Project acronym CHOLINOMIRS
Project CholinomiRs: MicroRNA Regulators of Cholinergic Signalling in the Neuro-Immune Interface
Researcher (PI) Hermona Soreq
Host Institution (HI) THE HEBREW UNIVERSITY OF JERUSALEM
Call Details Advanced Grant (AdG), LS5, ERC-2012-ADG_20120314
Summary "Communication between the nervous and the immune system is pivotal for maintaining homeostasis and ensuring rapid and efficient reaction to stress and infection insults. The emergence of microRNAs (miRs) as regulators of gene expression and of acetylcholine (ACh) signalling as regulator of anxiety and inflammation provides a model for studying this interaction. My hypothesis is that 1) a specific sub-group of miRs, designated ""CholinomiRs"", may silence multiple target genes in the neuro-immune interface; 2) these miRs compete with each other on the interaction with their targets, and 3) mutations interfering with miR binding lead to inherited susceptibility to anxiety and inflammation disorders by modifying these interactions. Our preliminary findings have shown that by targeting acetylcholinesterase (AChE), CholinomiR-132 can intensify acute stress, resolve intestinal inflammation and change post-ischemic stroke responses. Further, we have identified clustered single nucleotide polymorphisms (SNPs) interfering with AChE silencing by several miRs which associate with elevated trait anxiety, blood pressure and inflammation. To further study miR regulators of ACh signalling, I plan to: (1) Identify anxiety and inflammation-induced changes in CholinomiRs and their targets in challenged brain and immune cells. (2) Establish the roles of these targets for one selected CholinomiR by tissue-specific manipulations. (3) Study primate-specific CholinomiRs by continued human DNA screens to identify SNPs and in ""humanized"" mice with knocked-in human AChE and transgenic CholinomiR-608. (4) Test if therapeutic modulation of aberrant CholinomiR expression can restore homeostasis. This research will clarify how miRs interact with each other in health and disease, introduce the dimension of complexity of multi-target competition and miR interactions and make a conceptual change in miRs research while enhancing the ability to intervene with diseases involving impaired ACh signalling."
Summary
"Communication between the nervous and the immune system is pivotal for maintaining homeostasis and ensuring rapid and efficient reaction to stress and infection insults. The emergence of microRNAs (miRs) as regulators of gene expression and of acetylcholine (ACh) signalling as regulator of anxiety and inflammation provides a model for studying this interaction. My hypothesis is that 1) a specific sub-group of miRs, designated ""CholinomiRs"", may silence multiple target genes in the neuro-immune interface; 2) these miRs compete with each other on the interaction with their targets, and 3) mutations interfering with miR binding lead to inherited susceptibility to anxiety and inflammation disorders by modifying these interactions. Our preliminary findings have shown that by targeting acetylcholinesterase (AChE), CholinomiR-132 can intensify acute stress, resolve intestinal inflammation and change post-ischemic stroke responses. Further, we have identified clustered single nucleotide polymorphisms (SNPs) interfering with AChE silencing by several miRs which associate with elevated trait anxiety, blood pressure and inflammation. To further study miR regulators of ACh signalling, I plan to: (1) Identify anxiety and inflammation-induced changes in CholinomiRs and their targets in challenged brain and immune cells. (2) Establish the roles of these targets for one selected CholinomiR by tissue-specific manipulations. (3) Study primate-specific CholinomiRs by continued human DNA screens to identify SNPs and in ""humanized"" mice with knocked-in human AChE and transgenic CholinomiR-608. (4) Test if therapeutic modulation of aberrant CholinomiR expression can restore homeostasis. This research will clarify how miRs interact with each other in health and disease, introduce the dimension of complexity of multi-target competition and miR interactions and make a conceptual change in miRs research while enhancing the ability to intervene with diseases involving impaired ACh signalling."
Max ERC Funding
2 375 600 €
Duration
Start date: 2013-03-01, End date: 2018-02-28
Project acronym CIRCUIT
Project Neural circuits for space representation in the mammalian cortex
Researcher (PI) Edvard Ingjald Moser
Host Institution (HI) NORGES TEKNISK-NATURVITENSKAPELIGE UNIVERSITET NTNU
Call Details Advanced Grant (AdG), LS5, ERC-2008-AdG
Summary Neuroscience is one of the fastest-developing areas of science, but it is fair to say that we are still far from understanding how the brain produces subjective experience. For example, simple questions about the origin of thought, imagination, social interaction, or feelings lack even rudimentary answers. We have learnt much about the workings of individual cells and synapses, but psychological phenomena cannot be understood only at this level. These phenomena all emerge from interactions between large numbers of diverse cells in intermingled neural circuits. A major obstacle has been the absence of concepts and tools for investigating neural computation at the circuit level. The aim of this proposal is to combine new transgenic methods for cell type-specific intervention with large-scale multisite single-cell recording to determine how a basic cognitive function self-localization is generated in a functionally well-described mammalian neural circuit. We shall use our recent discovery of entorhinal grid cells as an access ramp. Grid cells fire only when the animal moves through certain locations. For each cell, these locations define a periodic triangular array spanning the whole environment. Grid cells co-exist with other entorhinal cell types encoding head direction, geometric borders, or conjunctions of features. This network is thought to form an essential part of the brain s coordinate system for metric navigation but the detailed wiring, the mechanism of grid formation, and the function of each morphological and functional cell type all remain to be determined. We shall address these open questions by measuring how dynamic spatial representation is affected by transgene-induced activation or inactivation of the individual components of the circuit. The endeavour will pioneer the functional analysis of neural circuits and may, perhaps for the first time, provide us with mechanistic insight into a non-sensory cognitive function in the mammalian cortex.
Summary
Neuroscience is one of the fastest-developing areas of science, but it is fair to say that we are still far from understanding how the brain produces subjective experience. For example, simple questions about the origin of thought, imagination, social interaction, or feelings lack even rudimentary answers. We have learnt much about the workings of individual cells and synapses, but psychological phenomena cannot be understood only at this level. These phenomena all emerge from interactions between large numbers of diverse cells in intermingled neural circuits. A major obstacle has been the absence of concepts and tools for investigating neural computation at the circuit level. The aim of this proposal is to combine new transgenic methods for cell type-specific intervention with large-scale multisite single-cell recording to determine how a basic cognitive function self-localization is generated in a functionally well-described mammalian neural circuit. We shall use our recent discovery of entorhinal grid cells as an access ramp. Grid cells fire only when the animal moves through certain locations. For each cell, these locations define a periodic triangular array spanning the whole environment. Grid cells co-exist with other entorhinal cell types encoding head direction, geometric borders, or conjunctions of features. This network is thought to form an essential part of the brain s coordinate system for metric navigation but the detailed wiring, the mechanism of grid formation, and the function of each morphological and functional cell type all remain to be determined. We shall address these open questions by measuring how dynamic spatial representation is affected by transgene-induced activation or inactivation of the individual components of the circuit. The endeavour will pioneer the functional analysis of neural circuits and may, perhaps for the first time, provide us with mechanistic insight into a non-sensory cognitive function in the mammalian cortex.
