Project acronym ABATSYNAPSE
Project Evolution of Alzheimer’s Disease: From dynamics of single synapses to memory loss
Researcher (PI) Inna Slutsky
Host Institution (HI) TEL AVIV UNIVERSITY
Call Details Starting Grant (StG), LS5, ERC-2011-StG_20101109
Summary A persistent challenge in unravelling mechanisms that regulate memory function is how to bridge the gap between inter-molecular dynamics of single proteins, activity of individual synapses and emerging properties of neuronal circuits. The prototype condition of disintegrating neuronal circuits is Alzheimer’s Disease (AD). Since the early time of Alois Alzheimer at the turn of the 20th century, scientists have been searching for a molecular entity that is in the roots of the cognitive deficits. Although diverse lines of evidence suggest that the amyloid-beta peptide (Abeta) plays a central role in synaptic dysfunctions of AD, several key questions remain unresolved. First, endogenous Abeta peptides are secreted by neurons throughout life, but their physiological functions are largely unknown. Second, experience-dependent physiological mechanisms that initiate the changes in Abeta composition in sporadic, the most frequent form of AD, are unidentified. And finally, molecular mechanisms that trigger Abeta-induced synaptic failure and memory decline remain elusive.
To target these questions, I propose to develop an integrative approach to correlate structure and function at the level of single synapses in hippocampal circuits. State-of-the-art techniques will enable the simultaneous real-time visualization of inter-molecular dynamics within signalling complexes and functional synaptic modifications. Utilizing FRET spectroscopy, high-resolution optical imaging, electrophysiology, molecular biology and biochemistry we will determine the casual relationship between ongoing neuronal activity, temporo-spatial dynamics and molecular composition of Abeta, structural rearrangements within the Abeta signalling complexes and plasticity of single synapses and whole networks. The proposed research will elucidate fundamental principles of neuronal circuits function and identify critical steps that initiate primary synaptic dysfunctions at the very early stages of sporadic AD.
Summary
A persistent challenge in unravelling mechanisms that regulate memory function is how to bridge the gap between inter-molecular dynamics of single proteins, activity of individual synapses and emerging properties of neuronal circuits. The prototype condition of disintegrating neuronal circuits is Alzheimer’s Disease (AD). Since the early time of Alois Alzheimer at the turn of the 20th century, scientists have been searching for a molecular entity that is in the roots of the cognitive deficits. Although diverse lines of evidence suggest that the amyloid-beta peptide (Abeta) plays a central role in synaptic dysfunctions of AD, several key questions remain unresolved. First, endogenous Abeta peptides are secreted by neurons throughout life, but their physiological functions are largely unknown. Second, experience-dependent physiological mechanisms that initiate the changes in Abeta composition in sporadic, the most frequent form of AD, are unidentified. And finally, molecular mechanisms that trigger Abeta-induced synaptic failure and memory decline remain elusive.
To target these questions, I propose to develop an integrative approach to correlate structure and function at the level of single synapses in hippocampal circuits. State-of-the-art techniques will enable the simultaneous real-time visualization of inter-molecular dynamics within signalling complexes and functional synaptic modifications. Utilizing FRET spectroscopy, high-resolution optical imaging, electrophysiology, molecular biology and biochemistry we will determine the casual relationship between ongoing neuronal activity, temporo-spatial dynamics and molecular composition of Abeta, structural rearrangements within the Abeta signalling complexes and plasticity of single synapses and whole networks. The proposed research will elucidate fundamental principles of neuronal circuits function and identify critical steps that initiate primary synaptic dysfunctions at the very early stages of sporadic AD.
