Project acronym ABC
Project Targeting Multidrug Resistant Cancer
Researcher (PI) Gergely Szakacs
Host Institution (HI) MAGYAR TUDOMANYOS AKADEMIA TERMESZETTUDOMANYI KUTATOKOZPONT
Call Details Starting Grant (StG), LS7, ERC-2010-StG_20091118
Summary Despite considerable advances in drug discovery, resistance to anticancer chemotherapy confounds the effective treatment of patients. Cancer cells can acquire broad cross-resistance to mechanistically and structurally unrelated drugs. P-glycoprotein (Pgp) actively extrudes many types of drugs from cancer cells, thereby conferring resistance to those agents. The central tenet of my work is that Pgp, a universally accepted biomarker of drug resistance, should in addition be considered as a molecular target of multidrug-resistant (MDR) cancer cells. Successful targeting of MDR cells would reduce the tumor burden and would also enable the elimination of ABC transporter-overexpressing cancer stem cells that are responsible for the replenishment of tumors. The proposed project is based on the following observations:
- First, by using a pharmacogenomic approach, I have revealed the hidden vulnerability of MDRcells (Szakács et al. 2004, Cancer Cell 6, 129-37);
- Second, I have identified a series of MDR-selective compounds with increased toxicity toPgp-expressing cells
(Turk et al.,Cancer Res, 2009. 69(21));
- Third, I have shown that MDR-selective compounds can be used to prevent theemergence of MDR (Ludwig, Szakács et al. 2006, Cancer Res 66, 4808-15);
- Fourth, we have generated initial pharmacophore models for cytotoxicity and MDR-selectivity (Hall et al. 2009, J Med Chem 52, 3191-3204).
I propose a comprehensive series of studies that will address thefollowing critical questions:
- First, what is the scope of MDR-selective compounds?
- Second, what is their mechanism of action?
- Third, what is the optimal therapeutic modality?
Extensive biological, pharmacological and bioinformatic analyses will be utilized to address four major specific aims. These aims address basic questions concerning the physiology of MDR ABC transporters in determining the mechanism of action of MDR-selective compounds, setting the stage for a fresh therapeutic approach that may eventually translate into improved patient care.
Summary
Despite considerable advances in drug discovery, resistance to anticancer chemotherapy confounds the effective treatment of patients. Cancer cells can acquire broad cross-resistance to mechanistically and structurally unrelated drugs. P-glycoprotein (Pgp) actively extrudes many types of drugs from cancer cells, thereby conferring resistance to those agents. The central tenet of my work is that Pgp, a universally accepted biomarker of drug resistance, should in addition be considered as a molecular target of multidrug-resistant (MDR) cancer cells. Successful targeting of MDR cells would reduce the tumor burden and would also enable the elimination of ABC transporter-overexpressing cancer stem cells that are responsible for the replenishment of tumors. The proposed project is based on the following observations:
- First, by using a pharmacogenomic approach, I have revealed the hidden vulnerability of MDRcells (Szakács et al. 2004, Cancer Cell 6, 129-37);
- Second, I have identified a series of MDR-selective compounds with increased toxicity toPgp-expressing cells
(Turk et al.,Cancer Res, 2009. 69(21));
- Third, I have shown that MDR-selective compounds can be used to prevent theemergence of MDR (Ludwig, Szakács et al. 2006, Cancer Res 66, 4808-15);
- Fourth, we have generated initial pharmacophore models for cytotoxicity and MDR-selectivity (Hall et al. 2009, J Med Chem 52, 3191-3204).
I propose a comprehensive series of studies that will address thefollowing critical questions:
- First, what is the scope of MDR-selective compounds?
- Second, what is their mechanism of action?
- Third, what is the optimal therapeutic modality?
Extensive biological, pharmacological and bioinformatic analyses will be utilized to address four major specific aims. These aims address basic questions concerning the physiology of MDR ABC transporters in determining the mechanism of action of MDR-selective compounds, setting the stage for a fresh therapeutic approach that may eventually translate into improved patient care.
Max ERC Funding
1 499 640 €
Duration
Start date: 2012-01-01, End date: 2016-12-31
Project acronym BRAINCANNABINOIDS
Project Understanding the molecular blueprint and functional complexity of the endocannabinoid metabolome in the brain
Researcher (PI) István Katona
Host Institution (HI) INSTITUTE OF EXPERIMENTAL MEDICINE - HUNGARIAN ACADEMY OF SCIENCES
Call Details Starting Grant (StG), LS5, ERC-2009-StG
Summary We and others have recently delineated the molecular architecture of a new feedback pathway in brain synapses, which operates as a synaptic circuit breaker. This pathway is supposed to use a group of lipid messengers as retrograde synaptic signals, the so-called endocannabinoids. Although heterogeneous in their chemical structures, these molecules along with the psychoactive compound in cannabis are thought to target the same effector in the brain, the CB1 receptor. However, the molecular catalog of these bioactive lipids and their metabolic enzymes has been expanding rapidly by recent advances in lipidomics and proteomics raising the possibility that these lipids may also serve novel, yet unidentified physiological functions. Thus, the overall aim of our research program is to define the molecular and anatomical organization of these endocannabinoid-mediated pathways and to determine their functional significance. In the present proposal, we will focus on understanding how these novel pathways regulate synaptic and extrasynaptic signaling in hippocampal neurons. Using combination of lipidomic, genetic and high-resolution anatomical approaches, we will identify distinct chemical species of endocannabinoids and will show how their metabolic enzymes are segregated into different subcellular compartments in cell type- and synapse-specific manner. Subsequently, we will use genetically encoded gain-of-function, loss-of-function and reporter constructs in imaging experiments and electrophysiological recordings to gain insights into the diverse tasks that these new pathways serve in synaptic transmission and extrasynaptic signal processing. Our proposed experiments will reveal fundamental principles of intercellular and intracellular endocannabinoid signaling in the brain.
Summary
We and others have recently delineated the molecular architecture of a new feedback pathway in brain synapses, which operates as a synaptic circuit breaker. This pathway is supposed to use a group of lipid messengers as retrograde synaptic signals, the so-called endocannabinoids. Although heterogeneous in their chemical structures, these molecules along with the psychoactive compound in cannabis are thought to target the same effector in the brain, the CB1 receptor. However, the molecular catalog of these bioactive lipids and their metabolic enzymes has been expanding rapidly by recent advances in lipidomics and proteomics raising the possibility that these lipids may also serve novel, yet unidentified physiological functions. Thus, the overall aim of our research program is to define the molecular and anatomical organization of these endocannabinoid-mediated pathways and to determine their functional significance. In the present proposal, we will focus on understanding how these novel pathways regulate synaptic and extrasynaptic signaling in hippocampal neurons. Using combination of lipidomic, genetic and high-resolution anatomical approaches, we will identify distinct chemical species of endocannabinoids and will show how their metabolic enzymes are segregated into different subcellular compartments in cell type- and synapse-specific manner. Subsequently, we will use genetically encoded gain-of-function, loss-of-function and reporter constructs in imaging experiments and electrophysiological recordings to gain insights into the diverse tasks that these new pathways serve in synaptic transmission and extrasynaptic signal processing. Our proposed experiments will reveal fundamental principles of intercellular and intracellular endocannabinoid signaling in the brain.
Max ERC Funding
1 638 000 €
Duration
Start date: 2009-11-01, End date: 2014-10-31
Project acronym CholAminCo
Project Synergy and antagonism of cholinergic and dopaminergic systems in associative learning
Researcher (PI) Balazs Gyoergy HANGYA
Host Institution (HI) INSTITUTE OF EXPERIMENTAL MEDICINE - HUNGARIAN ACADEMY OF SCIENCES
Call Details Starting Grant (StG), LS5, ERC-2016-STG
Summary Neuromodulators such as acetylcholine and dopamine are able to rapidly reprogram neuronal information processing and dynamically change brain states. Degeneration or dysfunction of cholinergic and dopaminergic neurons can lead to neuropsychiatric conditions like schizophrenia and addiction or cognitive diseases such as Alzheimer’s. Neuromodulatory systems control overlapping cognitive processes and often have similar modes of action; therefore it is important to reveal cooperation and competition between different systems to understand their unique contributions to cognitive functions like learning, memory and attention. This is only possible by direct comparison, which necessitates monitoring multiple neuromodulatory systems under identical experimental conditions. Moreover, simultaneous recording of different neuromodulatory cell types goes beyond phenomenological description of similarities and differences by revealing the underlying correlation structure at the level of action potential timing. However, such data allowing direct comparison of neuromodulatory actions are still sparse. As a first step to bridge this gap, I propose to elucidate the unique versus complementary roles of two “classical” neuromodulatory systems, the cholinergic and dopaminergic projection system implicated in various cognitive functions including associative learning and plasticity. First, we will record optogenetically identified cholinergic and dopaminergic neurons simultaneously using chronic extracellular recording in mice undergoing classical and operant conditioning. Second, we will determine the postsynaptic impact of cholinergic and dopaminergic neurons by manipulating them both separately and simultaneously while recording consequential changes in cortical neuronal activity and learning behaviour. These experiments will reveal how major neuromodulatory systems interact to mediate similar or different aspects of the same cognitive functions.
Summary
Neuromodulators such as acetylcholine and dopamine are able to rapidly reprogram neuronal information processing and dynamically change brain states. Degeneration or dysfunction of cholinergic and dopaminergic neurons can lead to neuropsychiatric conditions like schizophrenia and addiction or cognitive diseases such as Alzheimer’s. Neuromodulatory systems control overlapping cognitive processes and often have similar modes of action; therefore it is important to reveal cooperation and competition between different systems to understand their unique contributions to cognitive functions like learning, memory and attention. This is only possible by direct comparison, which necessitates monitoring multiple neuromodulatory systems under identical experimental conditions. Moreover, simultaneous recording of different neuromodulatory cell types goes beyond phenomenological description of similarities and differences by revealing the underlying correlation structure at the level of action potential timing. However, such data allowing direct comparison of neuromodulatory actions are still sparse. As a first step to bridge this gap, I propose to elucidate the unique versus complementary roles of two “classical” neuromodulatory systems, the cholinergic and dopaminergic projection system implicated in various cognitive functions including associative learning and plasticity. First, we will record optogenetically identified cholinergic and dopaminergic neurons simultaneously using chronic extracellular recording in mice undergoing classical and operant conditioning. Second, we will determine the postsynaptic impact of cholinergic and dopaminergic neurons by manipulating them both separately and simultaneously while recording consequential changes in cortical neuronal activity and learning behaviour. These experiments will reveal how major neuromodulatory systems interact to mediate similar or different aspects of the same cognitive functions.