Max ERC Funding
2 499 112 €
Duration
Start date: 2009-01-01, End date: 2013-12-31
Project acronym CLUE-BGD
Project Closing the Loop between Understanding and Effective Treatment of the Basal Ganglia and their Disorders
Researcher (PI) Hagai Bergman
Host Institution (HI) THE HEBREW UNIVERSITY OF JERUSALEM
Call Details Advanced Grant (AdG), LS5, ERC-2012-ADG_20120314
Summary In this project, the basal ganglia are defined as actor-critic reinforcement learning networks that aim at an optimal tradeoff between the maximization of future cumulative rewards and the minimization of the cost (the reinforcement driven multi objective optimization RDMOO model).
This computational model will be tested by multiple neuron recordings in the major basal ganglia structures of monkeys engaged in a similar behavioral task. We will further validate the RMDOO computational model of the basal ganglia by extending our previous studies of neural activity in the MPTP primate model of Parkinson's disease to a primate model of central serotonin depletion and emotional dysregulation disorders. The findings in the primate model of emotional dysregulation will then be compared to electrophysiological recordings carried out in human patients with treatment-resistant major depression and obsessive compulsive disorder during deep brain stimulation (DBS) procedures. I aim to find neural signatures (e.g., synchronous gamma oscillations in the actor part of the basal ganglia as predicted by the RMDOO model) characterizing these emotional disorders and to use them as triggers for closed loop adaptive DBS. Our working hypothesis holds that, as for the MPTP model of Parkinson's disease, closed loop DBS will lead to greater amelioration of the emotional deficits in serotonin depleted monkeys.
This project incorporates extensive collaborations with a team of neurosurgeons, neurologists, psychiatrists, and computer science/ neural network researchers. If successful, the findings will provide a firm understanding of the computational physiology of the basal ganglia networks and their disorders. Importantly, they will pave the way to better treatment of human patients with severe mental disorders.
Summary
In this project, the basal ganglia are defined as actor-critic reinforcement learning networks that aim at an optimal tradeoff between the maximization of future cumulative rewards and the minimization of the cost (the reinforcement driven multi objective optimization RDMOO model).
This computational model will be tested by multiple neuron recordings in the major basal ganglia structures of monkeys engaged in a similar behavioral task. We will further validate the RMDOO computational model of the basal ganglia by extending our previous studies of neural activity in the MPTP primate model of Parkinson's disease to a primate model of central serotonin depletion and emotional dysregulation disorders. The findings in the primate model of emotional dysregulation will then be compared to electrophysiological recordings carried out in human patients with treatment-resistant major depression and obsessive compulsive disorder during deep brain stimulation (DBS) procedures. I aim to find neural signatures (e.g., synchronous gamma oscillations in the actor part of the basal ganglia as predicted by the RMDOO model) characterizing these emotional disorders and to use them as triggers for closed loop adaptive DBS. Our working hypothesis holds that, as for the MPTP model of Parkinson's disease, closed loop DBS will lead to greater amelioration of the emotional deficits in serotonin depleted monkeys.
This project incorporates extensive collaborations with a team of neurosurgeons, neurologists, psychiatrists, and computer science/ neural network researchers. If successful, the findings will provide a firm understanding of the computational physiology of the basal ganglia networks and their disorders. Importantly, they will pave the way to better treatment of human patients with severe mental disorders.
Max ERC Funding
2 476 922 €
Duration
Start date: 2013-12-01, End date: 2018-11-30
Project acronym ENSEMBLE
Project Neural mechanisms for memory retrieval
Researcher (PI) May-Britt Moser
Host Institution (HI) NORGES TEKNISK-NATURVITENSKAPELIGE UNIVERSITET NTNU
Call Details Advanced Grant (AdG), LS5, ERC-2010-AdG_20100317
Summary Memory is one of the most extraordinary phenomena in biology. The mammalian brain stores billions of bits of information but the most remarkable property of memory is perhaps not its capacity but the speed at which the correct information can be retrieved from a pool of thousands or millions of competing alternatives. Despite more than hundred years of systematic study of the phenomenon, scientists are still largely ignorant about the mechanisms that enable mammalian brains to outperform even the best search engines. One of the greatest challenges has been the dynamic nature of memory. Whereas memories can be retrieved over time periods as short as milliseconds, underlying coding principles are normally inferred from activity time-averaged across many minutes. In the present proposal, I shall introduce a new ¿teleportation procedure¿ developed in my lab to monitor the representation of past and present environments in large ensembles of rat hippocampal neurons at ethologically valid time scales. By monitoring the evolution of hippocampal ensemble representations at millisecond resolution during retrieval of a non-local experience, I shall ask
(i) what is the minimum temporal unit of a hippocampal representation,
(ii) how is one representational unit replaced by the next in a sequence,
(iii) what external signals control switches between alternative representations,
(iv) how are representations synchronized across anatomical space, and
(v) when do adult-like retrieval mechanisms appear during ontogenesis of the nervous system and to what extent can their early absence be linked to infantile amnesia.
The proposed research programme is expected to identify some of the key principles for dynamic representation and retrieval of episodic memory in the mammalian hippocampus.