Max ERC Funding
2 000 000 €
Duration
Start date: 2011-12-01, End date: 2017-09-30
Project acronym ALPROS
Project Artificial Life-like Processive Systems
Researcher (PI) Roeland Johannes Maria Nolte
Host Institution (HI) STICHTING KATHOLIEKE UNIVERSITEIT
Call Details Advanced Grant (AdG), PE5, ERC-2011-ADG_20110209
Summary Toroidal processive enzymes (e.g. enzymes/proteins that are able to thread onto biopolymers and to perform stepwise reactions along the polymer chain) are among the most fascinating tools involved in the clockwork machinery of life. Processive catalysis is ubiquitous in Nature, viz. DNA polymerases, endo- and exo-nucleases and; it plays a crucial role in numerous events of the cell’s life, including most of the replication, transmission, and expression and repair processes of the genetic information. In the case of DNA polymerases the protein catalyst encircles the DNA and whilst moving along it, make copies of high fidelity. Although numerous works have been reported in relation with the synthesis of natural enzymes' analogues, very few efforts have been paid in comparison to mimic these processive properties. It is the goal of this proposal to rectify this oversight and unravel the essential components of Nature’s polymer catalysts. The individual projects are designed to specifically target the essential aspects of processive catalysis, i.e. rate of motion, rate of catalysis, and transfer of information. One project is aimed at extending the research into a processive catalytic system that is more suitable for industrial application. Two projects involve more farsighted studies and are designed to push the research way beyond the current boundaries into the area of Turing machines and bio-rotaxane catalysts which can modify DNA in a non-natural process. The vision of this proposal is to open up the field of ‘processive catalysis’ and invigorate the next generation of chemists to develop information transfer and toroidal processive catalysts. The construction of synthetic analogues of processive enzymes could open a gate toward a large range of applications, ranging from intelligent tailoring of polymers to information storage and processing.
Summary
Toroidal processive enzymes (e.g. enzymes/proteins that are able to thread onto biopolymers and to perform stepwise reactions along the polymer chain) are among the most fascinating tools involved in the clockwork machinery of life. Processive catalysis is ubiquitous in Nature, viz. DNA polymerases, endo- and exo-nucleases and; it plays a crucial role in numerous events of the cell’s life, including most of the replication, transmission, and expression and repair processes of the genetic information. In the case of DNA polymerases the protein catalyst encircles the DNA and whilst moving along it, make copies of high fidelity. Although numerous works have been reported in relation with the synthesis of natural enzymes' analogues, very few efforts have been paid in comparison to mimic these processive properties. It is the goal of this proposal to rectify this oversight and unravel the essential components of Nature’s polymer catalysts. The individual projects are designed to specifically target the essential aspects of processive catalysis, i.e. rate of motion, rate of catalysis, and transfer of information. One project is aimed at extending the research into a processive catalytic system that is more suitable for industrial application. Two projects involve more farsighted studies and are designed to push the research way beyond the current boundaries into the area of Turing machines and bio-rotaxane catalysts which can modify DNA in a non-natural process. The vision of this proposal is to open up the field of ‘processive catalysis’ and invigorate the next generation of chemists to develop information transfer and toroidal processive catalysts. The construction of synthetic analogues of processive enzymes could open a gate toward a large range of applications, ranging from intelligent tailoring of polymers to information storage and processing.
Max ERC Funding
1 603 699 €
Duration
Start date: 2012-02-01, End date: 2017-01-31
Project acronym AMPRO
Project Advanced Electronic Materials and Devices through Novel Processing Paradigms
Researcher (PI) Thomas Anthopoulos
Host Institution (HI) IMPERIAL COLLEGE OF SCIENCE TECHNOLOGY AND MEDICINE
Call Details Starting Grant (StG), PE5, ERC-2011-StG_20101014
Summary "I propose a structured multidisciplinary research programme that seeks to combine advanced materials, such as metal oxides and organics, with novel fabrication methods to develop devices for application in: (1) large area electronics, (2) integrated nanoelectronics and (3) sensors. At the heart of this programme lies the development of novel oxide semiconductors. These will be synthesised from solution using precursors. Chemical doping via physical blending will be explored for the tuning of the electronic properties of these compounds. This simple approach will enable the rapid development of a library of materials far beyond those accessible by traditional methods. Oxides will then be combined with inorganic/organic dielectrics to demonstrate low power transistors. Ultimate target for application area (1) is the development of transistors with hole/electron mobilities exceeding 20/200 cm^2/Vs respectively. For application area (2) I will combine the precursor formulations with advanced scanning thermochemical nanolithography. A heated atomic force microscope tip will be used for the local chemical conversion of the precursor to oxide with sub-50 nm resolution. This will enable patterning of nanostructures with desirable shape and size. Sequential patterning of semi/conductive layers combined with SAM dielectrics would enable fabrication of nano-sized devices and circuits. For application area (3), research effort will focus on novel hybrid phototransistors. Use of different light absorbing organic dyes functionalised onto the oxide channel will be explored as a mean for developing high sensitivity phototransistors and full colour sensing arrays. Organic dyes will also be combined with nano-sized transistors to demonstrate integrated nano-scale optoelectronics. The unique combination of bottom-up and top-down strategies adopted in this project will lead to the development of novel high performance devices with a host of existing and new applications."
