Project acronym 2D4QT
Project 2D Materials for Quantum Technology
Researcher (PI) Christoph STAMPFER
Host Institution (HI) RHEINISCH-WESTFAELISCHE TECHNISCHE HOCHSCHULE AACHEN
Call Details Consolidator Grant (CoG), PE3, ERC-2018-COG
Summary Since its discovery, graphene has been indicated as a promising platform for quantum technologies (QT). The number of theoretical proposal dedicated to this vision has grown steadily, exploring a wide range of directions, ranging from spin and valley qubits, to topologically-protected states. The experimental confirmation of these ideas lagged so far significantly behind, mostly because of material quality problems. The quality of graphene-based devices has however improved dramatically in the past five years, thanks to the advent of the so-called van der Waals (vdW) heteostructures - artificial solids formed by mechanically stacking layers of different two dimensional (2D) materials, such as graphene, hexagonal boron nitride and transition metal dichalcogenides. These new advances open now finally the door to put several of those theoretical proposals to test.
The goal of this project is to assess experimentally the potential of graphene-based heterostructures for QT applications. Specifically, I will push the development of an advanced technological platform for vdW heterostructures, which will allow to give quantitative answers to the following open questions: i) what are the relaxation and coherence times of spin and valley qubits in isotopically purified bilayer graphene (BLG); ii) what is the efficiency of a Cooper-pair splitter based on BLG; and iii) what are the characteristic energy scales of topologically protected quantum states engineered in graphene-based heterostructures.
At the end of this project, I aim at being in the position of saying whether graphene is the horse-worth-betting-on predicted by theory, or whether it still hides surprises in terms of fundamental physics. The technological advancements developed in this project for integrating nanostructured layers into vdW heterostructures will reach even beyond this goal, opening the door to new research directions and possible applications.
Summary
Since its discovery, graphene has been indicated as a promising platform for quantum technologies (QT). The number of theoretical proposal dedicated to this vision has grown steadily, exploring a wide range of directions, ranging from spin and valley qubits, to topologically-protected states. The experimental confirmation of these ideas lagged so far significantly behind, mostly because of material quality problems. The quality of graphene-based devices has however improved dramatically in the past five years, thanks to the advent of the so-called van der Waals (vdW) heteostructures - artificial solids formed by mechanically stacking layers of different two dimensional (2D) materials, such as graphene, hexagonal boron nitride and transition metal dichalcogenides. These new advances open now finally the door to put several of those theoretical proposals to test.
The goal of this project is to assess experimentally the potential of graphene-based heterostructures for QT applications. Specifically, I will push the development of an advanced technological platform for vdW heterostructures, which will allow to give quantitative answers to the following open questions: i) what are the relaxation and coherence times of spin and valley qubits in isotopically purified bilayer graphene (BLG); ii) what is the efficiency of a Cooper-pair splitter based on BLG; and iii) what are the characteristic energy scales of topologically protected quantum states engineered in graphene-based heterostructures.
At the end of this project, I aim at being in the position of saying whether graphene is the horse-worth-betting-on predicted by theory, or whether it still hides surprises in terms of fundamental physics. The technological advancements developed in this project for integrating nanostructured layers into vdW heterostructures will reach even beyond this goal, opening the door to new research directions and possible applications.
Max ERC Funding
1 806 250 €
Duration
Start date: 2019-09-01, End date: 2024-08-31
Project acronym 3D Reloaded
Project 3D Reloaded: Novel Algorithms for 3D Shape Inference and Analysis
Researcher (PI) Daniel Cremers
Host Institution (HI) TECHNISCHE UNIVERSITAET MUENCHEN
Call Details Consolidator Grant (CoG), PE6, ERC-2014-CoG
Summary Despite their amazing success, we believe that computer vision algorithms have only scratched the surface of what can be done in terms of modeling and understanding our world from images. We believe that novel image analysis techniques will be a major enabler and driving force behind next-generation technologies, enhancing everyday life and opening up radically new possibilities. And we believe that the key to achieving this is to develop algorithms for reconstructing and analyzing the 3D structure of our world.
In this project, we will focus on three lines of research:
A) We will develop algorithms for 3D reconstruction from standard color cameras and from RGB-D cameras. In particular, we will promote real-time-capable direct and dense methods. In contrast to the classical two-stage approach of sparse feature-point based motion estimation and subsequent dense reconstruction, these methods optimally exploit all color information to jointly estimate dense geometry and camera motion.
B) We will develop algorithms for 3D shape analysis, including rigid and non-rigid matching, decomposition and interpretation of 3D shapes. We will focus on algorithms which are optimal or near-optimal. One of the major computational challenges lies in generalizing existing 2D shape analysis techniques to shapes in 3D and 4D (temporal evolutions of 3D shape).
C) We will develop shape priors for 3D reconstruction. These can be learned from sample shapes or acquired during the reconstruction process. For example, when reconstructing a larger office algorithms may exploit the geometric self-similarity of the scene, storing a model of a chair and its multiple instances only once rather than multiple times.
Advancing the state of the art in geometric reconstruction and geometric analysis will have a profound impact well beyond computer vision. We strongly believe that we have the necessary competence to pursue this project. Preliminary results have been well received by the community.
Summary
Despite their amazing success, we believe that computer vision algorithms have only scratched the surface of what can be done in terms of modeling and understanding our world from images. We believe that novel image analysis techniques will be a major enabler and driving force behind next-generation technologies, enhancing everyday life and opening up radically new possibilities. And we believe that the key to achieving this is to develop algorithms for reconstructing and analyzing the 3D structure of our world.
In this project, we will focus on three lines of research:
A) We will develop algorithms for 3D reconstruction from standard color cameras and from RGB-D cameras. In particular, we will promote real-time-capable direct and dense methods. In contrast to the classical two-stage approach of sparse feature-point based motion estimation and subsequent dense reconstruction, these methods optimally exploit all color information to jointly estimate dense geometry and camera motion.
B) We will develop algorithms for 3D shape analysis, including rigid and non-rigid matching, decomposition and interpretation of 3D shapes. We will focus on algorithms which are optimal or near-optimal. One of the major computational challenges lies in generalizing existing 2D shape analysis techniques to shapes in 3D and 4D (temporal evolutions of 3D shape).
C) We will develop shape priors for 3D reconstruction. These can be learned from sample shapes or acquired during the reconstruction process. For example, when reconstructing a larger office algorithms may exploit the geometric self-similarity of the scene, storing a model of a chair and its multiple instances only once rather than multiple times.
Advancing the state of the art in geometric reconstruction and geometric analysis will have a profound impact well beyond computer vision. We strongly believe that we have the necessary competence to pursue this project. Preliminary results have been well received by the community.
Max ERC Funding
2 000 000 €
Duration
Start date: 2015-09-01, End date: 2020-08-31
Project acronym 3D2DPrint
Project 3D Printing of Novel 2D Nanomaterials: Adding Advanced 2D Functionalities to Revolutionary Tailored 3D Manufacturing
Researcher (PI) Valeria Nicolosi
Host Institution (HI) THE PROVOST, FELLOWS, FOUNDATION SCHOLARS & THE OTHER MEMBERS OF BOARD OF THE COLLEGE OF THE HOLY & UNDIVIDED TRINITY OF QUEEN ELIZABETH NEAR DUBLIN
Call Details Consolidator Grant (CoG), PE8, ERC-2015-CoG
Summary My vision is to establish, within the framework of an ERC CoG, a multidisciplinary group which will work in concert towards pioneering the integration of novel 2-Dimensional nanomaterials with novel additive fabrication techniques to develop a unique class of energy storage devices.
Batteries and supercapacitors are two very complementary types of energy storage devices. Batteries store much higher energy densities; supercapacitors, on the other hand, hold one tenth of the electricity per unit of volume or weight as compared to batteries but can achieve much higher power densities. Technology is currently striving to improve the power density of batteries and the energy density of supercapacitors. To do so it is imperative to develop new materials, chemistries and manufacturing strategies.
3D2DPrint aims to develop micro-energy devices (both supercapacitors and batteries), technologies particularly relevant in the context of the emergent industry of micro-electro-mechanical systems and constantly downsized electronics. We plan to use novel two-dimensional (2D) nanomaterials obtained by liquid-phase exfoliation. This method offers a new, economic and easy way to prepare ink of a variety of 2D systems, allowing to produce wide device performance window through elegant and simple constituent control at the point of fabrication. 3D2DPrint will use our expertise and know-how to allow development of advanced AM methods to integrate dissimilar nanomaterial blends and/or “hybrids” into fully embedded 3D printed energy storage devices, with the ultimate objective to realise a range of products that contain the above described nanomaterials subcomponent devices, electrical connections and traditional micro-fabricated subcomponents (if needed) ideally using a single tool.
Summary
My vision is to establish, within the framework of an ERC CoG, a multidisciplinary group which will work in concert towards pioneering the integration of novel 2-Dimensional nanomaterials with novel additive fabrication techniques to develop a unique class of energy storage devices.
Batteries and supercapacitors are two very complementary types of energy storage devices. Batteries store much higher energy densities; supercapacitors, on the other hand, hold one tenth of the electricity per unit of volume or weight as compared to batteries but can achieve much higher power densities. Technology is currently striving to improve the power density of batteries and the energy density of supercapacitors. To do so it is imperative to develop new materials, chemistries and manufacturing strategies.
3D2DPrint aims to develop micro-energy devices (both supercapacitors and batteries), technologies particularly relevant in the context of the emergent industry of micro-electro-mechanical systems and constantly downsized electronics. We plan to use novel two-dimensional (2D) nanomaterials obtained by liquid-phase exfoliation. This method offers a new, economic and easy way to prepare ink of a variety of 2D systems, allowing to produce wide device performance window through elegant and simple constituent control at the point of fabrication. 3D2DPrint will use our expertise and know-how to allow development of advanced AM methods to integrate dissimilar nanomaterial blends and/or “hybrids” into fully embedded 3D printed energy storage devices, with the ultimate objective to realise a range of products that contain the above described nanomaterials subcomponent devices, electrical connections and traditional micro-fabricated subcomponents (if needed) ideally using a single tool.
Max ERC Funding
2 499 942 €
Duration
Start date: 2016-10-01, End date: 2021-09-30
Project acronym 4DRepLy
Project Closing the 4D Real World Reconstruction Loop
Researcher (PI) Christian THEOBALT
Host Institution (HI) MAX-PLANCK-GESELLSCHAFT ZUR FORDERUNG DER WISSENSCHAFTEN EV
Call Details Consolidator Grant (CoG), PE6, ERC-2017-COG
Summary 4D reconstruction, the camera-based dense dynamic scene reconstruction, is a grand challenge in computer graphics and computer vision. Despite great progress, 4D capturing the complex, diverse real world outside a studio is still far from feasible. 4DRepLy builds a new generation of high-fidelity 4D reconstruction (4DRecon) methods. They will be the first to efficiently capture all types of deformable objects (humans and other types) in crowded real world scenes with a single color or depth camera. They capture space-time coherent deforming geometry, motion, high-frequency reflectance and illumination at unprecedented detail, and will be the first to handle difficult occlusions, topology changes and large groups of interacting objects. They automatically adapt to new scene types, yet deliver models with meaningful, interpretable parameters. This requires far reaching contributions: First, we develop groundbreaking new plasticity-enhanced model-based 4D reconstruction methods that automatically adapt to new scenes. Second, we develop radically new machine learning-based dense 4D reconstruction methods. Third, these model- and learning-based methods are combined in two revolutionary new classes of 4DRecon methods: 1) advanced fusion-based methods and 2) methods with deep architectural integration. Both, 1) and 2), are automatically designed in the 4D Real World Reconstruction Loop, a revolutionary new design paradigm in which 4DRecon methods refine and adapt themselves while continuously processing unlabeled real world input. This overcomes the previously unbreakable scalability barrier to real world scene diversity, complexity and generality. This paradigm shift opens up a new research direction in graphics and vision and has far reaching relevance across many scientific fields. It enables new applications of profound social pervasion and significant economic impact, e.g., for visual media and virtual/augmented reality, and for future autonomous and robotic systems.
Summary
4D reconstruction, the camera-based dense dynamic scene reconstruction, is a grand challenge in computer graphics and computer vision. Despite great progress, 4D capturing the complex, diverse real world outside a studio is still far from feasible. 4DRepLy builds a new generation of high-fidelity 4D reconstruction (4DRecon) methods. They will be the first to efficiently capture all types of deformable objects (humans and other types) in crowded real world scenes with a single color or depth camera. They capture space-time coherent deforming geometry, motion, high-frequency reflectance and illumination at unprecedented detail, and will be the first to handle difficult occlusions, topology changes and large groups of interacting objects. They automatically adapt to new scene types, yet deliver models with meaningful, interpretable parameters. This requires far reaching contributions: First, we develop groundbreaking new plasticity-enhanced model-based 4D reconstruction methods that automatically adapt to new scenes. Second, we develop radically new machine learning-based dense 4D reconstruction methods. Third, these model- and learning-based methods are combined in two revolutionary new classes of 4DRecon methods: 1) advanced fusion-based methods and 2) methods with deep architectural integration. Both, 1) and 2), are automatically designed in the 4D Real World Reconstruction Loop, a revolutionary new design paradigm in which 4DRecon methods refine and adapt themselves while continuously processing unlabeled real world input. This overcomes the previously unbreakable scalability barrier to real world scene diversity, complexity and generality. This paradigm shift opens up a new research direction in graphics and vision and has far reaching relevance across many scientific fields. It enables new applications of profound social pervasion and significant economic impact, e.g., for visual media and virtual/augmented reality, and for future autonomous and robotic systems.
Max ERC Funding
1 977 000 €
Duration
Start date: 2018-09-01, End date: 2023-08-31
Project acronym A-DIET
Project Metabolomics based biomarkers of dietary intake- new tools for nutrition research
Researcher (PI) Lorraine Brennan
Host Institution (HI) UNIVERSITY COLLEGE DUBLIN, NATIONAL UNIVERSITY OF IRELAND, DUBLIN
Call Details Consolidator Grant (CoG), LS7, ERC-2014-CoG
Summary In todays advanced technological world, we can track the exact movement of individuals, analyse their genetic makeup and predict predisposition to certain diseases. However, we are unable to accurately assess an individual’s dietary intake. This is without a doubt one of the main stumbling blocks in assessing the link between diet and disease/health. The present proposal (A-DIET) will address this issue with the overarching objective to develop novel strategies for assessment of dietary intake.
Using approaches to (1) identify biomarkers of specific foods (2) classify people into dietary patterns (nutritypes) and (3) develop a tool for integration of dietary and biomarker data, A-DIET has the potential to dramatically enhance our ability to accurately assess dietary intake. The ultimate output from A-DIET will be a dietary assessment tool which can be used to obtain an accurate assessment of dietary intake by combining dietary and biomarker data which in turn will allow investigations into relationships between diet, health and disease. New biomarkers of specific foods will be identified and validated using intervention studies and metabolomic analyses. Methods will be developed to classify individuals into dietary patterns based on biomarker/metabolomic profiles thus demonstrating the novel concept of nutritypes. Strategies for integration of dietary and biomarker data will be developed and translated into a tool that will be made available to the wider scientific community.
Advances made in A-DIET will enable nutrition epidemiologist’s to properly examine the relationship between diet and disease and develop clear public health messages with regard to diet and health. Additionally results from A-DIET will allow researchers to accurately assess people’s diet and implement health promotion strategies and enable dieticians in a clinical environment to assess compliance to therapeutic diets such as adherence to a high fibre diet or a gluten free diet.
Summary
In todays advanced technological world, we can track the exact movement of individuals, analyse their genetic makeup and predict predisposition to certain diseases. However, we are unable to accurately assess an individual’s dietary intake. This is without a doubt one of the main stumbling blocks in assessing the link between diet and disease/health. The present proposal (A-DIET) will address this issue with the overarching objective to develop novel strategies for assessment of dietary intake.
Using approaches to (1) identify biomarkers of specific foods (2) classify people into dietary patterns (nutritypes) and (3) develop a tool for integration of dietary and biomarker data, A-DIET has the potential to dramatically enhance our ability to accurately assess dietary intake. The ultimate output from A-DIET will be a dietary assessment tool which can be used to obtain an accurate assessment of dietary intake by combining dietary and biomarker data which in turn will allow investigations into relationships between diet, health and disease. New biomarkers of specific foods will be identified and validated using intervention studies and metabolomic analyses. Methods will be developed to classify individuals into dietary patterns based on biomarker/metabolomic profiles thus demonstrating the novel concept of nutritypes. Strategies for integration of dietary and biomarker data will be developed and translated into a tool that will be made available to the wider scientific community.
Advances made in A-DIET will enable nutrition epidemiologist’s to properly examine the relationship between diet and disease and develop clear public health messages with regard to diet and health. Additionally results from A-DIET will allow researchers to accurately assess people’s diet and implement health promotion strategies and enable dieticians in a clinical environment to assess compliance to therapeutic diets such as adherence to a high fibre diet or a gluten free diet.
Max ERC Funding
1 995 548 €
Duration
Start date: 2015-08-01, End date: 2020-07-31
Project acronym ABSOLUTESPIN
Project Absolute Spin Dynamics in Quantum Materials
Researcher (PI) Christian Reinhard Ast
Host Institution (HI) MAX-PLANCK-GESELLSCHAFT ZUR FORDERUNG DER WISSENSCHAFTEN EV
Call Details Consolidator Grant (CoG), PE3, ERC-2015-CoG
Summary One of the greatest challenges in exploiting the electron spin for information processing is that it is not a conserved quantity like the electron charge. In addition, spin lifetimes are rather short and correspondingly coherence is quickly lost. This challenge culminates in the coherent manipulation and detection of information from a single spin. Except in a few special systems, so far, single spins cannot be manipulated coherently on the atomic scale, while spin coherence times can only be measured on spin ensembles. A new concept is needed for coherence measurements on arbitrary single spins. Here, the principal investigator (PI) will combine a novel time- and spin-resolved low-temperature scanning tunneling microscope (STM) with the concept of pulsed electron paramagnetic resonance. With this unique and innovative setup, he will be able to address long-standing problems, such as relaxation and coherence times of arbitrary single spin systems on the atomic scale as well as individual spin interactions with the immediate surroundings. Spin readout will be realized through the detection of the absolute spin polarization in the tunneling current by a superconducting tip based on the Meservey-Tedrow-Fulde effect, which the PI has recently demonstrated for the first time in STM. For the coherent excitation, a specially designed pulsed GHz light source will be implemented. The goal is to better understand the spin dynamics and coherence times of single spin systems as well as the spin interactions involved in the decay mechanisms. This will have direct impact on the feasibility of quantum spin information processing with single spin systems on different decoupling surfaces and their scalability at the atomic level. A successful demonstration will enhance the detection limit of spins by several orders of magnitude and fill important missing links in the understanding of spin dynamics and quantum computing with single spins.
Summary
One of the greatest challenges in exploiting the electron spin for information processing is that it is not a conserved quantity like the electron charge. In addition, spin lifetimes are rather short and correspondingly coherence is quickly lost. This challenge culminates in the coherent manipulation and detection of information from a single spin. Except in a few special systems, so far, single spins cannot be manipulated coherently on the atomic scale, while spin coherence times can only be measured on spin ensembles. A new concept is needed for coherence measurements on arbitrary single spins. Here, the principal investigator (PI) will combine a novel time- and spin-resolved low-temperature scanning tunneling microscope (STM) with the concept of pulsed electron paramagnetic resonance. With this unique and innovative setup, he will be able to address long-standing problems, such as relaxation and coherence times of arbitrary single spin systems on the atomic scale as well as individual spin interactions with the immediate surroundings. Spin readout will be realized through the detection of the absolute spin polarization in the tunneling current by a superconducting tip based on the Meservey-Tedrow-Fulde effect, which the PI has recently demonstrated for the first time in STM. For the coherent excitation, a specially designed pulsed GHz light source will be implemented. The goal is to better understand the spin dynamics and coherence times of single spin systems as well as the spin interactions involved in the decay mechanisms. This will have direct impact on the feasibility of quantum spin information processing with single spin systems on different decoupling surfaces and their scalability at the atomic level. A successful demonstration will enhance the detection limit of spins by several orders of magnitude and fill important missing links in the understanding of spin dynamics and quantum computing with single spins.