Max ERC Funding
1 499 463 €
Duration
Start date: 2017-05-01, End date: 2022-04-30
Project acronym COLLMOT
Project Complex structure and dynamics of collective motion
Researcher (PI) Tamás Vicsek
Host Institution (HI) EOTVOS LORAND TUDOMANYEGYETEM
Call Details Advanced Grant (AdG), PE3, ERC-2008-AdG
Summary Collective behaviour is a widespread phenomenon in nature and technology making it a very important subject to study in various contexts. The main goal we intend to achieve in our multidisciplinary research is the identification and documentation of new unifying principles describing the essential aspects of collective motion, being one of the most relevant and spectacular manifestations of collective behaviour. We shall carry out novel type of experiments, design models that are both simple and realistic enough to reproduce the observations and develop concepts for a better interpretation of the complexity of systems consisting of many organisms and such non-living objects as interacting robots. We plan to study systems ranging from cultures of migrating tissue cells through flocks of birds to collectively moving devices. The interrelation of these systems will be considered in order to deepen the understanding of the main patterns of group motion in both living and non-living systems by learning about the similar phenomena in the two domains of nature. Thus, we plan to understand the essential ingredients of flocking of birds by building collectively moving unmanned aerial vehicles while, in turn, high resolution spatiotemporal GPS data of pigeon flocks will be used to make helpful conclusions for the best designs for swarms of robots. In particular, we shall construct and build a set of vehicles that will be capable, for the first time, to exhibit flocking behaviour in the three-dimensional space. The methods we shall adopt will range from approaches used in statistical physics and network theory to various new techniques in cell biology and collective robotics. All this will be based on numerous prior results (both ours and others) published in leading interdisciplinary journals. The planned research will have the potential of leading to ground breaking results with significant implications in various fields of science and technology.
Summary
Collective behaviour is a widespread phenomenon in nature and technology making it a very important subject to study in various contexts. The main goal we intend to achieve in our multidisciplinary research is the identification and documentation of new unifying principles describing the essential aspects of collective motion, being one of the most relevant and spectacular manifestations of collective behaviour. We shall carry out novel type of experiments, design models that are both simple and realistic enough to reproduce the observations and develop concepts for a better interpretation of the complexity of systems consisting of many organisms and such non-living objects as interacting robots. We plan to study systems ranging from cultures of migrating tissue cells through flocks of birds to collectively moving devices. The interrelation of these systems will be considered in order to deepen the understanding of the main patterns of group motion in both living and non-living systems by learning about the similar phenomena in the two domains of nature. Thus, we plan to understand the essential ingredients of flocking of birds by building collectively moving unmanned aerial vehicles while, in turn, high resolution spatiotemporal GPS data of pigeon flocks will be used to make helpful conclusions for the best designs for swarms of robots. In particular, we shall construct and build a set of vehicles that will be capable, for the first time, to exhibit flocking behaviour in the three-dimensional space. The methods we shall adopt will range from approaches used in statistical physics and network theory to various new techniques in cell biology and collective robotics. All this will be based on numerous prior results (both ours and others) published in leading interdisciplinary journals. The planned research will have the potential of leading to ground breaking results with significant implications in various fields of science and technology.
Max ERC Funding
1 248 000 €
Duration
Start date: 2009-03-01, End date: 2015-02-28
Project acronym COOPAIRENT
Project Cooper pairs as a source of entanglement
Researcher (PI) Szabolcs Csonka
Host Institution (HI) BUDAPESTI MUSZAKI ES GAZDASAGTUDOMANYI EGYETEM
Call Details Starting Grant (StG), PE3, ERC-2010-StG_20091028
Summary Entanglement and non-locality are spectacular fundamentals of quantum mechanics and basic resources of future quantum computation algorithms. Electronic entanglement has attracted increasing attention during the last years. The electron spin as a purely quantum mechanical two level system has been put forward as a promising candidate for storing quantum information in solid state. Recently, great progress has been achieved in manipulation and read-out of quantum dot based spin Qubits. However, electron spin is also suitable to transfer quantum information, since mobile electrons can be coherently transmitted in a solid state device preserving the spin information. Thus, electron spin could provide a general platform for on-chip quantum computation and information processing.
Although several theoretical concepts have been worked out to address spin entangled mobile electrons, the absence of an entangler device has not allowed their realization so far. The aim of the present proposal is to overcome this experimental challenge and explore the entanglement of spatially separated electron pairs. Superconductors provide a natural source of entanglement, because their ground-state is composed of Cooper pairs in a spin-singlet state. However, the splitting of the Cooper pairs into separate electrons has to be enforced, which has been very recently realized by the applicant in two quantum dot Y-junction. This Y-junction will be used as a central building block to split Cooper pairs in a controlled fashion and the non-local nature of spin and charge correlations will be addressed in various device configurations.
Our research project will lead to a fundamental understanding of the production, manipulation and detection of spin entangled mobile electron pairs, thus it will significantly extend the frontiers of quantum coherence and opens a new horizon in the field of on-chip quantum information technologies.
Summary
Entanglement and non-locality are spectacular fundamentals of quantum mechanics and basic resources of future quantum computation algorithms. Electronic entanglement has attracted increasing attention during the last years. The electron spin as a purely quantum mechanical two level system has been put forward as a promising candidate for storing quantum information in solid state. Recently, great progress has been achieved in manipulation and read-out of quantum dot based spin Qubits. However, electron spin is also suitable to transfer quantum information, since mobile electrons can be coherently transmitted in a solid state device preserving the spin information. Thus, electron spin could provide a general platform for on-chip quantum computation and information processing.
Although several theoretical concepts have been worked out to address spin entangled mobile electrons, the absence of an entangler device has not allowed their realization so far. The aim of the present proposal is to overcome this experimental challenge and explore the entanglement of spatially separated electron pairs. Superconductors provide a natural source of entanglement, because their ground-state is composed of Cooper pairs in a spin-singlet state. However, the splitting of the Cooper pairs into separate electrons has to be enforced, which has been very recently realized by the applicant in two quantum dot Y-junction. This Y-junction will be used as a central building block to split Cooper pairs in a controlled fashion and the non-local nature of spin and charge correlations will be addressed in various device configurations.
Our research project will lead to a fundamental understanding of the production, manipulation and detection of spin entangled mobile electron pairs, thus it will significantly extend the frontiers of quantum coherence and opens a new horizon in the field of on-chip quantum information technologies.
Max ERC Funding
1 496 112 €
Duration
Start date: 2011-02-01, End date: 2016-10-31
Project acronym DeCode
Project Dendrites and memory: role of dendritic spikes in information coding by hippocampal CA3 pyramidal neurons
Researcher (PI) Judit MAKARA
Host Institution (HI) INSTITUTE OF EXPERIMENTAL MEDICINE - HUNGARIAN ACADEMY OF SCIENCES
Call Details Consolidator Grant (CoG), LS5, ERC-2017-COG
Summary The hippocampus is essential for building episodic memories. Coding of locations, contexts or events in the hippocampus is based on the correlated activity of neuronal ensembles; however, the mechanisms promoting the recruitment of individual neurons into information-coding ensembles are poorly understood.
In particular, the recurrent synaptic network of pyramidal cells (PCs) in the hippocampal CA3 area, receiving external inputs from the entorhinal cortex and the dentate gyrus, is thought to be essential for associative memory. Current models of the associative functions of CA3 are mainly based on plasticity of these synaptic connections. Recent work by us and others however suggests that active, voltage-dependent properties of CA3PC dendrites may also promote ensemble functions. Dendritic voltage-dependent ion channels allow nonlinear amplification of spatiotemporally correlated synaptic inputs (such as those produced by ensemble activity) and can even generate local dendritic spikes, which may elicit specific action potential patterns and induce synaptic plasticity. Furthermore, dendritic processing may be modulated by activity-dependent regulation of dendritic ion channels. However, still little is known about the active properties of CA3PC dendrites and their functions during spatial coding or memory tasks.
The general aim of my research program is to understand the cellular mechanisms that underlie the formation of hippocampal memory-coding neuronal ensembles. Specifically, we will test the hypothesis that active input integration by dendrites of individual CA3PCs plays an important role in their recruitment into specific context-coding ensembles. By combining in vitro (patch-clamp electrophysiology and two-photon (2P) microscopy in slices) and in vivo (2P imaging and activity-dependent labelling in behaving rodents) approaches, we will provide an in-depth understanding of the dendritic components contributing to the generation of the CA3 ensemble code.
Summary
The hippocampus is essential for building episodic memories. Coding of locations, contexts or events in the hippocampus is based on the correlated activity of neuronal ensembles; however, the mechanisms promoting the recruitment of individual neurons into information-coding ensembles are poorly understood.
In particular, the recurrent synaptic network of pyramidal cells (PCs) in the hippocampal CA3 area, receiving external inputs from the entorhinal cortex and the dentate gyrus, is thought to be essential for associative memory. Current models of the associative functions of CA3 are mainly based on plasticity of these synaptic connections. Recent work by us and others however suggests that active, voltage-dependent properties of CA3PC dendrites may also promote ensemble functions. Dendritic voltage-dependent ion channels allow nonlinear amplification of spatiotemporally correlated synaptic inputs (such as those produced by ensemble activity) and can even generate local dendritic spikes, which may elicit specific action potential patterns and induce synaptic plasticity. Furthermore, dendritic processing may be modulated by activity-dependent regulation of dendritic ion channels. However, still little is known about the active properties of CA3PC dendrites and their functions during spatial coding or memory tasks.
The general aim of my research program is to understand the cellular mechanisms that underlie the formation of hippocampal memory-coding neuronal ensembles. Specifically, we will test the hypothesis that active input integration by dendrites of individual CA3PCs plays an important role in their recruitment into specific context-coding ensembles. By combining in vitro (patch-clamp electrophysiology and two-photon (2P) microscopy in slices) and in vivo (2P imaging and activity-dependent labelling in behaving rodents) approaches, we will provide an in-depth understanding of the dendritic components contributing to the generation of the CA3 ensemble code.
Max ERC Funding
1 990 314 €
Duration
Start date: 2018-06-01, End date: 2023-05-31
Project acronym EVOLOR
Project Cognitive Ageing in Dogs
Researcher (PI) Eniko Kubinyi
Host Institution (HI) EOTVOS LORAND TUDOMANYEGYETEM
Call Details Starting Grant (StG), LS9, ERC-2015-STG
Summary The aim of this project is to understand the causal factors contributing to the cognitive decline during senescence and to develop sensitive and standardized behaviour tests for early detection in order to increase the welfare of affected species. With the rapidly ageing population of Europe, related research is a priority in the European Union.
We will focus both on characterising the ageing phenotype and the underlying biological processes in dogs as a well-established natural animal model. We develop a reliable and valid test battery applying innovative multidisciplinary methods (e.g. eye-tracking, motion path analysis, identification of behaviour using inertial sensors, EEG, fMRI, candidate gene, and epigenetics) in both longitudinal and cross-sectional studies. We expect to reveal specific environmental risk factors which hasten ageing and also protective factors which may postpone it. We aim to provide objective criteria (behavioural, physiological and genetic biomarkers) to assess and predict the ageing trajectory for specific individual dogs. This would help veterinarians to recognise the symptoms early, and initiate necessary counter actions.
This approach establishes the framework for answering the broad question that how we can extend the healthy life of ageing dogs which indirectly also contributes to the welfare of the owner and decreases veterinary expenses. The detailed description of the ageing phenotype may also facilitate the use of dogs as a natural model for human senescence, including the development and application of pharmaceutical interventions.
We expect that our approach offers the scientific foundation to delay the onset of cognitive ageing in dog populations by 1-2 years, and also increase the proportion of dogs that enjoy healthy ageing.
Summary
The aim of this project is to understand the causal factors contributing to the cognitive decline during senescence and to develop sensitive and standardized behaviour tests for early detection in order to increase the welfare of affected species. With the rapidly ageing population of Europe, related research is a priority in the European Union.
