecture of mature brain tissue and its influence on neural circuitry are only partially explored. Deciphering these aspects is essential to link neural circuit development, structure and function, and to understand the aetiology of neurodevelopmental disorders.
We have recently established transgenic strategies to simultaneously track the lineage of multiple individual neural stem cells in the intact developing brain and experimentally perturb their development. We will use these approaches in combination with recent large-volume imaging methods for high-throughput analysis of individual neural and glial clones in the mouse cortex. This will allow us to assay neural progenitor potentialities and equivalence, characterize developmental changes occurring in the neurogenic niche, describe the clonal organization of the mature cortex and study its link with neural connectivity. To decipher intrinsic and extrinsic mechanisms regulating neural progenitor activity and understand how they produce appropriate numbers of cells, we will assay the outcome of functional perturbations targeting key steps of neural development, introduced in precursors or in their local environment. These experiments will reveal how neural stem cell output might be regulated by cell interactions and intercellular signals. This multidisciplinary project will set the basis for quantitative analysis of brain development with single-cell resolution in normal and pathological conditions.
Summary
The brain is an extraordinary complex assembly of neuronal and glial cells that underpins cognitive functions. How adequate numbers of these cells are generated by neural stem cells in embryonic and early postnatal development and how they distribute and interconnect within brain tissue is still debated. In particular, the potentialities of individual neural stem cells, their potential heterogeneity and the mechanisms regulating their function are still poorly characterized in situ; likewise, the clonal architecture of mature brain tissue and its influence on neural circuitry are only partially explored. Deciphering these aspects is essential to link neural circuit development, structure and function, and to understand the aetiology of neurodevelopmental disorders.
We have recently established transgenic strategies to simultaneously track the lineage of multiple individual neural stem cells in the intact developing brain and experimentally perturb their development. We will use these approaches in combination with recent large-volume imaging methods for high-throughput analysis of individual neural and glial clones in the mouse cortex. This will allow us to assay neural progenitor potentialities and equivalence, characterize developmental changes occurring in the neurogenic niche, describe the clonal organization of the mature cortex and study its link with neural connectivity. To decipher intrinsic and extrinsic mechanisms regulating neural progenitor activity and understand how they produce appropriate numbers of cells, we will assay the outcome of functional perturbations targeting key steps of neural development, introduced in precursors or in their local environment. These experiments will reveal how neural stem cell output might be regulated by cell interactions and intercellular signals. This multidisciplinary project will set the basis for quantitative analysis of brain development with single-cell resolution in normal and pathological conditions.
Max ERC Funding
1 929 713 €
Duration
Start date: 2015-07-01, End date: 2020-06-30
Project acronym CANALOHMICS
Project Biophysical networks underlying the robustness of neuronal excitability
Researcher (PI) Jean-Marc Goaillard
Host Institution (HI) INSTITUT NATIONAL DE LA SANTE ET DE LA RECHERCHE MEDICALE
Call Details Consolidator Grant (CoG), LS5, ERC-2013-CoG
Summary The mammalian nervous system is in some respect surprisingly robust to perturbations, as suggested by the virtually complete recovery of brain function after strokes or the pre-clinical asymptomatic phase of Parkinson’s disease. Ultimately though, cognitive and behavioral robustness relies on the ability of single neurons to cope with perturbations, and in particular to maintain a constant and reliable transfer of information.
So far, the main facet of robustness that has been studied at the neuronal level is homeostatic plasticity of electrical activity, which refers to the ability of neurons to stabilize their activity level in response to external perturbations. But neurons are also able to maintain their function when one of the major ion channels underlying their activity is deleted or mutated: the number of ion channel subtypes expressed by most excitable cells by far exceeds the minimal number of components necessary to achieve function, offering great potential for compensation when one of the channel’s function is altered. How ion channels are dynamically co-regulated to maintain the appropriate pattern of activity has yet to be determined.