Max ERC Funding
2 469 136 €
Duration
Start date: 2016-07-01, End date: 2021-06-30
Project acronym Acclimatize
Project Hypothalamic mechanisms of thermal homeostasis and adaptation
Researcher (PI) Jan SIEMENS
Host Institution (HI) UNIVERSITATSKLINIKUM HEIDELBERG
Call Details Consolidator Grant (CoG), LS5, ERC-2017-COG
Summary Mammalian organisms possess the remarkable ability to maintain internal body temperature (Tcore) within a narrow range close to 37°C despite wide environmental temperature variations. The brain’s neural “thermostat” is made up by central circuits in the hypothalamic preoptic area (POA), which orchestrate peripheral thermoregulatory responses to maintain Tcore. Thermogenesis requires metabolic fuel, suggesting intricate connections between the thermoregulatory centre and hypothalamic circuits controlling energy balance. How the POA detects and integrates temperature and metabolic information to achieve thermal balance is largely unknown. A major question is whether this circuitry could be harnessed therapeutically to treat obesity.
We have recently identified the first known molecular temperature sensor in thermoregulatory neurons of the POA, transient receptor potential melastatin 2 (TRPM2), a thermo-sensitive ion channel. I aim to use TRPM2 as a molecular marker to gain access to and probe the function of thermoregulatory neurons in vivo. I propose a multidisciplinary approach, combining local, in vivo POA temperature stimulation with optogenetic circuit-mapping to uncover the molecular and cellular logic of the hypothalamic thermoregulatory centre and to assess its medical potential to counteract metabolic syndrome.
Acclimation is a beneficial adaptive process that fortifies thermal responses upon environmental temperature challenges. Thermoregulatory neuron plasticity is thought to mediate acclimation. Conversely, maladaptive thermoregulatory changes affect obesity. The cell-type-specific neuronal plasticity mechanisms underlying these changes within the POA, however, are unknown.
Using ex-vivo slice electrophysiology and in vivo imaging, I propose to characterize acclimation- and obesity-induced plasticity of thermoregulatory neurons. Ultimately, I aim to manipulate thermoregulatory neuron plasticity to test its potential counter-balancing effect on obesity.
Summary
Mammalian organisms possess the remarkable ability to maintain internal body temperature (Tcore) within a narrow range close to 37°C despite wide environmental temperature variations. The brain’s neural “thermostat” is made up by central circuits in the hypothalamic preoptic area (POA), which orchestrate peripheral thermoregulatory responses to maintain Tcore. Thermogenesis requires metabolic fuel, suggesting intricate connections between the thermoregulatory centre and hypothalamic circuits controlling energy balance. How the POA detects and integrates temperature and metabolic information to achieve thermal balance is largely unknown. A major question is whether this circuitry could be harnessed therapeutically to treat obesity.
We have recently identified the first known molecular temperature sensor in thermoregulatory neurons of the POA, transient receptor potential melastatin 2 (TRPM2), a thermo-sensitive ion channel. I aim to use TRPM2 as a molecular marker to gain access to and probe the function of thermoregulatory neurons in vivo. I propose a multidisciplinary approach, combining local, in vivo POA temperature stimulation with optogenetic circuit-mapping to uncover the molecular and cellular logic of the hypothalamic thermoregulatory centre and to assess its medical potential to counteract metabolic syndrome.
Acclimation is a beneficial adaptive process that fortifies thermal responses upon environmental temperature challenges. Thermoregulatory neuron plasticity is thought to mediate acclimation. Conversely, maladaptive thermoregulatory changes affect obesity. The cell-type-specific neuronal plasticity mechanisms underlying these changes within the POA, however, are unknown.
Using ex-vivo slice electrophysiology and in vivo imaging, I propose to characterize acclimation- and obesity-induced plasticity of thermoregulatory neurons. Ultimately, I aim to manipulate thermoregulatory neuron plasticity to test its potential counter-balancing effect on obesity.
Max ERC Funding
1 902 500 €
Duration
Start date: 2018-09-01, End date: 2023-08-31
Project acronym ACoolTouch
Project Neural mechanisms of multisensory perceptual binding
Researcher (PI) James Francis Alexander Poulet
Host Institution (HI) MAX DELBRUECK CENTRUM FUER MOLEKULARE MEDIZIN IN DER HELMHOLTZ-GEMEINSCHAFT (MDC)
Call Details Consolidator Grant (CoG), LS5, ERC-2015-CoG
Summary Sensory perception involves the discrimination and binding of multiple modalities of sensory input. This is especially evident in the somatosensory system where different modalities of sensory input, including thermal and mechanosensory, are combined to generate a unified percept. The neural mechanisms of multisensory binding are unknown, in part because sensory perception is typically studied within a single modality in a single brain region. I propose a multi-level approach to investigate thermo-tactile processing in the mouse forepaw system from the primary sensory afferent neurons to thalamo-cortical circuits and behaviour.
The mouse forepaw system is the ideal system to investigate multisensory binding as the sensory afferent neurons are well investigated, cell type-specific lines are available, in vivo optogenetic manipulation is possible both in sensory afferent neurons and central circuits and we have developed high-resolution somatosensory perception behaviours. We have previously shown that mouse primary somatosensory forepaw cortical neurons respond to both tactile and thermal stimuli and are required for non-noxious cooling perception. With multimodal neurons how, then, is it possible to both discriminate and bind thermal and tactile stimuli?
I propose 3 objectives to address this question. We will first, perform functional mapping of the thermal and tactile pathways to cortex; second, investigate the neural mechanisms of thermo-tactile discrimination in behaving mice; and third, compare neural processing during two thermo-tactile binding tasks, the first using passively applied stimuli, and the second, active manipulation of thermal objects.
At each stage we will perform cell type-specific neural recordings and causal optogenetic manipulations in awake and behaving mice. Our multi-level approach will provide a comprehensive investigation into how the brain performs multisensory perceptual binding: a fundamental yet unsolved problem in neuroscience.
Summary
Sensory perception involves the discrimination and binding of multiple modalities of sensory input. This is especially evident in the somatosensory system where different modalities of sensory input, including thermal and mechanosensory, are combined to generate a unified percept. The neural mechanisms of multisensory binding are unknown, in part because sensory perception is typically studied within a single modality in a single brain region. I propose a multi-level approach to investigate thermo-tactile processing in the mouse forepaw system from the primary sensory afferent neurons to thalamo-cortical circuits and behaviour.
The mouse forepaw system is the ideal system to investigate multisensory binding as the sensory afferent neurons are well investigated, cell type-specific lines are available, in vivo optogenetic manipulation is possible both in sensory afferent neurons and central circuits and we have developed high-resolution somatosensory perception behaviours. We have previously shown that mouse primary somatosensory forepaw cortical neurons respond to both tactile and thermal stimuli and are required for non-noxious cooling perception. With multimodal neurons how, then, is it possible to both discriminate and bind thermal and tactile stimuli?
I propose 3 objectives to address this question. We will first, perform functional mapping of the thermal and tactile pathways to cortex; second, investigate the neural mechanisms of thermo-tactile discrimination in behaving mice; and third, compare neural processing during two thermo-tactile binding tasks, the first using passively applied stimuli, and the second, active manipulation of thermal objects.
At each stage we will perform cell type-specific neural recordings and causal optogenetic manipulations in awake and behaving mice. Our multi-level approach will provide a comprehensive investigation into how the brain performs multisensory perceptual binding: a fundamental yet unsolved problem in neuroscience.
Max ERC Funding
1 999 877 €
Duration
Start date: 2016-09-01, End date: 2021-08-31
Project acronym ACOPS
Project Advanced Coherent Ultrafast Laser Pulse Stacking
Researcher (PI) Jens Limpert
Host Institution (HI) FRIEDRICH-SCHILLER-UNIVERSITAT JENA
Call Details Consolidator Grant (CoG), PE2, ERC-2013-CoG
Summary "An important driver of scientific progress has always been the envisioning of applications far beyond existing technological capabilities. Such thinking creates new challenges for physicists, driven by the groundbreaking nature of the anticipated application. In the case of laser physics, one of these applications is laser wake-field particle acceleration and possible future uses thereof, such as in collider experiments, or for medical applications such as cancer treatment. To accelerate electrons and positrons to TeV-energies, a laser architecture is required that allows for the combination of high efficiency, Petawatt peak powers, and Megawatt average powers. Developing such a laser system would be a challenging task that might take decades of aggressive research, development, and, most important, revolutionary approaches and innovative ideas.
The goal of the ACOPS project is to develop a compact, efficient, scalable, and cost-effective high-average and high-peak power ultra-short pulse laser concept.
The proposed approach to this goal relies on the spatially and temporally separated amplification of ultrashort laser pulses in waveguide structures, followed by coherent combination into a single train of pulses with increased average power and pulse energy. This combination can be realized through the coherent addition of the output beams of spatially separated amplifiers, combined with the pulse stacking of temporally separated pulses in passive enhancement cavities, employing a fast-switching element as cavity dumper.
Therefore, the three main tasks are the development of kW-class high-repetition-rate driving lasers, the investigation of non-steady state pulse enhancement in passive cavities, and the development of a suitable dumping element.
If successful, the proposed concept would undoubtedly provide a tool that would allow researchers to surpass the current limits in high-field physics and accelerator science."
Summary
"An important driver of scientific progress has always been the envisioning of applications far beyond existing technological capabilities. Such thinking creates new challenges for physicists, driven by the groundbreaking nature of the anticipated application. In the case of laser physics, one of these applications is laser wake-field particle acceleration and possible future uses thereof, such as in collider experiments, or for medical applications such as cancer treatment. To accelerate electrons and positrons to TeV-energies, a laser architecture is required that allows for the combination of high efficiency, Petawatt peak powers, and Megawatt average powers. Developing such a laser system would be a challenging task that might take decades of aggressive research, development, and, most important, revolutionary approaches and innovative ideas.
The goal of the ACOPS project is to develop a compact, efficient, scalable, and cost-effective high-average and high-peak power ultra-short pulse laser concept.
The proposed approach to this goal relies on the spatially and temporally separated amplification of ultrashort laser pulses in waveguide structures, followed by coherent combination into a single train of pulses with increased average power and pulse energy. This combination can be realized through the coherent addition of the output beams of spatially separated amplifiers, combined with the pulse stacking of temporally separated pulses in passive enhancement cavities, employing a fast-switching element as cavity dumper.
Therefore, the three main tasks are the development of kW-class high-repetition-rate driving lasers, the investigation of non-steady state pulse enhancement in passive cavities, and the development of a suitable dumping element.
If successful, the proposed concept would undoubtedly provide a tool that would allow researchers to surpass the current limits in high-field physics and accelerator science."
Max ERC Funding
1 881 040 €
Duration
Start date: 2014-02-01, End date: 2019-01-31
Project acronym Active-DNA
Project Computationally Active DNA Nanostructures
Researcher (PI) Damien WOODS
Host Institution (HI) NATIONAL UNIVERSITY OF IRELAND MAYNOOTH
Call Details Consolidator Grant (CoG), PE6, ERC-2017-COG
Summary During the 20th century computer technology evolved from bulky, slow, special purpose mechanical engines to the now ubiquitous silicon chips and software that are one of the pinnacles of human ingenuity. The goal of the field of molecular programming is to take the next leap and build a new generation of matter-based computers using DNA, RNA and proteins. This will be accomplished by computer scientists, physicists and chemists designing molecules to execute ``wet'' nanoscale programs in test tubes. The workflow includes proposing theoretical models, mathematically proving their computational properties, physical modelling and implementation in the wet-lab.
The past decade has seen remarkable progress at building static 2D and 3D DNA nanostructures. However, unlike biological macromolecules and complexes that are built via specified self-assembly pathways, that execute robotic-like movements, and that undergo evolution, the activity of human-engineered nanostructures is severely limited. We will need sophisticated algorithmic ideas to build structures that rival active living systems. Active-DNA, aims to address this challenge by achieving a number of objectives on computation, DNA-based self-assembly and molecular robotics. Active-DNA research work will range from defining models and proving theorems that characterise the computational and expressive capabilities of such active programmable materials to experimental work implementing active DNA nanostructures in the wet-lab.
Summary
During the 20th century computer technology evolved from bulky, slow, special purpose mechanical engines to the now ubiquitous silicon chips and software that are one of the pinnacles of human ingenuity. The goal of the field of molecular programming is to take the next leap and build a new generation of matter-based computers using DNA, RNA and proteins. This will be accomplished by computer scientists, physicists and chemists designing molecules to execute ``wet'' nanoscale programs in test tubes. The workflow includes proposing theoretical models, mathematically proving their computational properties, physical modelling and implementation in the wet-lab.
The past decade has seen remarkable progress at building static 2D and 3D DNA nanostructures. However, unlike biological macromolecules and complexes that are built via specified self-assembly pathways, that execute robotic-like movements, and that undergo evolution, the activity of human-engineered nanostructures is severely limited. We will need sophisticated algorithmic ideas to build structures that rival active living systems. Active-DNA, aims to address this challenge by achieving a number of objectives on computation, DNA-based self-assembly and molecular robotics. Active-DNA research work will range from defining models and proving theorems that characterise the computational and expressive capabilities of such active programmable materials to experimental work implementing active DNA nanostructures in the wet-lab.
Max ERC Funding
2 349 603 €
Duration
Start date: 2018-11-01, End date: 2023-10-31
Project acronym AdaptoSCOPE
Project Using cis-regulatory mutations to highlight polygenic adaptation in natural plant systems
Researcher (PI) Juliette de Meaux
Host Institution (HI) UNIVERSITAET ZU KOELN
Call Details Consolidator Grant (CoG), LS8, ERC-2014-CoG
Summary The goal of this project is to demonstrate that novel aspects of the molecular basis of Darwinian adaptation can be discovered if the polygenic basis of adaptation is taken into account. This project will use the genome-wide distribution of cis-regulatory variants to discover the molecular pathways that are optimized during adaptation via accumulation of small effect mutations. Current approaches include scans for outlier genes with strong population genetics signatures of selection, or large effect QTL associating with fitness. They can only reveal a small subset of the molecular changes recruited along adaptive paths. Here, instead, the distribution of small effect mutations will be used to make inferences on the targets of polygenic adaptation across divergent populations in each of the two closely related species, A. thaliana and A. lyrata. These species are both found at diverse latitudes and show sign of local adaptation to climatic differences. Mutations affecting cis-regulation will be identified in leaves of plants exposed to various temperature regimes triggering phenotypic responses of adaptive relevance. Their distribution in clusters of functionally connected genes will be quantified. The phylogeographic differences in the distribution of the mutations will be used to disentangle neutral from adaptive clusters of functionally connected genes in each of the two species. This project will identify the molecular pathways subjected collectively to natural selection and provide a completely novel view on adaptive landscapes. It will further examine whether local adaptation occurs by convergent evolution of molecular systems in plants. This approach has the potential to find broad applications in ecology and agriculture.
Summary
The goal of this project is to demonstrate that novel aspects of the molecular basis of Darwinian adaptation can be discovered if the polygenic basis of adaptation is taken into account. This project will use the genome-wide distribution of cis-regulatory variants to discover the molecular pathways that are optimized during adaptation via accumulation of small effect mutations. Current approaches include scans for outlier genes with strong population genetics signatures of selection, or large effect QTL associating with fitness. They can only reveal a small subset of the molecular changes recruited along adaptive paths. Here, instead, the distribution of small effect mutations will be used to make inferences on the targets of polygenic adaptation across divergent populations in each of the two closely related species, A. thaliana and A. lyrata. These species are both found at diverse latitudes and show sign of local adaptation to climatic differences. Mutations affecting cis-regulation will be identified in leaves of plants exposed to various temperature regimes triggering phenotypic responses of adaptive relevance. Their distribution in clusters of functionally connected genes will be quantified. The phylogeographic differences in the distribution of the mutations will be used to disentangle neutral from adaptive clusters of functionally connected genes in each of the two species. This project will identify the molecular pathways subjected collectively to natural selection and provide a completely novel view on adaptive landscapes. It will further examine whether local adaptation occurs by convergent evolution of molecular systems in plants. This approach has the potential to find broad applications in ecology and agriculture.
Max ERC Funding
1 683 120 €
Duration
Start date: 2015-09-01, End date: 2020-08-31
Project acronym AEDMOS
Project Attosecond Electron Dynamics in MOlecular Systems
Researcher (PI) Reinhard Kienberger
Host Institution (HI) TECHNISCHE UNIVERSITAET MUENCHEN
Call Details Consolidator Grant (CoG), PE2, ERC-2014-CoG
Summary Advanced insight into ever smaller structures of matter and their ever faster dynamics hold promise for pushing the frontiers of many fields in science and technology. Time-domain investigations of ultrafast microscopic processes are most successfully carried out by pump/probe experiments. Intense waveform-controlled few-cycle near-infrared laser pulses combined with isolated sub-femtosecond XUV (extreme UV) pulses have made possible direct access to electron motion on the atomic scale. These tools along with the techniques of laser-field-controlled XUV photoemission (“attosecond streaking”) and ultrafast UV-pump/XUV-probe spectroscopy have permitted real-time observation of electronic motion in experiments performed on atoms in the gas phase and of electronic transport processes in solids.
The purpose of this project is to to get insight into intra- and inter-molecular electron dynamics by extending attosecond spectroscopy to these processes. AEDMOS will allow control and real-time observation of a wide range of hyperfast fundamental processes directly on their natural, i.e. attosecond (1 as = EXP-18 s) time scale in molecules and molecular structures. In previous work we have successfully developed attosecond tools and techniques. By combining them with our experience in UHV technology and target preparation in a new beamline to be created in the framework of this project, we aim at investigating charge migration and transport in supramolecular assemblies, ultrafast electron dynamics in photocatalysis and dynamics of electron correlation in high-TC superconductors. These dynamics – of electronic excitation, exciton formation, relaxation, electron correlation and wave packet motion – are of broad scientific interest reaching from biomedicine to chemistry and physics and are pertinent to the development of many modern technologies including molecular electronics, optoelectronics, photovoltaics, light-to-chemical energy conversion and lossless energy transfer.
Summary
Advanced insight into ever smaller structures of matter and their ever faster dynamics hold promise for pushing the frontiers of many fields in science and technology. Time-domain investigations of ultrafast microscopic processes are most successfully carried out by pump/probe experiments. Intense waveform-controlled few-cycle near-infrared laser pulses combined with isolated sub-femtosecond XUV (extreme UV) pulses have made possible direct access to electron motion on the atomic scale. These tools along with the techniques of laser-field-controlled XUV photoemission (“attosecond streaking”) and ultrafast UV-pump/XUV-probe spectroscopy have permitted real-time observation of electronic motion in experiments performed on atoms in the gas phase and of electronic transport processes in solids.
The purpose of this project is to to get insight into intra- and inter-molecular electron dynamics by extending attosecond spectroscopy to these processes. AEDMOS will allow control and real-time observation of a wide range of hyperfast fundamental processes directly on their natural, i.e. attosecond (1 as = EXP-18 s) time scale in molecules and molecular structures. In previous work we have successfully developed attosecond tools and techniques. By combining them with our experience in UHV technology and target preparation in a new beamline to be created in the framework of this project, we aim at investigating charge migration and transport in supramolecular assemblies, ultrafast electron dynamics in photocatalysis and dynamics of electron correlation in high-TC superconductors. These dynamics – of electronic excitation, exciton formation, relaxation, electron correlation and wave packet motion – are of broad scientific interest reaching from biomedicine to chemistry and physics and are pertinent to the development of many modern technologies including molecular electronics, optoelectronics, photovoltaics, light-to-chemical energy conversion and lossless energy transfer.
Max ERC Funding
1 999 375 €
Duration
Start date: 2015-05-01, End date: 2020-04-30
Project acronym AMPLIFY
Project Amplifying Human Perception Through Interactive Digital Technologies
Researcher (PI) Albrecht Schmidt
Host Institution (HI) LUDWIG-MAXIMILIANS-UNIVERSITAET MUENCHEN
Call Details Consolidator Grant (CoG), PE6, ERC-2015-CoG
Summary Current technical sensor systems offer capabilities that are superior to human perception. Cameras can capture a spectrum that is wider than visible light, high-speed cameras can show movements that are invisible to the human eye, and directional microphones can pick up sounds at long distances. The vision of this project is to lay a foundation for the creation of digital technologies that provide novel sensory experiences and new perceptual capabilities for humans that are natural and intuitive to use. In a first step, the project will assess the feasibility of creating artificial human senses that provide new perceptual channels to the human mind, without increasing the experienced cognitive load. A particular focus is on creating intuitive and natural control mechanisms for amplified senses using eye gaze, muscle activity, and brain signals. Through the creation of a prototype that provides mildly unpleasant stimulations in response to perceived information, the feasibility of implementing an artificial reflex will be experimentally explored. The project will quantify the effectiveness of new senses and artificial perceptual aids compared to the baseline of unaugmented perception. The overall objective is to systematically research, explore, and model new means for increasing the human intake of information in order to lay the foundation for new and improved human senses enabled through digital technologies and to enable artificial reflexes. The ground-breaking contributions of this project are (1) to demonstrate the feasibility of reliably implementing amplified senses and new perceptual capabilities, (2) to prove the possibility of creating an artificial reflex, (3) to provide an example implementation of amplified cognition that is empirically validated, and (4) to develop models, concepts, components, and platforms that will enable and ease the creation of interactive systems that measurably increase human perceptual capabilities.
