Project acronym Actanthrope
Project Computational Foundations of Anthropomorphic Action
Researcher (PI) Jean Paul Laumond
Host Institution (HI) CENTRE NATIONAL DE LA RECHERCHE SCIENTIFIQUE CNRS
Call Details Advanced Grant (AdG), PE7, ERC-2013-ADG
Summary Actanthrope intends to promote a neuro-robotics perspective to explore original models of anthropomorphic action. The project targets contributions to humanoid robot autonomy (for rescue and service robotics), to advanced human body simulation (for applications in ergonomics), and to a new theory of embodied intelligence (by promoting a motion-based semiotics of the human action).
Actions take place in the physical space while they originate in the –robot or human– sensory-motor space. Geometry is the core abstraction that makes the link between these spaces. Considering that the structure of actions inherits from that of the body, the underlying intuition is that actions can be segmented within discrete sub-spaces lying in the entire continuous posture space. Such sub-spaces are viewed as symbols bridging deliberative reasoning and reactive control. Actanthrope argues that geometric approaches to motion segmentation and generation as promising and innovative routes to explore embodied intelligence:
- Motion segmentation: what are the sub-manifolds that define the structure of a given action?
- Motion generation: among all the solution paths within a given sub-manifold, what is the underlying law that makes the selection?
In Robotics these questions are related to the competition between abstract symbol manipulation and physical signal processing. In Computational Neuroscience the questions refer to the quest of motion invariants. The ambition of the project is to promote a dual perspective: exploring the computational foundations of human action to make better robots, while simultaneously doing better robotics to better understand human action.
A unique “Anthropomorphic Action Factory” supports the methodology. It aims at attracting to a single lab, researchers with complementary know-how and solid mathematical background. All of them will benefit from unique equipments, while being stimulated by four challenges dealing with locomotion and manipulation actions.
Summary
Actanthrope intends to promote a neuro-robotics perspective to explore original models of anthropomorphic action. The project targets contributions to humanoid robot autonomy (for rescue and service robotics), to advanced human body simulation (for applications in ergonomics), and to a new theory of embodied intelligence (by promoting a motion-based semiotics of the human action).
Actions take place in the physical space while they originate in the –robot or human– sensory-motor space. Geometry is the core abstraction that makes the link between these spaces. Considering that the structure of actions inherits from that of the body, the underlying intuition is that actions can be segmented within discrete sub-spaces lying in the entire continuous posture space. Such sub-spaces are viewed as symbols bridging deliberative reasoning and reactive control. Actanthrope argues that geometric approaches to motion segmentation and generation as promising and innovative routes to explore embodied intelligence:
- Motion segmentation: what are the sub-manifolds that define the structure of a given action?
- Motion generation: among all the solution paths within a given sub-manifold, what is the underlying law that makes the selection?
In Robotics these questions are related to the competition between abstract symbol manipulation and physical signal processing. In Computational Neuroscience the questions refer to the quest of motion invariants. The ambition of the project is to promote a dual perspective: exploring the computational foundations of human action to make better robots, while simultaneously doing better robotics to better understand human action.
A unique “Anthropomorphic Action Factory” supports the methodology. It aims at attracting to a single lab, researchers with complementary know-how and solid mathematical background. All of them will benefit from unique equipments, while being stimulated by four challenges dealing with locomotion and manipulation actions.
Max ERC Funding
2 500 000 €
Duration
Start date: 2014-01-01, End date: 2018-12-31
Project acronym AsthmaVir
Project The roles of innate lymphoid cells and rhinovirus in asthma exacerbations
Researcher (PI) Hergen Spits
Host Institution (HI) ACADEMISCH MEDISCH CENTRUM BIJ DE UNIVERSITEIT VAN AMSTERDAM
Call Details Advanced Grant (AdG), LS6, ERC-2013-ADG
Summary Asthma exacerbations represent a high unmet medical need in particular in young children. Human Rhinoviruses (HRV) are the main triggers of these exacerbations. Till now Th2 cells were considered the main initiating effector cell type in asthma in general and asthma exacerbations in particular. However, exaggerated Th2 cell activities alone do not explain all aspects of asthma and exacerbations. Building on our recent discovery of type 2 human innate lymphoid cells (ILC2) capable of promptly producing high amounts of IL-5, IL-9 and IL-13 upon activation and on mouse data pointing to an essential role of these cells in asthma and asthma exacerbations, ILC2 may be the main initiating cells in asthma exacerbations in humans. Thus we hypothesize that HRV directly or indirectly stimulate ILC2s to produce cytokines driving the effector functions leading to the end organ effects that characterize this debilitating disease. Targeting ILC2 and HRV in parallel will provide a highly attractive therapeutic option for the treatment of asthma exacerbations. In depth study of the mechanisms of ILC2 differentiation and function will lead to the design effective drugs targeting these cells; thus the first two objectives of this project are: 1) To unravel the lineage relationship of ILC populations and to decipher the signal transduction pathways that regulate the function of ILCs, 2) to test the functions of lung-residing human ILCs and the effects of compounds that affect these functions in mice which harbour a human immune system and human lung epithelium under homeostatic conditions and after infections with respiratory viruses. The third objective of this project is developing reagents that target HRV; to this end we will develop broadly reacting highly neutralizing human monoclonal antibodies that can be used for prophylaxis and therapy of patients at high risk for developing severe asthma exacerbations.
Summary
Asthma exacerbations represent a high unmet medical need in particular in young children. Human Rhinoviruses (HRV) are the main triggers of these exacerbations. Till now Th2 cells were considered the main initiating effector cell type in asthma in general and asthma exacerbations in particular. However, exaggerated Th2 cell activities alone do not explain all aspects of asthma and exacerbations. Building on our recent discovery of type 2 human innate lymphoid cells (ILC2) capable of promptly producing high amounts of IL-5, IL-9 and IL-13 upon activation and on mouse data pointing to an essential role of these cells in asthma and asthma exacerbations, ILC2 may be the main initiating cells in asthma exacerbations in humans. Thus we hypothesize that HRV directly or indirectly stimulate ILC2s to produce cytokines driving the effector functions leading to the end organ effects that characterize this debilitating disease. Targeting ILC2 and HRV in parallel will provide a highly attractive therapeutic option for the treatment of asthma exacerbations. In depth study of the mechanisms of ILC2 differentiation and function will lead to the design effective drugs targeting these cells; thus the first two objectives of this project are: 1) To unravel the lineage relationship of ILC populations and to decipher the signal transduction pathways that regulate the function of ILCs, 2) to test the functions of lung-residing human ILCs and the effects of compounds that affect these functions in mice which harbour a human immune system and human lung epithelium under homeostatic conditions and after infections with respiratory viruses. The third objective of this project is developing reagents that target HRV; to this end we will develop broadly reacting highly neutralizing human monoclonal antibodies that can be used for prophylaxis and therapy of patients at high risk for developing severe asthma exacerbations.
Max ERC Funding
2 499 593 €
Duration
Start date: 2014-03-01, End date: 2019-02-28
Project acronym BacRafts
Project Architecture of bacterial lipid rafts; inhibition of virulence and antibiotic resistance using raft-disassembling small molecules
Researcher (PI) Daniel López Serrano
Host Institution (HI) AGENCIA ESTATAL CONSEJO SUPERIOR DEINVESTIGACIONES CIENTIFICAS
Call Details Starting Grant (StG), LS6, ERC-2013-StG
Summary Membranes of eukaryotic cells organize signal transduction proteins into microdomains or lipid rafts whose integrity is essential for numerous cellular processes. Lipid rafts has been considered a fundamental step to define the cellular complexity of eukaryotes, assuming that bacteria do not require such a sophisticated organization of their signaling networks. However, I have discovered that bacteria organize many signaling pathways in membrane microdomains similar to the eukaryotic lipid rafts. Perturbation of bacterial lipid rafts leads to a potent and simultaneous impairment of all raft-harbored signaling pathways. Consequently, the disassembly of lipid rafts in pathogens like Staphylococcus aureus generates a simultaneous inhibition of numerous infection-related processes that can be further explored to control bacterial infections. This unexpected sophistication in membrane organization is unprecedented in bacteria and hence, this proposal will explore the molecular basis of the assembly of bacterial lipid rafts and their role in the infection-related processes. These questions will be addressed in three main goals: First, I will elucidate the molecular components and the mechanism of assembly of bacterial lipid rafts using S. aureus as model organism. Second, I will dissect the molecular basis that links the functionality of the infection-related processes to the integrity of bacterial lipid rafts. Third, my collection of anti-raft small molecules that are able to disrupt lipid rafts will be tested as antimicrobial agents to prevent hospital-acquired infections, abrogate pre-existing infections and develop bacteria-free materials that can be used in clinical settings. I will use a number of molecular approaches in combination with cutting-edge techniques in flow cytometry, cell-imaging and transcriptomics to clarify the architecture and functionality of lipid rafts and demonstrate the feasibility of targeting lipid a new strategy for anti-microbial therapy.