We will focus both on characterising the ageing phenotype and the underlying biological processes in dogs as a well-established natural animal model. We develop a reliable and valid test battery applying innovative multidisciplinary methods (e.g. eye-tracking, motion path analysis, identification of behaviour using inertial sensors, EEG, fMRI, candidate gene, and epigenetics) in both longitudinal and cross-sectional studies. We expect to reveal specific environmental risk factors which hasten ageing and also protective factors which may postpone it. We aim to provide objective criteria (behavioural, physiological and genetic biomarkers) to assess and predict the ageing trajectory for specific individual dogs. This would help veterinarians to recognise the symptoms early, and initiate necessary counter actions.
This approach establishes the framework for answering the broad question that how we can extend the healthy life of ageing dogs which indirectly also contributes to the welfare of the owner and decreases veterinary expenses. The detailed description of the ageing phenotype may also facilitate the use of dogs as a natural model for human senescence, including the development and application of pharmaceutical interventions.
We expect that our approach offers the scientific foundation to delay the onset of cognitive ageing in dog populations by 1-2 years, and also increase the proportion of dogs that enjoy healthy ageing.
Max ERC Funding
1 202 500 €
Duration
Start date: 2016-06-01, End date: 2021-05-31
Project acronym FORCEMAP
Project Intramolecular force mapping of enzymes in action: the role of strain in motor mechanisms
Researcher (PI) András Málnási-Csizmadia
Host Institution (HI) EOTVOS LORAND TUDOMANYEGYETEM
Call Details Starting Grant (StG), LS1, ERC-2007-StG
Summary A fundamental but unexplored problem in biology is whether and how enzymes use mechanical strain during their functioning. It is now evident that the knowledge of atomic structures and chemical interactions is not sufficient to understand the intricate mechanisms underlying enzyme specificity and efficiency. Several lines of evidence suggest that mechanical effects play crucial roles in enzyme activity. Therefore we aim to create detailed force maps that reveal how the intramolecular distribution of mechanical strains changes during the enzyme cycle and how these rearrangements drive the enzyme processes. The applicability of current nanotechniques for the investigation of this problem is limited because they do not allow simultaneous measurement of mechanical and enzymatic parameters. Thus we seek to open new avenues of research by developing site-specific sensors and passive or photoinducible molecular springs to measure force-dependent chemical/structural changes with high spatiotemporal resolution in myosin. Since force perturbations occur very rapidly, we are able to combine experimental studies with quasi-realistic in silico simulations to describe the physical background of enzyme function. We expect that our research will yield fundamental insights into the role of intramolecular strains in enzymes and thus greatly aid the design and control of enzyme processes (specificity, activity, regulation). Our studies may also lead to new paradigms in the understanding of motor systems.
Summary
A fundamental but unexplored problem in biology is whether and how enzymes use mechanical strain during their functioning. It is now evident that the knowledge of atomic structures and chemical interactions is not sufficient to understand the intricate mechanisms underlying enzyme specificity and efficiency. Several lines of evidence suggest that mechanical effects play crucial roles in enzyme activity. Therefore we aim to create detailed force maps that reveal how the intramolecular distribution of mechanical strains changes during the enzyme cycle and how these rearrangements drive the enzyme processes. The applicability of current nanotechniques for the investigation of this problem is limited because they do not allow simultaneous measurement of mechanical and enzymatic parameters. Thus we seek to open new avenues of research by developing site-specific sensors and passive or photoinducible molecular springs to measure force-dependent chemical/structural changes with high spatiotemporal resolution in myosin. Since force perturbations occur very rapidly, we are able to combine experimental studies with quasi-realistic in silico simulations to describe the physical background of enzyme function. We expect that our research will yield fundamental insights into the role of intramolecular strains in enzymes and thus greatly aid the design and control of enzyme processes (specificity, activity, regulation). Our studies may also lead to new paradigms in the understanding of motor systems.
Max ERC Funding
750 000 €
Duration
Start date: 2008-09-01, End date: 2014-08-31
Project acronym FRONTHAL
Project Specificity of cortico-thalamic interactions and its role in frontal cortical functions
Researcher (PI) Laszlo ACSADY
Host Institution (HI) INSTITUTE OF EXPERIMENTAL MEDICINE - HUNGARIAN ACADEMY OF SCIENCES
Call Details Advanced Grant (AdG), LS5, ERC-2016-ADG
Summary Frontal cortical areas are responsible for a wide range of executive and cognitive functions. Frontal cortices communicate with the thalamus via bidirectional pathways and these connections are indispensable for frontal cortical operations. Still, we have very little information about the specificity of connections, synaptic interactions and plasticity between frontal cortex and thalamus and the roles of these interactions in frontal cortical functions.
In the present proposal, we will test the hypothesis that frontal cortical areas developed a highly specialized connectivity pattern with the thalamus. This supports unique interactions between the cortex and the thalamus according to the specific requirements of frontal cortical activity, including experience-dependent plastic changes.
The project will use cell type-specific viral tracing in mice and 3D electron microscopic reconstructions in mice and humans to identify circuit motifs that are evolutionarily conserved, yet, still specific to fronto-thalamic pathways. The physiological approach will employ in vivo optogenetics combined with intra-, juxta- and extracellular recordings. We will perform behavioral experiments by bidirectional modulation of well-defined elements in the network, in learning paradigms, which depend on the integrity of frontal cortex.
The project is the first systematic approach which aims to understand the nature of interaction between the frontal cortex and the thalamus. It will not only fill the tremendous gap in our knowledge regarding these pathways but will help us elucidate the functional organization of non-sensory thalamus in general.
Frontal cortices are involved in a wide range of major neurological disorders (e.g. Parkinson’s disease, epilepsy, schizophrenia, chronic pain) which affect executive functions and involve fronto-thalamic pathways. We believe that understanding fronto-thalamic interactions will lead to fundamentally novel insight into the nature of these diseases.
Summary
Frontal cortical areas are responsible for a wide range of executive and cognitive functions. Frontal cortices communicate with the thalamus via bidirectional pathways and these connections are indispensable for frontal cortical operations. Still, we have very little information about the specificity of connections, synaptic interactions and plasticity between frontal cortex and thalamus and the roles of these interactions in frontal cortical functions.
In the present proposal, we will test the hypothesis that frontal cortical areas developed a highly specialized connectivity pattern with the thalamus. This supports unique interactions between the cortex and the thalamus according to the specific requirements of frontal cortical activity, including experience-dependent plastic changes.
The project will use cell type-specific viral tracing in mice and 3D electron microscopic reconstructions in mice and humans to identify circuit motifs that are evolutionarily conserved, yet, still specific to fronto-thalamic pathways. The physiological approach will employ in vivo optogenetics combined with intra-, juxta- and extracellular recordings. We will perform behavioral experiments by bidirectional modulation of well-defined elements in the network, in learning paradigms, which depend on the integrity of frontal cortex.
The project is the first systematic approach which aims to understand the nature of interaction between the frontal cortex and the thalamus. It will not only fill the tremendous gap in our knowledge regarding these pathways but will help us elucidate the functional organization of non-sensory thalamus in general.
Frontal cortices are involved in a wide range of major neurological disorders (e.g. Parkinson’s disease, epilepsy, schizophrenia, chronic pain) which affect executive functions and involve fronto-thalamic pathways. We believe that understanding fronto-thalamic interactions will lead to fundamentally novel insight into the nature of these diseases.
Max ERC Funding
1 597 575 €
Duration
Start date: 2017-09-01, End date: 2022-08-31
Project acronym FunctionalProteomics
Project Proteomic fingerprinting of functionally characterized single synapses
Researcher (PI) Zoltan NUSSER
Host Institution (HI) INSTITUTE OF EXPERIMENTAL MEDICINE - HUNGARIAN ACADEMY OF SCIENCES
Call Details Advanced Grant (AdG), LS5, ERC-2017-ADG
Summary Our astonishing cognitive abilities are the consequence of complex connectivity within our neuronal networks and the large functional diversity of excitable nerve cells and their synapses. Investigations over the past half a century revealed dramatic diversity in shape, size and functional properties among synapses established by distinct cell types in different brain regions and demonstrated that the functional differences are partly due to different molecular mechanisms. However, synaptic diversity is also observed among synapses established by molecularly and morphologically uniform presynaptic cells on molecularly and morphologically uniform postsynaptic cells. Our hypothesis is that quantitative molecular differences underlie the functional diversity of such synapses. We will focus on hippocampal CA1 pyramidal cell (PC) to mGluR1α+ O-LM cell synapses, which show remarkable functional and molecular heterogeneity. In vitro multiple cell patch-clamp recordings followed by quantal analysis will be performed to quantify well-defined biophysical properties of these synapses. The molecular composition of the functionally characterized single synapses will be determined following the development of a novel postembedding immunolocalization method. Correlations between the molecular content and functional properties will be established and genetic up- and downregulation of individual synaptic proteins will be conducted to reveal causal relationships. Finally, correlations of the activity history and the functional properties of the synapses will be established by performing in vivo two-photon Ca2+ imaging in head-fixed behaving animals followed by in vitro functional characterization of their synapses. Our results will reveal quantitative molecular fingerprints of functional properties, allowing us to render dynamic behaviour to billions of synapses when the connectome of the hippocampal circuit is created using array tomography.
Summary
Our astonishing cognitive abilities are the consequence of complex connectivity within our neuronal networks and the large functional diversity of excitable nerve cells and their synapses. Investigations over the past half a century revealed dramatic diversity in shape, size and functional properties among synapses established by distinct cell types in different brain regions and demonstrated that the functional differences are partly due to different molecular mechanisms. However, synaptic diversity is also observed among synapses established by molecularly and morphologically uniform presynaptic cells on molecularly and morphologically uniform postsynaptic cells. Our hypothesis is that quantitative molecular differences underlie the functional diversity of such synapses. We will focus on hippocampal CA1 pyramidal cell (PC) to mGluR1α+ O-LM cell synapses, which show remarkable functional and molecular heterogeneity. In vitro multiple cell patch-clamp recordings followed by quantal analysis will be performed to quantify well-defined biophysical properties of these synapses. The molecular composition of the functionally characterized single synapses will be determined following the development of a novel postembedding immunolocalization method. Correlations between the molecular content and functional properties will be established and genetic up- and downregulation of individual synaptic proteins will be conducted to reveal causal relationships. Finally, correlations of the activity history and the functional properties of the synapses will be established by performing in vivo two-photon Ca2+ imaging in head-fixed behaving animals followed by in vitro functional characterization of their synapses. Our results will reveal quantitative molecular fingerprints of functional properties, allowing us to render dynamic behaviour to billions of synapses when the connectome of the hippocampal circuit is created using array tomography.
Max ERC Funding
2 498 750 €
Duration
Start date: 2018-10-01, End date: 2023-09-30
Project acronym GENECLOCKS
Project Reconstructing a dated tree of life using phylogenetic incongruence
Researcher (PI) Gergely Janos SZOLLOSI
Host Institution (HI) EOTVOS LORAND TUDOMANYEGYETEM
Call Details Starting Grant (StG), LS8, ERC-2016-STG
Summary With the advent of genome-scale sequencing, molecular phylogeny, which reconstructs gene trees from homologous sequences, has reached an impasse. Instead of answering open questions, new genomes have reignited old debates. The problem is clear, gene trees are not species trees, each is the unique result of series of evolutionary events. If, however, we model these differences in the context of a common species tree, we can access a wealth of information on genome evolution and the diversification of species that is not available to traditional methods. For example, as horizontal gene transfer (HGT) can only occur between coexisting species, HGTs provide information on the order of speciations. When HGT is rare, lineage sorting can generate incongruence between gene trees and the dating problem can be formulated in terms of biologically meaningful parameters (such as population size), that are informative on the rate of evolution and hence invaluable to molecular dating.