Summary
Current technical sensor systems offer capabilities that are superior to human perception. Cameras can capture a spectrum that is wider than visible light, high-speed cameras can show movements that are invisible to the human eye, and directional microphones can pick up sounds at long distances. The vision of this project is to lay a foundation for the creation of digital technologies that provide novel sensory experiences and new perceptual capabilities for humans that are natural and intuitive to use. In a first step, the project will assess the feasibility of creating artificial human senses that provide new perceptual channels to the human mind, without increasing the experienced cognitive load. A particular focus is on creating intuitive and natural control mechanisms for amplified senses using eye gaze, muscle activity, and brain signals. Through the creation of a prototype that provides mildly unpleasant stimulations in response to perceived information, the feasibility of implementing an artificial reflex will be experimentally explored. The project will quantify the effectiveness of new senses and artificial perceptual aids compared to the baseline of unaugmented perception. The overall objective is to systematically research, explore, and model new means for increasing the human intake of information in order to lay the foundation for new and improved human senses enabled through digital technologies and to enable artificial reflexes. The ground-breaking contributions of this project are (1) to demonstrate the feasibility of reliably implementing amplified senses and new perceptual capabilities, (2) to prove the possibility of creating an artificial reflex, (3) to provide an example implementation of amplified cognition that is empirically validated, and (4) to develop models, concepts, components, and platforms that will enable and ease the creation of interactive systems that measurably increase human perceptual capabilities.
Max ERC Funding
1 925 250 €
Duration
Start date: 2016-07-01, End date: 2021-06-30
Project acronym AMPLITUDES
Project Novel structures in scattering amplitudes
Researcher (PI) Johannes Martin HENN
Host Institution (HI) JOHANNES GUTENBERG-UNIVERSITAT MAINZ
Call Details Consolidator Grant (CoG), PE2, ERC-2016-COG
Summary This project focuses on developing quantum field theory methods and applying them to the phenomenology of elementary particles. At the Large Hadron Collider (LHC) our current best theoretical understanding of particle physics is being tested against experiment by measuring e.g. properties of the recently discovered Higgs boson. With run two of the LHC, currently underway, the experimental accuracy will further increase. Theoretical predictions matching the latter are urgently needed. Obtaining these requires extremely difficult calculations of scattering amplitudes and cross sections in quantum field theory, including calculations to correctly describe large contributions due to long-distance physics in the latter. Major obstacles in such computations are the large number of Feynman diagrams that are difficult to handle, even with the help of modern computers, and the computation of Feynman loop integrals. To address these issues, we will develop innovative methods that are inspired by new structures found in supersymmetric field theories. We will extend the scope of the differential equations method for computing Feynman integrals, and apply it to scattering processes that are needed for phenomenology, but too complicated to analyze using current methods. Our results will help measure fundamental parameters of Nature, such as, for example, couplings of the Higgs boson, with unprecedented precision. Moreover, by accurately predicting backgrounds from known physics, our results will also be invaluable for searches of new particles.
Summary
This project focuses on developing quantum field theory methods and applying them to the phenomenology of elementary particles. At the Large Hadron Collider (LHC) our current best theoretical understanding of particle physics is being tested against experiment by measuring e.g. properties of the recently discovered Higgs boson. With run two of the LHC, currently underway, the experimental accuracy will further increase. Theoretical predictions matching the latter are urgently needed. Obtaining these requires extremely difficult calculations of scattering amplitudes and cross sections in quantum field theory, including calculations to correctly describe large contributions due to long-distance physics in the latter. Major obstacles in such computations are the large number of Feynman diagrams that are difficult to handle, even with the help of modern computers, and the computation of Feynman loop integrals. To address these issues, we will develop innovative methods that are inspired by new structures found in supersymmetric field theories. We will extend the scope of the differential equations method for computing Feynman integrals, and apply it to scattering processes that are needed for phenomenology, but too complicated to analyze using current methods. Our results will help measure fundamental parameters of Nature, such as, for example, couplings of the Higgs boson, with unprecedented precision. Moreover, by accurately predicting backgrounds from known physics, our results will also be invaluable for searches of new particles.
Max ERC Funding
2 000 000 €
Duration
Start date: 2017-10-01, End date: 2022-09-30
Project acronym APOLLO
Project Advanced Signal Processing Technologies for Wireless Powered Communications
Researcher (PI) Ioannis Krikidis
Host Institution (HI) UNIVERSITY OF CYPRUS
Call Details Consolidator Grant (CoG), PE7, ERC-2018-COG
Summary Wireless power transfer (WPT), pioneered by Tesla, is an idea at least as old as radio communications. However, on the one hand, due to health concerns and the large antenna dimensions required for transmission of high energy levels, until recently WPT has been limited mostly to very short distance applications. On the other hand, recent advances in silicon technology have significantly reduced the energy needs of electronic systems, making WPT over radio waves a potential source of energy for low power devices. Although WPT through radio waves has already found various short-range applications (such as the radio-frequency identification technology, healthcare monitoring etc.), its integration as a building block in the operation of wireless communications systems is still unexploited. On the other hand, conventional radio wave based information and energy transmissions have largely been designed separately. However, many applications can benefit from simultaneous wireless information and power transfer (SWIPT).
The overall objective of the APOLLO project is to study the integration of WPT/SWIPT technology into future wireless communication systems. Compared to past and current research efforts in this area, our technical approach is deeply interdisciplinary and more comprehensive, combining the expertise of wireless communications, control theory, information theory, optimization, and electronics/microwave engineering.
The key outcomes of the project include: 1) a rigorous and complete mathematical theory for WPT/SWIPT via information/communication/control theoretic studies; 2) new physical and cross-layer mechanisms that will enable the integration of WPT/SWIPT into future communication systems; 3) new network architectures that will fully exploit potential benefits of WPT/SWIPT; and 4) development of a proof-of-concept by implementing highly-efficient and multi-band metamaterial energy harvesting sensors for SWIPT.
Summary
Wireless power transfer (WPT), pioneered by Tesla, is an idea at least as old as radio communications. However, on the one hand, due to health concerns and the large antenna dimensions required for transmission of high energy levels, until recently WPT has been limited mostly to very short distance applications. On the other hand, recent advances in silicon technology have significantly reduced the energy needs of electronic systems, making WPT over radio waves a potential source of energy for low power devices. Although WPT through radio waves has already found various short-range applications (such as the radio-frequency identification technology, healthcare monitoring etc.), its integration as a building block in the operation of wireless communications systems is still unexploited. On the other hand, conventional radio wave based information and energy transmissions have largely been designed separately. However, many applications can benefit from simultaneous wireless information and power transfer (SWIPT).
The overall objective of the APOLLO project is to study the integration of WPT/SWIPT technology into future wireless communication systems. Compared to past and current research efforts in this area, our technical approach is deeply interdisciplinary and more comprehensive, combining the expertise of wireless communications, control theory, information theory, optimization, and electronics/microwave engineering.
The key outcomes of the project include: 1) a rigorous and complete mathematical theory for WPT/SWIPT via information/communication/control theoretic studies; 2) new physical and cross-layer mechanisms that will enable the integration of WPT/SWIPT into future communication systems; 3) new network architectures that will fully exploit potential benefits of WPT/SWIPT; and 4) development of a proof-of-concept by implementing highly-efficient and multi-band metamaterial energy harvesting sensors for SWIPT.
Max ERC Funding
1 930 625 €
Duration
Start date: 2019-07-01, End date: 2024-06-30
Project acronym APOSITE
Project Apoptotic foci: composition, structure and dynamics
Researcher (PI) Ana GARCIA SAEZ
Host Institution (HI) EBERHARD KARLS UNIVERSITAET TUEBINGEN
Call Details Consolidator Grant (CoG), LS3, ERC-2018-COG
Summary Apoptotic cell death is essential for development, immune function or tissue homeostasis, and it is often deregulated in disease. Mitochondrial outer membrane permeabilization (MOMP) is central for apoptosis execution and plays a key role in its inflammatory outcome. Knowing the architecture of the macromolecular machineries mediating MOMP is crucial for understanding their function and for the clinical use of apoptosis.
Our recent work reveals that Bax and Bak dimers form distinct line, arc and ring assemblies at specific apoptotic foci to mediate MOMP. However, the molecular structure and mechanisms controlling the spatiotemporal formation and range of action of the apoptotic foci are missing. To address this fundamental gap in our knowledge, we aim to unravel the composition, dynamics and structure of apoptotic foci and to understand how they are integrated to orchestrate function. We will reach this goal by building on our expertise in cell death and cutting-edge imaging and by developing a new analytical pipeline to:
1) Identify the composition of apoptotic foci using in situ proximity-dependent labeling and extraction of near-native Bax/Bak membrane complexes coupled to mass spectrometry.
2) Define their contribution to apoptosis and its immunogenicity and establish their assembly dynamics to correlate it with apoptosis progression by live cell imaging.
3) Determine the stoichiometry and structural organization of the apoptotic foci by combining single molecule fluorescence and advanced electron microscopies.
This multidisciplinary approach offers high chances to solve the long-standing question of how Bax and Bak mediate MOMP. APOSITE will provide textbook knowledge of the mitochondrial contribution to cell death and inflammation. The implementation of this new analytical framework will open novel research avenues in membrane and organelle biology. Ultimately, understanding of Bax and Bak structure/function will help develop apoptosis modulators for medicine.
Summary
Apoptotic cell death is essential for development, immune function or tissue homeostasis, and it is often deregulated in disease. Mitochondrial outer membrane permeabilization (MOMP) is central for apoptosis execution and plays a key role in its inflammatory outcome. Knowing the architecture of the macromolecular machineries mediating MOMP is crucial for understanding their function and for the clinical use of apoptosis.
Our recent work reveals that Bax and Bak dimers form distinct line, arc and ring assemblies at specific apoptotic foci to mediate MOMP. However, the molecular structure and mechanisms controlling the spatiotemporal formation and range of action of the apoptotic foci are missing. To address this fundamental gap in our knowledge, we aim to unravel the composition, dynamics and structure of apoptotic foci and to understand how they are integrated to orchestrate function. We will reach this goal by building on our expertise in cell death and cutting-edge imaging and by developing a new analytical pipeline to:
1) Identify the composition of apoptotic foci using in situ proximity-dependent labeling and extraction of near-native Bax/Bak membrane complexes coupled to mass spectrometry.
2) Define their contribution to apoptosis and its immunogenicity and establish their assembly dynamics to correlate it with apoptosis progression by live cell imaging.
3) Determine the stoichiometry and structural organization of the apoptotic foci by combining single molecule fluorescence and advanced electron microscopies.
This multidisciplinary approach offers high chances to solve the long-standing question of how Bax and Bak mediate MOMP. APOSITE will provide textbook knowledge of the mitochondrial contribution to cell death and inflammation. The implementation of this new analytical framework will open novel research avenues in membrane and organelle biology. Ultimately, understanding of Bax and Bak structure/function will help develop apoptosis modulators for medicine.
Max ERC Funding
2 000 000 €
Duration
Start date: 2019-04-01, End date: 2024-03-31
Project acronym ASIAPAST
Project From herds to empire: Biomolecular and zooarchaeological investigations of mobile pastoralism in the ancient Eurasian steppe
Researcher (PI) Cheryl Ann Makarewicz
Host Institution (HI) CHRISTIAN-ALBRECHTS-UNIVERSITAET ZU KIEL
Call Details Consolidator Grant (CoG), SH6, ERC-2017-COG
Summary The emergence of mobile pastoralism in the Eurasian steppe five thousand years ago marked a unique transformation in human lifeways where, for the first time, people relied almost exclusively on herd animals of sheep, goat, cattle, and horses for sustenance and as symbols. Mobile pastoralism also generated altogether new forms of socio-political organization exceptional to the steppe that ultimately laid the foundation for nomadic states and empires. However, there remain striking gaps in our knowledge of how the pastoralist niche spread and evolved across Eurasia in the past and influenced cultural trajectories that frame the human-herd systems of today. Little is known about the scale of pastoralist movements connected with the initial translocation of domesticated animals, how mobility became embedded in pastoralist life, or how movement contributed to the formation of sophisticated political networks. There is a poor understanding of the character of herd animal husbandry strategies that were central to pastoralist subsistence and how these co-evolved alongside pastoralist dietary intake and ritual use of herd animals. We have a remarkably poor understanding of what pastoralists ate, especially the dietary contribution of dairy products - the quintessential dietary cornerstone food of pastoralist societies.
ASIAPAST addresses these gaps through a biomolecular approach that recovers the dietary and mobility histories of pastoralists and their animals recorded in bones, teeth, and pottery. This project pairs these methods to detailed analyses of the economic and symbolic use of herd animals preserved in zooarchaeological archives. These investigations draw from materials obtained from key sites that capture the transition to mobile pastoralism, its intensification, and emergence of trans-regional political structures located across the culturally connected regions of Mongolia, Kazakhstan, Russia, Kyrgyzstan, and Uzbekistan.
Summary
The emergence of mobile pastoralism in the Eurasian steppe five thousand years ago marked a unique transformation in human lifeways where, for the first time, people relied almost exclusively on herd animals of sheep, goat, cattle, and horses for sustenance and as symbols. Mobile pastoralism also generated altogether new forms of socio-political organization exceptional to the steppe that ultimately laid the foundation for nomadic states and empires. However, there remain striking gaps in our knowledge of how the pastoralist niche spread and evolved across Eurasia in the past and influenced cultural trajectories that frame the human-herd systems of today. Little is known about the scale of pastoralist movements connected with the initial translocation of domesticated animals, how mobility became embedded in pastoralist life, or how movement contributed to the formation of sophisticated political networks. There is a poor understanding of the character of herd animal husbandry strategies that were central to pastoralist subsistence and how these co-evolved alongside pastoralist dietary intake and ritual use of herd animals. We have a remarkably poor understanding of what pastoralists ate, especially the dietary contribution of dairy products - the quintessential dietary cornerstone food of pastoralist societies.
ASIAPAST addresses these gaps through a biomolecular approach that recovers the dietary and mobility histories of pastoralists and their animals recorded in bones, teeth, and pottery. This project pairs these methods to detailed analyses of the economic and symbolic use of herd animals preserved in zooarchaeological archives. These investigations draw from materials obtained from key sites that capture the transition to mobile pastoralism, its intensification, and emergence of trans-regional political structures located across the culturally connected regions of Mongolia, Kazakhstan, Russia, Kyrgyzstan, and Uzbekistan.
Max ERC Funding
1 999 145 €
Duration
Start date: 2018-04-01, End date: 2023-03-31
Project acronym ASTROFLOW
Project The influence of stellar outflows on exoplanetary mass loss
Researcher (PI) Aline VIDOTTO
Host Institution (HI) THE PROVOST, FELLOWS, FOUNDATION SCHOLARS & THE OTHER MEMBERS OF BOARD OF THE COLLEGE OF THE HOLY & UNDIVIDED TRINITY OF QUEEN ELIZABETH NEAR DUBLIN
Call Details Consolidator Grant (CoG), PE9, ERC-2018-COG
Summary ASTROFLOW aims to make ground-breaking progress in our physical understanding of exoplanetary mass loss, by quantifying the influence of stellar outflows on atmospheric escape of close-in exoplanets. Escape plays a key role in planetary evolution, population, and potential to develop life. Stellar irradiation and outflows affect planetary mass loss: irradiation heats planetary atmospheres, which inflate and more likely escape; outflows cause pressure confinement around otherwise freely escaping atmospheres. This external pressure can increase, reduce or even suppress escape rates; its effects on exoplanetary mass loss remain largely unexplored due to the complexity of such interactions. I will fill this knowledge gap by developing a novel modelling framework of atmospheric escape that will, for the first time, consider the effects of realistic stellar outflows on exoplanetary mass loss. My expertise in stellar wind theory and 3D magnetohydrodynamic simulations is crucial for producing the next-generation models of planetary escape. My framework will consist of state-of-the-art, time-dependent, 3D simulations of stellar outflows (Method 1), which will be coupled to novel 3D simulations of atmospheric escape (Method 2). My models will account for the major underlying physical processes of mass loss. With this, I will determine the response of planetary mass loss to realistic stellar particle, magnetic and radiation environments and will characterise the physical conditions of the escaping material. I will compute how its extinction varies during transit and compare synthetic line profiles to atmospheric escape observations from, eg, Hubble and our NASA cubesat CUTE. Strong synergy with upcoming observations (JWST, TESS, SPIRou, CARMENES) also exists. Determining the lifetime of planetary atmospheres is essential to understanding populations of exoplanets. ASTROFLOW’s work will be the foundation for future research of how exoplanets evolve under mass-loss processes.
Summary
ASTROFLOW aims to make ground-breaking progress in our physical understanding of exoplanetary mass loss, by quantifying the influence of stellar outflows on atmospheric escape of close-in exoplanets. Escape plays a key role in planetary evolution, population, and potential to develop life. Stellar irradiation and outflows affect planetary mass loss: irradiation heats planetary atmospheres, which inflate and more likely escape; outflows cause pressure confinement around otherwise freely escaping atmospheres. This external pressure can increase, reduce or even suppress escape rates; its effects on exoplanetary mass loss remain largely unexplored due to the complexity of such interactions. I will fill this knowledge gap by developing a novel modelling framework of atmospheric escape that will, for the first time, consider the effects of realistic stellar outflows on exoplanetary mass loss. My expertise in stellar wind theory and 3D magnetohydrodynamic simulations is crucial for producing the next-generation models of planetary escape. My framework will consist of state-of-the-art, time-dependent, 3D simulations of stellar outflows (Method 1), which will be coupled to novel 3D simulations of atmospheric escape (Method 2). My models will account for the major underlying physical processes of mass loss. With this, I will determine the response of planetary mass loss to realistic stellar particle, magnetic and radiation environments and will characterise the physical conditions of the escaping material. I will compute how its extinction varies during transit and compare synthetic line profiles to atmospheric escape observations from, eg, Hubble and our NASA cubesat CUTE. Strong synergy with upcoming observations (JWST, TESS, SPIRou, CARMENES) also exists. Determining the lifetime of planetary atmospheres is essential to understanding populations of exoplanets. ASTROFLOW’s work will be the foundation for future research of how exoplanets evolve under mass-loss processes.
Max ERC Funding
1 999 956 €
Duration
Start date: 2019-09-01, End date: 2024-08-31
Project acronym ASTRUm
Project Astrophysics with Stored Highy Charged Radionuclides
Researcher (PI) Yury Litvinov
Host Institution (HI) GSI HELMHOLTZZENTRUM FUER SCHWERIONENFORSCHUNG GMBH
Call Details Consolidator Grant (CoG), PE2, ERC-2015-CoG
Summary The main goal of ASTRUm is to employ stored and cooled radioactive ions for forefront nuclear astrophysics research. Four key experiments are proposed to be conducted at GSI in Darmstadt, which holds the only facility to date capable of storing highly charged radionuclides in the required element and energy range. The proposed experiments can hardly be conducted by any other technique or method.
The weak decay matrix element for the transition between the 2.3 keV state in 205Pb and the ground state of 205Tl will be measured via the bound state beta decay measurement of fully ionized 205Tl81+. This will provide the required data to determine the solar pp-neutrino flux integrated over the last 5 million years and will allow us to unveil the astrophysical conditions prior to the formation of the solar system.
The measurements of the alpha-decay width of the 4.033 MeV excited state in 19Ne will allow us to constrain the conditions for the ignition of the rp-process in X-ray bursters.
ASTRUm will open a new field by enabling for the first time measurements of proton- and alpha-capture reaction cross-sections on radioactive nuclei of interest for the p-process of nucleosynthesis.
Last but not least, broad band mass and half-life measurements in a ring is the only technique to precisely determine these key nuclear properties for nuclei with half-lives as short as a millisecond and production rates of below one ion per day.
To accomplish these measurements with highest efficiency, sensitivity and precision, improved detector systems will be developed within ASTRUm. Possible applications of these systems go beyond ASTRUm objectives and will be used in particular in accelerator physics.
The instrumentation and experience gained within ASTRUm will be indispensable for planning the future, next generation storage ring projects, which are launched or proposed at several radioactive ion beam facilities.