Summary
Memory is one of the most extraordinary phenomena in biology. The mammalian brain stores billions of bits of information but the most remarkable property of memory is perhaps not its capacity but the speed at which the correct information can be retrieved from a pool of thousands or millions of competing alternatives. Despite more than hundred years of systematic study of the phenomenon, scientists are still largely ignorant about the mechanisms that enable mammalian brains to outperform even the best search engines. One of the greatest challenges has been the dynamic nature of memory. Whereas memories can be retrieved over time periods as short as milliseconds, underlying coding principles are normally inferred from activity time-averaged across many minutes. In the present proposal, I shall introduce a new ¿teleportation procedure¿ developed in my lab to monitor the representation of past and present environments in large ensembles of rat hippocampal neurons at ethologically valid time scales. By monitoring the evolution of hippocampal ensemble representations at millisecond resolution during retrieval of a non-local experience, I shall ask
(i) what is the minimum temporal unit of a hippocampal representation,
(ii) how is one representational unit replaced by the next in a sequence,
(iii) what external signals control switches between alternative representations,
(iv) how are representations synchronized across anatomical space, and
(v) when do adult-like retrieval mechanisms appear during ontogenesis of the nervous system and to what extent can their early absence be linked to infantile amnesia.
The proposed research programme is expected to identify some of the key principles for dynamic representation and retrieval of episodic memory in the mammalian hippocampus.
Max ERC Funding
2 499 074 €
Duration
Start date: 2011-11-01, End date: 2017-10-31
Project acronym GRIDCODE
Project Cortical maps for space
Researcher (PI) Edvard Ingjald Moser
Host Institution (HI) NORGES TEKNISK-NATURVITENSKAPELIGE UNIVERSITET NTNU
Call Details Advanced Grant (AdG), LS5, ERC-2013-ADG
Summary The ultimate goal of neuroscience is to understand the neural basis of subjective experience and behaviour. With our discovery of grid cells as the brain´s metric for space in 2005, spatial navigation became one of the first non-sensory ‘cognitive’ functions of the brain to be accessible for mechanistic analysis. Grid cells are cells with spatially localized firing fields that tile environments with a periodic hexagonal firing pattern in a manner that enables accurate self-localization. Because this activity matrix is generated in the brain, in elaborate neural circuits far away from specific sensory inputs, grid cells provide us with unprecedented access to algorithms of neural coding in the higher cortices. The present proposal will take advantage of this emerging opportunity. The overall objective is to decipher how function is coded, divided and integrated among components of the grid-cell circuit of the medial entorhinal cortex and associated regions. Using a combination of transgenic interventions, intracellular recording and multisite multichannel tetrode recording, we shall establish the mechanisms by which grid cells organize into functionally independent modules, as well as the factors specifying quantitative relationships between grid modules. We shall determine how grid modules are formed during development, test the hypothesis that grid patterns are derived from the local recurrent inhibitory network in layer II, and establish how spatial signals in the entorhinal cortex are transformed to place-cell signals in the hippocampus. Collectively, these studies will pioneer the understanding of functional organization and neural-circuit coding in a non-sensory non-motor mammalian cortex.
Summary
The ultimate goal of neuroscience is to understand the neural basis of subjective experience and behaviour. With our discovery of grid cells as the brain´s metric for space in 2005, spatial navigation became one of the first non-sensory ‘cognitive’ functions of the brain to be accessible for mechanistic analysis. Grid cells are cells with spatially localized firing fields that tile environments with a periodic hexagonal firing pattern in a manner that enables accurate self-localization. Because this activity matrix is generated in the brain, in elaborate neural circuits far away from specific sensory inputs, grid cells provide us with unprecedented access to algorithms of neural coding in the higher cortices. The present proposal will take advantage of this emerging opportunity. The overall objective is to decipher how function is coded, divided and integrated among components of the grid-cell circuit of the medial entorhinal cortex and associated regions. Using a combination of transgenic interventions, intracellular recording and multisite multichannel tetrode recording, we shall establish the mechanisms by which grid cells organize into functionally independent modules, as well as the factors specifying quantitative relationships between grid modules. We shall determine how grid modules are formed during development, test the hypothesis that grid patterns are derived from the local recurrent inhibitory network in layer II, and establish how spatial signals in the entorhinal cortex are transformed to place-cell signals in the hippocampus. Collectively, these studies will pioneer the understanding of functional organization and neural-circuit coding in a non-sensory non-motor mammalian cortex.
Max ERC Funding
2 500 000 €
Duration
Start date: 2014-06-01, End date: 2019-05-31
Project acronym HOWPER
Project An open or closed process: Determining the global scheme of perception
Researcher (PI) Ehud AHISSAR
Host Institution (HI) WEIZMANN INSTITUTE OF SCIENCE
Call Details Advanced Grant (AdG), LS5, ERC-2017-ADG
Summary Despite decades of intensive research, there is no agreement about the general scheme of perception: Is the external object a trigger for a brain-internal process (open-loop perception, OLP) or is the object included in brain dynamics during the entire perceptual process (closed-loop perception, CLP)? HOWPER is designed to provide a definite answer to this question in the cases of human touch and vision. What enables this critical test is our development of an explicit CLP hypothesis, which will be contrasted, via specific testable predictions, with the OLP scheme. In the event that CLP is validated, HOWPER will introduce a radical paradigm shift in the study of perception, since almost all current experiments are guided, implicitly or explicitly, by the OLP scheme. If OLP is confirmed, HOWPER will provide the first formal affirmation for its superiority over CLP.
Our approach in this novel paradigm is based on a triangle of interactive efforts comprising theory, analytical experiments, and synthetic experiments. The theoretical effort (WP1) will be based on the core theoretical framework already developed in our lab. The analytical experiments (WP2) will involve human perceivers. The synthetic experiments (WP3) will be performed on synthesized artificial perceivers. The fourth WP will exploit our novel rat-machine hybrid model for testing the neural applicability of the insights gained in the other WPs, whereas the fifth WP will translate our insights into novel visual-to-tactile sensory substitution algorithms.
HOWPER is expected to either revolutionize or significantly advance the field of human perception, to greatly improve visual to tactile sensory substitution approaches and to contribute novel biomimetic algorithms for autonomous robotic agents.
Summary
Despite decades of intensive research, there is no agreement about the general scheme of perception: Is the external object a trigger for a brain-internal process (open-loop perception, OLP) or is the object included in brain dynamics during the entire perceptual process (closed-loop perception, CLP)? HOWPER is designed to provide a definite answer to this question in the cases of human touch and vision. What enables this critical test is our development of an explicit CLP hypothesis, which will be contrasted, via specific testable predictions, with the OLP scheme. In the event that CLP is validated, HOWPER will introduce a radical paradigm shift in the study of perception, since almost all current experiments are guided, implicitly or explicitly, by the OLP scheme. If OLP is confirmed, HOWPER will provide the first formal affirmation for its superiority over CLP.