My first goal is to develop methods that systematically extract information on the pattern and timing of genomic evolution by explaining differences between gene trees. This will allow us to, for the first time, reconstruct a dated tree of life from genome-scale data. We will use parallel programming to maximise the number of genomes analysed.
My second goal is to apply these methods to open problems, e.g.: i) to resolve the timing of microbial evolution and its relationship to Earth history, where the extreme paucity of fossils limits the use of molecular dating methods, by using HGT events as “molecular fossils”; ii) to reconstruct rooted phylogenies from complete genomes and harness phylogenetic incongruence to answer long standing questions, such as the of diversification of animals or the position of eukaryotes among archaea; and iii) for eukaryotic groups such as Fungi, where evidence of significant amounts of HGT is emerging our methods will also allow the quantification of the extent of HGT.
Summary
With the advent of genome-scale sequencing, molecular phylogeny, which reconstructs gene trees from homologous sequences, has reached an impasse. Instead of answering open questions, new genomes have reignited old debates. The problem is clear, gene trees are not species trees, each is the unique result of series of evolutionary events. If, however, we model these differences in the context of a common species tree, we can access a wealth of information on genome evolution and the diversification of species that is not available to traditional methods. For example, as horizontal gene transfer (HGT) can only occur between coexisting species, HGTs provide information on the order of speciations. When HGT is rare, lineage sorting can generate incongruence between gene trees and the dating problem can be formulated in terms of biologically meaningful parameters (such as population size), that are informative on the rate of evolution and hence invaluable to molecular dating.
My first goal is to develop methods that systematically extract information on the pattern and timing of genomic evolution by explaining differences between gene trees. This will allow us to, for the first time, reconstruct a dated tree of life from genome-scale data. We will use parallel programming to maximise the number of genomes analysed.
My second goal is to apply these methods to open problems, e.g.: i) to resolve the timing of microbial evolution and its relationship to Earth history, where the extreme paucity of fossils limits the use of molecular dating methods, by using HGT events as “molecular fossils”; ii) to reconstruct rooted phylogenies from complete genomes and harness phylogenetic incongruence to answer long standing questions, such as the of diversification of animals or the position of eukaryotes among archaea; and iii) for eukaryotic groups such as Fungi, where evidence of significant amounts of HGT is emerging our methods will also allow the quantification of the extent of HGT.
Max ERC Funding
1 453 542 €
Duration
Start date: 2017-07-01, End date: 2022-06-30
Project acronym INTERIMPACT
Project Impact of identified interneurons on cellular network mechanisms in the human and rodent neocortex
Researcher (PI) Gábor Tamás
Host Institution (HI) Szegedi Tudomanyegyetem - Hungarian-Netherlands School of Educational Management
Call Details Advanced Grant (AdG), LS5, ERC-2010-AdG_20100317
Summary This application addresses mechanisms linking the activity of single neurons with network events by defining the function of identified cell types in the cerebral cortex. The key hypotheses emerged from our experiments and propose that neurogliaform cells and axo-axonic cells achieve their function in the cortex through extreme forms of unspecificity and specificity, respectively. The project capitalizes on our discovery that neurogliaform cells reach GABAA and GABAB receptors on target cells through unitary volume transmission going beyond the classical theory which states that single cortical neurons act in or around synaptic junctions. We propose that the spatial unspecificity of neurotransmitter action leads to unprecedented functional capabilities for a single neuron simultaneously acting on neuronal, glial and vascular components of the surrounding area allowing neurogliaform cells to synchronize metabolic demand and supply in microcircuits. In contrast, axo-axonic cells represent extreme spatial specificity in the brain: terminals of axo-axonic cells exclusively target the axon initial segment of pyramidal neurons. Axo-axonic cells were considered as the most potent inhibitory neurons of the cortex. However, our experiments suggested that axo-axonic cells can be the most powerful excitatory neurons known to date by triggering complex network events. Our unprecedented recordings in the human cortex show that axo-axonic cells are crucial in activating functional assemblies which were implicated in higher order cognitive representations. We aim to define interactions between active cortical networks and axo-axonic cell triggered assemblies with an emphasis on mechanisms modulated by neurogliaform cells and commonly prescribed drugs.
Summary
This application addresses mechanisms linking the activity of single neurons with network events by defining the function of identified cell types in the cerebral cortex. The key hypotheses emerged from our experiments and propose that neurogliaform cells and axo-axonic cells achieve their function in the cortex through extreme forms of unspecificity and specificity, respectively. The project capitalizes on our discovery that neurogliaform cells reach GABAA and GABAB receptors on target cells through unitary volume transmission going beyond the classical theory which states that single cortical neurons act in or around synaptic junctions. We propose that the spatial unspecificity of neurotransmitter action leads to unprecedented functional capabilities for a single neuron simultaneously acting on neuronal, glial and vascular components of the surrounding area allowing neurogliaform cells to synchronize metabolic demand and supply in microcircuits. In contrast, axo-axonic cells represent extreme spatial specificity in the brain: terminals of axo-axonic cells exclusively target the axon initial segment of pyramidal neurons. Axo-axonic cells were considered as the most potent inhibitory neurons of the cortex. However, our experiments suggested that axo-axonic cells can be the most powerful excitatory neurons known to date by triggering complex network events. Our unprecedented recordings in the human cortex show that axo-axonic cells are crucial in activating functional assemblies which were implicated in higher order cognitive representations. We aim to define interactions between active cortical networks and axo-axonic cell triggered assemblies with an emphasis on mechanisms modulated by neurogliaform cells and commonly prescribed drugs.
Max ERC Funding
2 391 695 €
Duration
Start date: 2011-06-01, End date: 2017-05-31
Project acronym MicroCONtACT
Project Microglial control of neuronal activity in the healthy and the injured brain
Researcher (PI) Adam DENES
Host Institution (HI) INSTITUTE OF EXPERIMENTAL MEDICINE - HUNGARIAN ACADEMY OF SCIENCES
Call Details Consolidator Grant (CoG), LS5, ERC-2016-COG
Summary Microglia are the main immune cells of the brain, but their role in brain injury is highly controversial due to the difficulties in selectively manipulating and imaging microglial actions in real time. Specifically, it is unclear whether microglia control neuronal survival after injury via shaping the activity of complex neuronal networks in vivo. To this end, we have combined fast in vivo two-photon imaging of neuronal calcium responses with selective microglial manipulation for the first time. Our data suggest that microglia constantly monitor and control neuronal network activity and these actions are essential to limit excitotoxicity and neuronal death after acute brain injury. We also identify microglia as key regulators of spreading depolarization in vivo. However, the underlying mechanisms remained unexplored. Here, I propose that microglia control neuronal excitability and based on preliminary data I set out to investigate how this occurs. We will combine selective, CSF1R-mediated microglia depletion with advanced neurophysiological methods such as in vivo calcium imaging and intracranial EEG for the first time, to reveal how microglia shape activity of complex neuronal networks in the healthy and the injured brain. Then, we will study microglia-neuron interactions from the network level to nanoscale level using in vivo two-photon imaging and super-resolution microscopy. We will apply novel chemogenic and optogenetic approaches to manipulate microglia in real time, assess their role in neuronal activity changes and investigate the molecular mechanisms in vitro and in vivo. Our unpublished data also suggest that inflammation – a key contributor to brain diseases – could disrupt microglia-neuron signaling and we set out to investigate the underlying mechanisms. By using state-of the-art research tools that had not been applied previously in this context, our studies are likely to reveal novel pathophysiological mechanisms relevant for common brain diseases.
Summary
Microglia are the main immune cells of the brain, but their role in brain injury is highly controversial due to the difficulties in selectively manipulating and imaging microglial actions in real time. Specifically, it is unclear whether microglia control neuronal survival after injury via shaping the activity of complex neuronal networks in vivo. To this end, we have combined fast in vivo two-photon imaging of neuronal calcium responses with selective microglial manipulation for the first time. Our data suggest that microglia constantly monitor and control neuronal network activity and these actions are essential to limit excitotoxicity and neuronal death after acute brain injury. We also identify microglia as key regulators of spreading depolarization in vivo. However, the underlying mechanisms remained unexplored. Here, I propose that microglia control neuronal excitability and based on preliminary data I set out to investigate how this occurs. We will combine selective, CSF1R-mediated microglia depletion with advanced neurophysiological methods such as in vivo calcium imaging and intracranial EEG for the first time, to reveal how microglia shape activity of complex neuronal networks in the healthy and the injured brain. Then, we will study microglia-neuron interactions from the network level to nanoscale level using in vivo two-photon imaging and super-resolution microscopy. We will apply novel chemogenic and optogenetic approaches to manipulate microglia in real time, assess their role in neuronal activity changes and investigate the molecular mechanisms in vitro and in vivo. Our unpublished data also suggest that inflammation – a key contributor to brain diseases – could disrupt microglia-neuron signaling and we set out to investigate the underlying mechanisms. By using state-of the-art research tools that had not been applied previously in this context, our studies are likely to reveal novel pathophysiological mechanisms relevant for common brain diseases.
Max ERC Funding
2 000 000 €
Duration
Start date: 2017-04-01, End date: 2022-03-31
Project acronym MOLECMAP
Project Quantitative Molecular Map of the Neuronal Surface
Researcher (PI) Zoltan Jozsef Nusser
Host Institution (HI) INSTITUTE OF EXPERIMENTAL MEDICINE - HUNGARIAN ACADEMY OF SCIENCES
Call Details Advanced Grant (AdG), LS5, ERC-2011-ADG_20110310
Summary The most fundamental roles of nerve cells are the detection of chemical neurotransmitters to generate synaptic potentials; the summation of these potentials to create their output signals; and the consequent release of their own neurotransmitter molecules. All of these functions require the orchestrated work of hundreds of molecules targeted to specialized regions of the cells. In nerve cells, more than in any other cell type, a single molecule could fulfill very different functional roles depending on its subcellular location. For example, dendritic voltage-gated Ca2+ channels play a role in the integration and plasticity of synaptic inputs, whereas the same channels when concentrated in presynaptic active zones are essential for neurotransmitter release. Thus, the function of a protein in nerve cells cannot be understood from its expression or lack of it, but its precise subcellular location, density and molecular environment needs to be determined. The major aim of the present proposal is to create a quantitative molecular map of the surface of hippocampal pyramidal cells (PCs). We will start by examining voltage-gated ion channels due to their pivotal roles in input summation, output generation and neurotransmitter release. We will apply high resolution quantitative molecular neuroanatomical techniques to reveal their densities in 19 different axo-somato-dendritic plasma membrane compartments of CA1 PCs. Functional predictions will be generated using detailed, morphologically realistic multicompartmental PC models with experimentally determined ion channel distributions and densities. Such predictions will be tested by combining in vitro patch-clamp electrophysiology and imaging techniques with correlated light- and electron microscopy. Our results will provide the first quantitative molecular map of the neuronal surface and will reveal new mechanisms that increase the computational power and the functional diversity of nerve cells.