Summary
The main goal of ASTRUm is to employ stored and cooled radioactive ions for forefront nuclear astrophysics research. Four key experiments are proposed to be conducted at GSI in Darmstadt, which holds the only facility to date capable of storing highly charged radionuclides in the required element and energy range. The proposed experiments can hardly be conducted by any other technique or method.
The weak decay matrix element for the transition between the 2.3 keV state in 205Pb and the ground state of 205Tl will be measured via the bound state beta decay measurement of fully ionized 205Tl81+. This will provide the required data to determine the solar pp-neutrino flux integrated over the last 5 million years and will allow us to unveil the astrophysical conditions prior to the formation of the solar system.
The measurements of the alpha-decay width of the 4.033 MeV excited state in 19Ne will allow us to constrain the conditions for the ignition of the rp-process in X-ray bursters.
ASTRUm will open a new field by enabling for the first time measurements of proton- and alpha-capture reaction cross-sections on radioactive nuclei of interest for the p-process of nucleosynthesis.
Last but not least, broad band mass and half-life measurements in a ring is the only technique to precisely determine these key nuclear properties for nuclei with half-lives as short as a millisecond and production rates of below one ion per day.
To accomplish these measurements with highest efficiency, sensitivity and precision, improved detector systems will be developed within ASTRUm. Possible applications of these systems go beyond ASTRUm objectives and will be used in particular in accelerator physics.
The instrumentation and experience gained within ASTRUm will be indispensable for planning the future, next generation storage ring projects, which are launched or proposed at several radioactive ion beam facilities.
Max ERC Funding
1 874 750 €
Duration
Start date: 2016-04-01, End date: 2021-03-31
Project acronym AUDADAPT
Project The listening challenge: How ageing brains adapt
Researcher (PI) Jonas Ferdinand Obleser
Host Institution (HI) UNIVERSITAT ZU LUBECK
Call Details Consolidator Grant (CoG), SH4, ERC-2014-CoG
Summary Humans in principle adapt well to sensory degradations. In order to do so, our cognitive strategies need to adjust accordingly (a process we term “adaptive control”).The auditory sensory modality poses an excellent, although under-utilised, research model to understand these adjustments, their neural basis, and their large variation amongst individuals. Hearing abilities begin to decline already in the fourth life decade, and our guiding hypothesis is that individuals differ in the extent to which they are neurally, cognitively, and psychologically equipped to adapt to this sensory decline.
The project will pursue three specific aims: (1) We will first specify the neural dynamics of “adaptive control” in the under-studied target group of middle-aged listeners compared to young listeners. We will employ advanced multi-modal neuroimaging (EEG and fMRI) markers and a flexible experimental design of listening challenges. (2) Based on the parameters established in (1), we will explain interindividual differences in adaptive control in a large-scale sample of middle-aged listeners, and aim to re-test each individual again after approximately two years. These data will lead to (3) where we will employ statistical models that incorporate a broader context of audiological, cognitive skill, and personality markers and reconstructs longitudinal “trajectories of change” in adaptive control over the middle-age life span.
Pursuing these aims will help establish a new theoretical framework for the adaptive ageing brain. The project will further break new ground for future classification and treatment of hearing difficulties, and for developing individualised hearing solutions. Profiting from an excellent research environment and the principle investigator’s pre-established laboratory, this research has the potential to challenge and to transform current understanding and concepts of the ageing human individual.
Summary
Humans in principle adapt well to sensory degradations. In order to do so, our cognitive strategies need to adjust accordingly (a process we term “adaptive control”).The auditory sensory modality poses an excellent, although under-utilised, research model to understand these adjustments, their neural basis, and their large variation amongst individuals. Hearing abilities begin to decline already in the fourth life decade, and our guiding hypothesis is that individuals differ in the extent to which they are neurally, cognitively, and psychologically equipped to adapt to this sensory decline.
The project will pursue three specific aims: (1) We will first specify the neural dynamics of “adaptive control” in the under-studied target group of middle-aged listeners compared to young listeners. We will employ advanced multi-modal neuroimaging (EEG and fMRI) markers and a flexible experimental design of listening challenges. (2) Based on the parameters established in (1), we will explain interindividual differences in adaptive control in a large-scale sample of middle-aged listeners, and aim to re-test each individual again after approximately two years. These data will lead to (3) where we will employ statistical models that incorporate a broader context of audiological, cognitive skill, and personality markers and reconstructs longitudinal “trajectories of change” in adaptive control over the middle-age life span.
Pursuing these aims will help establish a new theoretical framework for the adaptive ageing brain. The project will further break new ground for future classification and treatment of hearing difficulties, and for developing individualised hearing solutions. Profiting from an excellent research environment and the principle investigator’s pre-established laboratory, this research has the potential to challenge and to transform current understanding and concepts of the ageing human individual.
Max ERC Funding
1 967 000 €
Duration
Start date: 2016-01-01, End date: 2020-12-31
Project acronym AutoClean
Project Cell-free reconstitution of autophagy to dissect molecular mechanisms
Researcher (PI) Claudine Simone Kraft
Host Institution (HI) UNIVERSITAETSKLINIKUM FREIBURG
Call Details Consolidator Grant (CoG), LS1, ERC-2017-COG
Summary Autophagy, a lysosomal degradation pathway in which the cell digests its own components, is an essential biological pathway that promotes organismal health and longevity and helps combat cancer and neurodegenerative diseases. Accordingly, the 2016 Nobel Prize in Physiology or Medicine was awarded for research in autophagy. Although autophagy has been extensively studied from yeast to mammals, the molecular events that underlie its induction and progression remain elusive. A highly conserved protein kinase, Atg1, plays a unique and essential role in initiating autophagy, yet despite this pivotal importance it has taken over twenty years for its first downstream target to be discovered. However, whilst our identification of the autophagy related membrane protein Atg9 as the first Atg1 substrate is an important advance, the molecular mechanisms that enable the extensive remodelling of cellular membranes that occurs during autophagy is still completely undefined. A detailed knowledge of the inputs and outputs of the Atg1 kinase will enable us to provide a definitive mechanistic understanding of autophagy. We have devised a novel permeabilized cell assay that reconstitutes the pathway in vitro, allowing us to recapitulate key steps in the autophagic process and thereby determine how the individual steps that lead up to autophagy are controlled. We will use this system to dissect the functional role of Atg1 kinase in autophagosome-vacuole fusion (Objective 1), and to determine the origin of the autophagic membrane and the role of Atg1 in expanding these (Objective 2). To reveal how Atg1/ULK1 kinase is activated in mammalian cells, we will apply the unique and carefully tailored synthetic in vivo approaches that we have recently developed (Objective 3). By focusing on the activation of the Atg1 kinase and the molecular events that it executes, we will be able to explain its central role in regulating the autophagic process and define the mechanistic steps in the pathway.
Summary
Autophagy, a lysosomal degradation pathway in which the cell digests its own components, is an essential biological pathway that promotes organismal health and longevity and helps combat cancer and neurodegenerative diseases. Accordingly, the 2016 Nobel Prize in Physiology or Medicine was awarded for research in autophagy. Although autophagy has been extensively studied from yeast to mammals, the molecular events that underlie its induction and progression remain elusive. A highly conserved protein kinase, Atg1, plays a unique and essential role in initiating autophagy, yet despite this pivotal importance it has taken over twenty years for its first downstream target to be discovered. However, whilst our identification of the autophagy related membrane protein Atg9 as the first Atg1 substrate is an important advance, the molecular mechanisms that enable the extensive remodelling of cellular membranes that occurs during autophagy is still completely undefined. A detailed knowledge of the inputs and outputs of the Atg1 kinase will enable us to provide a definitive mechanistic understanding of autophagy. We have devised a novel permeabilized cell assay that reconstitutes the pathway in vitro, allowing us to recapitulate key steps in the autophagic process and thereby determine how the individual steps that lead up to autophagy are controlled. We will use this system to dissect the functional role of Atg1 kinase in autophagosome-vacuole fusion (Objective 1), and to determine the origin of the autophagic membrane and the role of Atg1 in expanding these (Objective 2). To reveal how Atg1/ULK1 kinase is activated in mammalian cells, we will apply the unique and carefully tailored synthetic in vivo approaches that we have recently developed (Objective 3). By focusing on the activation of the Atg1 kinase and the molecular events that it executes, we will be able to explain its central role in regulating the autophagic process and define the mechanistic steps in the pathway.
Max ERC Funding
1 955 666 €
Duration
Start date: 2018-06-01, End date: 2023-05-31
Project acronym AVS-ISS
Project Analysis, Verification, and Synthesis for Infinite-State Systems
Researcher (PI) Joel Olivier Ouaknine
Host Institution (HI) MAX-PLANCK-GESELLSCHAFT ZUR FORDERUNG DER WISSENSCHAFTEN EV
Call Details Consolidator Grant (CoG), PE6, ERC-2014-CoG
Summary The central objective of this project is to investigate key algorithmic verification questions concerning two fundamental mathematical structures used to model and analyse infinite-state systems, namely discrete linear dynamical systems and counter automata, in both ordinary and parametric form. Motivated especially by applications to software model checking (more specifically the termination of linear loops and predicate abstraction computations), as well as parametric real-time reasoning and the verification of Markov chains, we will focus on model-checking, module-checking, and synthesis problems for linear dynamical systems and one-counter automata against various fragments and extensions of Linear Temporal Logic (LTL) specifications. The key deliverables will be novel verification algorithms along with a map of the complexity landscape. A second objective is then to transfer algorithmic insights into practical verification methodologies and tools, in collaboration with colleagues in academia and industrial research laboratories.
We will build on a series of recent advances and breakthroughs in these areas (some of which from the PI’s team) to attack a range of specific algorithmic problems. We believe that this line of research will not only result in fundamental theoretical contributions and insights in their own right—potentially answering mathematical questions that have been open for years or even decades—but will also impact the practice of formal verification and lead to new and more powerful methods and tools for the use of engineers and programmers.
Summary
The central objective of this project is to investigate key algorithmic verification questions concerning two fundamental mathematical structures used to model and analyse infinite-state systems, namely discrete linear dynamical systems and counter automata, in both ordinary and parametric form. Motivated especially by applications to software model checking (more specifically the termination of linear loops and predicate abstraction computations), as well as parametric real-time reasoning and the verification of Markov chains, we will focus on model-checking, module-checking, and synthesis problems for linear dynamical systems and one-counter automata against various fragments and extensions of Linear Temporal Logic (LTL) specifications. The key deliverables will be novel verification algorithms along with a map of the complexity landscape. A second objective is then to transfer algorithmic insights into practical verification methodologies and tools, in collaboration with colleagues in academia and industrial research laboratories.
We will build on a series of recent advances and breakthroughs in these areas (some of which from the PI’s team) to attack a range of specific algorithmic problems. We believe that this line of research will not only result in fundamental theoretical contributions and insights in their own right—potentially answering mathematical questions that have been open for years or even decades—but will also impact the practice of formal verification and lead to new and more powerful methods and tools for the use of engineers and programmers.
Max ERC Funding
1 834 975 €
Duration
Start date: 2015-08-01, End date: 2020-07-31
Project acronym BACTERIAL SYRINGES
Project Protein Translocation Through Bacterial Syringes
Researcher (PI) Stefan Raunser
Host Institution (HI) MAX-PLANCK-GESELLSCHAFT ZUR FORDERUNG DER WISSENSCHAFTEN EV
Call Details Consolidator Grant (CoG), LS1, ERC-2013-CoG
Summary "The main objective of this application is to study the molecular basis of cellular infection by bacterial ABC-type toxins (Tc). Tc complexes are important virulence factors of a range of bacteria, including Photorhabdus luminescens and Yersinia pseudotuberculosis that infect insects and humans. Belonging to the class of pore-forming toxins, tripartite Tc complexes perforate the host membrane by forming channels that translocate toxic enzymes into the host.
In our previous cryo-EM work on the P. luminescens Tc complex we discovered that Tcs use a special syringe-like device for cell entry. Building on these results, we now intend to unravel the molecular mechanism through which this unusual and complicated injection system allows membrane permeation and protein translocation. We will use a hybrid approach, including biochemical reconstitution, structural analysis by cryo-EM and X-ray crystallography, fluorescence-based assays and site-directed mutagenesis to provide a comprehensive description of the molecular mechanism of infection at an unprecedented level of molecular detail.
Our results will be paradigmatic for understanding the mechanism of action of ABC-type toxins and will shed new light on the interactions of bacterial pathogens with their hosts."
Summary
"The main objective of this application is to study the molecular basis of cellular infection by bacterial ABC-type toxins (Tc). Tc complexes are important virulence factors of a range of bacteria, including Photorhabdus luminescens and Yersinia pseudotuberculosis that infect insects and humans. Belonging to the class of pore-forming toxins, tripartite Tc complexes perforate the host membrane by forming channels that translocate toxic enzymes into the host.
In our previous cryo-EM work on the P. luminescens Tc complex we discovered that Tcs use a special syringe-like device for cell entry. Building on these results, we now intend to unravel the molecular mechanism through which this unusual and complicated injection system allows membrane permeation and protein translocation. We will use a hybrid approach, including biochemical reconstitution, structural analysis by cryo-EM and X-ray crystallography, fluorescence-based assays and site-directed mutagenesis to provide a comprehensive description of the molecular mechanism of infection at an unprecedented level of molecular detail.
Our results will be paradigmatic for understanding the mechanism of action of ABC-type toxins and will shed new light on the interactions of bacterial pathogens with their hosts."
Max ERC Funding
1 999 992 €
Duration
Start date: 2014-07-01, End date: 2019-06-30
Project acronym BCM-UPS
Project Dissecting the role of the ubiquitin proteasome system in the pathogenesis and therapy of B-cell malignancies
Researcher (PI) Florian Christoph Bassermann
Host Institution (HI) KLINIKUM RECHTS DER ISAR DER TECHNISCHEN UNIVERSITAT MUNCHEN
Call Details Consolidator Grant (CoG), LS4, ERC-2015-CoG
Summary B-cell malignancies are characterized by high levels of genomic instability, which critically contribute to their pathogenesis and evolution. Recently, the fundamental role of the ubiquitin proteasome system (UPS) in maintaining genome integrity has been appreciated. Two major new therapeutic modalities in B-cell malignancies, proteasome inhibitors and imunomodulatory drugs (IMiDs), target the UPS and demonstrate particular efficacy in multiple myeloma (MM) and mantle cell lymphoma (MCL), two incurable entities with poor prognosis. This suggests the presence of aberrant ubiquitylation events, whose identities have however remained mostly elusive.
Our recent studies identify fundamental roles of orphan ubiquitin ligases of the Cullin Ring ligase family (CRLs) and their counterparts, the deubiquitylating enzymes (DUBs) in the cellular DNA damage response machinery, and characterize these candidates as novel oncogenes or tumour suppressors in MM and MCL. These findings provide the foundation for our hypothesis that deregulated ubiquitylation events involving CRLs and DUBs have a far reaching impact on the pathogenesis of B-cell malignancies and can serve as new therapeutic targets and biomarkers.
We therefore propose a multistep strategy in which we will (1) characterize previously orphan CRLs and DUBs, which we have distinguished as candidate oncogenes and tumour suppressors in MM (FBXO3, USP24), MCL (FBXO25), or MM and MCL (CRBN), respectively; (2) decipher the global role of CRLs and DUBs in MM and MCL using defined genetic screens; (3) identify relevant substrates of CRLs/DUBs discovered in (2) using mass spectrometry; and (4) validate CRL/DUB candidates in preclinical mouse models and defined patient cohorts as to their disease relevance.
We expect that our interdisciplinary approach will unravel the overall role of the UPS in the pathophysiology, evolution and treatment of B-cell malignancies.
Summary
B-cell malignancies are characterized by high levels of genomic instability, which critically contribute to their pathogenesis and evolution. Recently, the fundamental role of the ubiquitin proteasome system (UPS) in maintaining genome integrity has been appreciated. Two major new therapeutic modalities in B-cell malignancies, proteasome inhibitors and imunomodulatory drugs (IMiDs), target the UPS and demonstrate particular efficacy in multiple myeloma (MM) and mantle cell lymphoma (MCL), two incurable entities with poor prognosis. This suggests the presence of aberrant ubiquitylation events, whose identities have however remained mostly elusive.
Our recent studies identify fundamental roles of orphan ubiquitin ligases of the Cullin Ring ligase family (CRLs) and their counterparts, the deubiquitylating enzymes (DUBs) in the cellular DNA damage response machinery, and characterize these candidates as novel oncogenes or tumour suppressors in MM and MCL. These findings provide the foundation for our hypothesis that deregulated ubiquitylation events involving CRLs and DUBs have a far reaching impact on the pathogenesis of B-cell malignancies and can serve as new therapeutic targets and biomarkers.
We therefore propose a multistep strategy in which we will (1) characterize previously orphan CRLs and DUBs, which we have distinguished as candidate oncogenes and tumour suppressors in MM (FBXO3, USP24), MCL (FBXO25), or MM and MCL (CRBN), respectively; (2) decipher the global role of CRLs and DUBs in MM and MCL using defined genetic screens; (3) identify relevant substrates of CRLs/DUBs discovered in (2) using mass spectrometry; and (4) validate CRL/DUB candidates in preclinical mouse models and defined patient cohorts as to their disease relevance.
We expect that our interdisciplinary approach will unravel the overall role of the UPS in the pathophysiology, evolution and treatment of B-cell malignancies.
Max ERC Funding
1 973 255 €
Duration
Start date: 2016-09-01, End date: 2021-08-31
Project acronym BETACONTROL
Project Control of amyloid formation via beta-hairpin molecular recognition features
Researcher (PI) Wolfgang HOYER
Host Institution (HI) HEINRICH-HEINE-UNIVERSITAET DUESSELDORF
Call Details Consolidator Grant (CoG), PE5, ERC-2016-COG
Summary The aggregation of proteins into amyloid fibrils is involved in various diseases which place a high burden on patients, families, caregivers, and healthcare systems, including Alzheimer’s disease, Parkinson’s disease and type 2 diabetes. While the therapeutic potential of the inhibition of amyloid formation and spreading has been recognized, there is a lack of effective strategies targeting the early steps of the aggregation reaction.
In BETACONTROL, I want to establish a structure-guided approach to the control of amyloid formation and spreading. I will develop small molecule and polypeptide-based ligands that interfere with the initial phases of amyloid formation and thereby suppress any toxic oligomeric or fibrillar assemblies. The ligands will target beta-hairpin molecular recognition features, which I found to be readily accessible in disease-related amyloidogenic proteins. Targeting beta-hairpins enables retardation of protein aggregation by substoichiometric amounts of the ligand, affording inhibition of amyloid formation at low compound concentrations. As the strategy addresses the common propensity of amyloidogenic proteins to adopt beta-structure, it will be applicable to a wide range of proteins associated with various diseases.
BETACONTROL will yield molecular-level insight into the mechanistic basis of amyloid formation and spreading. Furthermore, it will elucidate the significance of beta-hairpins as molecular recognition features in intrinsically disordered proteins (IDPs) and highlight the applicability of these features as targets for interference with protein-protein interactions of IDPs. Ultimately, BETACONTROL will provide a novel therapeutic approach to a range of devastating diseases.
Summary
The aggregation of proteins into amyloid fibrils is involved in various diseases which place a high burden on patients, families, caregivers, and healthcare systems, including Alzheimer’s disease, Parkinson’s disease and type 2 diabetes. While the therapeutic potential of the inhibition of amyloid formation and spreading has been recognized, there is a lack of effective strategies targeting the early steps of the aggregation reaction.
In BETACONTROL, I want to establish a structure-guided approach to the control of amyloid formation and spreading. I will develop small molecule and polypeptide-based ligands that interfere with the initial phases of amyloid formation and thereby suppress any toxic oligomeric or fibrillar assemblies. The ligands will target beta-hairpin molecular recognition features, which I found to be readily accessible in disease-related amyloidogenic proteins. Targeting beta-hairpins enables retardation of protein aggregation by substoichiometric amounts of the ligand, affording inhibition of amyloid formation at low compound concentrations. As the strategy addresses the common propensity of amyloidogenic proteins to adopt beta-structure, it will be applicable to a wide range of proteins associated with various diseases.
BETACONTROL will yield molecular-level insight into the mechanistic basis of amyloid formation and spreading. Furthermore, it will elucidate the significance of beta-hairpins as molecular recognition features in intrinsically disordered proteins (IDPs) and highlight the applicability of these features as targets for interference with protein-protein interactions of IDPs. Ultimately, BETACONTROL will provide a novel therapeutic approach to a range of devastating diseases.