In the current project, we will develop a systems-level approach to robustness of neuronal activity based on the combination of electrophysiology, microfluidic single-cell qPCR and computational modeling. We propose to i) characterize the electrical phenotype of dopaminergic neurons following different types of perturbations (ion channel KO, chronic pharmacological treatment), ii) measure the quantitatives changes in ion channel transcriptome (40 voltage-dependent ion channels) associated with these perturbations and iii) determine the mathematical relationships between quantitative changes in ion channel expression and electrical phenotype. Although focused on dopaminergic neurons, this project will provide a general framework that could be applied to any type of excitable cell to decipher its code of robustness.
Summary
The mammalian nervous system is in some respect surprisingly robust to perturbations, as suggested by the virtually complete recovery of brain function after strokes or the pre-clinical asymptomatic phase of Parkinson’s disease. Ultimately though, cognitive and behavioral robustness relies on the ability of single neurons to cope with perturbations, and in particular to maintain a constant and reliable transfer of information.
So far, the main facet of robustness that has been studied at the neuronal level is homeostatic plasticity of electrical activity, which refers to the ability of neurons to stabilize their activity level in response to external perturbations. But neurons are also able to maintain their function when one of the major ion channels underlying their activity is deleted or mutated: the number of ion channel subtypes expressed by most excitable cells by far exceeds the minimal number of components necessary to achieve function, offering great potential for compensation when one of the channel’s function is altered. How ion channels are dynamically co-regulated to maintain the appropriate pattern of activity has yet to be determined.
In the current project, we will develop a systems-level approach to robustness of neuronal activity based on the combination of electrophysiology, microfluidic single-cell qPCR and computational modeling. We propose to i) characterize the electrical phenotype of dopaminergic neurons following different types of perturbations (ion channel KO, chronic pharmacological treatment), ii) measure the quantitatives changes in ion channel transcriptome (40 voltage-dependent ion channels) associated with these perturbations and iii) determine the mathematical relationships between quantitative changes in ion channel expression and electrical phenotype. Although focused on dopaminergic neurons, this project will provide a general framework that could be applied to any type of excitable cell to decipher its code of robustness.
Max ERC Funding
1 972 797 €
Duration
Start date: 2014-05-01, End date: 2019-04-30
Project acronym CIRCUS
Project An end-to-end verification architecture for building Certified Implementations of Robust, Cryptographically Secure web applications
Researcher (PI) Karthikeyan Bhargavan
Host Institution (HI) INSTITUT NATIONAL DE RECHERCHE ENINFORMATIQUE ET AUTOMATIQUE
Call Details Consolidator Grant (CoG), PE6, ERC-2015-CoG
Summary The security of modern web applications depends on a variety of critical components including cryptographic libraries, Transport Layer Security (TLS), browser security mechanisms, and single sign-on protocols. Although these components are widely used, their security guarantees remain poorly understood, leading to subtle bugs and frequent attacks.
Rather than fixing one attack at a time, we advocate the use of formal security verification to identify and eliminate entire classes of vulnerabilities in one go. With the aid of my ERC starting grant, I have built a team that has already achieved landmark results in this direction. We built the first TLS implementation with a cryptographic proof of security. We discovered high-profile vulnerabilities such as the recent Triple Handshake and FREAK attacks, both of which triggered critical security updates to all major web browsers and TLS libraries.
So far, our security theorems only apply to carefully-written standalone reference implementations. CIRCUS proposes to take on the next great challenge: verifying the end-to-end security of web applications running in mainstream software. The key idea is to identify the core security components of web browsers and servers and replace them by rigorously verified components that offer the same functionality but with robust security guarantees.
Our goal is ambitious and there are many challenges to overcome, but we believe this is an opportune time for this proposal. In response to the Snowden reports, many cryptographic libraries and protocols are currently being audited and redesigned. Standards bodies and software developers are inviting researchers to help analyse their designs and code. Responding to their call requires a team of researchers who are willing to deal with the messy details of nascent standards and legacy code, and at the same time prove strong security theorems based on precise cryptographic assumptions. We are able, we are willing, and the time is now.