Our approach in this novel paradigm is based on a triangle of interactive efforts comprising theory, analytical experiments, and synthetic experiments. The theoretical effort (WP1) will be based on the core theoretical framework already developed in our lab. The analytical experiments (WP2) will involve human perceivers. The synthetic experiments (WP3) will be performed on synthesized artificial perceivers. The fourth WP will exploit our novel rat-machine hybrid model for testing the neural applicability of the insights gained in the other WPs, whereas the fifth WP will translate our insights into novel visual-to-tactile sensory substitution algorithms.
HOWPER is expected to either revolutionize or significantly advance the field of human perception, to greatly improve visual to tactile sensory substitution approaches and to contribute novel biomimetic algorithms for autonomous robotic agents.
Max ERC Funding
2 493 441 €
Duration
Start date: 2018-06-01, End date: 2023-05-31
Project acronym IMMUNE/MEMORY AGING
Project Can immune system rejuvenation restore age-related memory loss?
Researcher (PI) Michal Eisenbach-Schwartz
Host Institution (HI) WEIZMANN INSTITUTE OF SCIENCE
Call Details Advanced Grant (AdG), LS5, ERC-2008-AdG
Summary With increased life expectancy, there has been a critical growth in the portion of the population that suffers from age-related cognitive decline and dementia. Attempts are therefore being made to find ways to slow brain-aging processes; successful therapies would have a significant impact on the quality of life of individuals, and decrease healthcare expenditures. Aging of the immune system has never been suggested as a factor in memory loss. My group formulated the concept of protective autoimmunity , suggesting a linkage between immunity and self-maintenance in the context of the brain in health and disease. Recently, we showed that T lymphocytes recognizing brain-self antigens have a pivotal role in maintaining hippocampal plasticity, as manifested by reduced neurogenesis and impaired cognitive abilities in T-cell deficient mice. Taken together, our novel observations that T cell immunity contributes to hippocampal plasticity, and the fact that T cell immunity decreases with progressive aging create the basis for the present proposal. We will focus on the following questions: (a) Which aspects of cognition are supported by the immune system- learning, memory or both; (b) whether aging of the immune system is sufficient to induce aging of the brain; (c) whether activation of the immune system is sufficient to reverse age-related cognitive decline; (d) the mechanism underlying the effect of peripheral immunity on brain cognition; and (e) potential therapeutic implications of our findings. Our preliminary results demonstrate that the immune system contributes to spatial memory, and that imposing an immune deficiency is sufficient to cause a reversible memory deficit. These findings give strong reason for optimism that memory loss in the elderly is preventable and perhaps reversible by immune-based therapies; we hope that, in the not too distant future, our studies will enable development of a vaccine to prevent CNS aging and cognitive loss in elderly.
Summary
With increased life expectancy, there has been a critical growth in the portion of the population that suffers from age-related cognitive decline and dementia. Attempts are therefore being made to find ways to slow brain-aging processes; successful therapies would have a significant impact on the quality of life of individuals, and decrease healthcare expenditures. Aging of the immune system has never been suggested as a factor in memory loss. My group formulated the concept of protective autoimmunity , suggesting a linkage between immunity and self-maintenance in the context of the brain in health and disease. Recently, we showed that T lymphocytes recognizing brain-self antigens have a pivotal role in maintaining hippocampal plasticity, as manifested by reduced neurogenesis and impaired cognitive abilities in T-cell deficient mice. Taken together, our novel observations that T cell immunity contributes to hippocampal plasticity, and the fact that T cell immunity decreases with progressive aging create the basis for the present proposal. We will focus on the following questions: (a) Which aspects of cognition are supported by the immune system- learning, memory or both; (b) whether aging of the immune system is sufficient to induce aging of the brain; (c) whether activation of the immune system is sufficient to reverse age-related cognitive decline; (d) the mechanism underlying the effect of peripheral immunity on brain cognition; and (e) potential therapeutic implications of our findings. Our preliminary results demonstrate that the immune system contributes to spatial memory, and that imposing an immune deficiency is sufficient to cause a reversible memory deficit. These findings give strong reason for optimism that memory loss in the elderly is preventable and perhaps reversible by immune-based therapies; we hope that, in the not too distant future, our studies will enable development of a vaccine to prevent CNS aging and cognitive loss in elderly.
Max ERC Funding
1 650 000 €
Duration
Start date: 2009-01-01, End date: 2012-12-31
Project acronym ImmuneCheckpointsAD
Project Immune checkpoint blockade for fighting Alzheimer’s disease
Researcher (PI) Michal EISENBACH-SCHWARTZ
Host Institution (HI) WEIZMANN INSTITUTE OF SCIENCE
Call Details Advanced Grant (AdG), LS5, ERC-2016-ADG
Summary Understanding, and ultimately treating Alzheimer’s disease (AD) is a major need in Western countries. Currently, there is no available treatment to modify the disease. Several pioneering discoveries made by my team, attributing a key role to systemic immunity in brain maintenance and repair, and identifying unique interface between the brain’s borders through which the immune system assists the brain, led us to our recent discovery that transient reduction of systemic immune suppression could modify disease pathology, and reverse cognitive loss in mouse models of AD (Nature Communications, 2015; Nature Medicine, 2016; Science, 2014). This discovery emphasizes that AD is not restricted to the brain, but is associated with systemic immune dysfunction. Thus, the goal of addressing numerous risk factors that go awry in the AD brain, many of which are -as yet- unknown, could be accomplished by immunotherapy, using immune checkpoint blockade directed at the Programmed-death (PD)-1 pathway, to empower the immune system. In this proposal, we will adopt our new experimental paradigm to discover mechanisms through which the immune system supports the brain, and to identify key/novel molecular and cellular processes at various stages of the disease that are responsible for cognitive decline long before neurons are lost, and whose reversal or modification is needed to mitigate AD pathology, and prevent cognitive loss. Achieving our goals requires the multidisciplinary approaches and expertise at our disposal, including state-of-the art immunological, cellular, molecular, and genomic tools. The results will pave the way for developing a novel next-generation immunotherapy, by targeting additional selective immune checkpoint pathways, or identifying a specific immune-based therapeutic target, for prevention and treatment of AD. We expect that our results will help attain the ultimate goal of converting an escalating untreatable disease into a chronic treatable one.