Max ERC Funding
1 920 697 €
Duration
Start date: 2017-06-01, End date: 2022-05-31
Project acronym BeyondOpposition
Project Opposing Sexual and Gender Rights and Equalities: Transforming Everyday Spaces
Researcher (PI) Katherine Browne
Host Institution (HI) NATIONAL UNIVERSITY OF IRELAND MAYNOOTH
Call Details Consolidator Grant (CoG), SH2, ERC-2018-COG
Summary OPPSEXRIGHTS will be the first large-scale, transnational study to consider the effects of recent Sexual and Gender Rights and Equalities (SGRE) on those who oppose them, by exploring opponents’ experiences of the transformation of everyday spaces. It will work beyond contemporary polarisations, creating new possibilities for social transformation. This cutting-edge research engages with the dramatically altered social and political landscapes in the late 20th and early 21st Century created through the development of lesbian, gay, bisexual, and trans, and women’s rights. Recent reactionary politics highlight the pressing need to understand the position of those who experience these new social orders as a loss. The backlash to SGRE has coalesced into various resistances that are tangibly different to the classic vilification of homosexuality, or those that are anti-woman. Some who oppose SGRE have found themselves the subject of public critique; in the workplace, their jobs threatened, while at home, engagements with schools can cause family conflicts. This is particularly visible in the case studies of Ireland, UK and Canada because of SGRE. A largescale transnational systematic database will be created using low risk (media and organisational discourses; participant observation at oppositional events) and higher risk (online data collection and interviews) methods. Experimenting with social transformation, OPPSEXRIGHTS will work to build bridges between ‘enemies’, including families and communities, through innovative discussion and arts-based workshops. This ambitious project has the potential to create tangible solutions that tackle contemporary societal issues, which are founded in polarisations that are seemingly insurmountable.
Summary
OPPSEXRIGHTS will be the first large-scale, transnational study to consider the effects of recent Sexual and Gender Rights and Equalities (SGRE) on those who oppose them, by exploring opponents’ experiences of the transformation of everyday spaces. It will work beyond contemporary polarisations, creating new possibilities for social transformation. This cutting-edge research engages with the dramatically altered social and political landscapes in the late 20th and early 21st Century created through the development of lesbian, gay, bisexual, and trans, and women’s rights. Recent reactionary politics highlight the pressing need to understand the position of those who experience these new social orders as a loss. The backlash to SGRE has coalesced into various resistances that are tangibly different to the classic vilification of homosexuality, or those that are anti-woman. Some who oppose SGRE have found themselves the subject of public critique; in the workplace, their jobs threatened, while at home, engagements with schools can cause family conflicts. This is particularly visible in the case studies of Ireland, UK and Canada because of SGRE. A largescale transnational systematic database will be created using low risk (media and organisational discourses; participant observation at oppositional events) and higher risk (online data collection and interviews) methods. Experimenting with social transformation, OPPSEXRIGHTS will work to build bridges between ‘enemies’, including families and communities, through innovative discussion and arts-based workshops. This ambitious project has the potential to create tangible solutions that tackle contemporary societal issues, which are founded in polarisations that are seemingly insurmountable.
Max ERC Funding
1 988 652 €
Duration
Start date: 2019-10-01, End date: 2024-09-30
Project acronym bi-BLOCK
Project Building and bypassing plant polyspermy blocks
Researcher (PI) Rita Helene Groß-Hardt
Host Institution (HI) UNIVERSITAET BREMEN
Call Details Consolidator Grant (CoG), LS3, ERC-2014-CoG
Summary The ultimate goal for the survival of all species on earth is to reproduce. This uncompromising principle has triggered the evolution of numerous adaptations. One strategy commonly employed by sexually reproducing eukaryotes is the production of tremendous amounts of sperm to maximize the likelihood of an egg becoming fertilised. High sperm to egg ratios are, however, associated with an increased risk of supernumerary sperm fusion. This so-called polyspermy is lethal in many organisms. Accordingly, eukaryotes have evolved polyspermy barriers, which are implemented at different levels in the reproductive process. Flowering plants tightly control the number of sperm-transporting pollen tubes approaching a single ovule by a so-called pollen tube block. We have recently shown that the pollen tube block is relaxed in ethylene hyposensitive plants. Capitalizing on these results, this project aims at identifying and characterising the molecular mechanisms underlying plant polyspermy barriers.
Summary
The ultimate goal for the survival of all species on earth is to reproduce. This uncompromising principle has triggered the evolution of numerous adaptations. One strategy commonly employed by sexually reproducing eukaryotes is the production of tremendous amounts of sperm to maximize the likelihood of an egg becoming fertilised. High sperm to egg ratios are, however, associated with an increased risk of supernumerary sperm fusion. This so-called polyspermy is lethal in many organisms. Accordingly, eukaryotes have evolved polyspermy barriers, which are implemented at different levels in the reproductive process. Flowering plants tightly control the number of sperm-transporting pollen tubes approaching a single ovule by a so-called pollen tube block. We have recently shown that the pollen tube block is relaxed in ethylene hyposensitive plants. Capitalizing on these results, this project aims at identifying and characterising the molecular mechanisms underlying plant polyspermy barriers.
Max ERC Funding
1 910 769 €
Duration
Start date: 2015-09-01, End date: 2020-08-31
Project acronym BRAIN-MATCH
Project Matching CNS Lineage Maps with Molecular Brain Tumor Portraits for Translational Exploitation
Researcher (PI) Stefan PFISTER
Host Institution (HI) DEUTSCHES KREBSFORSCHUNGSZENTRUM HEIDELBERG
Call Details Consolidator Grant (CoG), LS2, ERC-2018-COG
Summary Brain tumors represent an extremely heterogeneous group of more than 100 different molecularly distinct diseases, many of which are still almost uniformly lethal despite five decades of clinical trials. In contrast to hematologic malignancies and carcinomas, the cell-of-origin for the vast majority of these entities is unknown. This knowledge gap currently precludes a comprehensive understanding of tumor biology and also limits translational exploitation (e.g., utilizing lineage targets for novel therapies and circulating brain tumor cells for liquid biopsies).
The BRAIN-MATCH project represents an ambitious program to address this challenge and unmet medical need by taking an approach that (i) extensively utilizes existing molecular profiles of more than 30,000 brain tumor samples covering more than 100 different entities, publicly available single-cell sequencing data of normal brain regions, and bulk normal tissue data at different times of development across different species; (ii) generates unprecedented maps of normal human CNS development by using state-of-the art novel technologies; (iii) matches these molecular portraits of normal cell types with tumor datasets in order to identify specific cell-of-origin populations for individual tumor entities; and (iv) validates the most promising cell-of-origin populations and tumor-specific lineage and/or surface markers in vivo.
The expected outputs of BRAIN-MATCH are four-fold: (i) delivery of an unprecedented atlas of human normal CNS development, which will also be of great relevance for diverse fields other than cancer; (ii) functional validation of at least three lineage targets; (iii) isolation and molecular characterization of circulating brain tumor cells from patients´ blood for at least five tumor entities; and (iv) generation of at least three novel mouse models of brain tumor entities for which currently no faithful models exist.
Summary
Brain tumors represent an extremely heterogeneous group of more than 100 different molecularly distinct diseases, many of which are still almost uniformly lethal despite five decades of clinical trials. In contrast to hematologic malignancies and carcinomas, the cell-of-origin for the vast majority of these entities is unknown. This knowledge gap currently precludes a comprehensive understanding of tumor biology and also limits translational exploitation (e.g., utilizing lineage targets for novel therapies and circulating brain tumor cells for liquid biopsies).
The BRAIN-MATCH project represents an ambitious program to address this challenge and unmet medical need by taking an approach that (i) extensively utilizes existing molecular profiles of more than 30,000 brain tumor samples covering more than 100 different entities, publicly available single-cell sequencing data of normal brain regions, and bulk normal tissue data at different times of development across different species; (ii) generates unprecedented maps of normal human CNS development by using state-of-the art novel technologies; (iii) matches these molecular portraits of normal cell types with tumor datasets in order to identify specific cell-of-origin populations for individual tumor entities; and (iv) validates the most promising cell-of-origin populations and tumor-specific lineage and/or surface markers in vivo.
The expected outputs of BRAIN-MATCH are four-fold: (i) delivery of an unprecedented atlas of human normal CNS development, which will also be of great relevance for diverse fields other than cancer; (ii) functional validation of at least three lineage targets; (iii) isolation and molecular characterization of circulating brain tumor cells from patients´ blood for at least five tumor entities; and (iv) generation of at least three novel mouse models of brain tumor entities for which currently no faithful models exist.
Max ERC Funding
1 999 875 €
Duration
Start date: 2019-05-01, End date: 2024-04-30
Project acronym BrainModes
Project Personalized whole brain simulations: linking connectomics and dynamics in the human brain
Researcher (PI) Petra Ritter
Host Institution (HI) CHARITE - UNIVERSITAETSMEDIZIN BERLIN
Call Details Consolidator Grant (CoG), LS5, ERC-2015-CoG
Summary Background. We have detailed maps of brain structure and function, yet are lacking understanding of how the highly connected units interact and give rise to mental processes. The Virtual Brain (TVB), a whole brain simulation framework, aims to bridge that gap. Yet it is still developing. We are proposing here breakthrough advances that reveal mechanisms of brain function and foster collaboration between research groups. Vision. Clinical applications that simulate individual patient brains and predict trajectories of recovery or decline or test therapies to select the best one for that person. Goal. Using biologically realistic brain models and multimodal functional and structural imaging data to elucidate control mechanisms of the human brain in aging. A database collects key data and allows identifying most generic models and mechanisms below the spatial and temporal resolution of non-invasive imaging techniques taking into account the complex interaction in the brain that without a model would be impossible to keep track of. Objectives. 1) Parameter optimization for large parameter space search and a library of dynamical regimes linking dynamical regimes and underlying mechanisms to biological (cognitive) age. 2) Identifying the role of intrinsic plasticity for network reconfigurations in the resting state and its age dependency. 3) Model based identification of task related plasticity mechanisms and their functional consequences for network reconfigurations in coordination learning in aging. 4) An interactive tool that provides access to the dynamical regimes library and makes pre-computed simulations easily accessible allowing researchers to benefit and learn from existing work. Impact. Understanding development, aging and brain disorders from the perspective of disruption of information processing architectures provides an opportunity for new interventions that re-establish control in brain pathology hence posing a breakthrough in the health and biotech sector.
Summary
Background. We have detailed maps of brain structure and function, yet are lacking understanding of how the highly connected units interact and give rise to mental processes. The Virtual Brain (TVB), a whole brain simulation framework, aims to bridge that gap. Yet it is still developing. We are proposing here breakthrough advances that reveal mechanisms of brain function and foster collaboration between research groups. Vision. Clinical applications that simulate individual patient brains and predict trajectories of recovery or decline or test therapies to select the best one for that person. Goal. Using biologically realistic brain models and multimodal functional and structural imaging data to elucidate control mechanisms of the human brain in aging. A database collects key data and allows identifying most generic models and mechanisms below the spatial and temporal resolution of non-invasive imaging techniques taking into account the complex interaction in the brain that without a model would be impossible to keep track of. Objectives. 1) Parameter optimization for large parameter space search and a library of dynamical regimes linking dynamical regimes and underlying mechanisms to biological (cognitive) age. 2) Identifying the role of intrinsic plasticity for network reconfigurations in the resting state and its age dependency. 3) Model based identification of task related plasticity mechanisms and their functional consequences for network reconfigurations in coordination learning in aging. 4) An interactive tool that provides access to the dynamical regimes library and makes pre-computed simulations easily accessible allowing researchers to benefit and learn from existing work. Impact. Understanding development, aging and brain disorders from the perspective of disruption of information processing architectures provides an opportunity for new interventions that re-establish control in brain pathology hence posing a breakthrough in the health and biotech sector.
Max ERC Funding
1 870 588 €
Duration
Start date: 2016-08-01, End date: 2021-07-31
Project acronym BuddhistRoad
Project Dynamics in Buddhist Networks in Eastern Central Asia, 6th-14th Centuries
Researcher (PI) Carmen Else Maria Angelika MEINERT
Host Institution (HI) RUHR-UNIVERSITAET BOCHUM
Call Details Consolidator Grant (CoG), SH5, ERC-2016-COG
Summary The objective of this proposal is to create a new framework to enable understanding of the complexities in the dynamics of cultural encounter and religious transfer in pre-modern Eastern Central Asia—the vast area extending from the Taklamakan desert to Northeast China. This region was the crossroads of ancient civilisations. Its uniqueness was determined by complex dynamics of religious and cultural exchanges gravitating around an ancient communication artery, known as the Silk Road. Buddhism was one major factor in this exchange; its transfer predetermined the transfer of adjacent aspects of culture. The religious exchange involved a variety of cultures and civilisations, which were modified and shaped by their adoption of Buddhism. This process overrode the ethnic and linguistic boundaries of the Buddhist universe. One specific aspect of this process was the rise of the local forms of Buddhism. This project intends to investigate such Buddhist localisations between the 6th–14th centuries.
I will create a new trans-regional and trans-cultural vision of the religious transfer in Eastern Central Asian history and will reconstruct this Buddhist network with its entities and relations. It will incorporate the fascinating, but as yet under-researched field of Eastern Central Asian Buddhism into a broader research agenda of Comparative Religious Studies. It will establish a new research approach by bringing together many research fields and agendas (such as Philology, Art History, Archaeology, Religious Studies) into one synthesising narrative based on a unique perspective, in which, religious exchange in Eastern Central Asia will be analysed as a dynamic network emerging in its spatial and temporal aspects. For the first time the multi-layered relationships between the trans-regional Buddhist traditions (Chinese, Indian, Tibetan) and those based on local Buddhist cultures (Khotanese, Uyghur, Tangut, Kitan) will be explored in a systematic way.
Summary
The objective of this proposal is to create a new framework to enable understanding of the complexities in the dynamics of cultural encounter and religious transfer in pre-modern Eastern Central Asia—the vast area extending from the Taklamakan desert to Northeast China. This region was the crossroads of ancient civilisations. Its uniqueness was determined by complex dynamics of religious and cultural exchanges gravitating around an ancient communication artery, known as the Silk Road. Buddhism was one major factor in this exchange; its transfer predetermined the transfer of adjacent aspects of culture. The religious exchange involved a variety of cultures and civilisations, which were modified and shaped by their adoption of Buddhism. This process overrode the ethnic and linguistic boundaries of the Buddhist universe. One specific aspect of this process was the rise of the local forms of Buddhism. This project intends to investigate such Buddhist localisations between the 6th–14th centuries.
I will create a new trans-regional and trans-cultural vision of the religious transfer in Eastern Central Asian history and will reconstruct this Buddhist network with its entities and relations. It will incorporate the fascinating, but as yet under-researched field of Eastern Central Asian Buddhism into a broader research agenda of Comparative Religious Studies. It will establish a new research approach by bringing together many research fields and agendas (such as Philology, Art History, Archaeology, Religious Studies) into one synthesising narrative based on a unique perspective, in which, religious exchange in Eastern Central Asia will be analysed as a dynamic network emerging in its spatial and temporal aspects. For the first time the multi-layered relationships between the trans-regional Buddhist traditions (Chinese, Indian, Tibetan) and those based on local Buddhist cultures (Khotanese, Uyghur, Tangut, Kitan) will be explored in a systematic way.
Max ERC Funding
1 998 717 €
Duration
Start date: 2017-08-01, End date: 2022-07-31
Project acronym C18Signaling
Project Regulation of Cellular Growth and Metabolism by C18:0
Researcher (PI) Aurelio TELEMAN
Host Institution (HI) DEUTSCHES KREBSFORSCHUNGSZENTRUM HEIDELBERG
Call Details Consolidator Grant (CoG), LS3, ERC-2016-COG
Summary My lab studies how cells regulate their growth and metabolism during normal development and in disease. Recent work in my lab, published last year in Nature, identified the metabolite stearic acid (C18:0) as a novel regulator of mitochondrial function. We showed that dietary C18:0 acts via a novel signaling route whereby it covalently modifies the cell-surface Transferrin Receptor (TfR1) to regulate mitochondrial morphology. We found that modification of TfR1 by C18:0 ('stearoylation') is analogous to protein palmitoylation by C16:0 - it is a covalent thio-ester link and requires a transferase enzyme. This work made two conceptual contributions. 1) It uncovered a novel signaling route regulating mitochondrial function. 2) Relevant to this grant application, we found by mass spectrometry multiple other proteins that are stearoylated in mammalian cells. This thereby opens a new avenue of research, suggesting that C18:0 signals via several target proteins to regulate cellular growth and metabolism. I propose here to study this C18:0 signaling.
To study C18:0 signaling we will exploit tools recently developed in my lab to 1) identify as complete a set as possible of proteins that are stearoylated in human and Drosophila cells, thereby characterizing the cellular 'stearylome', 2) study how stearoylation affects the molecular function of these target proteins, and thereby cellular growth and metabolism, and 3) study how stearoylation is added, and possibly removed, from target proteins.
This work will change the way we view C18:0 from simply being a metabolite to being an important dietary signaling molecule that links nutritional uptake to cellular physiology. Via unknown mechanisms, dietary C18:0 is clinically known to have special properties for cardiovascular risk. Hence this proposal, discovering how C18:0 signals to regulate cells, will have implications for both normal development and for disease.
Summary
My lab studies how cells regulate their growth and metabolism during normal development and in disease. Recent work in my lab, published last year in Nature, identified the metabolite stearic acid (C18:0) as a novel regulator of mitochondrial function. We showed that dietary C18:0 acts via a novel signaling route whereby it covalently modifies the cell-surface Transferrin Receptor (TfR1) to regulate mitochondrial morphology. We found that modification of TfR1 by C18:0 ('stearoylation') is analogous to protein palmitoylation by C16:0 - it is a covalent thio-ester link and requires a transferase enzyme. This work made two conceptual contributions. 1) It uncovered a novel signaling route regulating mitochondrial function. 2) Relevant to this grant application, we found by mass spectrometry multiple other proteins that are stearoylated in mammalian cells. This thereby opens a new avenue of research, suggesting that C18:0 signals via several target proteins to regulate cellular growth and metabolism. I propose here to study this C18:0 signaling.
To study C18:0 signaling we will exploit tools recently developed in my lab to 1) identify as complete a set as possible of proteins that are stearoylated in human and Drosophila cells, thereby characterizing the cellular 'stearylome', 2) study how stearoylation affects the molecular function of these target proteins, and thereby cellular growth and metabolism, and 3) study how stearoylation is added, and possibly removed, from target proteins.
This work will change the way we view C18:0 from simply being a metabolite to being an important dietary signaling molecule that links nutritional uptake to cellular physiology. Via unknown mechanisms, dietary C18:0 is clinically known to have special properties for cardiovascular risk. Hence this proposal, discovering how C18:0 signals to regulate cells, will have implications for both normal development and for disease.
Max ERC Funding
2 000 000 €
Duration
Start date: 2017-03-01, End date: 2022-02-28
Project acronym CABUM
Project An investigation of the mechanisms at the interaction between cavitation bubbles and contaminants
Researcher (PI) Matevz DULAR
Host Institution (HI) UNIVERZA V LJUBLJANI
Call Details Consolidator Grant (CoG), PE8, ERC-2017-COG
Summary A sudden decrease in pressure triggers the formation of vapour and gas bubbles inside a liquid medium (also called cavitation). This leads to many (key) engineering problems: material loss, noise and vibration of hydraulic machinery. On the other hand, cavitation is a potentially a useful phenomenon: the extreme conditions are increasingly used for a wide variety of applications such as surface cleaning, enhanced chemistry, and waste water treatment (bacteria eradication and virus inactivation).
Despite this significant progress a large gap persists between the understanding of the mechanisms that contribute to the effects of cavitation and its application. Although engineers are already commercializing devices that employ cavitation, we are still not able to answer the fundamental question: What precisely are the mechanisms how bubbles can clean, disinfect, kill bacteria and enhance chemical activity? The overall objective of the project is to understand and determine the fundamental physics of the interaction of cavitation bubbles with different contaminants. To address this issue, the CABUM project will investigate the physical background of cavitation from physical, biological and engineering perspective on three complexity scales: i) on single bubble level, ii) on organised and iii) on random bubble clusters, producing a progressive multidisciplinary synergetic effect.
The proposed synergetic approach builds on the PI's preliminary research and employs novel experimental and numerical methodologies, some of which have been developed by the PI and his research group, to explore the physics of cavitation behaviour in interaction with bacteria and viruses.
Understanding the fundamental physical background of cavitation in interaction with contaminants will have a ground-breaking implications in various scientific fields (engineering, chemistry and biology) and will, in the future, enable the exploitation of cavitation in water and soil treatment processes.