Summary
"I propose a structured multidisciplinary research programme that seeks to combine advanced materials, such as metal oxides and organics, with novel fabrication methods to develop devices for application in: (1) large area electronics, (2) integrated nanoelectronics and (3) sensors. At the heart of this programme lies the development of novel oxide semiconductors. These will be synthesised from solution using precursors. Chemical doping via physical blending will be explored for the tuning of the electronic properties of these compounds. This simple approach will enable the rapid development of a library of materials far beyond those accessible by traditional methods. Oxides will then be combined with inorganic/organic dielectrics to demonstrate low power transistors. Ultimate target for application area (1) is the development of transistors with hole/electron mobilities exceeding 20/200 cm^2/Vs respectively. For application area (2) I will combine the precursor formulations with advanced scanning thermochemical nanolithography. A heated atomic force microscope tip will be used for the local chemical conversion of the precursor to oxide with sub-50 nm resolution. This will enable patterning of nanostructures with desirable shape and size. Sequential patterning of semi/conductive layers combined with SAM dielectrics would enable fabrication of nano-sized devices and circuits. For application area (3), research effort will focus on novel hybrid phototransistors. Use of different light absorbing organic dyes functionalised onto the oxide channel will be explored as a mean for developing high sensitivity phototransistors and full colour sensing arrays. Organic dyes will also be combined with nano-sized transistors to demonstrate integrated nano-scale optoelectronics. The unique combination of bottom-up and top-down strategies adopted in this project will lead to the development of novel high performance devices with a host of existing and new applications."
Max ERC Funding
1 497 798 €
Duration
Start date: 2012-01-01, End date: 2016-12-31
Project acronym ASMIDIAS
Project Asymmetric microenvironments by directed assembly: Control of geometry, topography, surface biochemistry and mechanical properties via a microscale modular design principle
Researcher (PI) Holger Dr. Schönherr
Host Institution (HI) UNIVERSITAET SIEGEN
Call Details Starting Grant (StG), PE5, ERC-2011-StG_20101014
Summary The interaction of cells with the extracellular matrix or neighboring cells plays a crucial role in many cellular functions, such as motility, differentiation and controlled cell death. Expanding on pioneering studies on defined 2-D model systems, the role of the currently known determinants (geometry, topography, biochemical functionality and mechanical properties) is currently addressed in more relevant 3-D matrices. However, there is a clear lack in currently available approaches to fabricate well defined microenvironments, which are asymmetric or in which these factors can be varied independently. The central objective of ASMIDIAS is the development of a novel route to asymmetric microenvironments for cell-matrix interaction studies. Inspired by molecular self-assembly on the one hand and guided macroscale assembly on the other hand, directed assembly of highly defined microfabricated building blocks will be exploited to this end. In this modular design approach different building blocks position themselves during assembly on pre-structured surfaces to afford enclosed volumes that are restricted by the walls of the blocks. The project relies on two central elements. For the guided assembly, the balance of attractive and repulsive interactions between the building blocks (and its dependence on the object dimensions) and the structured surface shall be controlled by appropriate surface chemistry and suitable guiding structures. To afford the required functionality, new approaches to (i) topographically structure, (ii) biochemically functionalize and pattern selected sides of the microscale building blocks and (iii) to control their surface elastic properties via surface-attached polymers and hydrogels, will be developed.The resulting unique asymmetric environments will facilitate novel insight into cell-matrix interactions, which possess considerable relevance in the areas of tissue engineering, cell (de)differentiation, bacteria-surface interactions and beyond.