Summary
Membranes of eukaryotic cells organize signal transduction proteins into microdomains or lipid rafts whose integrity is essential for numerous cellular processes. Lipid rafts has been considered a fundamental step to define the cellular complexity of eukaryotes, assuming that bacteria do not require such a sophisticated organization of their signaling networks. However, I have discovered that bacteria organize many signaling pathways in membrane microdomains similar to the eukaryotic lipid rafts. Perturbation of bacterial lipid rafts leads to a potent and simultaneous impairment of all raft-harbored signaling pathways. Consequently, the disassembly of lipid rafts in pathogens like Staphylococcus aureus generates a simultaneous inhibition of numerous infection-related processes that can be further explored to control bacterial infections. This unexpected sophistication in membrane organization is unprecedented in bacteria and hence, this proposal will explore the molecular basis of the assembly of bacterial lipid rafts and their role in the infection-related processes. These questions will be addressed in three main goals: First, I will elucidate the molecular components and the mechanism of assembly of bacterial lipid rafts using S. aureus as model organism. Second, I will dissect the molecular basis that links the functionality of the infection-related processes to the integrity of bacterial lipid rafts. Third, my collection of anti-raft small molecules that are able to disrupt lipid rafts will be tested as antimicrobial agents to prevent hospital-acquired infections, abrogate pre-existing infections and develop bacteria-free materials that can be used in clinical settings. I will use a number of molecular approaches in combination with cutting-edge techniques in flow cytometry, cell-imaging and transcriptomics to clarify the architecture and functionality of lipid rafts and demonstrate the feasibility of targeting lipid a new strategy for anti-microbial therapy.
Max ERC Funding
1 493 126 €
Duration
Start date: 2014-03-01, End date: 2019-02-28
Project acronym BACTERIAL RESPONSE
Project New Concepts in Bacterial Response to their Surroundings
Researcher (PI) Sigal Ben-Yehuda
Host Institution (HI) THE HEBREW UNIVERSITY OF JERUSALEM
Call Details Advanced Grant (AdG), LS6, ERC-2013-ADG
Summary Bacteria in nature exhibit remarkable capacity to sense their surroundings and rapidly adapt to diverse conditions by gaining new beneficial traits. This extraordinary feature facilitates their survival when facing extreme environments. Utilizing Bacillus subtilis as our primary model organism, we propose to study two facets of this vital bacterial attribute: communication via extracellular nanotubes, and persistence as resilient spores while maintaining the potential to revive. Exploring these fascinating aspects of bacterial physiology is likely to change our view as to how bacteria sense, respond, endure and communicate with their extracellular environment.
We have recently discovered a previously uncharacterized mode of bacterial communication, mediated by tubular extensions (nanotubes) that bridge neighboring cells, providing a route for exchange of intracellular molecules. Nanotube-mediated molecular sharing may represent a key form of bacterial communication in nature, allowing for the emergence of new phenotypes and increasing survival in fluctuating environments. Here we propose to develop strategies for observing nanotube formation and molecular exchange in living bacterial cells, and to characterize the molecular composition of nanotubes. We will explore the premise that nanotubes serve as a strategy to expand the cell surface, and will determine whether nanotubes provide a conduit for phage infection and spreading. Furthermore, the formation and functionality of interspecies nanotubes will be explored. An additional mode employed by bacteria to achieve extreme robustness is the ability to reside as long lasting spores. Previously held views considered the spore to be dormant and metabolically inert. However, we have recently shown that at least one week following spore formation, during an adaptive period, the spore senses and responds to environmental cues and undergoes corresponding molecular changes, influencing subsequent emergence from quiescence.
Summary
Bacteria in nature exhibit remarkable capacity to sense their surroundings and rapidly adapt to diverse conditions by gaining new beneficial traits. This extraordinary feature facilitates their survival when facing extreme environments. Utilizing Bacillus subtilis as our primary model organism, we propose to study two facets of this vital bacterial attribute: communication via extracellular nanotubes, and persistence as resilient spores while maintaining the potential to revive. Exploring these fascinating aspects of bacterial physiology is likely to change our view as to how bacteria sense, respond, endure and communicate with their extracellular environment.
We have recently discovered a previously uncharacterized mode of bacterial communication, mediated by tubular extensions (nanotubes) that bridge neighboring cells, providing a route for exchange of intracellular molecules. Nanotube-mediated molecular sharing may represent a key form of bacterial communication in nature, allowing for the emergence of new phenotypes and increasing survival in fluctuating environments. Here we propose to develop strategies for observing nanotube formation and molecular exchange in living bacterial cells, and to characterize the molecular composition of nanotubes. We will explore the premise that nanotubes serve as a strategy to expand the cell surface, and will determine whether nanotubes provide a conduit for phage infection and spreading. Furthermore, the formation and functionality of interspecies nanotubes will be explored. An additional mode employed by bacteria to achieve extreme robustness is the ability to reside as long lasting spores. Previously held views considered the spore to be dormant and metabolically inert. However, we have recently shown that at least one week following spore formation, during an adaptive period, the spore senses and responds to environmental cues and undergoes corresponding molecular changes, influencing subsequent emergence from quiescence.
Max ERC Funding
1 497 800 €
Duration
Start date: 2014-04-01, End date: 2019-03-31
Project acronym BETTERSENSE
Project Nanodevice Engineering for a Better Chemical Gas Sensing Technology
Researcher (PI) Juan Daniel Prades Garcia
Host Institution (HI) UNIVERSITAT DE BARCELONA
Call Details Starting Grant (StG), PE7, ERC-2013-StG
Summary BetterSense aims to solve the two main problems in current gas sensor technologies: the high power consumption and the poor selectivity. For the former, we propose a radically new approach: to integrate the sensing components and the energy sources intimately, at the nanoscale, in order to achieve a new kind of sensor concept featuring zero power consumption. For the latter, we will mimic the biological receptors designing a kit of gas-specific molecular organic functionalizations to reach ultra-high gas selectivity figures, comparable to those of biological processes. Both cutting-edge concepts will be developed in parallel an integrated together to render a totally new gas sensing technology that surpasses the state-of-the-art.
As a matter of fact, the project will enable, for the first time, the integration of gas detectors in energetically autonomous sensors networks. Additionally, BetterSense will provide an integral solution to the gas sensing challenge by producing a full set of gas-specific sensors over the same platform to ease their integration in multi-analyte systems. Moreover, the project approach will certainly open opportunities in adjacent fields in which power consumption, specificity and nano/micro integration are a concern, such as liquid chemical and biological sensing.
In spite of the promising evidences that demonstrate the feasibility of this proposal, there are still many scientific and technological issues to solve, most of them in the edge of what is known and what is possible today in nano-fabrication and nano/micro integration. For this reason, BetterSense also aims to contribute to the global challenge of making nanodevices compatible with scalable, cost-effective, microelectronic technologies.
For all this, addressing this challenging proposal in full requires a funding scheme compatible with a high-risk/high-gain vision to finance the full dedication of a highly motivated research team with multidisciplinary skill
Summary
BetterSense aims to solve the two main problems in current gas sensor technologies: the high power consumption and the poor selectivity. For the former, we propose a radically new approach: to integrate the sensing components and the energy sources intimately, at the nanoscale, in order to achieve a new kind of sensor concept featuring zero power consumption. For the latter, we will mimic the biological receptors designing a kit of gas-specific molecular organic functionalizations to reach ultra-high gas selectivity figures, comparable to those of biological processes. Both cutting-edge concepts will be developed in parallel an integrated together to render a totally new gas sensing technology that surpasses the state-of-the-art.
As a matter of fact, the project will enable, for the first time, the integration of gas detectors in energetically autonomous sensors networks. Additionally, BetterSense will provide an integral solution to the gas sensing challenge by producing a full set of gas-specific sensors over the same platform to ease their integration in multi-analyte systems. Moreover, the project approach will certainly open opportunities in adjacent fields in which power consumption, specificity and nano/micro integration are a concern, such as liquid chemical and biological sensing.