Summary
A sudden decrease in pressure triggers the formation of vapour and gas bubbles inside a liquid medium (also called cavitation). This leads to many (key) engineering problems: material loss, noise and vibration of hydraulic machinery. On the other hand, cavitation is a potentially a useful phenomenon: the extreme conditions are increasingly used for a wide variety of applications such as surface cleaning, enhanced chemistry, and waste water treatment (bacteria eradication and virus inactivation).
Despite this significant progress a large gap persists between the understanding of the mechanisms that contribute to the effects of cavitation and its application. Although engineers are already commercializing devices that employ cavitation, we are still not able to answer the fundamental question: What precisely are the mechanisms how bubbles can clean, disinfect, kill bacteria and enhance chemical activity? The overall objective of the project is to understand and determine the fundamental physics of the interaction of cavitation bubbles with different contaminants. To address this issue, the CABUM project will investigate the physical background of cavitation from physical, biological and engineering perspective on three complexity scales: i) on single bubble level, ii) on organised and iii) on random bubble clusters, producing a progressive multidisciplinary synergetic effect.
The proposed synergetic approach builds on the PI's preliminary research and employs novel experimental and numerical methodologies, some of which have been developed by the PI and his research group, to explore the physics of cavitation behaviour in interaction with bacteria and viruses.
Understanding the fundamental physical background of cavitation in interaction with contaminants will have a ground-breaking implications in various scientific fields (engineering, chemistry and biology) and will, in the future, enable the exploitation of cavitation in water and soil treatment processes.
Max ERC Funding
1 904 565 €
Duration
Start date: 2018-07-01, End date: 2023-06-30
Project acronym CaLA
Project The Capillary Lock Actuator: A novel bistable microfluidic actuator for cost-effective high-density actuator arrays suitable for large-scale graphical tactile displays
Researcher (PI) Bastian Rapp
Host Institution (HI) ALBERT-LUDWIGS-UNIVERSITAET FREIBURG
Call Details Consolidator Grant (CoG), PE7, ERC-2018-COG
Summary According to the World Health Organization more than 285 million people worldwide are visually impaired. In a world where graphics and online content (images, webpages) become increasingly important the inability to perceive information visually is the primary inhibitor for inclusion. In contrast to display technology for sighted people, tactile displays which translate text and graphics to touchable pixels (taxels) have seen little progress in recent decades. So-called Braille lines which display only a single line of text are still the norm. The reason why graphical tactile displays do not exist is the lack of a suitable actuator technology which allows generating massively parallelized individually addressable cost-effective taxel arrays.
This ERC Consolidator project aims at a revolution in microactuator array technology with a fundamentally new concept termed the Capillary Lock Actuator (CaLA). CaLA is a novel bistable massively parallelizable microfluidic microactuator which overcomes many of the limitations currently associated with microactuators. It can be operated with low-voltage control signals and requires virtually no power for actuation. CaLA harnesses three concepts inherent to microfluidics: positive capillary pressure, segmented flow and controllable locally confined changes in wetting. The project will use CaLA actuator arrays for setting up the very first portable tactile graphic display with 30.000 individually addressable taxels thereby significantly outperforming the state-of-the-art. It will be based on manufacturing techniques for highly complex microstructures in glass invented by my group.
CaLA will be a significant breakthrough in actuator technology and enabling for many applications in microsystem technology. Most importantly, it will be a significant step towards making the information technology inclusive for the visually impaired by providing the first robust cost-effective solution to large-scale tactile displays.
Summary
According to the World Health Organization more than 285 million people worldwide are visually impaired. In a world where graphics and online content (images, webpages) become increasingly important the inability to perceive information visually is the primary inhibitor for inclusion. In contrast to display technology for sighted people, tactile displays which translate text and graphics to touchable pixels (taxels) have seen little progress in recent decades. So-called Braille lines which display only a single line of text are still the norm. The reason why graphical tactile displays do not exist is the lack of a suitable actuator technology which allows generating massively parallelized individually addressable cost-effective taxel arrays.
This ERC Consolidator project aims at a revolution in microactuator array technology with a fundamentally new concept termed the Capillary Lock Actuator (CaLA). CaLA is a novel bistable massively parallelizable microfluidic microactuator which overcomes many of the limitations currently associated with microactuators. It can be operated with low-voltage control signals and requires virtually no power for actuation. CaLA harnesses three concepts inherent to microfluidics: positive capillary pressure, segmented flow and controllable locally confined changes in wetting. The project will use CaLA actuator arrays for setting up the very first portable tactile graphic display with 30.000 individually addressable taxels thereby significantly outperforming the state-of-the-art. It will be based on manufacturing techniques for highly complex microstructures in glass invented by my group.
CaLA will be a significant breakthrough in actuator technology and enabling for many applications in microsystem technology. Most importantly, it will be a significant step towards making the information technology inclusive for the visually impaired by providing the first robust cost-effective solution to large-scale tactile displays.
Max ERC Funding
1 999 750 €
Duration
Start date: 2019-05-01, End date: 2024-04-30
Project acronym CancerHetero
Project Dissection of tumor heterogeneity in vivo
Researcher (PI) Haikun Liu
Host Institution (HI) DEUTSCHES KREBSFORSCHUNGSZENTRUM HEIDELBERG
Call Details Consolidator Grant (CoG), LS2, ERC-2014-CoG
Summary It is now widely accepted that tumors are composed of heterogeneous population of cells, which contribute
to many aspects of treatment resistance observed in clinic. Despite the acknowledgment of the tumor cell
heterogeneity, little evidence was shown about complexity and dynamics of this heterogeneity in vivo,
mainly because of lacking flexible genetic tools which allow sophisticated analysis in primary tumors. We
recently developed a very efficient mouse somatic brain tumor model which have a full penetrance of high
grade glioma development. Combination of this model with several transgenic mouse lines allow us to
isolate and track different population of cells in primary tumors, most importantly, we also confirmed that
this can be done on single cell level. Here I propose to use this set of valuable genetic tools to dissect the
cellular heterogeneity in mouse gliomas. First we will perform several single cell lineage tracing experiment
to demonstrate the contribution of brain tumor stem cell, tumor progenitors as well as the relatively
differentiated cells, which will provide a complete data sets of clonal dynamics of different tumor cell types.
Second we will further perform this tracing experiment with the presence of conventional chemotherapy.
Third we will perform single cell RNA sequencing experiment to capture the molecular signature, which
determines the cellular heterogeneity, discovered by single cell tracing. This result will be further validated
by analysis of this molecular signatures in human primary tumors. We will also use our established in vivo
target validation approach to manipulate the candidate molecular regulators to establish the functional
correlation between molecular signature and phenotypic heterogeneity. This project will greatly improve our
understanding of tumor heterogeneity, and possibly provide novel approaches and strategies of targeting
human glioblastomas.
Summary
It is now widely accepted that tumors are composed of heterogeneous population of cells, which contribute
to many aspects of treatment resistance observed in clinic. Despite the acknowledgment of the tumor cell
heterogeneity, little evidence was shown about complexity and dynamics of this heterogeneity in vivo,
mainly because of lacking flexible genetic tools which allow sophisticated analysis in primary tumors. We
recently developed a very efficient mouse somatic brain tumor model which have a full penetrance of high
grade glioma development. Combination of this model with several transgenic mouse lines allow us to
isolate and track different population of cells in primary tumors, most importantly, we also confirmed that
this can be done on single cell level. Here I propose to use this set of valuable genetic tools to dissect the
cellular heterogeneity in mouse gliomas. First we will perform several single cell lineage tracing experiment
to demonstrate the contribution of brain tumor stem cell, tumor progenitors as well as the relatively
differentiated cells, which will provide a complete data sets of clonal dynamics of different tumor cell types.
Second we will further perform this tracing experiment with the presence of conventional chemotherapy.
Third we will perform single cell RNA sequencing experiment to capture the molecular signature, which
determines the cellular heterogeneity, discovered by single cell tracing. This result will be further validated
by analysis of this molecular signatures in human primary tumors. We will also use our established in vivo
target validation approach to manipulate the candidate molecular regulators to establish the functional
correlation between molecular signature and phenotypic heterogeneity. This project will greatly improve our
understanding of tumor heterogeneity, and possibly provide novel approaches and strategies of targeting
human glioblastomas.
Max ERC Funding
2 000 000 €
Duration
Start date: 2015-06-01, End date: 2020-05-31
Project acronym CaTs n DOCs
Project Chemically and Thermally Stable Nano-sized Discrete Organic Cage Compounds
Researcher (PI) Michael Günther MASTALERZ
Host Institution (HI) RUPRECHT-KARLS-UNIVERSITAET HEIDELBERG
Call Details Consolidator Grant (CoG), PE5, ERC-2016-COG
Summary Shape-persistent organic cage compounds consisting only of covalent bonds are fascinating synthetically targets, because they are studied as hosts for the selective recognition of guest molecules, such as artificial lectins, for catalysis in confined space or for the construction of a new type of porous material. For the latter, the shape-persistency and rigidity of the cage cavity is of utmost importance. There are in principle two existing strategies for the synthesis of shape-persistent organic cage compounds. Strategy I: A stepwise approach by irreversible reactions. Here, the advantage is the chemical stability of the target compound due to the intrinsic stabilities of the formed bonds. The disadvantage of this approach is in general the low overall yield, because the system does not allow any ‘self-correction’ of once formed bonds. This is different for the other approach used in Strategy II: By using dynamic covalent bond formation as synthetic tool, shape-persistent organic cages can be constructed from rather simple molecular building blocks in one step. Here, the yields are usually very high or even quantitatively, because the reversibility of the reaction allows the system to self-correct. Unfortunately, the resulting compounds are more prone to chemical cleavage of the cages than those synthesized by the irreversible approach.
Within this project, we will combine the advantages of both strategies to synthesize chemically and thermally stable nano-sized discrete organic cage compounds in a two-step approach in high yields. To demonstrate the versatility and synthetic power of this approach, pure hydrocarbon cages will be synthesized in a few steps in high yields. Finally, this strategy will make for the first time open and closed-shell fullerenes and heterofullerenes that are isomerically pure, accessible.
Summary
Shape-persistent organic cage compounds consisting only of covalent bonds are fascinating synthetically targets, because they are studied as hosts for the selective recognition of guest molecules, such as artificial lectins, for catalysis in confined space or for the construction of a new type of porous material. For the latter, the shape-persistency and rigidity of the cage cavity is of utmost importance. There are in principle two existing strategies for the synthesis of shape-persistent organic cage compounds. Strategy I: A stepwise approach by irreversible reactions. Here, the advantage is the chemical stability of the target compound due to the intrinsic stabilities of the formed bonds. The disadvantage of this approach is in general the low overall yield, because the system does not allow any ‘self-correction’ of once formed bonds. This is different for the other approach used in Strategy II: By using dynamic covalent bond formation as synthetic tool, shape-persistent organic cages can be constructed from rather simple molecular building blocks in one step. Here, the yields are usually very high or even quantitatively, because the reversibility of the reaction allows the system to self-correct. Unfortunately, the resulting compounds are more prone to chemical cleavage of the cages than those synthesized by the irreversible approach.
Within this project, we will combine the advantages of both strategies to synthesize chemically and thermally stable nano-sized discrete organic cage compounds in a two-step approach in high yields. To demonstrate the versatility and synthetic power of this approach, pure hydrocarbon cages will be synthesized in a few steps in high yields. Finally, this strategy will make for the first time open and closed-shell fullerenes and heterofullerenes that are isomerically pure, accessible.
Max ERC Funding
1 996 000 €
Duration
Start date: 2017-04-01, End date: 2022-03-31
Project acronym CellStructure
Project Structural cell biology in situ using superresolution microscopy
Researcher (PI) Jonas RIES
Host Institution (HI) EUROPEAN MOLECULAR BIOLOGY LABORATORY
Call Details Consolidator Grant (CoG), PE3, ERC-2016-COG
Summary Supra-molecular protein machineries control diverse cellular processes. Knowing their structural organization is crucial for understanding their function. As classical structural biology techniques are limited in studying such assemblies in their natural cellular environment, there is a critical methodological gap inhibiting a direct link between structure and function. Consequently, the structural intermediates underlying a full activity cycle of a large multi-protein complex have been impossible to visualize. Recent advances in fluorescence microscopy, in particular the development of groundbreaking superresolution microscopy (SRM) methods, can now help bridge this gap. With this interdisciplinary proposal, my group will develop unique and innovative optical, biological and computational imaging technologies to determine the structural organization of multi-protein assemblies in their functional cellular context.
We will reach this goal by developing a method to robustly measure the precise 3D arrangements of proteins in supra-molecular assemblies in situ with nanometer isotropic resolution based on supercritical-angle detection and by measuring their absolute stoichiometries with engineered counting standards. We will also develop new data analysis tools to statistically analyze such data, taking into account the functional cellular context measured with correlative superresolution and electron microscopy, multi-color SRM and molecular biology tools. We will apply these new methods to address key questions on endocytosis, a fundamental membrane trafficking process. Our aim is to determine a time-resolved 3D superresolution localization map of the yeast endocytic proteins during the major functional transitions and to integrate these data into a mechanistic model of endocytosis. Importantly, the methods we develop here can be applied to many other large protein-based machines, and thus have the potential to have high impact in other key areas of cell biology.
Summary
Supra-molecular protein machineries control diverse cellular processes. Knowing their structural organization is crucial for understanding their function. As classical structural biology techniques are limited in studying such assemblies in their natural cellular environment, there is a critical methodological gap inhibiting a direct link between structure and function. Consequently, the structural intermediates underlying a full activity cycle of a large multi-protein complex have been impossible to visualize. Recent advances in fluorescence microscopy, in particular the development of groundbreaking superresolution microscopy (SRM) methods, can now help bridge this gap. With this interdisciplinary proposal, my group will develop unique and innovative optical, biological and computational imaging technologies to determine the structural organization of multi-protein assemblies in their functional cellular context.
We will reach this goal by developing a method to robustly measure the precise 3D arrangements of proteins in supra-molecular assemblies in situ with nanometer isotropic resolution based on supercritical-angle detection and by measuring their absolute stoichiometries with engineered counting standards. We will also develop new data analysis tools to statistically analyze such data, taking into account the functional cellular context measured with correlative superresolution and electron microscopy, multi-color SRM and molecular biology tools. We will apply these new methods to address key questions on endocytosis, a fundamental membrane trafficking process. Our aim is to determine a time-resolved 3D superresolution localization map of the yeast endocytic proteins during the major functional transitions and to integrate these data into a mechanistic model of endocytosis. Importantly, the methods we develop here can be applied to many other large protein-based machines, and thus have the potential to have high impact in other key areas of cell biology.
Max ERC Funding
1 686 469 €
Duration
Start date: 2017-06-01, End date: 2022-05-31
Project acronym cenRNA
Project The role of RNA in centromere biology and genome integrity
Researcher (PI) Sylvia Erhardt
Host Institution (HI) RUPRECHT-KARLS-UNIVERSITAET HEIDELBERG
Call Details Consolidator Grant (CoG), LS1, ERC-2015-CoG
Summary One of the most astonishing processes in the life of a cell is the division into two daughter cells. Such a highly organized process would presumably be regulated tightly by the underlying centromeric DNA sequence; however, the sites of chromosome attachment to the microtubule spindle are regulated by epigenetic mechanisms. The best-characterized epigenetic mark for centromeres is the histone H3-variant CENP-A, which replaces H3 in some of the nucleosomes within centromeric chromatin. Centromeres are embedded in pericentromeric heterochromatin and it has become apparent in recent years that heterochromatin is transcribed into non-coding RNAs. We have recently shown that a long non-coding RNA from pericentromeric heterochromatin of the X chromosome (SATIII) in Drosophila melanogaster localizes in trans to centromeres of all other chromosomes and is an essential component for correct loading and maintenance of CENP-A and, therefore, genome stability. Additional RNAs in Drosophila and RNAs from other species have been linked to centromeric chromatin, but their function is not understood. We propose that a complex, RNA-based epigenetic mechanism regulates centromere establishment and function.
This proposal is designed to the precise function of SATIII RNA by identifying the associated protein complexes as well as structural and post-transcriptional features of SATIII. We will evaluate the mechanisms by which SATIII functions as a heritable mark of centromeres through generations, during the developing germ line, and species separation. In parallel, we will systematically identify and characterize centromere-associated RNAs (cenRNAs) in Drosophila and human cells. We will elucidate their function in centromere biology and chromosome segregation, essentially as we have done and propose to do for SATIII. These experiments are designed to provide a detailed understanding of the essential, RNA-based epigenetic regulation of centromeres.
Summary
One of the most astonishing processes in the life of a cell is the division into two daughter cells. Such a highly organized process would presumably be regulated tightly by the underlying centromeric DNA sequence; however, the sites of chromosome attachment to the microtubule spindle are regulated by epigenetic mechanisms. The best-characterized epigenetic mark for centromeres is the histone H3-variant CENP-A, which replaces H3 in some of the nucleosomes within centromeric chromatin. Centromeres are embedded in pericentromeric heterochromatin and it has become apparent in recent years that heterochromatin is transcribed into non-coding RNAs. We have recently shown that a long non-coding RNA from pericentromeric heterochromatin of the X chromosome (SATIII) in Drosophila melanogaster localizes in trans to centromeres of all other chromosomes and is an essential component for correct loading and maintenance of CENP-A and, therefore, genome stability. Additional RNAs in Drosophila and RNAs from other species have been linked to centromeric chromatin, but their function is not understood. We propose that a complex, RNA-based epigenetic mechanism regulates centromere establishment and function.
This proposal is designed to the precise function of SATIII RNA by identifying the associated protein complexes as well as structural and post-transcriptional features of SATIII. We will evaluate the mechanisms by which SATIII functions as a heritable mark of centromeres through generations, during the developing germ line, and species separation. In parallel, we will systematically identify and characterize centromere-associated RNAs (cenRNAs) in Drosophila and human cells. We will elucidate their function in centromere biology and chromosome segregation, essentially as we have done and propose to do for SATIII. These experiments are designed to provide a detailed understanding of the essential, RNA-based epigenetic regulation of centromeres.
Max ERC Funding
1 896 250 €
Duration
Start date: 2016-07-01, End date: 2021-06-30
Project acronym ChaperoneRegulome
Project ChaperoneRegulome: Understanding cell-type-specificity of chaperone regulation
Researcher (PI) Ritwick SAWARKAR
Host Institution (HI) MAX-PLANCK-GESELLSCHAFT ZUR FORDERUNG DER WISSENSCHAFTEN EV
Call Details Consolidator Grant (CoG), LS3, ERC-2018-COG
Summary Protein misfolding causes devastating health conditions such as neurodegeneration. Although the disease-causing protein is widely expressed, its misfolding occurs only in certain cell-types such as neurons. What governs the susceptibility of some tissues to misfolding is a fundamental question with biomedical relevance.
Molecular chaperones help cellular proteins fold into their native conformation. Despite the generality of their function, chaperones are differentially expressed across various tissues. Moreover exposure to misfolding stress changes chaperone expression in a cell-type-dependent manner. Thus cell-type-specific regulation of chaperones is a major determinant of susceptibility to misfolding. The molecular mechanisms governing chaperone levels in different cell-types are not understood, forming the basis of this proposal. We will take a multidisciplinary approach to address two key questions: (1) How are chaperone levels co-ordinated with tissue-specific demands on protein folding? (2) How do different cell-types regulate chaperone genes when exposed to the same misfolding stress?
Cellular chaperone levels and their response to misfolding stress are both driven by transcriptional changes and influenced by chromatin. The proposed work will bring the conceptual, technological and computational advances of chromatin/ transcription field to understand chaperone biology and misfolding diseases. Using in vivo mouse model and in vitro differentiation model, we will investigate molecular mechanisms that control chaperone levels in relevant tissues. Our work will provide insights into functional specialization of chaperones driven by tissue-specific folding demands. We will develop a novel and ambitious approach to assess protein-folding capacity in single cells moving the chaperone field beyond state-of-the-art. Thus by implementing genetic, computational and biochemical approaches, we aim to understand cell-type-specificity of chaperone regulation.
Summary
Protein misfolding causes devastating health conditions such as neurodegeneration. Although the disease-causing protein is widely expressed, its misfolding occurs only in certain cell-types such as neurons. What governs the susceptibility of some tissues to misfolding is a fundamental question with biomedical relevance.