Summary
The interaction of cells with the extracellular matrix or neighboring cells plays a crucial role in many cellular functions, such as motility, differentiation and controlled cell death. Expanding on pioneering studies on defined 2-D model systems, the role of the currently known determinants (geometry, topography, biochemical functionality and mechanical properties) is currently addressed in more relevant 3-D matrices. However, there is a clear lack in currently available approaches to fabricate well defined microenvironments, which are asymmetric or in which these factors can be varied independently. The central objective of ASMIDIAS is the development of a novel route to asymmetric microenvironments for cell-matrix interaction studies. Inspired by molecular self-assembly on the one hand and guided macroscale assembly on the other hand, directed assembly of highly defined microfabricated building blocks will be exploited to this end. In this modular design approach different building blocks position themselves during assembly on pre-structured surfaces to afford enclosed volumes that are restricted by the walls of the blocks. The project relies on two central elements. For the guided assembly, the balance of attractive and repulsive interactions between the building blocks (and its dependence on the object dimensions) and the structured surface shall be controlled by appropriate surface chemistry and suitable guiding structures. To afford the required functionality, new approaches to (i) topographically structure, (ii) biochemically functionalize and pattern selected sides of the microscale building blocks and (iii) to control their surface elastic properties via surface-attached polymers and hydrogels, will be developed.The resulting unique asymmetric environments will facilitate novel insight into cell-matrix interactions, which possess considerable relevance in the areas of tissue engineering, cell (de)differentiation, bacteria-surface interactions and beyond.
Max ERC Funding
1 484 100 €
Duration
Start date: 2011-11-01, End date: 2016-10-31
Project acronym AstroFunc
Project Molecular Studies of Astrocyte Function in Health and Disease
Researcher (PI) Matthew Guy Holt
Host Institution (HI) VIB
Call Details Starting Grant (StG), LS5, ERC-2011-StG_20101109
Summary Brain consists of two basic cell types – neurons and glia. However, the study of glia in brain function has traditionally been neglected in favor of their more “illustrious” counter-parts – neurons that are classed as the computational units of the brain. Glia have usually been classed as “brain glue” - a supportive matrix on which neurons grow and function. However, recent evidence suggests that glia are more than passive “glue” and actually modulate neuronal function. This has lead to the proposal of a “tripartite synapse”, which recognizes pre- and postsynaptic neuronal elements and glia as a unit.
However, what is still lacking is rudimentary information on how these cells actually function in situ. Here we propose taking a “bottom-up” approach, by identifying the molecules (and interactions) that control glial function in situ. This is complicated by the fact that glia show profound changes when placed into culture. To circumvent this, we will use recently developed cell sorting techniques, to rapidly isolate genetically marked glial cells from brain – which can then be analyzed using advanced biochemical and physiological techniques. The long-term aim is to identify proteins that can be “tagged” using transgenic technologies to allow protein function to be studied in real-time in vivo, using sophisticated imaging techniques. Given the number of proteins that may be identified we envisage developing new methods of generating transgenic animals that provide an attractive alternative to current “state-of-the art” technology.
The importance of studying glial function is given by the fact that every major brain pathology shows reactive gliosis. In the time it takes to read this abstract, 5 people in the EU will have suffered a stroke – not to mention those who suffer other forms of neurotrauma. Thus, understanding glial function is not only critical to understanding normal brain function, but also for relieving the burden of severe neurological injury and disease
Summary
Brain consists of two basic cell types – neurons and glia. However, the study of glia in brain function has traditionally been neglected in favor of their more “illustrious” counter-parts – neurons that are classed as the computational units of the brain. Glia have usually been classed as “brain glue” - a supportive matrix on which neurons grow and function. However, recent evidence suggests that glia are more than passive “glue” and actually modulate neuronal function. This has lead to the proposal of a “tripartite synapse”, which recognizes pre- and postsynaptic neuronal elements and glia as a unit.
However, what is still lacking is rudimentary information on how these cells actually function in situ. Here we propose taking a “bottom-up” approach, by identifying the molecules (and interactions) that control glial function in situ. This is complicated by the fact that glia show profound changes when placed into culture. To circumvent this, we will use recently developed cell sorting techniques, to rapidly isolate genetically marked glial cells from brain – which can then be analyzed using advanced biochemical and physiological techniques. The long-term aim is to identify proteins that can be “tagged” using transgenic technologies to allow protein function to be studied in real-time in vivo, using sophisticated imaging techniques. Given the number of proteins that may be identified we envisage developing new methods of generating transgenic animals that provide an attractive alternative to current “state-of-the art” technology.