Summary
The most fundamental roles of nerve cells are the detection of chemical neurotransmitters to generate synaptic potentials; the summation of these potentials to create their output signals; and the consequent release of their own neurotransmitter molecules. All of these functions require the orchestrated work of hundreds of molecules targeted to specialized regions of the cells. In nerve cells, more than in any other cell type, a single molecule could fulfill very different functional roles depending on its subcellular location. For example, dendritic voltage-gated Ca2+ channels play a role in the integration and plasticity of synaptic inputs, whereas the same channels when concentrated in presynaptic active zones are essential for neurotransmitter release. Thus, the function of a protein in nerve cells cannot be understood from its expression or lack of it, but its precise subcellular location, density and molecular environment needs to be determined. The major aim of the present proposal is to create a quantitative molecular map of the surface of hippocampal pyramidal cells (PCs). We will start by examining voltage-gated ion channels due to their pivotal roles in input summation, output generation and neurotransmitter release. We will apply high resolution quantitative molecular neuroanatomical techniques to reveal their densities in 19 different axo-somato-dendritic plasma membrane compartments of CA1 PCs. Functional predictions will be generated using detailed, morphologically realistic multicompartmental PC models with experimentally determined ion channel distributions and densities. Such predictions will be tested by combining in vitro patch-clamp electrophysiology and imaging techniques with correlated light- and electron microscopy. Our results will provide the first quantitative molecular map of the neuronal surface and will reveal new mechanisms that increase the computational power and the functional diversity of nerve cells.
Max ERC Funding
2 494 446 €
Duration
Start date: 2012-02-01, End date: 2017-01-31
Project acronym MOLINFLAM
Project Molecular dissection of inflammatory pathways
Researcher (PI) Attila Mocsai
Host Institution (HI) SEMMELWEIS EGYETEM
Call Details Starting Grant (StG), LS3, ERC-2007-StG
Summary Inflammatory diseases are highly prevalent, often chronic diseases that cause diminished quality of life and are connected with major causes of death in Western societies. Despite their societal impact, their pathomechanism is incompletely understood, hindering development of novel therapeutic strategies. In particular, little is known about the intracellular signal transduction processes involved in the tissue destruction phase of aggressive autoimmune diseases such as rheumatoid arthritis. The present proposal aims to clarify this issue using in vivo and in vitro studies on genetically manipulated mice. During the proposed studies, mice deficient in various signal transduction molecules such as Syk, PLCg2, Gab2 and p190 RhoGAPs will be used to test their contribution to inflammatory responses. In vitro studies will test the activation of major effector cells of inflammation (neutrophils, macrophages and osteoclasts) while in vivo studies will utilize mouse models such as autoantibody- and cytokine-induced inflammatory arthritis or autoantibody-induced glomerulonephritis. Further studies will be performed to test the contribution of the above signaling molecules to disease pathogenesis in a lineage-restricted manner, using the Cre-lox approach. Finally, wild type and mutant versions of the signaling molecules tested will be retrovirally re-expressed into the relevant knockout hematopoietic stem cells in vivo to allow structure-function studies during in vivo inflammation. Two novel transgenic strains and a knock-in (floxed) mutant will also be generated during the course of the project. Using state-of-the-art approaches and techniques, this project will provide information at unprecedented molecular detail on signal transduction mechanisms involved in inflammatory diseases, and is expected to point to possible future targets of novel anti-inflammatory therapies.
Summary
Inflammatory diseases are highly prevalent, often chronic diseases that cause diminished quality of life and are connected with major causes of death in Western societies. Despite their societal impact, their pathomechanism is incompletely understood, hindering development of novel therapeutic strategies. In particular, little is known about the intracellular signal transduction processes involved in the tissue destruction phase of aggressive autoimmune diseases such as rheumatoid arthritis. The present proposal aims to clarify this issue using in vivo and in vitro studies on genetically manipulated mice. During the proposed studies, mice deficient in various signal transduction molecules such as Syk, PLCg2, Gab2 and p190 RhoGAPs will be used to test their contribution to inflammatory responses. In vitro studies will test the activation of major effector cells of inflammation (neutrophils, macrophages and osteoclasts) while in vivo studies will utilize mouse models such as autoantibody- and cytokine-induced inflammatory arthritis or autoantibody-induced glomerulonephritis. Further studies will be performed to test the contribution of the above signaling molecules to disease pathogenesis in a lineage-restricted manner, using the Cre-lox approach. Finally, wild type and mutant versions of the signaling molecules tested will be retrovirally re-expressed into the relevant knockout hematopoietic stem cells in vivo to allow structure-function studies during in vivo inflammation. Two novel transgenic strains and a knock-in (floxed) mutant will also be generated during the course of the project. Using state-of-the-art approaches and techniques, this project will provide information at unprecedented molecular detail on signal transduction mechanisms involved in inflammatory diseases, and is expected to point to possible future targets of novel anti-inflammatory therapies.
Max ERC Funding
1 200 000 €
Duration
Start date: 2008-10-01, End date: 2014-03-31
Project acronym Multicellularity
Project The genetic basis of the convergent evolution of fungal multicellularity
Researcher (PI) Laszlo NAGY
Host Institution (HI) MAGYAR TUDOMANYOS AKADEMIA SZEGEDIBIOLOGIAI KUTATOKOZPONT
Call Details Starting Grant (StG), LS8, ERC-2017-STG
Summary The evolution of multicellularity (MC) has been one of the major transitions in the history of life. Despite immense interest in its evolutionary origins, the genomic changes leading to the emergence of MC, especially that of complex MC (differentiated 3-dimensional structures) are poorly known. Previous comparative genomics projects aiming to understand the genetic bases of MC in one way or another relied on gene content-based analyses. However, a pattern emerging from these studies is that gene content provides only an incomplete explanation for the evolution of MC even at ancient timescales. We hypothesize that besides gene duplications, changes to cis-regulatory elements and gene expression patterns (including protein isoforms) have significantly contributed to the evolution of MC. To test this hypothesis, we will deploy a combination of computational methods, phylogenomics, comparative transcriptomics and genome-wide assays of regulatory elements. Our research focuses on fungi as a model system, where complex MC evolved convergently and in subsequent two steps. Fungi are ideal models to tackle this question for several reasons: a) multicellularity in fungi evolved multiple times, b) there are rich genomic resources (>500 complete genomes), c) complex multicellular structures can be routinely grown in the lab and d) genetic manipulations are feasible for several cornerstone species. We set out to examine which genes participate in the building of simple and complex multicellular structures and whether the evolution of regulome complexity and gene expression patterns can explain the evolution of MC better than can traditionally assayed sources of genetic innovations (e.g. gene duplications). Ultimately, our goal is to reach a general synthesis on the genetic bases of the evolution of MC and that of organismal complexity.
Summary
The evolution of multicellularity (MC) has been one of the major transitions in the history of life. Despite immense interest in its evolutionary origins, the genomic changes leading to the emergence of MC, especially that of complex MC (differentiated 3-dimensional structures) are poorly known. Previous comparative genomics projects aiming to understand the genetic bases of MC in one way or another relied on gene content-based analyses. However, a pattern emerging from these studies is that gene content provides only an incomplete explanation for the evolution of MC even at ancient timescales. We hypothesize that besides gene duplications, changes to cis-regulatory elements and gene expression patterns (including protein isoforms) have significantly contributed to the evolution of MC. To test this hypothesis, we will deploy a combination of computational methods, phylogenomics, comparative transcriptomics and genome-wide assays of regulatory elements. Our research focuses on fungi as a model system, where complex MC evolved convergently and in subsequent two steps. Fungi are ideal models to tackle this question for several reasons: a) multicellularity in fungi evolved multiple times, b) there are rich genomic resources (>500 complete genomes), c) complex multicellular structures can be routinely grown in the lab and d) genetic manipulations are feasible for several cornerstone species. We set out to examine which genes participate in the building of simple and complex multicellular structures and whether the evolution of regulome complexity and gene expression patterns can explain the evolution of MC better than can traditionally assayed sources of genetic innovations (e.g. gene duplications). Ultimately, our goal is to reach a general synthesis on the genetic bases of the evolution of MC and that of organismal complexity.
Max ERC Funding
1 486 500 €
Duration
Start date: 2018-01-01, End date: 2022-12-31
Project acronym nanoAXON
Project Nano-physiology of small glutamatergic axon terminals
Researcher (PI) Janos SZABADICS
Host Institution (HI) INSTITUTE OF EXPERIMENTAL MEDICINE - HUNGARIAN ACADEMY OF SCIENCES
Call Details Consolidator Grant (CoG), LS5, ERC-2017-COG
Summary We will reveal the neuronal mechanisms of fundamental hippocampal and axonal functions using direct patch clamp recordings from the small axon terminals of the major glutamatergic afferent and efferent pathways of the dentate gyrus region. Specifically, we will investigate the intrinsic axonal properties and unitary synaptic functions of the axons in the dentate gyrus that originate from the entorhinal cortex, the hilar mossy cells and the hypothalamic supramammillary nucleus. The fully controlled access to the activity of individual neuronal projections allows us to address the crucial questions how upstream regions of the dentate gyrus convey physiologically relevant spike activities and how these activities are translated to unitary synaptic responses in individual dentate gyrus neurons. The successful information transfers by these mechanisms ultimately generate specific dentate gyrus cell activity that contributes to hippocampal memory functions. Comprehensive mechanistic insights are essential to understand the impacts of the activity patterns associated with fundamental physiological functions and attainable with the necessary details only with direct recordings from individual axons. For example, these knowledge are necessary to understand how single cell activities in the entorhinal cortex (carrying primary spatial information) contribute to spatial representation in the dentate (i.e. place fields). Furthermore, because the size of these recorded axon terminals matches that of the majority of cortical synapses, our discoveries will demonstrate basic biophysical and neuronal principles of axonal signaling that are relevant for universal neuronal functions throughout the CNS. Thus, an exceptional repertoire of methods, including recording from anatomically identified individual small axon terminals, voltage- and calcium imaging and computational simulations, places us in an advantaged position for revealing unprecedented information about neuronal circuits.
Summary
We will reveal the neuronal mechanisms of fundamental hippocampal and axonal functions using direct patch clamp recordings from the small axon terminals of the major glutamatergic afferent and efferent pathways of the dentate gyrus region. Specifically, we will investigate the intrinsic axonal properties and unitary synaptic functions of the axons in the dentate gyrus that originate from the entorhinal cortex, the hilar mossy cells and the hypothalamic supramammillary nucleus. The fully controlled access to the activity of individual neuronal projections allows us to address the crucial questions how upstream regions of the dentate gyrus convey physiologically relevant spike activities and how these activities are translated to unitary synaptic responses in individual dentate gyrus neurons. The successful information transfers by these mechanisms ultimately generate specific dentate gyrus cell activity that contributes to hippocampal memory functions. Comprehensive mechanistic insights are essential to understand the impacts of the activity patterns associated with fundamental physiological functions and attainable with the necessary details only with direct recordings from individual axons. For example, these knowledge are necessary to understand how single cell activities in the entorhinal cortex (carrying primary spatial information) contribute to spatial representation in the dentate (i.e. place fields). Furthermore, because the size of these recorded axon terminals matches that of the majority of cortical synapses, our discoveries will demonstrate basic biophysical and neuronal principles of axonal signaling that are relevant for universal neuronal functions throughout the CNS. Thus, an exceptional repertoire of methods, including recording from anatomically identified individual small axon terminals, voltage- and calcium imaging and computational simulations, places us in an advantaged position for revealing unprecedented information about neuronal circuits.