In spite of the promising evidences that demonstrate the feasibility of this proposal, there are still many scientific and technological issues to solve, most of them in the edge of what is known and what is possible today in nano-fabrication and nano/micro integration. For this reason, BetterSense also aims to contribute to the global challenge of making nanodevices compatible with scalable, cost-effective, microelectronic technologies.
For all this, addressing this challenging proposal in full requires a funding scheme compatible with a high-risk/high-gain vision to finance the full dedication of a highly motivated research team with multidisciplinary skill
Max ERC Funding
1 498 452 €
Duration
Start date: 2014-02-01, End date: 2019-01-31
Project acronym CON-HUMO
Project Control based on Human Models
Researcher (PI) Sandra Hirche
Host Institution (HI) TECHNISCHE UNIVERSITAET MUENCHEN
Call Details Starting Grant (StG), PE7, ERC-2013-StG
Summary "CON-HUMO focuses on novel concepts for automatic control based on data-driven human models and machine learning. This enables innovative control applications that are difficult if not impossible to realize using traditional control and identification methods, in particular in the challenging area of smart human-machine interaction. In order to achieve intuitive and efficient goal-oriented interaction, anticipation is key. For control selection based on prediction a dynamic model of the human interaction behavior is required, which, however, is difficult to obtain from first principles. In order to cope with the high complexity of human behavior with unknown inputs and only sparsely available training data we propose to use machine-learning techniques for statistical modeling of the dynamics. In this new field of human interaction modeling – data-driven and machine-learned – control methods with guaranteed properties do not exist. CON-HUMO addresses this niche.
Key methodological innovation and breakthrough is the merger of probabilistic learning with model-based control concepts through model confidence and prediction uncertainty. For the sake of concreteness and evaluation the focus is on one of the most challenging problem classes, namely physical human-machine interaction: Because of the physical contact between the human and the machine not only information, but also energy is exchanged posing fundamental challenges for real-time human-adaptive and safe decision making/control and requiring provable stability and performance guarantees. The developed methods are a direct enabler for societally important applications such as machine-based physical rehabilitation, mobility and manipulation aids for elderly, and collaborative human-machine production systems. With its fundamental results CON-HUMO lays the ground for the systematic control design for smart human-machine/infrastructure interaction."
Summary
"CON-HUMO focuses on novel concepts for automatic control based on data-driven human models and machine learning. This enables innovative control applications that are difficult if not impossible to realize using traditional control and identification methods, in particular in the challenging area of smart human-machine interaction. In order to achieve intuitive and efficient goal-oriented interaction, anticipation is key. For control selection based on prediction a dynamic model of the human interaction behavior is required, which, however, is difficult to obtain from first principles. In order to cope with the high complexity of human behavior with unknown inputs and only sparsely available training data we propose to use machine-learning techniques for statistical modeling of the dynamics. In this new field of human interaction modeling – data-driven and machine-learned – control methods with guaranteed properties do not exist. CON-HUMO addresses this niche.
Key methodological innovation and breakthrough is the merger of probabilistic learning with model-based control concepts through model confidence and prediction uncertainty. For the sake of concreteness and evaluation the focus is on one of the most challenging problem classes, namely physical human-machine interaction: Because of the physical contact between the human and the machine not only information, but also energy is exchanged posing fundamental challenges for real-time human-adaptive and safe decision making/control and requiring provable stability and performance guarantees. The developed methods are a direct enabler for societally important applications such as machine-based physical rehabilitation, mobility and manipulation aids for elderly, and collaborative human-machine production systems. With its fundamental results CON-HUMO lays the ground for the systematic control design for smart human-machine/infrastructure interaction."
Max ERC Funding
1 494 640 €
Duration
Start date: 2014-02-01, End date: 2019-01-31
Project acronym COXINEL
Project COherent Xray source INferred from Electrons accelerated by Laser
Researcher (PI) Marie-Emmanuelle Couprie
Host Institution (HI) SYNCHROTRON SOLEIL SOCIETE CIVILE
Call Details Advanced Grant (AdG), PE7, ERC-2013-ADG
Summary "Since the first laser discovery in 1960 and the first Free Electron Laser (FEL) in 1977, Linac based fourth generation light sources provide intense coherent fs pulses in the X-ray range for multidisciplinary investigations of matter. In parallel, Laser Wakefield Accelerator (LWFA) by using intense laser beams interacting with cm long plasmas can now provide high quality electron beams of very short bunches (few fs) with high peak currents (few kA). The so-called 5th generation light source aims at reducing the size and the cost of these FELs by replacing the linac by LWFA. Indeed, spontaneous emission from LWFA has already been observed, but the presently still rather large energy spread (1 %) and divergence (mrad) prevent from the FEL amplification. In 2012, two novel schemes in the transport proposed in the community, including my SOLEIL group, predict a laser gain increase by 3 or 4 orders of magnitudes. COXINEL aims at demonstrating the first lasing of an LWFA FEL and its detailed study in close interaction with future potential users. The key concept relies on an innovative electron beam longitudinal and transverse manipulation in the transport towards an undulator: a ""demixing"" chicane sorts the electrons in energy and reduces the spread from 1 % to a slice one of 0.1%, and the transverse density is maintained constant all along the undulator (supermatching). Simulations based on the performance of the 60 TW laser of the Laboratoire d’Optique Appliquée and existing undulators from SOLEIL suggest that the conditions for lasing are fulfilled. The SOLEIL environment also possesses the engineering fabrication capability for the actual realization of these theoretical ideas, with original undulators and innovative variable permanent compact magnets for the transport. COXINEL will enable to master in Europe advanced schemes scalable to shorter wavelengths and pulses, paving the way towards FEL light sources on laboratory size, for fs time resolved experiments."
Summary
"Since the first laser discovery in 1960 and the first Free Electron Laser (FEL) in 1977, Linac based fourth generation light sources provide intense coherent fs pulses in the X-ray range for multidisciplinary investigations of matter. In parallel, Laser Wakefield Accelerator (LWFA) by using intense laser beams interacting with cm long plasmas can now provide high quality electron beams of very short bunches (few fs) with high peak currents (few kA). The so-called 5th generation light source aims at reducing the size and the cost of these FELs by replacing the linac by LWFA. Indeed, spontaneous emission from LWFA has already been observed, but the presently still rather large energy spread (1 %) and divergence (mrad) prevent from the FEL amplification. In 2012, two novel schemes in the transport proposed in the community, including my SOLEIL group, predict a laser gain increase by 3 or 4 orders of magnitudes. COXINEL aims at demonstrating the first lasing of an LWFA FEL and its detailed study in close interaction with future potential users. The key concept relies on an innovative electron beam longitudinal and transverse manipulation in the transport towards an undulator: a ""demixing"" chicane sorts the electrons in energy and reduces the spread from 1 % to a slice one of 0.1%, and the transverse density is maintained constant all along the undulator (supermatching). Simulations based on the performance of the 60 TW laser of the Laboratoire d’Optique Appliquée and existing undulators from SOLEIL suggest that the conditions for lasing are fulfilled. The SOLEIL environment also possesses the engineering fabrication capability for the actual realization of these theoretical ideas, with original undulators and innovative variable permanent compact magnets for the transport. COXINEL will enable to master in Europe advanced schemes scalable to shorter wavelengths and pulses, paving the way towards FEL light sources on laboratory size, for fs time resolved experiments."
Max ERC Funding
2 500 000 €
Duration
Start date: 2014-01-01, End date: 2018-12-31
Project acronym DANCER
Project DAtacommunications based on NanophotoniC Resonators
Researcher (PI) John William Whelan-Curtin
Host Institution (HI) CORK INSTITUTE OF TECHNOLOGY
Call Details Starting Grant (StG), PE7, ERC-2013-StG
Summary A key challenge for the 21st century is, therefore to provide billions of people with the means to access, move and manipulate, what has become, huge volumes of information. The environmental and economic implications becoming serious, making energy efficient data communications key to the operation of today’s society.