The importance of studying glial function is given by the fact that every major brain pathology shows reactive gliosis. In the time it takes to read this abstract, 5 people in the EU will have suffered a stroke – not to mention those who suffer other forms of neurotrauma. Thus, understanding glial function is not only critical to understanding normal brain function, but also for relieving the burden of severe neurological injury and disease
Max ERC Funding
1 490 168 €
Duration
Start date: 2012-01-01, End date: 2016-12-31
Project acronym BRAINSIGNALS
Project Optical dissection of circuits underlying fast cholinergic signalling during cognitive behaviour
Researcher (PI) Huibert Mansvelder
Host Institution (HI) STICHTING VU
Call Details Starting Grant (StG), LS5, ERC-2011-StG_20101109
Summary Our ability to think, to memorize and focus our thoughts depends on acetylcholine signaling in the brain. The loss of cholinergic signalling in for instance Alzheimer’s disease strongly compromises these cognitive abilities. The traditional view on the role of cholinergic input to the neocortex is that slowly changing levels of extracellular acetylcholine (ACh) mediate different arousal states. This view has been challenged by recent studies demonstrating that rapid phasic changes in ACh levels at the scale of seconds are correlated with focus of attention, suggesting that these signals may mediate defined cognitive operations. Despite a wealth of anatomical data on the organization of the cholinergic system, very little understanding exists on its functional organization. How the relatively sparse input of cholinergic transmission in the prefrontal cortex elicits such a profound and specific control over attention is unknown. The main objective of this proposal is to develop a causal understanding of how cellular mechanisms of fast acetylcholine signalling are orchestrated during cognitive behaviour.
In a series of studies, I have identified several synaptic and cellular mechanisms by which the cholinergic system can alter neuronal circuitry function, both in cortical and subcortical areas. I have used a combination of behavioral, physiological and genetic methods in which I manipulated cholinergic receptor functionality in prefrontal cortex in a subunit specific manner and found that ACh receptors in the prefrontal cortex control attention performance. Recent advances in optogenetic and electrochemical methods now allow to rapidly manipulate and measure acetylcholine levels in freely moving, behaving animals. Using these techniques, I aim to uncover which cholinergic neurons are involved in fast cholinergic signaling during cognition and uncover the underlying neuronal mechanisms that alter prefrontal cortical network function.
Summary
Our ability to think, to memorize and focus our thoughts depends on acetylcholine signaling in the brain. The loss of cholinergic signalling in for instance Alzheimer’s disease strongly compromises these cognitive abilities. The traditional view on the role of cholinergic input to the neocortex is that slowly changing levels of extracellular acetylcholine (ACh) mediate different arousal states. This view has been challenged by recent studies demonstrating that rapid phasic changes in ACh levels at the scale of seconds are correlated with focus of attention, suggesting that these signals may mediate defined cognitive operations. Despite a wealth of anatomical data on the organization of the cholinergic system, very little understanding exists on its functional organization. How the relatively sparse input of cholinergic transmission in the prefrontal cortex elicits such a profound and specific control over attention is unknown. The main objective of this proposal is to develop a causal understanding of how cellular mechanisms of fast acetylcholine signalling are orchestrated during cognitive behaviour.
In a series of studies, I have identified several synaptic and cellular mechanisms by which the cholinergic system can alter neuronal circuitry function, both in cortical and subcortical areas. I have used a combination of behavioral, physiological and genetic methods in which I manipulated cholinergic receptor functionality in prefrontal cortex in a subunit specific manner and found that ACh receptors in the prefrontal cortex control attention performance. Recent advances in optogenetic and electrochemical methods now allow to rapidly manipulate and measure acetylcholine levels in freely moving, behaving animals. Using these techniques, I aim to uncover which cholinergic neurons are involved in fast cholinergic signaling during cognition and uncover the underlying neuronal mechanisms that alter prefrontal cortical network function.