Max ERC Funding
1 994 025 €
Duration
Start date: 2018-04-01, End date: 2023-03-31
Project acronym NanoFab2D
Project Novel 2D quantum device concepts enabled by sub-nanometre precision nanofabrication
Researcher (PI) Levente Tapaszto
Host Institution (HI) MAGYAR TUDOMANYOS AKADEMIA ENERGIATUDOMANYI KUTATOKOZPONT
Call Details Starting Grant (StG), PE3, ERC-2015-STG
Summary In today’s electronics, the information storage and processing are performed by independent technologies. The information-processing is based on semiconductor (silicon) devices, while non-volatile data storage relies on ferromagnetic metals. Integrating these tasks on a single chip and within the same material technology would enable disruptively new device concepts opening the way towards ultra-high speed electronic circuits. Due to the unique versatility of its electronic and magnetic properties, graphene has a strong potential as a platform for the implementation of such devices. By engineering their structure at the atomic level, graphene nanostructures of metallic, semiconducting, as well as magnetic properties can be realized. Here we propose that the unmatched precision and full edge orientation control of our STM-based nanofabrication technique enables the reliable implementation of such graphene nanostructures, as well as their complex, functional networks. In particular, we propose to experimentally demonstrate the feasibility of (1) semiconductor graphene nanostructures based on the quantum confinement effect, (2) spin-based devices from graphene nanostructures with magnetic edges, as well as (3) novel operation principles based on the interplay of the electronic and spin-degrees of freedom. We propose to demonstrate the electrical control of magnetism in graphene nanostructures, as well as a novel switching mechanism for graphene field effect transistors induced by the transition between two magnetic edge configurations. Exploiting such novel operation mechanisms in graphene nanostructure engineered at the atomic scale is expected to lay the foundations of disruptively new device concepts combining electronic and spin-based mechanisms that can overcome some of the fundamental limitations of today’s electronics.
Summary
In today’s electronics, the information storage and processing are performed by independent technologies. The information-processing is based on semiconductor (silicon) devices, while non-volatile data storage relies on ferromagnetic metals. Integrating these tasks on a single chip and within the same material technology would enable disruptively new device concepts opening the way towards ultra-high speed electronic circuits. Due to the unique versatility of its electronic and magnetic properties, graphene has a strong potential as a platform for the implementation of such devices. By engineering their structure at the atomic level, graphene nanostructures of metallic, semiconducting, as well as magnetic properties can be realized. Here we propose that the unmatched precision and full edge orientation control of our STM-based nanofabrication technique enables the reliable implementation of such graphene nanostructures, as well as their complex, functional networks. In particular, we propose to experimentally demonstrate the feasibility of (1) semiconductor graphene nanostructures based on the quantum confinement effect, (2) spin-based devices from graphene nanostructures with magnetic edges, as well as (3) novel operation principles based on the interplay of the electronic and spin-degrees of freedom. We propose to demonstrate the electrical control of magnetism in graphene nanostructures, as well as a novel switching mechanism for graphene field effect transistors induced by the transition between two magnetic edge configurations. Exploiting such novel operation mechanisms in graphene nanostructure engineered at the atomic scale is expected to lay the foundations of disruptively new device concepts combining electronic and spin-based mechanisms that can overcome some of the fundamental limitations of today’s electronics.
Max ERC Funding
1 496 500 €
Duration
Start date: 2016-07-01, End date: 2021-06-30
Project acronym NETWORK EVOLUTION
Project Integrated evolutionary analyses of genetic and drug interaction networks in yeast
Researcher (PI) Csaba Pal
Host Institution (HI) MAGYAR TUDOMANYOS AKADEMIA SZEGEDIBIOLOGIAI KUTATOKOZPONT
Call Details Starting Grant (StG), LS5, ERC-2007-StG
Summary The ability of cellular systems to adapt to genetic and environmental perturbations is a fundamental but poorly understood process both at the molecular and evolutionary level. There are both physiological and evolutionary reasonings why mutations often have limited impact on cellular growth. First, perturbations that hit one target often have no effect on the overall performance of a complex system (such as metabolic networks), as perturbations can be adjusted by reorganizing fluxes in metabolic networks, or changing regulation and expression of genes. Second, due to the fast evolvability of microbes, the effect of a perturbation can readily be alleviated by the evolution of compensatory mutations at other sites of the network. Understanding the extent of intrinsic and evolved robustness in cellular systems demands integrated analyses that combine functional genomics and computational systems biology with microbial evolutionary experiments. In collaboration with several leading research teams in the field, we plan to investigate the following issues. First, we will ask how accurately genome-scale metabolic network models can predict the impact of genetic deletions and other non-heritable perturbations. Second, to understand how the impact of genetic and drug perturbations can be mitigated during evolution, we will pursue a large-scale lab evolutionary protocol, and compare the results with predictions of computational models. Our work may suggest avenues of research on the general rules of acquired drug resistance in microbes.
Summary
The ability of cellular systems to adapt to genetic and environmental perturbations is a fundamental but poorly understood process both at the molecular and evolutionary level. There are both physiological and evolutionary reasonings why mutations often have limited impact on cellular growth. First, perturbations that hit one target often have no effect on the overall performance of a complex system (such as metabolic networks), as perturbations can be adjusted by reorganizing fluxes in metabolic networks, or changing regulation and expression of genes. Second, due to the fast evolvability of microbes, the effect of a perturbation can readily be alleviated by the evolution of compensatory mutations at other sites of the network. Understanding the extent of intrinsic and evolved robustness in cellular systems demands integrated analyses that combine functional genomics and computational systems biology with microbial evolutionary experiments. In collaboration with several leading research teams in the field, we plan to investigate the following issues. First, we will ask how accurately genome-scale metabolic network models can predict the impact of genetic deletions and other non-heritable perturbations. Second, to understand how the impact of genetic and drug perturbations can be mitigated during evolution, we will pursue a large-scale lab evolutionary protocol, and compare the results with predictions of computational models. Our work may suggest avenues of research on the general rules of acquired drug resistance in microbes.
Max ERC Funding
1 280 000 €
Duration
Start date: 2008-07-01, End date: 2013-06-30
Project acronym NewSpindleForce
Project A new class of microtubules in the spindle exerting forces on kinetochores
Researcher (PI) Iva Marija Tolic
Host Institution (HI) RUDER BOSKOVIC INSTITUTE
Call Details Consolidator Grant (CoG), LS3, ERC-2014-CoG
Summary At the onset of division the cell forms a spindle, a micro-machine made of microtubules, which divide the chromosomes by pulling on kinetochores, protein complexes on the chromosome. The central question in the field is how accurate chromosome segregation results from the interactions between kinetochores, microtubules and the associated proteins. According to the current paradigm, the forces on kinetochores are produced by k-fibers, bundles of microtubules extending between the spindle pole and the kinetochore. The proposed project is built upon a groundbreaking hypothesis that a new class of microtubules, which we term bridging microtubules, bridge sister kinetochores. Our preliminary results show that bridging microtubules are responsible for the positioning of kinetochores in HeLa and PtK1 cells. Bridging microtubules have not been studied before because this requires cutting-edge microscopy and laser microsurgery techniques. By applying these methods, with which I have extensive expertise, we will determine the organization of these microtubules, identify the proteins that link them with k-fibers, and uncover where and how the forces for kinetochore positioning and movement are generated. My strength is in taking an interdisciplinary approach, which I will use in this project by combining laser microsurgery with genetic perturbations, quantitative measurements of the responses and comparison with theoretical models. Understanding the role of bridging microtubules in force generation and chromosome movements will not only shed light on the mechanism of chromosome segregation, but may also increase the potential of mitotic anticancer strategies, as the spindle is a major target for chemotherapy. The proposed ERC funding is essential for the success of these timely and ambitious experiments, allowing me to strengthen my position as an international leader in research on cell division, thereby increasing Europe's foremost position in this field.
Summary
At the onset of division the cell forms a spindle, a micro-machine made of microtubules, which divide the chromosomes by pulling on kinetochores, protein complexes on the chromosome. The central question in the field is how accurate chromosome segregation results from the interactions between kinetochores, microtubules and the associated proteins. According to the current paradigm, the forces on kinetochores are produced by k-fibers, bundles of microtubules extending between the spindle pole and the kinetochore. The proposed project is built upon a groundbreaking hypothesis that a new class of microtubules, which we term bridging microtubules, bridge sister kinetochores. Our preliminary results show that bridging microtubules are responsible for the positioning of kinetochores in HeLa and PtK1 cells. Bridging microtubules have not been studied before because this requires cutting-edge microscopy and laser microsurgery techniques. By applying these methods, with which I have extensive expertise, we will determine the organization of these microtubules, identify the proteins that link them with k-fibers, and uncover where and how the forces for kinetochore positioning and movement are generated. My strength is in taking an interdisciplinary approach, which I will use in this project by combining laser microsurgery with genetic perturbations, quantitative measurements of the responses and comparison with theoretical models. Understanding the role of bridging microtubules in force generation and chromosome movements will not only shed light on the mechanism of chromosome segregation, but may also increase the potential of mitotic anticancer strategies, as the spindle is a major target for chemotherapy. The proposed ERC funding is essential for the success of these timely and ambitious experiments, allowing me to strengthen my position as an international leader in research on cell division, thereby increasing Europe's foremost position in this field.
Max ERC Funding
2 150 000 €
Duration
Start date: 2015-04-01, End date: 2020-03-31
Project acronym OscillInterference
Project Therapeutic Mechanisms and Long Term Effects of Directed Transcranial Alternating Current Stimulation in Epileptic Seizures
Researcher (PI) Antal Berényi
Host Institution (HI) Szegedi Tudomanyegyetem - Hungarian-Netherlands School of Educational Management
Call Details Starting Grant (StG), LS5, ERC-2013-StG
Summary A significant proportion of patients with epilepsy are refractive to pharmaceutical treatments. Recurrent, untreated epileptic seizures are associated with risk of adverse neurological, cognitive, and psychological outcomes. Despite years of study, there are still significant barriers to the management of these disorders. In my proposal I advance the hypothesis that time-targeted perturbation of neural network oscillations by transcranial electric stimulation (TES) decreases the duration of seizures. I hypothesize further that spatially focused TES and chronically applied TES intervention can also permanently reduce seizure occurrence. Our specific aims are designed to perform in vivo studies in rodent models of two seizure types (absence seizures and complex partial seizures) to evaluate the effectiveness of TES in abrogating pathologic network activity, and to use high resolution recording techniques and optogenetical methods to assess the neural mechanisms involved. Our results may help to establish general principles of the diverse epilepsy pathophysiology and introduce novel therapeutic approaches. We will establish a focal TES stimulation protocol to selectively interfere with brain regions previously identified as key structures in the pathomechanism of epilepsy. The deliverables of these experiments will make a significant advancement in the understanding of the pathomechanisms of these disorders, and will offer a new alternative treatment option as a complimentary therapeutic approach to the state of the art pharmaceutical products. The methods used in this project are unique and advanced as the first attempt to perform 512 channel extracellular recordings in the behaving animal to investigate the evolution of epileptic seizures at the neuronal network and cellular levels and by achieving spatially selective TES. The combination of these methods are deployed for both understanding the mechanisms of seizure evolution, and termination of seizures.