Summary
Understanding, and ultimately treating Alzheimer’s disease (AD) is a major need in Western countries. Currently, there is no available treatment to modify the disease. Several pioneering discoveries made by my team, attributing a key role to systemic immunity in brain maintenance and repair, and identifying unique interface between the brain’s borders through which the immune system assists the brain, led us to our recent discovery that transient reduction of systemic immune suppression could modify disease pathology, and reverse cognitive loss in mouse models of AD (Nature Communications, 2015; Nature Medicine, 2016; Science, 2014). This discovery emphasizes that AD is not restricted to the brain, but is associated with systemic immune dysfunction. Thus, the goal of addressing numerous risk factors that go awry in the AD brain, many of which are -as yet- unknown, could be accomplished by immunotherapy, using immune checkpoint blockade directed at the Programmed-death (PD)-1 pathway, to empower the immune system. In this proposal, we will adopt our new experimental paradigm to discover mechanisms through which the immune system supports the brain, and to identify key/novel molecular and cellular processes at various stages of the disease that are responsible for cognitive decline long before neurons are lost, and whose reversal or modification is needed to mitigate AD pathology, and prevent cognitive loss. Achieving our goals requires the multidisciplinary approaches and expertise at our disposal, including state-of-the art immunological, cellular, molecular, and genomic tools. The results will pave the way for developing a novel next-generation immunotherapy, by targeting additional selective immune checkpoint pathways, or identifying a specific immune-based therapeutic target, for prevention and treatment of AD. We expect that our results will help attain the ultimate goal of converting an escalating untreatable disease into a chronic treatable one.
Max ERC Funding
2 287 500 €
Duration
Start date: 2017-06-01, End date: 2022-05-31
Project acronym LocomotorIntegration
Project Functional connectome of brainstem circuits that control locomotion
Researcher (PI) Ole Kiehn
Host Institution (HI) KAROLINSKA INSTITUTET
Call Details Advanced Grant (AdG), LS5, ERC-2015-AdG
Summary Locomotion is a complex motor act that is used in many daily life activities and is the output measures of a plethora of brain behaviors. The planning and initiation of locomotion take place in the brain and brainstem, while the execution is accomplished by activity in neuronal networks in the spinal cord itself. Recent experiments have provided significant insight to the organization of the executive spinal locomotor networks. However, little is known about the brainstem control of these networks. Here, I propose to provide a unified understanding of the functional connectome of the key brainstem networks that control locomotion in mammals needed to select appropriate locomotor outputs. To obtain these goals we will develop a suite of transgenic mouse models with optogenetic or chemogenetic switches in defined populations of brainstem neurons combined with the possibility to use state-of-the-art cell-specific electrophysiological and anatomical connectivity studies. We will reveal the functional organization of ‘go’ and ‘stop’ command systems in the brainstem that are directly upstream from the spinal locomotor networks and the mechanisms for how spinal networks are selected. We will further functionally deconstruct the next network layer in midbrain structures that control the ‘go’ and ‘stop’ command systems. Our research takes a specific approach to provide mechanistic insight to the integrated movement function by building the motor matrix in a functional chain from the locomotor–related spinal cord neurons that have been identified to midbrain neurons. A segment of our research will link these networks to locomotor impairments after basal ganglia dysfunction. The work has the potential to make a breakthrough in our understanding of how complex movements are generated by the brain and has translational implications for patients with movement disorders. It will push boundaries in the universal effort that aims to comprehend how brain networks create behaviors.
Summary
Locomotion is a complex motor act that is used in many daily life activities and is the output measures of a plethora of brain behaviors. The planning and initiation of locomotion take place in the brain and brainstem, while the execution is accomplished by activity in neuronal networks in the spinal cord itself. Recent experiments have provided significant insight to the organization of the executive spinal locomotor networks. However, little is known about the brainstem control of these networks. Here, I propose to provide a unified understanding of the functional connectome of the key brainstem networks that control locomotion in mammals needed to select appropriate locomotor outputs. To obtain these goals we will develop a suite of transgenic mouse models with optogenetic or chemogenetic switches in defined populations of brainstem neurons combined with the possibility to use state-of-the-art cell-specific electrophysiological and anatomical connectivity studies. We will reveal the functional organization of ‘go’ and ‘stop’ command systems in the brainstem that are directly upstream from the spinal locomotor networks and the mechanisms for how spinal networks are selected. We will further functionally deconstruct the next network layer in midbrain structures that control the ‘go’ and ‘stop’ command systems. Our research takes a specific approach to provide mechanistic insight to the integrated movement function by building the motor matrix in a functional chain from the locomotor–related spinal cord neurons that have been identified to midbrain neurons. A segment of our research will link these networks to locomotor impairments after basal ganglia dysfunction. The work has the potential to make a breakthrough in our understanding of how complex movements are generated by the brain and has translational implications for patients with movement disorders. It will push boundaries in the universal effort that aims to comprehend how brain networks create behaviors.
Max ERC Funding
2 500 000 €
Duration
Start date: 2016-08-01, End date: 2021-07-31
Project acronym MEMFOLD
Project New approaches to the study of membrane-protein folding in vivo and in silico
Researcher (PI) Gunnar Von Heijne
Host Institution (HI) STOCKHOLMS UNIVERSITET
Call Details Advanced Grant (AdG), LS1, ERC-2008-AdG
Summary Membrane proteins are central players in many if not most cellular processes: cell-cell interaction, signal transduction, nerve conduction, small molecule transport, macromolecular trafficking, etc. A growing number of high-resolution membrane protein structures provide important insights not only into function but also into the general structural constraints imposed by the lipid bilayer. In contrast, almost no information is available concerning how membrane proteins fold in vivo. Mainly, this is because of a lack of suitable assays to follow the folding process. The main objective of this proposal is to develop a broad range of new methods, largely based on chemical-biology approaches combined with protein engineering, to study membrane protein insertion, folding, and assembly in vivo or under in vivo-like conditions. We will aim for quantitative studies whenever possible. Questions we will address include: What are the in vivo kinetics of transmembrane-helix integration? What are the energetics of membrane insertion of non-natural amino acid side chains with physico-chemical properties distinct from those of the 20 natural amino acids? What kinds of residue-residue interactions drive interactions between transmembrane helices and between membrane protein subunits? How should we best design and verify novel interacting transmembrane helices? Given the importance of membrane proteins in both basic and applied biological research, we expect that a deeper understanding of the molecular interactions that drive their folding and stabilize their structure in vivo will have a major impact across many areas of molecular life science.