Max ERC Funding
1 499 242 €
Duration
Start date: 2011-11-01, End date: 2016-10-31
Project acronym CCC
Project Cracking the Cerebellar Code
Researcher (PI) Christiaan Innocentius De Zeeuw
Host Institution (HI) ERASMUS UNIVERSITAIR MEDISCH CENTRUM ROTTERDAM
Call Details Advanced Grant (AdG), LS5, ERC-2011-ADG_20110310
Summary Spike trains transfer information to and from neurons. Most studies so far assume that the average firing rate or “rate coding” is the predominant way of information coding. However, spikes occur at millisecond precision, and their actual timing or “temporal coding” can in principle strongly increase the information content of spike trains. The two coding mechanisms are not mutually exclusive. Neurons may switch between rate and temporal coding, or use a combination of both coding mechanisms at the same time, which would increase the information content of spike trains even further. Here, we propose to investigate the hypothesis that temporal coding plays, next to rate coding, important and specific roles in cerebellar processing during learning. The cerebellum is ideal to study this timely topic, because it has a clear anatomy with well-organized modules and matrices, a well-described physiology of different types of neurons with distinguishable spiking activity, and a central role in various forms of tractable motor learning. Moreover, uniquely in the brain, the main types of neurons in the cerebellar system can be genetically manipulated in a cell-specific fashion, which will allow us to investigate the behavioural importance of both coding mechanisms following cell-specific interference and/or during cell-specific visual imaging. Thus, for this proposal we will create conditional mouse mutants that will be subjected to learning paradigms in which we can disentangle the contributions of rate coding and temporal coding using electrophysiological and optogenetic recordings and stimulation. Together, our experiments should elucidate how neurons in the brain communicate during natural learning behaviour and how one may be able to intervene in this process to affect or improve procedural learning skills.
Summary
Spike trains transfer information to and from neurons. Most studies so far assume that the average firing rate or “rate coding” is the predominant way of information coding. However, spikes occur at millisecond precision, and their actual timing or “temporal coding” can in principle strongly increase the information content of spike trains. The two coding mechanisms are not mutually exclusive. Neurons may switch between rate and temporal coding, or use a combination of both coding mechanisms at the same time, which would increase the information content of spike trains even further. Here, we propose to investigate the hypothesis that temporal coding plays, next to rate coding, important and specific roles in cerebellar processing during learning. The cerebellum is ideal to study this timely topic, because it has a clear anatomy with well-organized modules and matrices, a well-described physiology of different types of neurons with distinguishable spiking activity, and a central role in various forms of tractable motor learning. Moreover, uniquely in the brain, the main types of neurons in the cerebellar system can be genetically manipulated in a cell-specific fashion, which will allow us to investigate the behavioural importance of both coding mechanisms following cell-specific interference and/or during cell-specific visual imaging. Thus, for this proposal we will create conditional mouse mutants that will be subjected to learning paradigms in which we can disentangle the contributions of rate coding and temporal coding using electrophysiological and optogenetic recordings and stimulation. Together, our experiments should elucidate how neurons in the brain communicate during natural learning behaviour and how one may be able to intervene in this process to affect or improve procedural learning skills.
Max ERC Funding
2 499 600 €
Duration
Start date: 2012-04-01, End date: 2017-03-31
Project acronym CEIDNFSTTAIS
Project Controlling excitability in developing neurons: from synapses to the axon initial segment
Researcher (PI) Juan Burrone
Host Institution (HI) KING'S COLLEGE LONDON
Call Details Starting Grant (StG), LS5, ERC-2011-StG_20101109
Summary A critical question in neuroscience is to understand how neurons wire up to form a functional network. During the wiring of the brain it is important to establish mechanisms that act as safeguards to control and stabilize neuronal excitability in the face of large, chronic changes in neuronal or network activity. This is especially true for developing systems that undergo rapid and large scale forms of plasticity, which could easily lead to large imbalances in activity. If left unchecked, they could lead the network to its extremes: a complete loss of signal or epileptic-like activity. For this reason neurons employ different strategies to maintain their excitability within reasonable bounds. This proposal will focus on two crucial sites for neuronal information processing and integration: the synapse and the axon initial segment (AIS). Both sites undergo important structural and functional rearrangements in response to chronic activity changes, thus controlling the input-output function of a neuron and allowing the network to function efficiently. This proposal will explore novel forms of plasticity that occur during development and which are key to establishing a functional network. They range from understanding the role of activity during synapse formation to how pre- and postsynaptic structure and function become matched during development. Finally, it tackles a novel form of plasticity that lies downstream of synaptic inputs and is responsible for setting the threshold of action potential firing: the axon initial segment. Here, chronic changes in network activity results in a physical relocation of the AIS along the axon, which in turn alters the excitability of the neuron. This proposal will focus on the central issue of how a neuron alters both its input (synapses) and output (AIS) during development to maintain its activity levels within a set range and allow a functional network to form.