In this project, the Principal Investigator will develop a new framework for optical interconnects and provide a common platform that spans Fibre-to-the-home to chip-to-chip links, even as far as global on-chip interconnects. The project is based on the efficient coupling of the Photonic Crystal resonators with the outside world. These provide the ultimate confinement of light in both space and time allowing orders of magnitude improvements in performance relative to the state of the art, yet in a simpler simple system- the innovator’s dream. New versions of the key components of optical links- light sources, modulators and photo-detectors- will be realised in this new framework providing a new paradigm for energy efficient communication.
Summary
A key challenge for the 21st century is, therefore to provide billions of people with the means to access, move and manipulate, what has become, huge volumes of information. The environmental and economic implications becoming serious, making energy efficient data communications key to the operation of today’s society.
In this project, the Principal Investigator will develop a new framework for optical interconnects and provide a common platform that spans Fibre-to-the-home to chip-to-chip links, even as far as global on-chip interconnects. The project is based on the efficient coupling of the Photonic Crystal resonators with the outside world. These provide the ultimate confinement of light in both space and time allowing orders of magnitude improvements in performance relative to the state of the art, yet in a simpler simple system- the innovator’s dream. New versions of the key components of optical links- light sources, modulators and photo-detectors- will be realised in this new framework providing a new paradigm for energy efficient communication.
Max ERC Funding
1 495 450 €
Duration
Start date: 2013-12-01, End date: 2019-05-31
Project acronym Danger ATP
Project Regulation of inflammatory response by extracellular ATP and P2X7 receptor signalling: through and beyond the inflammasome
Researcher (PI) Pablo Pelegrin Vivancos
Host Institution (HI) FUNDACION PARA LA FORMACION E INVESTIGACION SANITARIAS DE LA REGION DE MURCIA
Call Details Consolidator Grant (CoG), LS6, ERC-2013-CoG
Summary Inflammatory diseases affect over 80 million people worldwide and accompany many diseases of industrialized countries, being the majority of them infection-free conditions. There are few efficient anti-inflammatory drugs to treat chronic inflammation and thus, there is an urgent need to validate novel targets. We now know that innate immunity is the main coordinator and driver of inflammation. Recently, we and others have shown that the activation of purinergic P2X7 receptors (P2X7R) in immune cells is a novel and increasingly validated pathway to initiate inflammation through the activation of the NLRP3 inflammasome and the release of IL-1β and IL-18 cytokines. However, how NLRP3 sense P2X7R activation is not fully understood. Furthermore, extracellular ATP, the physiological P2X7R agonist, is a crucial danger signal released by injured cells, and one of the most important mediators of infection-free inflammation. We have also identified novel signalling roles for P2X7R independent on the NLRP3 inflammasome, including the release of proteases or inflammatory lipids. Therefore, P2X7R has generated increasing interest as a therapeutic target in inflammatory diseases, being drug like P2X7R antagonist in clinical trials to treat inflammatory diseases. However, it is often questioned the functionality of P2X7R in vivo, where it is thought that extracellular ATP levels are below the threshold to activate P2X7R. The overall significance of this proposal relays to elucidate how extracellular ATP controls host-defence in vivo, ultimately depicting P2X7R signalling through and beyond inflammasome activation. We foresee that our results will generate a leading innovative knowledge about in vivo extracellular ATP signalling during the host response to infection and sterile danger.
Summary
Inflammatory diseases affect over 80 million people worldwide and accompany many diseases of industrialized countries, being the majority of them infection-free conditions. There are few efficient anti-inflammatory drugs to treat chronic inflammation and thus, there is an urgent need to validate novel targets. We now know that innate immunity is the main coordinator and driver of inflammation. Recently, we and others have shown that the activation of purinergic P2X7 receptors (P2X7R) in immune cells is a novel and increasingly validated pathway to initiate inflammation through the activation of the NLRP3 inflammasome and the release of IL-1β and IL-18 cytokines. However, how NLRP3 sense P2X7R activation is not fully understood. Furthermore, extracellular ATP, the physiological P2X7R agonist, is a crucial danger signal released by injured cells, and one of the most important mediators of infection-free inflammation. We have also identified novel signalling roles for P2X7R independent on the NLRP3 inflammasome, including the release of proteases or inflammatory lipids. Therefore, P2X7R has generated increasing interest as a therapeutic target in inflammatory diseases, being drug like P2X7R antagonist in clinical trials to treat inflammatory diseases. However, it is often questioned the functionality of P2X7R in vivo, where it is thought that extracellular ATP levels are below the threshold to activate P2X7R. The overall significance of this proposal relays to elucidate how extracellular ATP controls host-defence in vivo, ultimately depicting P2X7R signalling through and beyond inflammasome activation. We foresee that our results will generate a leading innovative knowledge about in vivo extracellular ATP signalling during the host response to infection and sterile danger.
Max ERC Funding
1 794 948 €
Duration
Start date: 2014-09-01, End date: 2019-08-31
Project acronym DCBIOX
Project Phagosome functions and antigen cross presentation in primary dendritic cells
Researcher (PI) Sebastian Amigorena
Host Institution (HI) INSTITUT CURIE
Call Details Advanced Grant (AdG), LS6, ERC-2013-ADG
Summary T cell cross priming (the initiation of CD8+ T cell responses to antigen that are not expressed by dendritic cells, DCs) requires the phagocytosis of antigens by DCs and their presentation on MHC class I molecules, a process referred to as “cross presentation”. Here, we propose a series of integrated approaches to address the most fundamental mechanisms of cross presentation and explore the use of this process for translational purposes in human cancer.
This proposal will pursue three main objectives:
1) To analyze the mechanisms of control of antigen cross presentation and phagocytic functions in DCs. We will use genome wide screens and conditional KO mice, associated to quantitative assays for phagosomal functions and cross presentation, to investigate the molecular mechanisms of cross presentation in vitro and in vivo.
2) To study the epigenetic programing of cross presentation during the ontogeny of mouse DC subpopulations. We will define a “cross presentation gene signature” that will be validated by systematic gene silencing in vitro and we will analyze the epigenetic basis of control of cross presentation-related genes developing DCs.
3) To investigate the regulation of cross presentation in human primary DCs and to develop translational approaches in cancer. We will study cross presentation and phagosome functions in primary human DC subpopulations and its regulation by innate receptors for the development of original immunomodulation and vaccination strategies. We will explore the use of DCs cross presentation abilities in solid tumor infiltrating DCs and their use for prognosis in cancer.
The results of this project will unravel fundamental mechanisms of phagocytosis and its control by innate signals in mice and humans. The proposal also aims at defining new possible strategies for cancer treatment and prognosis.
Summary
T cell cross priming (the initiation of CD8+ T cell responses to antigen that are not expressed by dendritic cells, DCs) requires the phagocytosis of antigens by DCs and their presentation on MHC class I molecules, a process referred to as “cross presentation”. Here, we propose a series of integrated approaches to address the most fundamental mechanisms of cross presentation and explore the use of this process for translational purposes in human cancer.
This proposal will pursue three main objectives:
1) To analyze the mechanisms of control of antigen cross presentation and phagocytic functions in DCs. We will use genome wide screens and conditional KO mice, associated to quantitative assays for phagosomal functions and cross presentation, to investigate the molecular mechanisms of cross presentation in vitro and in vivo.
2) To study the epigenetic programing of cross presentation during the ontogeny of mouse DC subpopulations. We will define a “cross presentation gene signature” that will be validated by systematic gene silencing in vitro and we will analyze the epigenetic basis of control of cross presentation-related genes developing DCs.
3) To investigate the regulation of cross presentation in human primary DCs and to develop translational approaches in cancer. We will study cross presentation and phagosome functions in primary human DC subpopulations and its regulation by innate receptors for the development of original immunomodulation and vaccination strategies. We will explore the use of DCs cross presentation abilities in solid tumor infiltrating DCs and their use for prognosis in cancer.
The results of this project will unravel fundamental mechanisms of phagocytosis and its control by innate signals in mice and humans. The proposal also aims at defining new possible strategies for cancer treatment and prognosis.
Max ERC Funding
2 500 000 €
Duration
Start date: 2014-09-01, End date: 2019-08-31
Project acronym DECRYPT
Project Decrypting signals in the crypt
Researcher (PI) Philippe, Joseph Sansonetti
Host Institution (HI) INSTITUT PASTEUR
Call Details Advanced Grant (AdG), LS6, ERC-2013-ADG
Summary Pathogens and symbionts: War and Peace at mucosal surface in intestinal crypts.