Summary
Membrane proteins are central players in many if not most cellular processes: cell-cell interaction, signal transduction, nerve conduction, small molecule transport, macromolecular trafficking, etc. A growing number of high-resolution membrane protein structures provide important insights not only into function but also into the general structural constraints imposed by the lipid bilayer. In contrast, almost no information is available concerning how membrane proteins fold in vivo. Mainly, this is because of a lack of suitable assays to follow the folding process. The main objective of this proposal is to develop a broad range of new methods, largely based on chemical-biology approaches combined with protein engineering, to study membrane protein insertion, folding, and assembly in vivo or under in vivo-like conditions. We will aim for quantitative studies whenever possible. Questions we will address include: What are the in vivo kinetics of transmembrane-helix integration? What are the energetics of membrane insertion of non-natural amino acid side chains with physico-chemical properties distinct from those of the 20 natural amino acids? What kinds of residue-residue interactions drive interactions between transmembrane helices and between membrane protein subunits? How should we best design and verify novel interacting transmembrane helices? Given the importance of membrane proteins in both basic and applied biological research, we expect that a deeper understanding of the molecular interactions that drive their folding and stabilize their structure in vivo will have a major impact across many areas of molecular life science.
Max ERC Funding
1 999 999 €
Duration
Start date: 2009-04-01, End date: 2015-03-31
Project acronym MEMORYSTICK
Project Plasticity and formation of lasting memories in health and disease. Genetic modeling of key regulators in adult and aging mammals and in neurodegenerative disease
Researcher (PI) Lars Olson
Host Institution (HI) KAROLINSKA INSTITUTET
Call Details Advanced Grant (AdG), LS5, ERC-2012-ADG_20120314
Summary When an adult mammal acquires new skills and new knowledge, the degree to which transition will occur from temporary to permanent memories of such events is governed by factors such as emotional weight and importance of the experiences for survival. To execute the necessary structural synaptic reorganisations needed to permanently embed novel memories in the brain, a complex and precisely orchestrated molecular machinery is activated. We have found that rapid down-regulation of Nogo receptor 1 (NgR1) is one key element needed to allow permanent memories to form. Thus, our MemoFlex mice, with inducible overexpression of NgR1 in forebrain neurons, are severely impaired with respect to the ability to form lasting memories. When transgenic NgR1 is turned off in these mice, the ability to form lasting memories is restored. Several other genes are also involved in the process of consolidation of memories, including prompt activity-driven upregulation of BDNF. Very recently, we have discovered that Lotus, a newly identified negative regulator of NgR1, is also upregulated by activity, thus providing additional efficacy to the process of causing nerve endings to become temporarily insensitive to Nogo when plasticity is needed. Based on our experience with neurotrophic factors and the Nogo signaling system, and using additional transgenic mouse models, including the mtDNA Mutator mouse with premature, yet typical aging, NgR1 KO mice and mice modeling neurodegenerative diseases (such as APPSwePSEN mice and our MitoPark mice to model aspects of Alzheimer’s and Parkinson’s disease, respectively) we will examine the formation of lasting normal and pathological (addiction, posttraumatic stress disorder) memories in adult and aging individuals with and without additional neurodegenerative genotypes known to include cognitive impariment. This research will further the understanding of mechanisms behind memory dysfunction and help the design of memory-improving stratetegies.
Summary
When an adult mammal acquires new skills and new knowledge, the degree to which transition will occur from temporary to permanent memories of such events is governed by factors such as emotional weight and importance of the experiences for survival. To execute the necessary structural synaptic reorganisations needed to permanently embed novel memories in the brain, a complex and precisely orchestrated molecular machinery is activated. We have found that rapid down-regulation of Nogo receptor 1 (NgR1) is one key element needed to allow permanent memories to form. Thus, our MemoFlex mice, with inducible overexpression of NgR1 in forebrain neurons, are severely impaired with respect to the ability to form lasting memories. When transgenic NgR1 is turned off in these mice, the ability to form lasting memories is restored. Several other genes are also involved in the process of consolidation of memories, including prompt activity-driven upregulation of BDNF. Very recently, we have discovered that Lotus, a newly identified negative regulator of NgR1, is also upregulated by activity, thus providing additional efficacy to the process of causing nerve endings to become temporarily insensitive to Nogo when plasticity is needed. Based on our experience with neurotrophic factors and the Nogo signaling system, and using additional transgenic mouse models, including the mtDNA Mutator mouse with premature, yet typical aging, NgR1 KO mice and mice modeling neurodegenerative diseases (such as APPSwePSEN mice and our MitoPark mice to model aspects of Alzheimer’s and Parkinson’s disease, respectively) we will examine the formation of lasting normal and pathological (addiction, posttraumatic stress disorder) memories in adult and aging individuals with and without additional neurodegenerative genotypes known to include cognitive impariment. This research will further the understanding of mechanisms behind memory dysfunction and help the design of memory-improving stratetegies.
Max ERC Funding
2 330 974 €
Duration
Start date: 2013-03-01, End date: 2018-02-28
Project acronym METSTEM
Project DNA methylation in stem cells
Researcher (PI) Howard Cedar
Host Institution (HI) THE HEBREW UNIVERSITY OF JERUSALEM
Call Details Advanced Grant (AdG), LS1, ERC-2010-AdG_20100317
Summary Embryonic and adult stem cells constitute an important component of biology by providing a pool of pluri- and multi-potent cells that supply a variety of different cell lineages. Little is known about the mechanisms involved in establishing and maintaining cell ¿stemness,¿ but it is most likely controlled by epigenetic signals such as DNA methylation. This proposal aims to understand these mechanisms and decipher the molecular logic used to program this plasticity.
We have developed a new strategy for studying the ¿DNA methylation potential¿ of any cell type throughout normal development. This utilizes a unique set of transgenic vectors programmed to detect both de novo methylation as well as the ability to protect CpG islands, and will, for the first time, allow one to evaluate the role of demethylation in normal stem cells and during reprogramming. This will be done using a new technique called ¿reverse epigenetics¿.
Preliminary studies indicate that embryonic stem cells differentiated in vitro undergo extensive aberrant methylation that does not reflect the normal pattern of methylation found in vivo. This artifact may be responsible for our inability to attain efficient differentiation in culture and may generate cells that are unhealthy and prone to cancer. We will characterize the causes of this phenomenon and decipher its underlying mechanism. This research should lead to the development of improved methods for tissue generation in vitro.