Summary
A critical question in neuroscience is to understand how neurons wire up to form a functional network. During the wiring of the brain it is important to establish mechanisms that act as safeguards to control and stabilize neuronal excitability in the face of large, chronic changes in neuronal or network activity. This is especially true for developing systems that undergo rapid and large scale forms of plasticity, which could easily lead to large imbalances in activity. If left unchecked, they could lead the network to its extremes: a complete loss of signal or epileptic-like activity. For this reason neurons employ different strategies to maintain their excitability within reasonable bounds. This proposal will focus on two crucial sites for neuronal information processing and integration: the synapse and the axon initial segment (AIS). Both sites undergo important structural and functional rearrangements in response to chronic activity changes, thus controlling the input-output function of a neuron and allowing the network to function efficiently. This proposal will explore novel forms of plasticity that occur during development and which are key to establishing a functional network. They range from understanding the role of activity during synapse formation to how pre- and postsynaptic structure and function become matched during development. Finally, it tackles a novel form of plasticity that lies downstream of synaptic inputs and is responsible for setting the threshold of action potential firing: the axon initial segment. Here, chronic changes in network activity results in a physical relocation of the AIS along the axon, which in turn alters the excitability of the neuron. This proposal will focus on the central issue of how a neuron alters both its input (synapses) and output (AIS) during development to maintain its activity levels within a set range and allow a functional network to form.
Max ERC Funding
1 500 000 €
Duration
Start date: 2012-03-01, End date: 2017-02-28
Project acronym CHEMBIOSPHING
Project Chemical biology of sphingolipids: fundamental studies and clinical applications
Researcher (PI) Herman Steven Overkleeft
Host Institution (HI) UNIVERSITEIT LEIDEN
Call Details Advanced Grant (AdG), PE5, ERC-2011-ADG_20110209
Summary "Sphingolipids are major components of the human cell and are involved in human pathologies ranging from lysosomal storage disorders to type 2 diabetes. Here, we propose to establish an integrated research program for the study of sphingolipid metabolism, in health and disease. We will combine state-of-the-art synthetic organic chemistry, bioorganic chemistry, analytical chemistry, molecular biology and biochemistry techniques and concepts and apply these in an integrated chemical biology approach to study and manipulate sphingolipid metabolism in vivo and in vitro, using human cells and animal models. The program is subdivided in three individual research lines that are interconnected both in terms of technology development and in their biological context. 1) We will develop modified sphinganine derivatives and apply these to study sphingolipid homeostasis in cells derived from healthy and diseased (Gaucher, Fabry, Niemann-Pick A/B disease) individuals/animal models. This question will be addressed in a chemical metabolomics/lipidomics approach. 2) We will develop activity-based probes aimed at monitoring enzyme activity levels of glycosidases involved in (glyco)sphingolipid metabolism, in particular the enzymes that - when mutated and thereby reduced in activity- are responsible for the lysosomal storage disorders Gaucher disease and Fabry disease. 3) We will develop well-defined enzymes and chaperone proteins for directed correction of sphingolipid homeostasis in Gaucher, Fabry and Niemann-Pick A/B patients, via a newly designed semi-synthetic approach that combines sortase-mediated ligation with synthetic chemistry. Deliverables are a better understanding of the composition of the sphingolipid pool that are at the basis of lysosomal storage disorders, effective ways to in situ monitor the efficacy of therapies (enzyme inhibitors, chemical chaperones, recombinant enzymes) to treat these and improved semi-synthetic proteins for enzyme replacement therapy."
Summary
"Sphingolipids are major components of the human cell and are involved in human pathologies ranging from lysosomal storage disorders to type 2 diabetes. Here, we propose to establish an integrated research program for the study of sphingolipid metabolism, in health and disease. We will combine state-of-the-art synthetic organic chemistry, bioorganic chemistry, analytical chemistry, molecular biology and biochemistry techniques and concepts and apply these in an integrated chemical biology approach to study and manipulate sphingolipid metabolism in vivo and in vitro, using human cells and animal models. The program is subdivided in three individual research lines that are interconnected both in terms of technology development and in their biological context. 1) We will develop modified sphinganine derivatives and apply these to study sphingolipid homeostasis in cells derived from healthy and diseased (Gaucher, Fabry, Niemann-Pick A/B disease) individuals/animal models. This question will be addressed in a chemical metabolomics/lipidomics approach. 2) We will develop activity-based probes aimed at monitoring enzyme activity levels of glycosidases involved in (glyco)sphingolipid metabolism, in particular the enzymes that - when mutated and thereby reduced in activity- are responsible for the lysosomal storage disorders Gaucher disease and Fabry disease. 3) We will develop well-defined enzymes and chaperone proteins for directed correction of sphingolipid homeostasis in Gaucher, Fabry and Niemann-Pick A/B patients, via a newly designed semi-synthetic approach that combines sortase-mediated ligation with synthetic chemistry. Deliverables are a better understanding of the composition of the sphingolipid pool that are at the basis of lysosomal storage disorders, effective ways to in situ monitor the efficacy of therapies (enzyme inhibitors, chemical chaperones, recombinant enzymes) to treat these and improved semi-synthetic proteins for enzyme replacement therapy."