In the proposed program called DECRYPT, I wish to strengthen novel orientations of our laboratory aimed at decrypting the dialogue between the microbiota and the host, while keeping a balance with the study of pathogens, both being analyzed at their interface with the gut mucosa to further our knowledge of the homeostatic and pathogenic mechanisms that respectively characterize a healthy and a diseased gut. The intestinal crypt is a key location to study this dialogue because it contains the stem cells, the differentiation and transit amplifying/proliferative compartments that are essential for epithelial regeneration at homeostasis, and restitution following an aggression. It is also embedded in a niche of immune cells that participate in homeostatic and pathological processes under microbial stimuli. Thus the breaking nature of my project will bear on the demonstration that crypt homeostasis depends on signals “emitted” by the microbiota, thereby stressing the depth of our symbiosis with the microbial world, and on the demonstration that the crypt is also the target of enteric pathogens like Shigella, thus introducing the novel paradigm that pathogenesis is not only matter of inflammatory destruction of infected tissues, but also of altered epithelial restitution. An extension of this paradigm is that loss or subversion of the microbiota-crypt homeostasis may account not only for inflammatory bowel diseases (IBD), but also for colon cancer. This fundamental knowledge will also be the basis for translational research, particularly the search for molecules that boost antimicrobial defenses and comfort homeostasis. In summary, I propose a balanced combination between the “cellular microbiology of pathogens” and the “cellular microbiology of symbionts”.
Summary
Pathogens and symbionts: War and Peace at mucosal surface in intestinal crypts.
In the proposed program called DECRYPT, I wish to strengthen novel orientations of our laboratory aimed at decrypting the dialogue between the microbiota and the host, while keeping a balance with the study of pathogens, both being analyzed at their interface with the gut mucosa to further our knowledge of the homeostatic and pathogenic mechanisms that respectively characterize a healthy and a diseased gut. The intestinal crypt is a key location to study this dialogue because it contains the stem cells, the differentiation and transit amplifying/proliferative compartments that are essential for epithelial regeneration at homeostasis, and restitution following an aggression. It is also embedded in a niche of immune cells that participate in homeostatic and pathological processes under microbial stimuli. Thus the breaking nature of my project will bear on the demonstration that crypt homeostasis depends on signals “emitted” by the microbiota, thereby stressing the depth of our symbiosis with the microbial world, and on the demonstration that the crypt is also the target of enteric pathogens like Shigella, thus introducing the novel paradigm that pathogenesis is not only matter of inflammatory destruction of infected tissues, but also of altered epithelial restitution. An extension of this paradigm is that loss or subversion of the microbiota-crypt homeostasis may account not only for inflammatory bowel diseases (IBD), but also for colon cancer. This fundamental knowledge will also be the basis for translational research, particularly the search for molecules that boost antimicrobial defenses and comfort homeostasis. In summary, I propose a balanced combination between the “cellular microbiology of pathogens” and the “cellular microbiology of symbionts”.
Max ERC Funding
2 499 992 €
Duration
Start date: 2014-04-01, End date: 2019-03-31
Project acronym DIDYMUS
Project MICROMACHINED OPTOMECHANICAL DEVICES: looking at cells, tissues, and organs ... with a gentle touch
Researcher (PI) Davide Iannuzzi
Host Institution (HI) STICHTING VU
Call Details Consolidator Grant (CoG), PE7, ERC-2013-CoG
Summary Every time we grab an object to look at its geometrical details or to feel if it is hard or soft, we are ineluctably confronted with the limits of our senses. Behind its appearances, the object may still hide information that, encrypted in its microscopic features, remains undetected to our macroscopic assessment. In life sciences, those limits are more than just frustrating: they are an obstacle to study and detect life threatening conditions. Many different instruments may overcome those limits, but the vast majority of them rely either on “sight” (optics) or “touch” (mechanics) separately. On the contrary, I believe that it is from the combination of those two “senses” that we have more chances to tackle the future challenges of cell biology, tissue engineering, and medical diagnosis.
Inspired by this tantalizing perspective, and supported by a technology that I have brought from blackboard to market, I have now designed a scientific program to breach into the microscopic scale via an unbeaten path. The program develops along three projects addressing the three most relevant scales in life sciences: cells, tissues, and organs. In the first project, I will design and test a new optomechanical probe to investigate how a prolonged mechanical load on a brain cell of a living animal may trigger alterations in its Central Nervous System. With the second project, I will develop an optomechanical tactile instrument that can assess how subsurface tissues deform in response to a mechanical stroke – a study that may change the way physicians look at tissue classification. For the third project, I will deliver an acousto-optical gas trace sensors so compact that can penetrate inside the lungs of an adult patient, where it could be used for early detection of pulmonary life threatening diseases. Each project represents an opportunity to open an entire new field, where optics and micromechanics are combined to extend our senses well beyond their natural limits.
Summary
Every time we grab an object to look at its geometrical details or to feel if it is hard or soft, we are ineluctably confronted with the limits of our senses. Behind its appearances, the object may still hide information that, encrypted in its microscopic features, remains undetected to our macroscopic assessment. In life sciences, those limits are more than just frustrating: they are an obstacle to study and detect life threatening conditions. Many different instruments may overcome those limits, but the vast majority of them rely either on “sight” (optics) or “touch” (mechanics) separately. On the contrary, I believe that it is from the combination of those two “senses” that we have more chances to tackle the future challenges of cell biology, tissue engineering, and medical diagnosis.
Inspired by this tantalizing perspective, and supported by a technology that I have brought from blackboard to market, I have now designed a scientific program to breach into the microscopic scale via an unbeaten path. The program develops along three projects addressing the three most relevant scales in life sciences: cells, tissues, and organs. In the first project, I will design and test a new optomechanical probe to investigate how a prolonged mechanical load on a brain cell of a living animal may trigger alterations in its Central Nervous System. With the second project, I will develop an optomechanical tactile instrument that can assess how subsurface tissues deform in response to a mechanical stroke – a study that may change the way physicians look at tissue classification. For the third project, I will deliver an acousto-optical gas trace sensors so compact that can penetrate inside the lungs of an adult patient, where it could be used for early detection of pulmonary life threatening diseases. Each project represents an opportunity to open an entire new field, where optics and micromechanics are combined to extend our senses well beyond their natural limits.
Max ERC Funding
1 999 221 €
Duration
Start date: 2014-06-01, End date: 2019-05-31
Project acronym DIRECTEDINFO
Project Investigating Directed Information
Researcher (PI) Haim Permuter
Host Institution (HI) BEN-GURION UNIVERSITY OF THE NEGEV
Call Details Starting Grant (StG), PE7, ERC-2013-StG
Summary This research investigates a new measure that arises in information theory
called directed information. Recent advances, including our preliminary results, shows that
directed information arises in communication as the maximum rate that can be transmitted reliably
in channels with feedback. The directed information is multi-letter expression and therefore very
hard to optimize or compute.
Our plan is first of all to find an efficient methodology for optimizing the measure using the
dynamic programming framework and convex optimization tools. As an important by-product of
finding the fundamental limits is finding coding schemes that achieves the limits. Second, we
plan to find new roles for directed information in communication, especially in networks with
bi-directional communication and in data compression with causal conditions. Third, encouraged by
a preliminary work on interpretation of directed information in economics and estimation theory,
we plan to show that directed information has interpretation in additional fields such as
statistical physics. We plan to show that there is duality relation between different fields with
causal constraints. Due to the duality insights and breakthroughs in one problem will lead to new
insights in other problems. Finally, we will apply directed information as a statistical
inference of causal dependence. We will show how to estimate and use the directed information
estimator to measure causal inference between two or more process. In particular, one of the
questions we plan to answer is the influence of industrial activities (e.g., $\text{CO}_2$
volumes) on the global warming.
Our main focus will be to develop a deeper understanding of the mathematical properties of
directed information, a process that is instrumental to each problem. Due to their theoretical
proximity and their interdisciplinary nature, progress in one problem will lead to new insights
in other problems. A common set of mathematical tools developed in
Summary
This research investigates a new measure that arises in information theory
called directed information. Recent advances, including our preliminary results, shows that
directed information arises in communication as the maximum rate that can be transmitted reliably
in channels with feedback. The directed information is multi-letter expression and therefore very
hard to optimize or compute.