One of the most basic properties of adult stem cells is their ability to undergo asymmetric cell division that is often associated with unequal segregation of DNA. This mechanism is one of the most elemental, yet mysterious, aspects of stem cell biology. We have developed a completely new molecular model for this process that is based on the idea that non-symmetric DNA methylation serves as a strand-specific marker, and it is very likely that this will enable us to finally decipher this basic aspect of stem cells.
Summary
Embryonic and adult stem cells constitute an important component of biology by providing a pool of pluri- and multi-potent cells that supply a variety of different cell lineages. Little is known about the mechanisms involved in establishing and maintaining cell ¿stemness,¿ but it is most likely controlled by epigenetic signals such as DNA methylation. This proposal aims to understand these mechanisms and decipher the molecular logic used to program this plasticity.
We have developed a new strategy for studying the ¿DNA methylation potential¿ of any cell type throughout normal development. This utilizes a unique set of transgenic vectors programmed to detect both de novo methylation as well as the ability to protect CpG islands, and will, for the first time, allow one to evaluate the role of demethylation in normal stem cells and during reprogramming. This will be done using a new technique called ¿reverse epigenetics¿.
Preliminary studies indicate that embryonic stem cells differentiated in vitro undergo extensive aberrant methylation that does not reflect the normal pattern of methylation found in vivo. This artifact may be responsible for our inability to attain efficient differentiation in culture and may generate cells that are unhealthy and prone to cancer. We will characterize the causes of this phenomenon and decipher its underlying mechanism. This research should lead to the development of improved methods for tissue generation in vitro.
One of the most basic properties of adult stem cells is their ability to undergo asymmetric cell division that is often associated with unequal segregation of DNA. This mechanism is one of the most elemental, yet mysterious, aspects of stem cell biology. We have developed a completely new molecular model for this process that is based on the idea that non-symmetric DNA methylation serves as a strand-specific marker, and it is very likely that this will enable us to finally decipher this basic aspect of stem cells.
Max ERC Funding
1 941 930 €
Duration
Start date: 2011-04-01, End date: 2016-03-31
Project acronym NEURAL RENEWAL
Project Neurogenesis in the adult human brain
Researcher (PI) Jonas Kristoffer Frisén
Host Institution (HI) KAROLINSKA INSTITUTET
Call Details Advanced Grant (AdG), LS5, ERC-2010-AdG_20100317
Summary One of the characteristics of the central nervous system is its plasticity, with for example a remarkable capacity to store new information. It was for long time thought that there was very little plasticity in terms of exchanging cells and that we essentially were limited to the neurons we were born with. It is now well established that new neurons are added to certain regions of the adult brain in most mammals, although it has been very difficult to study in humans.
The proposed project aims to unveil the cell lineage producing new neurons in the adult human brain and to assess the extent of neurogenesis and how it may change in for example aging and neurological and psychiatric diseases. We propose to take advantage of the rapid development of sequencing technology to assess the origin and lineage of new cells in the human brain by phylogenetic fate mapping. This will be combined with the analysis of the turnover of neurons in the adult human brain by a retrospective birth dating methodology which we recently have developed based on the integration of nuclear bomb test derived 14C. This is a cross-disciplinary project that bridges from basic cell and molecular biology, latest generation DNA sequencing technology via clinical medicine and mathematical modeling to nuclear physics.
A possible role for alterations in adult neurogenesis in the etiology of both depression and schizophrenia has recently received much interest. However, the link between neurogenesis and psychiatric diseases is based on a series of indirect indications, mainly in experimental animals. It is pivotal to gain direct information on the relationship between neurogenesis and psychiatric and neurological diseases in humans.
Summary
One of the characteristics of the central nervous system is its plasticity, with for example a remarkable capacity to store new information. It was for long time thought that there was very little plasticity in terms of exchanging cells and that we essentially were limited to the neurons we were born with. It is now well established that new neurons are added to certain regions of the adult brain in most mammals, although it has been very difficult to study in humans.
The proposed project aims to unveil the cell lineage producing new neurons in the adult human brain and to assess the extent of neurogenesis and how it may change in for example aging and neurological and psychiatric diseases. We propose to take advantage of the rapid development of sequencing technology to assess the origin and lineage of new cells in the human brain by phylogenetic fate mapping. This will be combined with the analysis of the turnover of neurons in the adult human brain by a retrospective birth dating methodology which we recently have developed based on the integration of nuclear bomb test derived 14C. This is a cross-disciplinary project that bridges from basic cell and molecular biology, latest generation DNA sequencing technology via clinical medicine and mathematical modeling to nuclear physics.
A possible role for alterations in adult neurogenesis in the etiology of both depression and schizophrenia has recently received much interest. However, the link between neurogenesis and psychiatric diseases is based on a series of indirect indications, mainly in experimental animals. It is pivotal to gain direct information on the relationship between neurogenesis and psychiatric and neurological diseases in humans.
Max ERC Funding
2 491 235 €
Duration
Start date: 2011-06-01, End date: 2016-05-31
Project acronym NEUROGROWTH
Project Axonuclear Communication in Neuronal Growth Control
Researcher (PI) Michael Fainzilber
Host Institution (HI) WEIZMANN INSTITUTE OF SCIENCE
Call Details Advanced Grant (AdG), LS5, ERC-2013-ADG
Summary Neurons exhibit the most marked size differences and diversity in intrinsic growth rates of any class of cells. How then can a neuron coordinate between biosynthesis rates in the soma and the growth needs of different lengths of axons? The central hypothesis of this proposal is that neurons sense the lengths of the axonal microtubule cytoskeleton on an ongoing basis by bidirectional motor-dependent axon-nucleus communication, and that the oscillating retrograde signal generated by this mechanism provides input for the coordinated regulation of neuronal biosynthesis and axonal growth. We will test this hypothesis in a multidisciplinary work program that will characterize and quantify the link between biosynthesis levels and axon outgrowth rates and identify and validate the roles and functions of key molecules underlying this mechanism. This research program will elucidate how neuronal biosynthesis and axon growth are co-regulated. New mechanistic insights on this fundamental aspect of neuronal cell biology will have far-reaching implications. From the basic science perspective, this work will establish a new modality for encoding spatial information in biological signals, providing a one-dimensional solution to the three-dimensional problem of sensing cell size. Moreover, the proposed mechanism can explain intrinsic limits on regenerative neuronal growth and raises the intriguing possibility of opening new avenues to bypass such limits towards acceleration of axonal growth for effective neural repair.