Summary
The security of modern web applications depends on a variety of critical components including cryptographic libraries, Transport Layer Security (TLS), browser security mechanisms, and single sign-on protocols. Although these components are widely used, their security guarantees remain poorly understood, leading to subtle bugs and frequent attacks.
Rather than fixing one attack at a time, we advocate the use of formal security verification to identify and eliminate entire classes of vulnerabilities in one go. With the aid of my ERC starting grant, I have built a team that has already achieved landmark results in this direction. We built the first TLS implementation with a cryptographic proof of security. We discovered high-profile vulnerabilities such as the recent Triple Handshake and FREAK attacks, both of which triggered critical security updates to all major web browsers and TLS libraries.
So far, our security theorems only apply to carefully-written standalone reference implementations. CIRCUS proposes to take on the next great challenge: verifying the end-to-end security of web applications running in mainstream software. The key idea is to identify the core security components of web browsers and servers and replace them by rigorously verified components that offer the same functionality but with robust security guarantees.
Our goal is ambitious and there are many challenges to overcome, but we believe this is an opportune time for this proposal. In response to the Snowden reports, many cryptographic libraries and protocols are currently being audited and redesigned. Standards bodies and software developers are inviting researchers to help analyse their designs and code. Responding to their call requires a team of researchers who are willing to deal with the messy details of nascent standards and legacy code, and at the same time prove strong security theorems based on precise cryptographic assumptions. We are able, we are willing, and the time is now.
Max ERC Funding
1 885 248 €
Duration
Start date: 2016-04-01, End date: 2021-03-31
Project acronym DBA
Project Distributed Biological Algorithms
Researcher (PI) Amos Korman
Host Institution (HI) CENTRE NATIONAL DE LA RECHERCHE SCIENTIFIQUE CNRS
Call Details Consolidator Grant (CoG), PE6, ERC-2014-CoG
Summary This project proposes a new application for computational reasoning. More specifically, the purpose of this interdisciplinary project is to demonstrate the usefulness of an algorithmic perspective in studies of complex biological systems. We focus on the domain of collective behavior, and demonstrate the benefits of using techniques from the field of theoretical distributed computing in order to establish algorithmic insights regarding the behavior of biological ensembles. The project includes three related tasks, for which we have already obtained promising preliminary results. Each task contains a purely theoretical algorithmic component as well as one which integrates theoretical algorithmic studies with experiments. Most experiments are strategically designed by the PI based on computational insights, and are physically conducted by experimental biologists that have been carefully chosen by the PI. In turn, experimental outcomes will be theoretically analyzed via an algorithmic perspective. By this integration, we aim at deciphering how a biological individual (such as an ant) “thinks”, without having direct access to the neurological process within its brain, and how such limited individuals assemble into ensembles that appear to be far greater than the sum of their parts. The ultimate vision behind this project is to enable the formation of a new scientific field, called algorithmic biology, that bases biological studies on theoretical algorithmic insights.
Summary
This project proposes a new application for computational reasoning. More specifically, the purpose of this interdisciplinary project is to demonstrate the usefulness of an algorithmic perspective in studies of complex biological systems. We focus on the domain of collective behavior, and demonstrate the benefits of using techniques from the field of theoretical distributed computing in order to establish algorithmic insights regarding the behavior of biological ensembles. The project includes three related tasks, for which we have already obtained promising preliminary results. Each task contains a purely theoretical algorithmic component as well as one which integrates theoretical algorithmic studies with experiments. Most experiments are strategically designed by the PI based on computational insights, and are physically conducted by experimental biologists that have been carefully chosen by the PI. In turn, experimental outcomes will be theoretically analyzed via an algorithmic perspective. By this integration, we aim at deciphering how a biological individual (such as an ant) “thinks”, without having direct access to the neurological process within its brain, and how such limited individuals assemble into ensembles that appear to be far greater than the sum of their parts. The ultimate vision behind this project is to enable the formation of a new scientific field, called algorithmic biology, that bases biological studies on theoretical algorithmic insights.
Max ERC Funding
1 894 947 €
Duration
Start date: 2015-05-01, End date: 2021-04-30