Summary
A significant proportion of patients with epilepsy are refractive to pharmaceutical treatments. Recurrent, untreated epileptic seizures are associated with risk of adverse neurological, cognitive, and psychological outcomes. Despite years of study, there are still significant barriers to the management of these disorders. In my proposal I advance the hypothesis that time-targeted perturbation of neural network oscillations by transcranial electric stimulation (TES) decreases the duration of seizures. I hypothesize further that spatially focused TES and chronically applied TES intervention can also permanently reduce seizure occurrence. Our specific aims are designed to perform in vivo studies in rodent models of two seizure types (absence seizures and complex partial seizures) to evaluate the effectiveness of TES in abrogating pathologic network activity, and to use high resolution recording techniques and optogenetical methods to assess the neural mechanisms involved. Our results may help to establish general principles of the diverse epilepsy pathophysiology and introduce novel therapeutic approaches. We will establish a focal TES stimulation protocol to selectively interfere with brain regions previously identified as key structures in the pathomechanism of epilepsy. The deliverables of these experiments will make a significant advancement in the understanding of the pathomechanisms of these disorders, and will offer a new alternative treatment option as a complimentary therapeutic approach to the state of the art pharmaceutical products. The methods used in this project are unique and advanced as the first attempt to perform 512 channel extracellular recordings in the behaving animal to investigate the evolution of epileptic seizures at the neuronal network and cellular levels and by achieving spatially selective TES. The combination of these methods are deployed for both understanding the mechanisms of seizure evolution, and termination of seizures.
Max ERC Funding
1 419 000 €
Duration
Start date: 2013-11-01, End date: 2018-10-31
Project acronym resistance evolution
Project Bacterial evolution of hypersensitivity and resistance against antimicrobial peptides
Researcher (PI) Csaba Pal
Host Institution (HI) MAGYAR TUDOMANYOS AKADEMIA SZEGEDIBIOLOGIAI KUTATOKOZPONT
Call Details Consolidator Grant (CoG), LS8, ERC-2014-CoG
Summary Evolution of resistance towards a single drug simultaneously increases (cross-resistance) or decreases (collateral sensitivity) fitness to multiple other antimicrobial agents. The molecular mechanisms driving cross-resistance are relatively well described, but it remains largely unclear how frequently does genetic adaptation to a single drug increase the sensitivity to others and what the underlying molecular mechanisms of collateral sensitivity are. This proposal focuses on studying the bacterial evolution of resistance and collateral sensitivity against antimicrobial peptides (AMPs). Beyond their modulatory roles in the immune system, these naturally occurring peptides provide protection against pathogenic microbes, and are considered as promising novel alternatives to traditional antibiotics. However, there are concerns that evolution against therapeutic AMPs can readily develop and as a by-product this might compromise natural immunity. Our knowledge of these issues is limited due to the shortage of systematic evolutionary studies. Therefore, the three central questions we address are: Do bacteria resistant to multiple antibiotics become hypersensitive to certain antimicrobial peptides? What are the evolutionary mechanisms leading to AMP resistance and to what extent does this process induce cross-resistance/collateral sensitivity against other drugs? Last, are these evolutionary trade-offs predictable based on chemical and functional peptide properties? To investigate these issues rigorously, we integrate tools of laboratory evolution, high-throughput phenotypic assays, functional genomics, and computational systems biology. Our project will provide an insight into the evolutionary mechanisms that drive cross-resistance and collateral sensitivities with the aim to explore the vulnerable points of resistant bacteria. Another goal is to provide guidelines for the future design of antimicrobial peptides with desirable properties against bacterial pathogens.
Summary
Evolution of resistance towards a single drug simultaneously increases (cross-resistance) or decreases (collateral sensitivity) fitness to multiple other antimicrobial agents. The molecular mechanisms driving cross-resistance are relatively well described, but it remains largely unclear how frequently does genetic adaptation to a single drug increase the sensitivity to others and what the underlying molecular mechanisms of collateral sensitivity are. This proposal focuses on studying the bacterial evolution of resistance and collateral sensitivity against antimicrobial peptides (AMPs). Beyond their modulatory roles in the immune system, these naturally occurring peptides provide protection against pathogenic microbes, and are considered as promising novel alternatives to traditional antibiotics. However, there are concerns that evolution against therapeutic AMPs can readily develop and as a by-product this might compromise natural immunity. Our knowledge of these issues is limited due to the shortage of systematic evolutionary studies. Therefore, the three central questions we address are: Do bacteria resistant to multiple antibiotics become hypersensitive to certain antimicrobial peptides? What are the evolutionary mechanisms leading to AMP resistance and to what extent does this process induce cross-resistance/collateral sensitivity against other drugs? Last, are these evolutionary trade-offs predictable based on chemical and functional peptide properties? To investigate these issues rigorously, we integrate tools of laboratory evolution, high-throughput phenotypic assays, functional genomics, and computational systems biology. Our project will provide an insight into the evolutionary mechanisms that drive cross-resistance and collateral sensitivities with the aim to explore the vulnerable points of resistant bacteria. Another goal is to provide guidelines for the future design of antimicrobial peptides with desirable properties against bacterial pathogens.
Max ERC Funding
1 846 250 €
Duration
Start date: 2015-10-01, End date: 2021-09-30
Project acronym SERRACO
Project Modulation of cortical activity by median raphe neuronal assemblies with identified behavioural effects
Researcher (PI) Tamás Freund
Host Institution (HI) INSTITUTE OF EXPERIMENTAL MEDICINE - HUNGARIAN ACADEMY OF SCIENCES
Call Details Advanced Grant (AdG), LS5, ERC-2011-ADG_20110310
Summary Cortical operations are built up from states associated with distinct behaviour-dependent network activity patterns that subserve information aquisition, encoding, memory consolidation and retrieval. Thus, they can be considered as manifestations of different processing modes. Groups of modulatory, largely monoaminergic neurons located in subcortical nuclei innervating all forebrain areas are indispensable for the generation, stabilization and termination of cortical activity states. In recent years the concept of subcortical modulation has been expanded by the discovery of a fast type of modulatory action driving the rapid readjustment of cortical activity and associated behaviours. Thus, cortical networks are under the influence of a tonic, slow, as well as a phasic, rapid component of subcortical modulation that are acting in parallel. Results from our laboratory revealed that the median raphe (MR) nucleus, one of the main sources of serotonergic innervation of the limbic system , besides the non-synaptic diffuse action, also exerts a fast type of modulation via the selective innervation of cortical GABAergic interneurons. This selective effect on local inhibition may be ideal for the synchronous resetting of the target principal cell circuits, or for the continuous tuning of their activity. These discoveries, together with the methodological advances of recent years, enable us to map the neuronal network mechanisms behind transitions of brain states, as well as associated behaviours, induced by subcortical inputs. We will focus on the MR – limbic connection with the aim to unravel the physiological, pharmacological and anatomical features of MR neuronal assemblies, both the slow- and fast-acting, as well as the serotonergic and glutamatergic components (together with their cortical target circuits) that will have been shown - using optic stimulation of ChR2/eGFP virus-infected MR neurons - to evoke characteristic behaviours, such as anxiety and conditioned fear.
Summary
Cortical operations are built up from states associated with distinct behaviour-dependent network activity patterns that subserve information aquisition, encoding, memory consolidation and retrieval. Thus, they can be considered as manifestations of different processing modes. Groups of modulatory, largely monoaminergic neurons located in subcortical nuclei innervating all forebrain areas are indispensable for the generation, stabilization and termination of cortical activity states. In recent years the concept of subcortical modulation has been expanded by the discovery of a fast type of modulatory action driving the rapid readjustment of cortical activity and associated behaviours. Thus, cortical networks are under the influence of a tonic, slow, as well as a phasic, rapid component of subcortical modulation that are acting in parallel. Results from our laboratory revealed that the median raphe (MR) nucleus, one of the main sources of serotonergic innervation of the limbic system , besides the non-synaptic diffuse action, also exerts a fast type of modulation via the selective innervation of cortical GABAergic interneurons. This selective effect on local inhibition may be ideal for the synchronous resetting of the target principal cell circuits, or for the continuous tuning of their activity. These discoveries, together with the methodological advances of recent years, enable us to map the neuronal network mechanisms behind transitions of brain states, as well as associated behaviours, induced by subcortical inputs. We will focus on the MR – limbic connection with the aim to unravel the physiological, pharmacological and anatomical features of MR neuronal assemblies, both the slow- and fast-acting, as well as the serotonergic and glutamatergic components (together with their cortical target circuits) that will have been shown - using optic stimulation of ChR2/eGFP virus-infected MR neurons - to evoke characteristic behaviours, such as anxiety and conditioned fear.
Max ERC Funding
2 700 000 €
Duration
Start date: 2012-03-01, End date: 2017-02-28
Project acronym SYLO
Project Spin dynamics and transport at the quantum edge in low dimensional nanomaterials
Researcher (PI) Ferenc Simon
Host Institution (HI) BUDAPESTI MUSZAKI ES GAZDASAGTUDOMANYI EGYETEM
Call Details Starting Grant (StG), PE3, ERC-2010-StG_20091028
Summary Sustainable development in information technology calls for an ever increasing information processing and storage capability. A promising route to maintain exponential growth capability, i.e. to keep on the Moore's roadmap, is to turn to the electron spins as information carriers rather than their charge. This field, spintronics, has enormous potential whose exploitation requires solid knowledge in the fundamentals of spin dynamics and spin transport. Herein, novel nanomaterials are suggested for spintronics purposes, such as graphene and single-wall carbon nanotubes (SWCNTs). These, fundamental two- and one-dimensional carbon allotropes are promising candidates for such purposes, carbon being a light element with a low spin-orbit coupling which results in a long spin coherence. There are several fundamental open issues, e.g. the dominant spin orbit coupling mechanism in graphene, whether bulk electron spin resonance can be observed for this material, and the length of the spin diffusion length. For SWCNTs, the ground state of isolated metallic tubes is known to be the Tomonaga-Luttinger liquid (TLL), which greatly limit the spin coherence, but it is at present open whether this state is destroyed when an ensemble of interacting metallic tubes is studied. The decay time and spin symmetry of optical excitations (excitons) in semiconducting SWCNTs is yet unknown.
Our goal is to pursue electron spin resonance in graphene and carbon nanotubes and to perform optically detected magnetic resonance in carbon nanotubes. We will commission a magnetoptical spectrometer with a substantial added value.
The expected results are characterization of spin transport capabilities of these materials and understanding of the spin decoherence mechanisms. The PI leads magnetic resonance studies of these materials, shown by his more than 300 citations to this field (the total being over 470) and his 15 Physical Review Letters papers in this field (of which for 9 he is main Author).