Molecular chaperones help cellular proteins fold into their native conformation. Despite the generality of their function, chaperones are differentially expressed across various tissues. Moreover exposure to misfolding stress changes chaperone expression in a cell-type-dependent manner. Thus cell-type-specific regulation of chaperones is a major determinant of susceptibility to misfolding. The molecular mechanisms governing chaperone levels in different cell-types are not understood, forming the basis of this proposal. We will take a multidisciplinary approach to address two key questions: (1) How are chaperone levels co-ordinated with tissue-specific demands on protein folding? (2) How do different cell-types regulate chaperone genes when exposed to the same misfolding stress?
Cellular chaperone levels and their response to misfolding stress are both driven by transcriptional changes and influenced by chromatin. The proposed work will bring the conceptual, technological and computational advances of chromatin/ transcription field to understand chaperone biology and misfolding diseases. Using in vivo mouse model and in vitro differentiation model, we will investigate molecular mechanisms that control chaperone levels in relevant tissues. Our work will provide insights into functional specialization of chaperones driven by tissue-specific folding demands. We will develop a novel and ambitious approach to assess protein-folding capacity in single cells moving the chaperone field beyond state-of-the-art. Thus by implementing genetic, computational and biochemical approaches, we aim to understand cell-type-specificity of chaperone regulation.
Max ERC Funding
1 992 500 €
Duration
Start date: 2019-07-01, End date: 2024-06-30
Project acronym CHEMMINE
Project Chemical proteome mining for functional annotation of disease relevant proteins
Researcher (PI) Stephan SIEBER
Host Institution (HI) TECHNISCHE UNIVERSITAET MUENCHEN
Call Details Consolidator Grant (CoG), PE5, ERC-2016-COG
Summary Genome sequencing projects have provided unique insights into the cellular inventory of genes and their corresponding protein products. Despite this success, a large fraction of cellular proteins remains functionally uncharacterized. Their annotation represents a major challenge for contemporary research, reaching beyond the power of bioinformatic sequence similarity searches. Thus multidisciplinary strategies consolidating chemical and biological methods are required to close this gap. We here approach the challenge by two chemical proteomic platforms that focus on disease relevant sub-fractions of the uncharacterized proteome. The first platform utilizes functionalized cofactors that exploit cognate cellular uptake systems and report specific binding of large enzyme families. The molecules will be applied to mine cellular proteomes for unknown family members with crucial roles in diseases and assign their function. The second platform exploits phosphoaspartate as an important disease-related post-translational modification. Due to low stability, this transient modification currently escapes detection by established proteomic procedures. Moreover, little is known about the enzymes that catalyze aspartate phosphorylation. We here use specific nucleophilic traps that convert phosphoaspartate into stable modifications suitable for analytic detection. In addition, the complement of currently unknown phosphodonor proteins will be identified with customized tools. With these platforms we aim to functionally annotate sub-fractions of the uncharacterized proteome and utilize our tools for the identification of new drug targets by comparative analysis of healthy and diseased cells. Finally, we apply the camouflaged molecular design strategy in the synthesis of compound libraries to screen for candidate inhibitors against selected, disease-modulating targets. The previous record of my group in chemical proteomics provides a strong basis to achieve these challenging goals.
Summary
Genome sequencing projects have provided unique insights into the cellular inventory of genes and their corresponding protein products. Despite this success, a large fraction of cellular proteins remains functionally uncharacterized. Their annotation represents a major challenge for contemporary research, reaching beyond the power of bioinformatic sequence similarity searches. Thus multidisciplinary strategies consolidating chemical and biological methods are required to close this gap. We here approach the challenge by two chemical proteomic platforms that focus on disease relevant sub-fractions of the uncharacterized proteome. The first platform utilizes functionalized cofactors that exploit cognate cellular uptake systems and report specific binding of large enzyme families. The molecules will be applied to mine cellular proteomes for unknown family members with crucial roles in diseases and assign their function. The second platform exploits phosphoaspartate as an important disease-related post-translational modification. Due to low stability, this transient modification currently escapes detection by established proteomic procedures. Moreover, little is known about the enzymes that catalyze aspartate phosphorylation. We here use specific nucleophilic traps that convert phosphoaspartate into stable modifications suitable for analytic detection. In addition, the complement of currently unknown phosphodonor proteins will be identified with customized tools. With these platforms we aim to functionally annotate sub-fractions of the uncharacterized proteome and utilize our tools for the identification of new drug targets by comparative analysis of healthy and diseased cells. Finally, we apply the camouflaged molecular design strategy in the synthesis of compound libraries to screen for candidate inhibitors against selected, disease-modulating targets. The previous record of my group in chemical proteomics provides a strong basis to achieve these challenging goals.
Max ERC Funding
1 936 250 €
Duration
Start date: 2017-03-01, End date: 2022-02-28
Project acronym CHILE
Project A Comparative History of Insurance Law in Europe
Researcher (PI) Phillip Hellwege
Host Institution (HI) UNIVERSITAET AUGSBURG
Call Details Consolidator Grant (CoG), SH2, ERC-2014-CoG
Summary The objective of the project is to work out interactions between the national developments of insurance law in Europe, to explore the possibility of common historical roots of European insurance law, and to reassess the history of insurance law in Europe. The project does, thereby, aim at creating a historical basis for a European legal scholarship in the field of insurance law.
Today’s state of research in the field of the history of insurance law is unsatisfactory: with the exception of maritime insurance, modern research focuses on national developments and the history of insurance law is told differently in the European countries. Even though modern research suggests that there have been interactions between the national developments these interactions often appear to be only footnotes to a mainly national development.
For the first time, the project takes these points of interactions as a starting point for an in depth research into the history of insurance law in Europe. It is, to take an example involving England and Germany, known that English life and fire insurers where present on the German market since the late 18th century and that those who, in the beginning of the 19th century, were involved in founding the first commercial life and fire insurers in Germany had been working for English insurers. What needs to be explored is what impact this had on the practice and standard contract terms of German insurers. On the basis of the research into this and other points of interactions it will, for the first time, be possible to research into the doctrinal history of insurance law on a European level.
The project will help to reassess the history of insurance law in Europe and it will create a historical basis for a European scholarship in the field of insurance law: the harmonization of European insurance contract law is on the agenda. Comparative historical research will help to understand the existing differences between the insurance laws in Europe.
Summary
The objective of the project is to work out interactions between the national developments of insurance law in Europe, to explore the possibility of common historical roots of European insurance law, and to reassess the history of insurance law in Europe. The project does, thereby, aim at creating a historical basis for a European legal scholarship in the field of insurance law.
Today’s state of research in the field of the history of insurance law is unsatisfactory: with the exception of maritime insurance, modern research focuses on national developments and the history of insurance law is told differently in the European countries. Even though modern research suggests that there have been interactions between the national developments these interactions often appear to be only footnotes to a mainly national development.
For the first time, the project takes these points of interactions as a starting point for an in depth research into the history of insurance law in Europe. It is, to take an example involving England and Germany, known that English life and fire insurers where present on the German market since the late 18th century and that those who, in the beginning of the 19th century, were involved in founding the first commercial life and fire insurers in Germany had been working for English insurers. What needs to be explored is what impact this had on the practice and standard contract terms of German insurers. On the basis of the research into this and other points of interactions it will, for the first time, be possible to research into the doctrinal history of insurance law on a European level.
The project will help to reassess the history of insurance law in Europe and it will create a historical basis for a European scholarship in the field of insurance law: the harmonization of European insurance contract law is on the agenda. Comparative historical research will help to understand the existing differences between the insurance laws in Europe.
Max ERC Funding
1 992 500 €
Duration
Start date: 2015-09-01, End date: 2020-08-31
Project acronym CholangioConcept
Project Functional in vivo analysis of cholangiocarcinoma development, progression and metastasis.
Researcher (PI) Lars Zender
Host Institution (HI) EBERHARD KARLS UNIVERSITAET TUEBINGEN
Call Details Consolidator Grant (CoG), LS4, ERC-2014-CoG
Summary Genetic heterogeneity and complexity are hallmarks of metastatic solid tumors and therapy resistance inevitably develops upon treatment with cytotoxic drugs or molecular targeted therapies. Cholangiocarcinoma (CCC, or bile duct cancer) represents the second most frequent primary liver tumor and has emerged as a health problem with sharply increasing incidence rates, in particular of intrahepatic CCC (ICC). The reason for increased CCC incidence remains unclear, but influences of western lifestyle and a resulting altered hepatic metabolism have been discussed. Surgical resection represents the only curative option for the treatment of CCC, however, many tumors are irresectable at the time of diagnosis. CCC represents a highly aggressive and metastatic tumor type and currently no effective systemic therapy regimen exists. The overall molecular mechanisms driving CCC formation and progression remain poorly characterized and it thus becomes clear that a detailed molecular characterization of cholangiocarcinogenesis and the identification of robust therapeutic targets for CCC treatment are urgently needed. Taking advantage of our strong expertises in chimaeric (mosaic) liver cancer mouse models and stable in vivo shRNA technology, we here propose a comprehensive and innovative approach to i) dissect molecular mechanisms of cholangiocarcinogenesis, with a particular emphasis on Kras driven ICC development from adult hepatocytes and oncogenomic profiling of ICC metastasis, ii) to employ direct in vivo shRNA screening to functionally identify new therapeutic targets for CCC treatment and iii) to characterize the role of the gut microbiome for CCC progression and metastasis. We envision this ERC-funded project will yield important new insights into the molecular mechanisms of CCC development, progression and metastasis. As our work comprises direct and functional strategies to identify new vulnerabilities in CCC, the obtained data harbor a very high translational potential.
Summary
Genetic heterogeneity and complexity are hallmarks of metastatic solid tumors and therapy resistance inevitably develops upon treatment with cytotoxic drugs or molecular targeted therapies. Cholangiocarcinoma (CCC, or bile duct cancer) represents the second most frequent primary liver tumor and has emerged as a health problem with sharply increasing incidence rates, in particular of intrahepatic CCC (ICC). The reason for increased CCC incidence remains unclear, but influences of western lifestyle and a resulting altered hepatic metabolism have been discussed. Surgical resection represents the only curative option for the treatment of CCC, however, many tumors are irresectable at the time of diagnosis. CCC represents a highly aggressive and metastatic tumor type and currently no effective systemic therapy regimen exists. The overall molecular mechanisms driving CCC formation and progression remain poorly characterized and it thus becomes clear that a detailed molecular characterization of cholangiocarcinogenesis and the identification of robust therapeutic targets for CCC treatment are urgently needed. Taking advantage of our strong expertises in chimaeric (mosaic) liver cancer mouse models and stable in vivo shRNA technology, we here propose a comprehensive and innovative approach to i) dissect molecular mechanisms of cholangiocarcinogenesis, with a particular emphasis on Kras driven ICC development from adult hepatocytes and oncogenomic profiling of ICC metastasis, ii) to employ direct in vivo shRNA screening to functionally identify new therapeutic targets for CCC treatment and iii) to characterize the role of the gut microbiome for CCC progression and metastasis. We envision this ERC-funded project will yield important new insights into the molecular mechanisms of CCC development, progression and metastasis. As our work comprises direct and functional strategies to identify new vulnerabilities in CCC, the obtained data harbor a very high translational potential.
Max ERC Funding
1 998 898 €
Duration
Start date: 2015-09-01, End date: 2020-08-31
Project acronym CHROMADAPT
Project The role of chromatin in the long-term adaptation of plants to abiotic stress
Researcher (PI) Isabel BÄURLE
Host Institution (HI) UNIVERSITAET POTSDAM
Call Details Consolidator Grant (CoG), LS9, ERC-2016-COG
Summary Abiotic stress is a major threat to global crop yields and this problem is likely to be exacerbated in the future. Therefore, it is very important to engineer crop plants with improved stress tolerance. A large body of research has focussed on the immediate stress responses. However, in nature stress is frequently chronic or recurring, suggesting that temporal dynamics are an important, but under-researched, component of plant stress responses. Indeed, plants can be primed by a stress exposure such that they respond more efficiently to the next stress incident. Such stress priming and memory may be particularly beneficial to plants due to their sessile life style. Typically, the memory of priming lasts for several days after the end of the stress. During the past few years, my group has initiated a molecular analysis of heat stress memory in Arabidopsis thaliana. Heat stress memory is associated with sustained gene induction and transcriptional memory and we have demonstrated that this involves lasting chromatin changes. The underlying molecular mechanisms, however, remain poorly understood. Here, I propose to combine mechanistic dissection of heat stress memory in A. thaliana with concomitant translation of the results into the temperate cereal crop barley. In particular, we will study the following questions: What is the role of chromatin during heat stress memory? How do the transcription factors involved mediate memory-specific outputs? How does nucleosome positioning affect heat stress memory? How do histone modifications during stress memory interact with transcription, chromatin and nuclear organization? Is heat stress memory conserved in temperate cereal species? Can we engineer plants with improved stress memory? Using existing tools and new methodologies, the proposed analyses will yield unprecedented insight into the long-term adaptation of plants to abiotic stress and open up approaches for breeding of stress-tolerant crops.
Summary
Abiotic stress is a major threat to global crop yields and this problem is likely to be exacerbated in the future. Therefore, it is very important to engineer crop plants with improved stress tolerance. A large body of research has focussed on the immediate stress responses. However, in nature stress is frequently chronic or recurring, suggesting that temporal dynamics are an important, but under-researched, component of plant stress responses. Indeed, plants can be primed by a stress exposure such that they respond more efficiently to the next stress incident. Such stress priming and memory may be particularly beneficial to plants due to their sessile life style. Typically, the memory of priming lasts for several days after the end of the stress. During the past few years, my group has initiated a molecular analysis of heat stress memory in Arabidopsis thaliana. Heat stress memory is associated with sustained gene induction and transcriptional memory and we have demonstrated that this involves lasting chromatin changes. The underlying molecular mechanisms, however, remain poorly understood. Here, I propose to combine mechanistic dissection of heat stress memory in A. thaliana with concomitant translation of the results into the temperate cereal crop barley. In particular, we will study the following questions: What is the role of chromatin during heat stress memory? How do the transcription factors involved mediate memory-specific outputs? How does nucleosome positioning affect heat stress memory? How do histone modifications during stress memory interact with transcription, chromatin and nuclear organization? Is heat stress memory conserved in temperate cereal species? Can we engineer plants with improved stress memory? Using existing tools and new methodologies, the proposed analyses will yield unprecedented insight into the long-term adaptation of plants to abiotic stress and open up approaches for breeding of stress-tolerant crops.
Max ERC Funding
1 998 525 €
Duration
Start date: 2017-05-01, End date: 2022-04-30
Project acronym ChronHib
Project Chronologicon Hibernicum – A Probabilistic Chronological Framework for Dating Early Irish Language Developments and Literature
Researcher (PI) David Stifter
Host Institution (HI) NATIONAL UNIVERSITY OF IRELAND MAYNOOTH
Call Details Consolidator Grant (CoG), SH4, ERC-2014-CoG
Summary Early Medieval Irish literature (7th–10th centuries) is vast in extent and rich in genres, but owing to its mostly anonymous transmission, for most texts the precise time and circumstances of composition are unknown. Unless where texts contain historical references, the only clues for a rough chronological positioning of the texts are to be found in their linguistic peculiarities. Phonology, morphology, syntax and the lexicon of the Irish language changed considerably from Early Old Irish (7th c.) into Middle Irish (c. 10th–12th centuries). However, only the relative sequence of changes is well understood; for most sound changes very few narrow dates have been proposed so far.
It is the aim of Chronologicon Hibernicum to find a common solution for both problems: through the linguistic profiling of externally dated texts (esp. annalistic writing and sources with a clear historical anchorage) and through serialising the emerging linguistic and chronological data, progress will be made in assigning dates to the linguistic changes. Groundbreakingly, this will be done by using statistical methods for the seriation of the data, and for estimating dates using Bayesian inference.
The resultant information will then be used to find new dates for hitherto undated texts. On this basis, a much tighter chronological framework for the developments of the Early Medieval Irish language will be created. In a further step it will be possible to arrive at a better chronological description of medieval Irish literature as a whole, which will have repercussions on the study of the history and cultural and intellectual environment of medieval Ireland and on its connections with the wider world.
The data collected and analysed in this project will form the database Chronologicon Hibernicum which will serve as the authoritative guideline and reference point for the linguistic dating of Irish texts. In the future, the methodology will be transferable to other languages.
Summary
Early Medieval Irish literature (7th–10th centuries) is vast in extent and rich in genres, but owing to its mostly anonymous transmission, for most texts the precise time and circumstances of composition are unknown. Unless where texts contain historical references, the only clues for a rough chronological positioning of the texts are to be found in their linguistic peculiarities. Phonology, morphology, syntax and the lexicon of the Irish language changed considerably from Early Old Irish (7th c.) into Middle Irish (c. 10th–12th centuries). However, only the relative sequence of changes is well understood; for most sound changes very few narrow dates have been proposed so far.
It is the aim of Chronologicon Hibernicum to find a common solution for both problems: through the linguistic profiling of externally dated texts (esp. annalistic writing and sources with a clear historical anchorage) and through serialising the emerging linguistic and chronological data, progress will be made in assigning dates to the linguistic changes. Groundbreakingly, this will be done by using statistical methods for the seriation of the data, and for estimating dates using Bayesian inference.
The resultant information will then be used to find new dates for hitherto undated texts. On this basis, a much tighter chronological framework for the developments of the Early Medieval Irish language will be created. In a further step it will be possible to arrive at a better chronological description of medieval Irish literature as a whole, which will have repercussions on the study of the history and cultural and intellectual environment of medieval Ireland and on its connections with the wider world.
The data collected and analysed in this project will form the database Chronologicon Hibernicum which will serve as the authoritative guideline and reference point for the linguistic dating of Irish texts. In the future, the methodology will be transferable to other languages.
Max ERC Funding
1 804 230 €
Duration
Start date: 2015-09-01, End date: 2020-08-31
Project acronym CiliaTubulinCode
Project Self-organization of the cilium: the role of the tubulin code
Researcher (PI) Gaia PIGINO
Host Institution (HI) MAX-PLANCK-GESELLSCHAFT ZUR FORDERUNG DER WISSENSCHAFTEN EV
Call Details Consolidator Grant (CoG), LS1, ERC-2018-COG
Summary This project aims at understanding of the role of the tubulin code for self-organization of complex microtubule based structures. Cilia turn out to be the ideal structures for the proposed research.
A cilium is a sophisticated cellular machine that self-organizes from many protein complexes. It plays motility, sensory, and signaling roles in most eukaryotic cells, and its malfunction causes pathologies. The assembly of the cilium requires intraflagellar transport (IFT), a specialized bidirectional motility process that is mediated by adaptor proteins and direction specific molecular motors. Work from my lab shows that anterograde and retrograde IFT make exclusive use of the B-tubules and A-tubules, respectively. This insight answered a long standing question and shows that functional differentiation of tubules exists and is important for IFT.
Tubulin post-translational modifications (PTMs) contribute to a tubulin code, making microtubules suitable for specific functions. Mutation of tubulin-PTM enzymes can have dramatic effects on cilia function and assembly. However, we do not understand of the role of tubulin-PTMs in cilia. Therefore, I propose to address the hypotheses that the tubulin code contributes to regulating bidirectional IFT motility, and more generally, that the tubulin code is a key player in structuring complex cellular assembly processes in space and time.
This proposal aims at (i) understanding if tubulin-PTMs are necessary and/or sufficient to regulate the bidirectionality of IFT (ii) examining how the tubulin code regulates the assembly of cilia and (iii) generating a high-resolution atlas of tubulin-PTMs and their respective enzymes.
We will combine advanced techniques encompassing state-of-the-art cryo-electron tomography, biochemical imaging, fluorescent microscopy, and in vitro assays to achieve molecular and structural understanding of the role of the tubulin code in the self-organization of cilia and of microtubule based cellular structures.
Summary
This project aims at understanding of the role of the tubulin code for self-organization of complex microtubule based structures. Cilia turn out to be the ideal structures for the proposed research.
A cilium is a sophisticated cellular machine that self-organizes from many protein complexes. It plays motility, sensory, and signaling roles in most eukaryotic cells, and its malfunction causes pathologies. The assembly of the cilium requires intraflagellar transport (IFT), a specialized bidirectional motility process that is mediated by adaptor proteins and direction specific molecular motors. Work from my lab shows that anterograde and retrograde IFT make exclusive use of the B-tubules and A-tubules, respectively. This insight answered a long standing question and shows that functional differentiation of tubules exists and is important for IFT.
Tubulin post-translational modifications (PTMs) contribute to a tubulin code, making microtubules suitable for specific functions. Mutation of tubulin-PTM enzymes can have dramatic effects on cilia function and assembly. However, we do not understand of the role of tubulin-PTMs in cilia. Therefore, I propose to address the hypotheses that the tubulin code contributes to regulating bidirectional IFT motility, and more generally, that the tubulin code is a key player in structuring complex cellular assembly processes in space and time.