Max ERC Funding
2 999 600 €
Duration
Start date: 2012-06-01, End date: 2017-05-31
Project acronym CHEMCOMP
Project Building-up Chemical Complexity
into Multifunctional Molecule-based Hybrid Materials
Researcher (PI) Jose Ramon Galan Mascaros
Host Institution (HI) FUNDACIO PRIVADA INSTITUT CATALA D'INVESTIGACIO QUIMICA
Call Details Starting Grant (StG), PE5, ERC-2011-StG_20101014
Summary Molecular sciences offer unparalleled opportunities for the development of tailor-made materials. By chemical design, molecules with the desired features can be prepared and incorporated into hybrid systems to yield molecule-based materials with novel chemical and/or physical properties. The CHEMCOMP project aims to develop new hybrid materials targeting the study of new physical phenomena that have already been theoretically predicted or experimentally hinted. The main goals will be:
i) Molecules with memory: Memory effect at the molecular scale is of great interest because it represents the size limit in the miniaturization of information storage media. My goal will be to develop spin crossover molecules with bulk-like hysteretic behavior where the switching between the low spin ground state and the high spin metastable state can be controlled through external stimuli.
ii) Bistable organic conductors: Bistable molecules could also be embedded into hybrid organic conductors to induce structural phase transitions. This strategy will allow for the transport properties to be controlled through external stimuli in unprecedented switchable conducting media.
iii) Hybrid conducting magnets: Combination of magnetism and electrical conductivity has given rise to new phenomena in the past, such as spin glass behavior or giant magnetoresistance. We propose to incorporate Single Molecule Magnets (molecules with magnet-like behavior) into organic (super)conductors to understand and optimize the synergy between these two physical properties.
iv) Chiral magnets and conductors: New phenomena is expected to appear in optically active media. Experimental evidence for the so-called MagnetoChiral Dichroism has already been found. Electrical Magnetochiral Anisotropy has been predicted. I will develop systematic strategies for the preparation of hybrid chiral materials to understand and optimize the synergy between chirality and bulk physical properties.
Summary
Molecular sciences offer unparalleled opportunities for the development of tailor-made materials. By chemical design, molecules with the desired features can be prepared and incorporated into hybrid systems to yield molecule-based materials with novel chemical and/or physical properties. The CHEMCOMP project aims to develop new hybrid materials targeting the study of new physical phenomena that have already been theoretically predicted or experimentally hinted. The main goals will be:
i) Molecules with memory: Memory effect at the molecular scale is of great interest because it represents the size limit in the miniaturization of information storage media. My goal will be to develop spin crossover molecules with bulk-like hysteretic behavior where the switching between the low spin ground state and the high spin metastable state can be controlled through external stimuli.
ii) Bistable organic conductors: Bistable molecules could also be embedded into hybrid organic conductors to induce structural phase transitions. This strategy will allow for the transport properties to be controlled through external stimuli in unprecedented switchable conducting media.
iii) Hybrid conducting magnets: Combination of magnetism and electrical conductivity has given rise to new phenomena in the past, such as spin glass behavior or giant magnetoresistance. We propose to incorporate Single Molecule Magnets (molecules with magnet-like behavior) into organic (super)conductors to understand and optimize the synergy between these two physical properties.
iv) Chiral magnets and conductors: New phenomena is expected to appear in optically active media. Experimental evidence for the so-called MagnetoChiral Dichroism has already been found. Electrical Magnetochiral Anisotropy has been predicted. I will develop systematic strategies for the preparation of hybrid chiral materials to understand and optimize the synergy between chirality and bulk physical properties.
Max ERC Funding
1 940 396 €
Duration
Start date: 2012-01-01, End date: 2016-12-31