Our plan is first of all to find an efficient methodology for optimizing the measure using the
dynamic programming framework and convex optimization tools. As an important by-product of
finding the fundamental limits is finding coding schemes that achieves the limits. Second, we
plan to find new roles for directed information in communication, especially in networks with
bi-directional communication and in data compression with causal conditions. Third, encouraged by
a preliminary work on interpretation of directed information in economics and estimation theory,
we plan to show that directed information has interpretation in additional fields such as
statistical physics. We plan to show that there is duality relation between different fields with
causal constraints. Due to the duality insights and breakthroughs in one problem will lead to new
insights in other problems. Finally, we will apply directed information as a statistical
inference of causal dependence. We will show how to estimate and use the directed information
estimator to measure causal inference between two or more process. In particular, one of the
questions we plan to answer is the influence of industrial activities (e.g., $\text{CO}_2$
volumes) on the global warming.
Our main focus will be to develop a deeper understanding of the mathematical properties of
directed information, a process that is instrumental to each problem. Due to their theoretical
proximity and their interdisciplinary nature, progress in one problem will lead to new insights
in other problems. A common set of mathematical tools developed in
Max ERC Funding
1 224 600 €
Duration
Start date: 2013-08-01, End date: 2019-07-31
Project acronym E-MOBILE
Project Enhanced Modeling and Optimization of Batteries Incorporating Lithium-ion Elements
Researcher (PI) Mathieu Maurice Luisier
Host Institution (HI) EIDGENOESSISCHE TECHNISCHE HOCHSCHULE ZUERICH
Call Details Starting Grant (StG), PE7, ERC-2013-StG
Summary "Developing rechargeable batteries with larger storage capacity, higher output power, faster charge/discharge time, and longer calendar lifetime could significantly impact the economical and environmental future of the European Union. New generations of lithium-ion batteries (LIBs) based on nanostructured electrodes are perfect candidates to supply all-electrical vehicles and favor the usage of renewable energies instead of fossil fuels. Hence, the global LIB revenue is expected to expand from $11 billion in 2011 up to $50 billion in 2020. The goal of this project is therefore to provide an advanced simulation and optimization platform to design LIBs with improved performance and increase the competitiveness of Europe in this domain. The proposed computer aided design (CAD) tool must satisfy three key requirements in order to reach this ambitious objective: (i) computational efficiency, (ii) results accuracy, and (iii) automated predictability. Massively parallel computing has been identified as the enabling technology to handle the first requirement. The second one will be addressed by implementing a state-of-the-art device operation model relying on a multi-scale resolution of the battery electrodes, a detailed description of the electron and ion motions, a material parametrization derived from ab-initio quantum transport techniques, and a validation of the approach through comparisons with experimental measurements. Finally, to meet the last requirement, the operation model will be coupled to a genetic algorithm optimizer capable of automatically predicting the LIB configuration that best matches pre-defined performance targets. The resulting CAD tool will be released as an open source package so that the entire battery community can benefit from it."
Summary
"Developing rechargeable batteries with larger storage capacity, higher output power, faster charge/discharge time, and longer calendar lifetime could significantly impact the economical and environmental future of the European Union. New generations of lithium-ion batteries (LIBs) based on nanostructured electrodes are perfect candidates to supply all-electrical vehicles and favor the usage of renewable energies instead of fossil fuels. Hence, the global LIB revenue is expected to expand from $11 billion in 2011 up to $50 billion in 2020. The goal of this project is therefore to provide an advanced simulation and optimization platform to design LIBs with improved performance and increase the competitiveness of Europe in this domain. The proposed computer aided design (CAD) tool must satisfy three key requirements in order to reach this ambitious objective: (i) computational efficiency, (ii) results accuracy, and (iii) automated predictability. Massively parallel computing has been identified as the enabling technology to handle the first requirement. The second one will be addressed by implementing a state-of-the-art device operation model relying on a multi-scale resolution of the battery electrodes, a detailed description of the electron and ion motions, a material parametrization derived from ab-initio quantum transport techniques, and a validation of the approach through comparisons with experimental measurements. Finally, to meet the last requirement, the operation model will be coupled to a genetic algorithm optimizer capable of automatically predicting the LIB configuration that best matches pre-defined performance targets. The resulting CAD tool will be released as an open source package so that the entire battery community can benefit from it."
Max ERC Funding
1 492 800 €
Duration
Start date: 2013-10-01, End date: 2018-09-30
Project acronym ENLIGHTENED
Project Nanophotonic Nanomechanical Mass Spectrometry for Biology and Health
Researcher (PI) Sébastien Claude Hentz
Host Institution (HI) COMMISSARIAT A L ENERGIE ATOMIQUE ET AUX ENERGIES ALTERNATIVES
Call Details Consolidator Grant (CoG), PE7, ERC-2013-CoG
Summary « Mass Spectrometry has become a routine analytical tool in modern biological research, and has gained in recent years a foothold in the realm of clinical diagnostic and screening. However, it is still costly, complex and because its principle relies on ionization, it is incapable of analyzing biomolecules with masses greater than a few MDa. Averaging more than 100 million particles per measurement, it is also incapable of characterizing the diversity of such heavy entities. ENLIGHTENED aims at demonstrating a breakthrough concept based on Photonic Nano-Mechanical Mass Spectrometry, able to perform analysis of bioparticles of high biomedical significance, of ultra-high mass, never so far characterized, with single-molecule sensitivity and unprecedented resolution. The long-term vision beyond the current proposal is to provide the biologists with a tool which will be transformative for fundamental knowledge, and to make possible cheap, handheld devices for personalized medicine.
ENLIGHTENED proposes to use photons to shed light on unexplored species at the individual level, which is of high biomedical significance and will expand our understanding of simple life forms.”
Summary
« Mass Spectrometry has become a routine analytical tool in modern biological research, and has gained in recent years a foothold in the realm of clinical diagnostic and screening. However, it is still costly, complex and because its principle relies on ionization, it is incapable of analyzing biomolecules with masses greater than a few MDa. Averaging more than 100 million particles per measurement, it is also incapable of characterizing the diversity of such heavy entities. ENLIGHTENED aims at demonstrating a breakthrough concept based on Photonic Nano-Mechanical Mass Spectrometry, able to perform analysis of bioparticles of high biomedical significance, of ultra-high mass, never so far characterized, with single-molecule sensitivity and unprecedented resolution. The long-term vision beyond the current proposal is to provide the biologists with a tool which will be transformative for fundamental knowledge, and to make possible cheap, handheld devices for personalized medicine.
ENLIGHTENED proposes to use photons to shed light on unexplored species at the individual level, which is of high biomedical significance and will expand our understanding of simple life forms.”
Max ERC Funding
1 999 090 €
Duration
Start date: 2014-06-01, End date: 2020-05-31
Project acronym FICModFun
Project FIC-Mediated Post-Translational Modifications at the
Pathogen-Host Interface: Elucidating Structure, Function and Role in Infection
Researcher (PI) Christoph Georg Fritz Dehio
Host Institution (HI) UNIVERSITAT BASEL
Call Details Advanced Grant (AdG), LS6, ERC-2013-ADG
Summary The ubiquitous FIC domain catalyzes post-translational modifications (PTMs) of target proteins; i.e.
adenylylation (=AMPylation) and, more rarely, uridylylation and phosphocholination. Fic proteins are
thought to play critical roles in intrinsic signaling processes of prokaryotes and eukaryotes; however, a
subset encoded by bacterial pathogens is translocated via dedicated secretion systems into the cytoplasm of
mammalian host cells. Some of these host-targeted Fic proteins modify small GTPases leading to collapse of
the actin cytoskeleton and other drastic cellular changes. Recently, we described a large set of functionally
diverse homologues in pathogens of the genus Bartonella that are required for their “stealth attack” strategy
and persistent course of infection [1, 2]. Our preliminary functional analysis of some of these host-targeted
Fic proteins of Bartonella demonstrated adenylylation activity towards novel host targets (e.g. tubulin and
vimentin). Moreover, in addition to the canonical adenylylation activity they may also display a competing
kinase activity resulting from altered ATP binding to the FIC active site. Finally, we described a conserved
mechanism of FIC active site auto- inhibition that is relieved by a single amino acid exchange [1], thus
facilitating functional analysis of any Fic protein of interest. Despite this recent progress only a few Fic
proteins have been functionally characterized to date; our understanding of the functional plasticity of the
FIC domain in mediating diverse target PTMs and their specific roles in infection thus remains limited.