Summary
Sustainable development in information technology calls for an ever increasing information processing and storage capability. A promising route to maintain exponential growth capability, i.e. to keep on the Moore's roadmap, is to turn to the electron spins as information carriers rather than their charge. This field, spintronics, has enormous potential whose exploitation requires solid knowledge in the fundamentals of spin dynamics and spin transport. Herein, novel nanomaterials are suggested for spintronics purposes, such as graphene and single-wall carbon nanotubes (SWCNTs). These, fundamental two- and one-dimensional carbon allotropes are promising candidates for such purposes, carbon being a light element with a low spin-orbit coupling which results in a long spin coherence. There are several fundamental open issues, e.g. the dominant spin orbit coupling mechanism in graphene, whether bulk electron spin resonance can be observed for this material, and the length of the spin diffusion length. For SWCNTs, the ground state of isolated metallic tubes is known to be the Tomonaga-Luttinger liquid (TLL), which greatly limit the spin coherence, but it is at present open whether this state is destroyed when an ensemble of interacting metallic tubes is studied. The decay time and spin symmetry of optical excitations (excitons) in semiconducting SWCNTs is yet unknown.
Our goal is to pursue electron spin resonance in graphene and carbon nanotubes and to perform optically detected magnetic resonance in carbon nanotubes. We will commission a magnetoptical spectrometer with a substantial added value.
The expected results are characterization of spin transport capabilities of these materials and understanding of the spin decoherence mechanisms. The PI leads magnetic resonance studies of these materials, shown by his more than 300 citations to this field (the total being over 470) and his 15 Physical Review Letters papers in this field (of which for 9 he is main Author).
Max ERC Funding
1 230 000 €
Duration
Start date: 2010-11-01, End date: 2015-10-31
Project acronym SYM-BIOTICS
Project Dual exploitation of natural plant strategies in agriculture and public health: enhancing nitrogen-fixation and surmounting microbial infections
Researcher (PI) Eva Kondorosi
Host Institution (HI) MAGYAR TUDOMANYOS AKADEMIA SZEGEDIBIOLOGIAI KUTATOKOZPONT
Call Details Advanced Grant (AdG), LS9, ERC-2010-AdG_20100317
Summary With an unprecedented increase in the human population, higher agricultural production, enhanced food safety and the protection against alarming rise of antibiotic resistant pathogenic bacteria are amongst the main challenges of this century. This proposal centered on Rhizobium-legume symbiosis aims at contributing to these tasks by i) understanding the development of symbiotic nitrogen fixing cells for improvement of the eco-friendly biological nitrogen fixation, ii) gaining a comprehensive knowledge on polyploidy having a great impact on crop yields and iii) exploiting the strategies of symbiotic plant cells for the development of novel antibiotics. Symbiotic nitrogen fixation in Rhizobium-legume interactions is a major contributor to the combined nitrogen pool in the biosphere. It takes place in root nodules where giant plant cells host the nitrogen fixing bacteria. In Medicago nodules both the plant cells and the bacteria are polyploids and incapable for cell division. These polyploid plant cells produce hundreds of symbiotic peptides (symPEPs) that provoke terminal differentiation of bacteria in symbiosis and exhibit broad range antimicrobial activities in vitro. Permanent generation of polyploid cells is essential for the nodule development. It will be studied whether the complete genome is duplicated in consecutive endocycles, how different ploidy levels affect DNA methylation and expression profile and whether polyploidy is required for the expression of symPEP genes. The activity and mode of actions of symPEPs are in the focus of the proposal; i) how symPEPs achieve bacteroid differentiation and affect nitrogen fixation and ii) whether symPEP antimicrobial activities provide novel modes of antimicrobial actions and iii) whether ¿Sym-Biotics¿ could become widely used novel antibiotics. Their applicability as plant protecting and meat decontaminating agents as well as their in vivo efficiency in mouse septicemia models will be tested.
Summary
With an unprecedented increase in the human population, higher agricultural production, enhanced food safety and the protection against alarming rise of antibiotic resistant pathogenic bacteria are amongst the main challenges of this century. This proposal centered on Rhizobium-legume symbiosis aims at contributing to these tasks by i) understanding the development of symbiotic nitrogen fixing cells for improvement of the eco-friendly biological nitrogen fixation, ii) gaining a comprehensive knowledge on polyploidy having a great impact on crop yields and iii) exploiting the strategies of symbiotic plant cells for the development of novel antibiotics. Symbiotic nitrogen fixation in Rhizobium-legume interactions is a major contributor to the combined nitrogen pool in the biosphere. It takes place in root nodules where giant plant cells host the nitrogen fixing bacteria. In Medicago nodules both the plant cells and the bacteria are polyploids and incapable for cell division. These polyploid plant cells produce hundreds of symbiotic peptides (symPEPs) that provoke terminal differentiation of bacteria in symbiosis and exhibit broad range antimicrobial activities in vitro. Permanent generation of polyploid cells is essential for the nodule development. It will be studied whether the complete genome is duplicated in consecutive endocycles, how different ploidy levels affect DNA methylation and expression profile and whether polyploidy is required for the expression of symPEP genes. The activity and mode of actions of symPEPs are in the focus of the proposal; i) how symPEPs achieve bacteroid differentiation and affect nitrogen fixation and ii) whether symPEP antimicrobial activities provide novel modes of antimicrobial actions and iii) whether ¿Sym-Biotics¿ could become widely used novel antibiotics. Their applicability as plant protecting and meat decontaminating agents as well as their in vivo efficiency in mouse septicemia models will be tested.
Max ERC Funding
2 320 000 €
Duration
Start date: 2011-07-01, End date: 2017-06-30
Project acronym VISONby3DSTIM
Project Restoration of visual perception by artificial stimulation performed by 3D EAO microscopy
Researcher (PI) Jozsef Balázs Rózsa
Host Institution (HI) INSTITUTE OF EXPERIMENTAL MEDICINE - HUNGARIAN ACADEMY OF SCIENCES
Call Details Consolidator Grant (CoG), LS5, ERC-2015-CoG
Summary The long-term aim of the investigation is to assess the feasibility of creating an “artificial sense” and, thereby, a possible sensory (visual) prosthetic. While working towards this goal, we will have to address the question of how neural assembly activity relates to subjective perceptions. Finding and understanding these functional assemblies will make it possible to reactivate them in a precise, biologically relevant manner to elicit similar cortical activation as visual stimulation. Recent publications suggest that cortical connectivity can be mapped by two-photon microscopy. Here we want, therefore, to develop a novel 3D Electro-Acousto-Optical microscope for high-throughput assembly mapping. The microscope will be capable of scanning neuronal activity with one order of magnitude higher speed (300-500 kHz/ROI) and simultaneously photoactivate neurons with three order of magnitude higher efficiency (2,500 – 25,000 neurons/ms) than existing 3D microscopes while preserving the subcellular resolution required to simultaneously measure the somatic, the dendritic and axonal computation units in the entire V1 region of the cortex. The microscope will be based on our current 3D AO technology; on novel ultra-fast scanning technologies; new, 10-fold faster AO deflectors; and novel (multi-ROI) scanning strategies. Using our microscope in combination with novel caged neurotransmitters and optogenetic tools, we want to map cell assemblies and to understand how they form larger clusters and how they are associated with visual features. Furthermore, as a proof-of-concept of this grant, we want to restore visual perception by recreating previously mapped assembly patterns with 3D artificial photositmulation in behaving mice and see if the animal responds to the artificial stimulus in the same way as to the visual stimulus. Moreover, we want to restore visual information based spatial navigation in head restrained animals orienting and moving in a virtual labyrinth for reward.
Summary
The long-term aim of the investigation is to assess the feasibility of creating an “artificial sense” and, thereby, a possible sensory (visual) prosthetic. While working towards this goal, we will have to address the question of how neural assembly activity relates to subjective perceptions. Finding and understanding these functional assemblies will make it possible to reactivate them in a precise, biologically relevant manner to elicit similar cortical activation as visual stimulation. Recent publications suggest that cortical connectivity can be mapped by two-photon microscopy. Here we want, therefore, to develop a novel 3D Electro-Acousto-Optical microscope for high-throughput assembly mapping. The microscope will be capable of scanning neuronal activity with one order of magnitude higher speed (300-500 kHz/ROI) and simultaneously photoactivate neurons with three order of magnitude higher efficiency (2,500 – 25,000 neurons/ms) than existing 3D microscopes while preserving the subcellular resolution required to simultaneously measure the somatic, the dendritic and axonal computation units in the entire V1 region of the cortex. The microscope will be based on our current 3D AO technology; on novel ultra-fast scanning technologies; new, 10-fold faster AO deflectors; and novel (multi-ROI) scanning strategies. Using our microscope in combination with novel caged neurotransmitters and optogenetic tools, we want to map cell assemblies and to understand how they form larger clusters and how they are associated with visual features. Furthermore, as a proof-of-concept of this grant, we want to restore visual perception by recreating previously mapped assembly patterns with 3D artificial photositmulation in behaving mice and see if the animal responds to the artificial stimulus in the same way as to the visual stimulus. Moreover, we want to restore visual information based spatial navigation in head restrained animals orienting and moving in a virtual labyrinth for reward.
Max ERC Funding
2 000 000 €
Duration
Start date: 2016-05-01, End date: 2021-04-30
Project acronym X-CITED!
Project Electronic transitions and bistability: states, switches, transitions and dynamics studied with high-resolution X-ray spectroscopy
Researcher (PI) György Albert Vankó
Host Institution (HI) MAGYAR TUDOMANYOS AKADEMIA WIGNER FIZIKAI KUTATOKOZPONT
Call Details Starting Grant (StG), PE3, ERC-2010-StG_20091028
Summary We propose to study transition metal compounds of uncommon transport properties and excitation characteristics applying emerging high-resolution X-ray spectroscopy. The objective is to determine the microscopic origin of the unconventional behaviour of systems with strong electron correlation through systematic investigations, as well as to reveal bistability conditions and excitation characteristics of switchable molecular systems. The main techniques involved are synchrotron radiation (SR)-based spectroscopies, which can explore the fine details of the electronic structure. Besides using existing end stations of SR facilities, we plan to build a portable spectrometer that can be advantageously used both in a laboratory (e.g., with a radioactive source) and at specially dedicated beamlines of SR facilities, in order to benefit from their specializations in extreme conditions and advanced sample environments, in particular unconventional experiments. This spectrometer should also be able to work in a time-resolved mode so that it could address the dynamics of electronic excitations on the attosecond to nanosecond time scale. The suggested work is expected to push high-resolution X-ray spectroscopies toward maturity, which should open up new horizons in electronic structure and dynamics studies of condensed matter research.
Summary
We propose to study transition metal compounds of uncommon transport properties and excitation characteristics applying emerging high-resolution X-ray spectroscopy. The objective is to determine the microscopic origin of the unconventional behaviour of systems with strong electron correlation through systematic investigations, as well as to reveal bistability conditions and excitation characteristics of switchable molecular systems. The main techniques involved are synchrotron radiation (SR)-based spectroscopies, which can explore the fine details of the electronic structure. Besides using existing end stations of SR facilities, we plan to build a portable spectrometer that can be advantageously used both in a laboratory (e.g., with a radioactive source) and at specially dedicated beamlines of SR facilities, in order to benefit from their specializations in extreme conditions and advanced sample environments, in particular unconventional experiments. This spectrometer should also be able to work in a time-resolved mode so that it could address the dynamics of electronic excitations on the attosecond to nanosecond time scale. The suggested work is expected to push high-resolution X-ray spectroscopies toward maturity, which should open up new horizons in electronic structure and dynamics studies of condensed matter research.
Max ERC Funding
1 125 960 €
Duration
Start date: 2010-12-01, End date: 2015-11-30