This proposal aims at (i) understanding if tubulin-PTMs are necessary and/or sufficient to regulate the bidirectionality of IFT (ii) examining how the tubulin code regulates the assembly of cilia and (iii) generating a high-resolution atlas of tubulin-PTMs and their respective enzymes.
We will combine advanced techniques encompassing state-of-the-art cryo-electron tomography, biochemical imaging, fluorescent microscopy, and in vitro assays to achieve molecular and structural understanding of the role of the tubulin code in the self-organization of cilia and of microtubule based cellular structures.
Max ERC Funding
1 986 406 €
Duration
Start date: 2019-03-01, End date: 2024-02-29
Project acronym COBHUNI
Project Contemporary Bioethics and the History of the Unborn in Islam
Researcher (PI) Thomas Alexander Eich
Host Institution (HI) UNIVERSITAET HAMBURG
Call Details Consolidator Grant (CoG), SH5, ERC-2014-CoG
Summary COBHUNI will for the first time provide a comprehensive investigation of the History of the Unborn in Islam until today. This aims at diversifying our understanding of how pre-natal life is conceptualized in texts of Islamic normativity. At the center will be the analysis of statements in the Qur’an and the prophetic sayings (Hadith) relating to the unborn and the commentary tradition which evolved around them over ca. the last millennium. The objectives of COBHUNI: 1. Thematically: Showing how processes of communication a) between religious communities, b) different regions within the Muslim community, and c) the emergence of modern medicine impacted on the imagination of the unborn. 2. Conceptually: Drawing on three new approaches in the study of Islam: a) emergence of Islam within the context of late antiquity, b) canonization studies, and c) study of exegetical literature. 3. Methodologically: Developing and applying computerlinguistic approaches to Arabic text material and thus improving significantly on the state of the art of Arabic Digital Humanities. The realization will encompass the analysis of the text material along two axes. Vertical axis: citations and cross-referencing within the exegetical tradition; Horizontal axis: contextualizing the exegesis and scrutinizing links to other genres. I have been working on contemporary Islamic Bioethics since 2003 and since 2008 I have broadened my research to the historical scope of the topic. With my comprehensive experience in the study of Contemporary Islamic Bioethics and historical texts from Islamic Normativity and my knowledge in the study of Arabic Qur’an and Hadith exegesis I will be able to successfully lead this cutting-edge project. My team will generate additional data and enhance the IT applications necessary for its analysis. My project will offer powerful approaches to show the complex web of influences impacting on the imaginations of the unborn in Islam.
Summary
COBHUNI will for the first time provide a comprehensive investigation of the History of the Unborn in Islam until today. This aims at diversifying our understanding of how pre-natal life is conceptualized in texts of Islamic normativity. At the center will be the analysis of statements in the Qur’an and the prophetic sayings (Hadith) relating to the unborn and the commentary tradition which evolved around them over ca. the last millennium. The objectives of COBHUNI: 1. Thematically: Showing how processes of communication a) between religious communities, b) different regions within the Muslim community, and c) the emergence of modern medicine impacted on the imagination of the unborn. 2. Conceptually: Drawing on three new approaches in the study of Islam: a) emergence of Islam within the context of late antiquity, b) canonization studies, and c) study of exegetical literature. 3. Methodologically: Developing and applying computerlinguistic approaches to Arabic text material and thus improving significantly on the state of the art of Arabic Digital Humanities. The realization will encompass the analysis of the text material along two axes. Vertical axis: citations and cross-referencing within the exegetical tradition; Horizontal axis: contextualizing the exegesis and scrutinizing links to other genres. I have been working on contemporary Islamic Bioethics since 2003 and since 2008 I have broadened my research to the historical scope of the topic. With my comprehensive experience in the study of Contemporary Islamic Bioethics and historical texts from Islamic Normativity and my knowledge in the study of Arabic Qur’an and Hadith exegesis I will be able to successfully lead this cutting-edge project. My team will generate additional data and enhance the IT applications necessary for its analysis. My project will offer powerful approaches to show the complex web of influences impacting on the imaginations of the unborn in Islam.
Max ERC Funding
1 956 338 €
Duration
Start date: 2015-09-01, End date: 2020-08-31
Project acronym CODA
Project Custom-Made Ontology Based Data Access
Researcher (PI) Carsten Lutz
Host Institution (HI) UNIVERSITAET BREMEN
Call Details Consolidator Grant (CoG), PE6, ERC-2014-CoG
Summary The emerging and vibrant area of ontology-based data access (OBDA) is currently establishing itself as an important paradigm for processing incomplete and heterogeneous data. The goal of the CODA project is to make OBDA radically more useful for real-world applications by taking a ground-breaking new perspective on its foundations, algorithms, and tools. The project will rest on an ultimately fine-grained complexity analysis that allows to identify islands of tractability inside practically important ontology and query languages that are otherwise intractable. Based on these islands, novel OBDA querying tools will be developed that are custom-made for ontologies from applications in the sense that high computational cost is incurred only when unavoidable for the concrete ontology used (`pay as you go' behaviour). The key deliverables of the project are a set of tailor-made OBDA querying tools that form a precision tool belt for real-world OBDA applications, theoretical results regarding the structure and computational complexity of important islands of tractability, efficient algorithms that allow to put these to work in practice, and optimization techniques and heuristics that support the algorithms in the tools developed. We will also collect and make available a library of case studies for evaluating OBDA tools. The project is both timely and essential. It is timely because our economy and society are currently experiencing a revolution in data processing and availability, and dealing with incompleteness and heterogeneity is one of the major arising challenges. The project is essential because it has become apparent now that current OBDA tools cannot satisfy industry requirements. In particular, they do not adequately support the limited use of expressive features (`a little bit of disjunction') which intuitively should not result in high computational cost, but with current technology often does.
Summary
The emerging and vibrant area of ontology-based data access (OBDA) is currently establishing itself as an important paradigm for processing incomplete and heterogeneous data. The goal of the CODA project is to make OBDA radically more useful for real-world applications by taking a ground-breaking new perspective on its foundations, algorithms, and tools. The project will rest on an ultimately fine-grained complexity analysis that allows to identify islands of tractability inside practically important ontology and query languages that are otherwise intractable. Based on these islands, novel OBDA querying tools will be developed that are custom-made for ontologies from applications in the sense that high computational cost is incurred only when unavoidable for the concrete ontology used (`pay as you go' behaviour). The key deliverables of the project are a set of tailor-made OBDA querying tools that form a precision tool belt for real-world OBDA applications, theoretical results regarding the structure and computational complexity of important islands of tractability, efficient algorithms that allow to put these to work in practice, and optimization techniques and heuristics that support the algorithms in the tools developed. We will also collect and make available a library of case studies for evaluating OBDA tools. The project is both timely and essential. It is timely because our economy and society are currently experiencing a revolution in data processing and availability, and dealing with incompleteness and heterogeneity is one of the major arising challenges. The project is essential because it has become apparent now that current OBDA tools cannot satisfy industry requirements. In particular, they do not adequately support the limited use of expressive features (`a little bit of disjunction') which intuitively should not result in high computational cost, but with current technology often does.
Max ERC Funding
1 922 115 €
Duration
Start date: 2015-08-01, End date: 2020-07-31
Project acronym CODE4Vision
Project Computational Dissection of Effective Circuitry and Encoding in the Retina for Normal and Restored Vision
Researcher (PI) Tim Gollisch
Host Institution (HI) UNIVERSITAETSMEDIZIN GOETTINGEN - GEORG-AUGUST-UNIVERSITAET GOETTINGEN - STIFTUNG OEFFENTLICHEN RECHTS
Call Details Consolidator Grant (CoG), LS5, ERC-2016-COG
Summary Understanding how neural circuits process and encode information is a fundamental goal in neuroscience. For the neural network of the retina, such knowledge is also of concrete importance for the development of vision restoration therapies for patients suffering from degeneration of photoreceptors. Artificial stimulation of retinal neurons through electronic implants or inserted light-sensitive proteins (“optogenetics”) aims at reconstructing natural transmission of visual information to the brain. Recreating natural retinal activity, however, will require a thorough understanding of the complex and diverse neural code of the retina. The challenge lies in deciphering the various nonlinear operations and dynamics in the around 30 parallel signalling streams that emerge from the retina, represented by as many types of ganglion cells, the retina’s output neurons.
The CODE4Vision project will tackle this challenge by identifying the effective connectivity between the different types of retinal ganglion cells and their excitatory presynaptic partners, bipolar cells, and by determining the features of information processing between these neuronal layers. We will characterize the layout of bipolar cell inputs to large populations of ganglion cells with novel analyses that we derive from computational statistics and machine learning. We will then study the nonlinear and dynamical features of these connections by designing closed-loop experiments that automatically adjust visual stimuli to the identified layout of bipolar cells. These analyses will be supplemented by direct measurements of connections through simultaneous bipolar and ganglion cell recordings. The results will pave the way towards new models of how the retina encodes natural visual stimuli. Finally, we will apply this knowledge to mouse models of optogenetic vision restoration in order to develop stimulation schemes that emulate natural retinal stimulus encoding.
Summary
Understanding how neural circuits process and encode information is a fundamental goal in neuroscience. For the neural network of the retina, such knowledge is also of concrete importance for the development of vision restoration therapies for patients suffering from degeneration of photoreceptors. Artificial stimulation of retinal neurons through electronic implants or inserted light-sensitive proteins (“optogenetics”) aims at reconstructing natural transmission of visual information to the brain. Recreating natural retinal activity, however, will require a thorough understanding of the complex and diverse neural code of the retina. The challenge lies in deciphering the various nonlinear operations and dynamics in the around 30 parallel signalling streams that emerge from the retina, represented by as many types of ganglion cells, the retina’s output neurons.
The CODE4Vision project will tackle this challenge by identifying the effective connectivity between the different types of retinal ganglion cells and their excitatory presynaptic partners, bipolar cells, and by determining the features of information processing between these neuronal layers. We will characterize the layout of bipolar cell inputs to large populations of ganglion cells with novel analyses that we derive from computational statistics and machine learning. We will then study the nonlinear and dynamical features of these connections by designing closed-loop experiments that automatically adjust visual stimuli to the identified layout of bipolar cells. These analyses will be supplemented by direct measurements of connections through simultaneous bipolar and ganglion cell recordings. The results will pave the way towards new models of how the retina encodes natural visual stimuli. Finally, we will apply this knowledge to mouse models of optogenetic vision restoration in order to develop stimulation schemes that emulate natural retinal stimulus encoding.
Max ERC Funding
1 991 445 €
Duration
Start date: 2017-06-01, End date: 2022-05-31
Project acronym COMBAT
Project Computational Modeling and Design of Lithium-Ion Batteries
Researcher (PI) Timon Rabczuk
Host Institution (HI) BAUHAUS-UNIVERSITAET WEIMAR
Call Details Consolidator Grant (CoG), PE8, ERC-2013-CoG
Summary "Lithium-ion batteries (LIBs) are among the most promising solutions for energy storage. Compared with other resources such as bio-fuel, solar cells, fuel cells or lead acid batteries, rechargeable batteries are more portable and allow for quick energy storage and release. The higher power and energy density make batteries suitable as the energy resource for most portable elect. devices including future vehicles. Among the rechargeable batteries, LIBs have the most potential because of their quick charging rate and high power and energy density. However, ageing of LIBs and the related capacity and power fade is a major concern. For the improvement and future development of batteries, computational modeling and design is an important complementary part to experimental testing which is expensive, time-consuming and sometimes unfeasible.
In this project, the PI proposes to develop, implement, verify and validate a computational multifield and multiscale framework to support the design and optimization of new batteries. The computational framework will support the design and optimization of new anode, separator and cathode materials as well as their structure inside the battery. The measurable outcome of this research will be an open-source software package that can be used to support the design and optimization of LIBs.
Within the computational framework, different (mechanical-thermal-electro-chemical) fields will be linked over multiple scales: from fundamental physics to the design of new battery materials. We will quantify uncertainties in order to provide upper and lower bounds of our predictions and use graph-theory, error-estimation and adaptivity to choose the appropriate model and discretization. The computational framework will be verified and validated by comparison to experiments. Finally, multi-objective optimization over multiple scales will provide a new battery prototype that will be manufactured, tested and compared to the computational predictions."
Summary
"Lithium-ion batteries (LIBs) are among the most promising solutions for energy storage. Compared with other resources such as bio-fuel, solar cells, fuel cells or lead acid batteries, rechargeable batteries are more portable and allow for quick energy storage and release. The higher power and energy density make batteries suitable as the energy resource for most portable elect. devices including future vehicles. Among the rechargeable batteries, LIBs have the most potential because of their quick charging rate and high power and energy density. However, ageing of LIBs and the related capacity and power fade is a major concern. For the improvement and future development of batteries, computational modeling and design is an important complementary part to experimental testing which is expensive, time-consuming and sometimes unfeasible.
In this project, the PI proposes to develop, implement, verify and validate a computational multifield and multiscale framework to support the design and optimization of new batteries. The computational framework will support the design and optimization of new anode, separator and cathode materials as well as their structure inside the battery. The measurable outcome of this research will be an open-source software package that can be used to support the design and optimization of LIBs.
Within the computational framework, different (mechanical-thermal-electro-chemical) fields will be linked over multiple scales: from fundamental physics to the design of new battery materials. We will quantify uncertainties in order to provide upper and lower bounds of our predictions and use graph-theory, error-estimation and adaptivity to choose the appropriate model and discretization. The computational framework will be verified and validated by comparison to experiments. Finally, multi-objective optimization over multiple scales will provide a new battery prototype that will be manufactured, tested and compared to the computational predictions."
Max ERC Funding
1 975 071 €
Duration
Start date: 2014-06-01, End date: 2019-05-31
Project acronym COMBAT
Project Clearance Of Microbial Biofilms by Advancing diagnostics and Therapy
Researcher (PI) Susanne Christiane Haeussler
Host Institution (HI) HELMHOLTZ-ZENTRUM FUR INFEKTIONSFORSCHUNG GMBH
Call Details Consolidator Grant (CoG), LS6, ERC-2016-COG
Summary Every year chronic infections in patients due to biofilm formation of pathogenic bacteria are a multi-billion Euro burden to national healthcare systems. Despite improvements in technology and medical services, morbidity and mortality due to chronic infections have remained unchanged over the past decades. The emergence of a chronic infection disease burden calls for the development of modern diagnostics for biofilm resistance profiling and new therapeutic strategies to eradicate biofilm-associated infections. However, many unsuccessful attempts to address this need teach us that alternative perspectives are needed to meet the challenges.
The project is committed to develop innovative diagnostics and to strive for therapeutic solutions in patients suffering from biofilm-associated infections. The objective is to apply data-driven science to unlock the potential of microbial genomics. This new approach uses tools of advanced microbiological genomics and machine learning in genome-wide association studies on an existing unprecedentedly large dataset. This dataset has been generated in my group within the last five years and comprises sequence variation and gene expression information of a plethora of clinical Pseudomonas aeruginosa isolates. The wealth of patterns and characteristics of biofilm resistance are invisible at a smaller scale and will be interpreted within context and domain-specific knowledge.
The unique combination of basic molecular biology research, technology-driven approaches and data-driven science allows pioneer research dedicated to advance strategies to combat biofilm-associated infections. My approach does not only provide a prediction of biofilm resistance based on the bacteria´s genotype but also holds promise to transform treatment paradigms for the management of chronic infections and by interference with bacterial stress responses will promote the effectiveness of antimicrobials in clinical use to eradicate biofilm infections.
Summary
Every year chronic infections in patients due to biofilm formation of pathogenic bacteria are a multi-billion Euro burden to national healthcare systems. Despite improvements in technology and medical services, morbidity and mortality due to chronic infections have remained unchanged over the past decades. The emergence of a chronic infection disease burden calls for the development of modern diagnostics for biofilm resistance profiling and new therapeutic strategies to eradicate biofilm-associated infections. However, many unsuccessful attempts to address this need teach us that alternative perspectives are needed to meet the challenges.
The project is committed to develop innovative diagnostics and to strive for therapeutic solutions in patients suffering from biofilm-associated infections. The objective is to apply data-driven science to unlock the potential of microbial genomics. This new approach uses tools of advanced microbiological genomics and machine learning in genome-wide association studies on an existing unprecedentedly large dataset. This dataset has been generated in my group within the last five years and comprises sequence variation and gene expression information of a plethora of clinical Pseudomonas aeruginosa isolates. The wealth of patterns and characteristics of biofilm resistance are invisible at a smaller scale and will be interpreted within context and domain-specific knowledge.
The unique combination of basic molecular biology research, technology-driven approaches and data-driven science allows pioneer research dedicated to advance strategies to combat biofilm-associated infections. My approach does not only provide a prediction of biofilm resistance based on the bacteria´s genotype but also holds promise to transform treatment paradigms for the management of chronic infections and by interference with bacterial stress responses will promote the effectiveness of antimicrobials in clinical use to eradicate biofilm infections.
Max ERC Funding
1 998 750 €
Duration
Start date: 2017-05-01, End date: 2022-04-30
Project acronym COMOTION
Project Controlling the Motion of Complex Molecules and Particles
Researcher (PI) Jochen Küpper
Host Institution (HI) STIFTUNG DEUTSCHES ELEKTRONEN-SYNCHROTRON DESY
Call Details Consolidator Grant (CoG), PE4, ERC-2013-CoG
Summary "The main objective of COMOTION is to enable novel experiments for the investigation of the intrinsic properties of large molecules, including biological samples like proteins, viruses, and small cells
-X-ray free-electron lasers have enabled the observation of near-atomic-resolution structures in diffraction- before-destruction experiments, for instance, of isolated mimiviruses and of proteins from microscopic crystals. The goal to record molecular movies with spatial and temporal atomic-resolution (femtoseconds and picometers) of individual molecules is near.
-The investigation of ultrafast, sub-femtosecond electron dynamics in small molecules is providing first results. Its extension to large molecules promises the unraveling of charge migration and energy transport in complex (bio)molecules.
-Matter-wave experiments of large molecules, with currently up to some hundred atoms, are testing the limits of quantum mechanics, particle-wave duality, and coherence. These metrology experiments also allow the precise measurement of molecular properties.
The principal obstacle for these and similar experiments in molecular sciences is the controlled production of samples of identical molecules in the gas phase. We will develop novel concepts and technologies for the manipulation of complex molecules, ranging from amino acids to proteins, viruses, nano-objects, and small cells: We will implement new methods to inject complex molecules into vacuum, to rapidly cool them, and to manipulate the motion of these cold gas-phase samples using combinations of external electric and electromagnetic fields. These external-field handles enable the spatial separation of molecules according to size, shape, and isomer.
The generated controlled samples are ideally suited for the envisioned precision experiments. We will exploit them to record atomic-resolution molecular movies using the European XFEL, as well as to investigate the limits of quantum mechanics using matter-wave interferometry."
Summary
"The main objective of COMOTION is to enable novel experiments for the investigation of the intrinsic properties of large molecules, including biological samples like proteins, viruses, and small cells
-X-ray free-electron lasers have enabled the observation of near-atomic-resolution structures in diffraction- before-destruction experiments, for instance, of isolated mimiviruses and of proteins from microscopic crystals. The goal to record molecular movies with spatial and temporal atomic-resolution (femtoseconds and picometers) of individual molecules is near.
-The investigation of ultrafast, sub-femtosecond electron dynamics in small molecules is providing first results. Its extension to large molecules promises the unraveling of charge migration and energy transport in complex (bio)molecules.
-Matter-wave experiments of large molecules, with currently up to some hundred atoms, are testing the limits of quantum mechanics, particle-wave duality, and coherence. These metrology experiments also allow the precise measurement of molecular properties.
The principal obstacle for these and similar experiments in molecular sciences is the controlled production of samples of identical molecules in the gas phase. We will develop novel concepts and technologies for the manipulation of complex molecules, ranging from amino acids to proteins, viruses, nano-objects, and small cells: We will implement new methods to inject complex molecules into vacuum, to rapidly cool them, and to manipulate the motion of these cold gas-phase samples using combinations of external electric and electromagnetic fields. These external-field handles enable the spatial separation of molecules according to size, shape, and isomer.
The generated controlled samples are ideally suited for the envisioned precision experiments. We will exploit them to record atomic-resolution molecular movies using the European XFEL, as well as to investigate the limits of quantum mechanics using matter-wave interferometry."
Max ERC Funding
1 982 500 €
Duration
Start date: 2014-09-01, End date: 2019-08-31