In this project, we aim to study the vast repertoire of host-targeted Fic proteins of Bartonella to: 1)
identify novel target proteins and types of PTMs; 2) study their physiological consequences and molecular
mechanisms of action; and 3) analyze structure-function relationships critical for FIC-mediated PTMs and infer from these data determinants of target specificity, type of PTM and mode of regulation. At the forefront of infection biology research, this project is ground-breaking as (i) we will identify a
plethora of novel host target PTMs that are critical for a “stealth attack” infection strategy and thus will open
new avenues for investigating fundamental mechanisms of persistent infection; and (ii), we will unveil the
molecular basis of the remarkable functional versatility of the structurally conserved FIC domain.
Summary
The ubiquitous FIC domain catalyzes post-translational modifications (PTMs) of target proteins; i.e.
adenylylation (=AMPylation) and, more rarely, uridylylation and phosphocholination. Fic proteins are
thought to play critical roles in intrinsic signaling processes of prokaryotes and eukaryotes; however, a
subset encoded by bacterial pathogens is translocated via dedicated secretion systems into the cytoplasm of
mammalian host cells. Some of these host-targeted Fic proteins modify small GTPases leading to collapse of
the actin cytoskeleton and other drastic cellular changes. Recently, we described a large set of functionally
diverse homologues in pathogens of the genus Bartonella that are required for their “stealth attack” strategy
and persistent course of infection [1, 2]. Our preliminary functional analysis of some of these host-targeted
Fic proteins of Bartonella demonstrated adenylylation activity towards novel host targets (e.g. tubulin and
vimentin). Moreover, in addition to the canonical adenylylation activity they may also display a competing
kinase activity resulting from altered ATP binding to the FIC active site. Finally, we described a conserved
mechanism of FIC active site auto- inhibition that is relieved by a single amino acid exchange [1], thus
facilitating functional analysis of any Fic protein of interest. Despite this recent progress only a few Fic
proteins have been functionally characterized to date; our understanding of the functional plasticity of the
FIC domain in mediating diverse target PTMs and their specific roles in infection thus remains limited.
In this project, we aim to study the vast repertoire of host-targeted Fic proteins of Bartonella to: 1)
identify novel target proteins and types of PTMs; 2) study their physiological consequences and molecular
mechanisms of action; and 3) analyze structure-function relationships critical for FIC-mediated PTMs and infer from these data determinants of target specificity, type of PTM and mode of regulation. At the forefront of infection biology research, this project is ground-breaking as (i) we will identify a
plethora of novel host target PTMs that are critical for a “stealth attack” infection strategy and thus will open
new avenues for investigating fundamental mechanisms of persistent infection; and (ii), we will unveil the
molecular basis of the remarkable functional versatility of the structurally conserved FIC domain.
Max ERC Funding
1 699 858 €
Duration
Start date: 2014-02-01, End date: 2019-01-31
Project acronym FLAMMASEC
Project "Inflammasome-induced IL-1 Secretion: Route, Mechanism, and Cell Fate"
Researcher (PI) Olaf Groß
Host Institution (HI) UNIVERSITAETSKLINIKUM FREIBURG
Call Details Starting Grant (StG), LS6, ERC-2013-StG
Summary "Inflammasomes are intracellular danger-sensing protein complexes that are important for host protection. They initiate inflammation by controlling the activity of the proinflammatory cytokine interleukin-1β (IL-1β). Unlike most other cytokines, IL-1β is produced and retained in the cytoplasm in an inactive pro-form. Inflammasome-dependent maturation of proIL-1β is mediated by the common component of all inflammasomes, the protease caspase-1. Caspase-1 also controls the secretion of IL-1β, but the mechanism and route of secretion are unknown. We have recently demonstrated that the ability of caspase-1 to control IL-1β secretion is not dependent on its protease activity, but rather on a scaffold or adapter function of caspase-1. Furthermore, we and others could show that caspase-1 can control the secretion of non-substrates like IL-1α. These insights provide us with new and potentially revealing means to investigate the downstream effector functions of caspase-1, including the route and mechanism of IL-1 secretion. We will develop new tools to study the process of IL-1 secretion by microscopy and the novel mode-of-action of caspase-1 through the generation of transgenic models.
Despite the important role of IL-1 in host defence against infection, dysregulated inflammasome activation and IL-1 production has a causal role in a number of acquired and hereditary auto-inflammatory conditions. These include particle-induced sterile inflammation (as is seen in gout and asbestosis), hereditary periodic fever syndromes, and metabolic diseases like diabetes and atherosclerosis. Currently, recombinant proteins that block the IL-1 receptor or deplete secreted IL-1 are used to treat IL-1-dependent diseases. These are costly treatments, and are also therapeutically cumbersome since they are not orally available. We hope that a better understanding of caspase-1-mediated secretion of IL-1 will unveil mechanisms that may serve as targets for future therapies for these diseases."
Summary
"Inflammasomes are intracellular danger-sensing protein complexes that are important for host protection. They initiate inflammation by controlling the activity of the proinflammatory cytokine interleukin-1β (IL-1β). Unlike most other cytokines, IL-1β is produced and retained in the cytoplasm in an inactive pro-form. Inflammasome-dependent maturation of proIL-1β is mediated by the common component of all inflammasomes, the protease caspase-1. Caspase-1 also controls the secretion of IL-1β, but the mechanism and route of secretion are unknown. We have recently demonstrated that the ability of caspase-1 to control IL-1β secretion is not dependent on its protease activity, but rather on a scaffold or adapter function of caspase-1. Furthermore, we and others could show that caspase-1 can control the secretion of non-substrates like IL-1α. These insights provide us with new and potentially revealing means to investigate the downstream effector functions of caspase-1, including the route and mechanism of IL-1 secretion. We will develop new tools to study the process of IL-1 secretion by microscopy and the novel mode-of-action of caspase-1 through the generation of transgenic models.
Despite the important role of IL-1 in host defence against infection, dysregulated inflammasome activation and IL-1 production has a causal role in a number of acquired and hereditary auto-inflammatory conditions. These include particle-induced sterile inflammation (as is seen in gout and asbestosis), hereditary periodic fever syndromes, and metabolic diseases like diabetes and atherosclerosis. Currently, recombinant proteins that block the IL-1 receptor or deplete secreted IL-1 are used to treat IL-1-dependent diseases. These are costly treatments, and are also therapeutically cumbersome since they are not orally available. We hope that a better understanding of caspase-1-mediated secretion of IL-1 will unveil mechanisms that may serve as targets for future therapies for these diseases."
Max ERC Funding
1 495 533 €
Duration
Start date: 2014-03-01, End date: 2019-02-28
Project acronym HEART
Project "The Highly Efficient And Reliable smart Transformer (HEART), a new Heart for the Electric Distribution System"
Researcher (PI) Marco Liserre
Host Institution (HI) CHRISTIAN-ALBRECHTS-UNIVERSITAET ZU KIEL
Call Details Consolidator Grant (CoG), PE7, ERC-2013-CoG
Summary "In the last 10 years, power electronics has moved significantly towards the electric grid, making it more flexible and decentralized. Still important challenges remain. One of the most thrilling is re-inventing the distribution transformer after more than 125 years since its first use in the electrification of a city. In fact, actual distribution transformers can no longer fulfill the requirements of a modern electric grid highly dominated by distributed sources and new sizable loads, like heat pumps and electric vehicles.
This project proposes the invention of a novel “Smart Transformer” (ST), based on a modular architecture of units made by power electronics converters, that will be able to manage the energy and the information flows among sources and loads in the distribution area with the goal of decoupling it from the rest of the bulk power system. Actual proposals of Smart Transformers cannot compete in terms of cost, efficiency and reliability with traditional transformers.
This project has decided to take this challenge with a paradigm shift in how to approach it and a new set of methodologies. The breakthrough results of this research will be obtained taking the following high-risk high-gain bet: significantly influence the efficiency and the reliability of the Smart Transformer by routing the energy flows among its power converter units. A new understanding of how the energy flows are managed by the modular connection of power converter units will guide the design of new architectures for the ST allowing different routes for the energy. Graph theory will be used to find optimal paths for the energy flows with the goal of maximizing efficiency and reliability. The energy flows will be managed by relying on information coming from the electric distribution system sensors (requirements) and from the power module sensors (constraints).
The holy grail of this research is to provide a new durable heart to the electric distribution system."
Summary
"In the last 10 years, power electronics has moved significantly towards the electric grid, making it more flexible and decentralized. Still important challenges remain. One of the most thrilling is re-inventing the distribution transformer after more than 125 years since its first use in the electrification of a city. In fact, actual distribution transformers can no longer fulfill the requirements of a modern electric grid highly dominated by distributed sources and new sizable loads, like heat pumps and electric vehicles.
This project proposes the invention of a novel “Smart Transformer” (ST), based on a modular architecture of units made by power electronics converters, that will be able to manage the energy and the information flows among sources and loads in the distribution area with the goal of decoupling it from the rest of the bulk power system. Actual proposals of Smart Transformers cannot compete in terms of cost, efficiency and reliability with traditional transformers.
This project has decided to take this challenge with a paradigm shift in how to approach it and a new set of methodologies. The breakthrough results of this research will be obtained taking the following high-risk high-gain bet: significantly influence the efficiency and the reliability of the Smart Transformer by routing the energy flows among its power converter units. A new understanding of how the energy flows are managed by the modular connection of power converter units will guide the design of new architectures for the ST allowing different routes for the energy. Graph theory will be used to find optimal paths for the energy flows with the goal of maximizing efficiency and reliability. The energy flows will be managed by relying on information coming from the electric distribution system sensors (requirements) and from the power module sensors (constraints).
The holy grail of this research is to provide a new durable heart to the electric distribution system."
Max ERC Funding
1 996 720 €
Duration
Start date: 2014-05-01, End date: 2019-04-30
Project acronym HIVINNATE
Project Characterisation and Manipulation of Primate Lentiviral Interactions with Innate Immunity
Researcher (PI) Gregory John Towers
Host Institution (HI) UNIVERSITY COLLEGE LONDON
Call Details Advanced Grant (AdG), LS6, ERC-2013-ADG
Summary Our aim is to seek detailed molecular level understanding of the interactions between HIV-1 and innate immune sensors expressed in myeloid cells. We have demonstrated that HIV-1 replicates in primary human macrophages without triggering interferon production. However, by specific mutation of HIV-1 proteins or by manipulating interaction with host cofactors we can reveal the virus to innate immune receptors and activate an antiviral response leading to secretion of soluble type 1 interferon and cessation of replication. We propose to define the sensors and the details of the antiviral pathways that are activated in macrophages using proven RNA interference techniques reading out activation of innate immune responses by measurement of secreted interferon and induction of gene expression. We have also characterised small molecules that potently inhibit HIV-1 by revealing HIV-1 to innate immune sensors. In collaboration with crystallographers and medicinal chemists we aim to improve the potency and specificity of these drugs and to use them to study the anti-HIV-1 innate immune response. DC are sentinels of innate immunity and their infection induced maturation leads to interferon production and DC dependent T cell maturation that defines the nature and potency of the immune response. We will examine the effect of triggering innate responses in DC using HIV-1 mutants/drug treated wild type virus on allogeneic responses, by measurement of T cell proliferation and function and in an ex vivo CD8 T cell killing assays using peripheral blood CD8 cells from HIV‑1 infected patients. In this way we will uncover the molecular details of HIV-1’s interaction with innate immunity and discover how the virus replicates in primary immune cells without detection. This work will make a significant technical and intellectual contribution to an important emerging scientific field focusing on understanding and manipulating the complex relationship between HIV-1 and innate immunity.
Summary
Our aim is to seek detailed molecular level understanding of the interactions between HIV-1 and innate immune sensors expressed in myeloid cells. We have demonstrated that HIV-1 replicates in primary human macrophages without triggering interferon production. However, by specific mutation of HIV-1 proteins or by manipulating interaction with host cofactors we can reveal the virus to innate immune receptors and activate an antiviral response leading to secretion of soluble type 1 interferon and cessation of replication. We propose to define the sensors and the details of the antiviral pathways that are activated in macrophages using proven RNA interference techniques reading out activation of innate immune responses by measurement of secreted interferon and induction of gene expression. We have also characterised small molecules that potently inhibit HIV-1 by revealing HIV-1 to innate immune sensors. In collaboration with crystallographers and medicinal chemists we aim to improve the potency and specificity of these drugs and to use them to study the anti-HIV-1 innate immune response. DC are sentinels of innate immunity and their infection induced maturation leads to interferon production and DC dependent T cell maturation that defines the nature and potency of the immune response. We will examine the effect of triggering innate responses in DC using HIV-1 mutants/drug treated wild type virus on allogeneic responses, by measurement of T cell proliferation and function and in an ex vivo CD8 T cell killing assays using peripheral blood CD8 cells from HIV‑1 infected patients. In this way we will uncover the molecular details of HIV-1’s interaction with innate immunity and discover how the virus replicates in primary immune cells without detection. This work will make a significant technical and intellectual contribution to an important emerging scientific field focusing on understanding and manipulating the complex relationship between HIV-1 and innate immunity.
Max ERC Funding
2 499 643 €
Duration
Start date: 2014-02-01, End date: 2019-01-31
Project acronym HLA-DR15 in MS
Project Functional Role of the HLA-DR15 Haplotype in Multiple Sclerosis
Researcher (PI) Roland Michael Gunnar Martin
Host Institution (HI) UNIVERSITAT ZURICH
Call Details Advanced Grant (AdG), LS6, ERC-2013-ADG
Summary Multiple sclerosis (MS) is a prototypic CD4+ T cell-mediated autoimmune disease that damages the central nervous system. MS affects young adults and women twice as often as men. Neurological deficits cause substantial disability at an early age with high socioeconomic impact.
Both a complex genetic trait and environmental factors are involved in MS etiology. Similar to other autoimmune diseases it has been known for almost 40 years that certain HLA-class II genes, in MS the two DR15 alleles DRB1*15:01 and DRB5*01:01, confer by far most of the genetic risk. Despite this clear role remarkably little is known about the functional contribution of these genes to MS pathogenesis, and this holds also true for all other T cell-mediated autoimmune diseases. It is assumed that the DR15 alleles present peptides from organ-specific self-proteins to T cells and select an autoreactive CD4+ T cell repertoire that can be activated by certain environmental triggers. Interestingly, the effects of the three known environmental risk factors in MS, Epstein Barr virus (EBV), low vitamin D3 and smoking, are all amplified by DR15.
This core issue of research on autoimmune diseases and also MS, how disease-associated HLA-class II molecules contribute to disease development at the functional level, will be studied with state-of-the-art methodologies and a series of novel approaches. These will include in silico modeling approaches, studies of self-peptides, T cell receptor (TCR) repertoire and HLA-DR/peptide complexes, clonally expanded T cells from MS brain tissue and hypothesis-open methods such as combinatorial chemistry and tissue-derived cDNA libraries to identify target antigens. Finally, translational studies will investigate the relationship between the above aspects and MS disease heterogeneity and explore antigen-specific tolerization in proof-of concept clinical trials in MS.
Summary
Multiple sclerosis (MS) is a prototypic CD4+ T cell-mediated autoimmune disease that damages the central nervous system. MS affects young adults and women twice as often as men. Neurological deficits cause substantial disability at an early age with high socioeconomic impact.
Both a complex genetic trait and environmental factors are involved in MS etiology. Similar to other autoimmune diseases it has been known for almost 40 years that certain HLA-class II genes, in MS the two DR15 alleles DRB1*15:01 and DRB5*01:01, confer by far most of the genetic risk. Despite this clear role remarkably little is known about the functional contribution of these genes to MS pathogenesis, and this holds also true for all other T cell-mediated autoimmune diseases. It is assumed that the DR15 alleles present peptides from organ-specific self-proteins to T cells and select an autoreactive CD4+ T cell repertoire that can be activated by certain environmental triggers. Interestingly, the effects of the three known environmental risk factors in MS, Epstein Barr virus (EBV), low vitamin D3 and smoking, are all amplified by DR15.
This core issue of research on autoimmune diseases and also MS, how disease-associated HLA-class II molecules contribute to disease development at the functional level, will be studied with state-of-the-art methodologies and a series of novel approaches. These will include in silico modeling approaches, studies of self-peptides, T cell receptor (TCR) repertoire and HLA-DR/peptide complexes, clonally expanded T cells from MS brain tissue and hypothesis-open methods such as combinatorial chemistry and tissue-derived cDNA libraries to identify target antigens. Finally, translational studies will investigate the relationship between the above aspects and MS disease heterogeneity and explore antigen-specific tolerization in proof-of concept clinical trials in MS.
Max ERC Funding
2 368 068 €
Duration
Start date: 2015-01-01, End date: 2019-12-31