Summary
Neurons exhibit the most marked size differences and diversity in intrinsic growth rates of any class of cells. How then can a neuron coordinate between biosynthesis rates in the soma and the growth needs of different lengths of axons? The central hypothesis of this proposal is that neurons sense the lengths of the axonal microtubule cytoskeleton on an ongoing basis by bidirectional motor-dependent axon-nucleus communication, and that the oscillating retrograde signal generated by this mechanism provides input for the coordinated regulation of neuronal biosynthesis and axonal growth. We will test this hypothesis in a multidisciplinary work program that will characterize and quantify the link between biosynthesis levels and axon outgrowth rates and identify and validate the roles and functions of key molecules underlying this mechanism. This research program will elucidate how neuronal biosynthesis and axon growth are co-regulated. New mechanistic insights on this fundamental aspect of neuronal cell biology will have far-reaching implications. From the basic science perspective, this work will establish a new modality for encoding spatial information in biological signals, providing a one-dimensional solution to the three-dimensional problem of sensing cell size. Moreover, the proposed mechanism can explain intrinsic limits on regenerative neuronal growth and raises the intriguing possibility of opening new avenues to bypass such limits towards acceleration of axonal growth for effective neural repair.
Max ERC Funding
2 498 040 €
Duration
Start date: 2013-10-01, End date: 2018-09-30
Project acronym NEURONSINMOTION
Project Linking glutamatergic spinal cord and brainstem neuronal circuits to the control of locomotor behavior
Researcher (PI) Ole Kiehn
Host Institution (HI) KAROLINSKA INSTITUTET
Call Details Advanced Grant (AdG), LS5, ERC-2010-AdG_20100317
Summary Locomotion is an essential motor act that for the most part is controlled by neuronal circuits in the spinal cord itself, called central pattern generators (CPGs), although their activity is turned on from centers in the brainstem. Understanding the operation of CPG circuits in mammals has been a significant challenge to neuroscientists over the last 50 years. The CPG for walking generates rhythm, as well as the precise patterns of muscular activity. The neural assembly that is directly involved in generating the locomotor rhythm is completely unknown. There is strong evidence from pharmacological and lesion studies showing that glutamatergic neurons are responsible for this function. Here, I propose to identify these key glutamatergic neuronal CPG circuits. As a first step we will use state-of-the-art RNA-sequencing to obtain the complete transcriptome of glutamatergic subpopulations in the ventral spinal cord of the mouse to define new postnatally expressed molecular markers. To link glutamatergic neuronal subpopulations to the locomotor behavior we will use transgenic mouse systems to incorporate light-activated switches in a cell specific way. These tools will provide a new basis for functional and network studies needed to understand the CPG operation. We also propose to use mouse models with optogenetic switches to provide a molecular identification of the glutamatergic locomotor command systems and their integration in the CPG. Our analysis will provide a unified characterization of the neuronal organization of the mammalian CPG and its immediate control from the brain. Understanding the locomotor CPG and its control in mammals is of outmost importance for improving rehabilitation of spinal cord injured patients and designing new repair strategies.
Summary
Locomotion is an essential motor act that for the most part is controlled by neuronal circuits in the spinal cord itself, called central pattern generators (CPGs), although their activity is turned on from centers in the brainstem. Understanding the operation of CPG circuits in mammals has been a significant challenge to neuroscientists over the last 50 years. The CPG for walking generates rhythm, as well as the precise patterns of muscular activity. The neural assembly that is directly involved in generating the locomotor rhythm is completely unknown. There is strong evidence from pharmacological and lesion studies showing that glutamatergic neurons are responsible for this function. Here, I propose to identify these key glutamatergic neuronal CPG circuits. As a first step we will use state-of-the-art RNA-sequencing to obtain the complete transcriptome of glutamatergic subpopulations in the ventral spinal cord of the mouse to define new postnatally expressed molecular markers. To link glutamatergic neuronal subpopulations to the locomotor behavior we will use transgenic mouse systems to incorporate light-activated switches in a cell specific way. These tools will provide a new basis for functional and network studies needed to understand the CPG operation. We also propose to use mouse models with optogenetic switches to provide a molecular identification of the glutamatergic locomotor command systems and their integration in the CPG. Our analysis will provide a unified characterization of the neuronal organization of the mammalian CPG and its immediate control from the brain. Understanding the locomotor CPG and its control in mammals is of outmost importance for improving rehabilitation of spinal cord injured patients and designing new repair strategies.
Max ERC Funding
2 500 000 €
Duration
Start date: 2011-08-01, End date: 2016-07-31
Project acronym NOVRIB
Project Novel Insights into Multi-drug Resistance to Antibiotics and the Primordial Ribosome
Researcher (PI) Ada Yonath
Host Institution (HI) WEIZMANN INSTITUTE OF SCIENCE
Call Details Advanced Grant (AdG), LS1, ERC-2012-ADG_20120314
Summary Multi-drug resistant phenotype formation creates global severe clinical threat among the most important challenges facing medicine today, dictating an urgent need for novel approaches. We aim to reveal the scope and mechanisms of resistance in pathogens, by studies that have not been pursued so far worldwide. In parallel we initiated innovative research towards understanding the ribosome origin, aiming at illuminating the transition from the primordial RNA world to the contemporary coded translation era, alongside exploring new targets and providing useful clues for antibiotics design. We base our interdisciplinary objectives on our discoveries originating from the ribosomes high resolution structures, the results of our pioneering efforts and subsequent perseverance.
By revealing unique properties of genuine pathogens that facilitate their exclusive resistance pathways,instead of depending solely on benign eubacterial models, we expect to gain matchless new insights. As no crystals of ribosomes from pathogens are available, we have initiated crystallographic studies, and present here preliminary results on two pathogenic life threatening bacteria, Staphylococcus aureus (associated with MRSA resistance) and Mycobacterium tuberculosis via Mycobacterium smegmatis that serve as its medical diagnostic tool. We also aim at experimentally defining the intra-ribosome region suggested by us to be a vestige of a prebiotic apparatus (proto-ribosome) by designing autonomous molecular entities with catalytic capabilities. Constructs the bind substrates have already been obtained. The expected enhancement in understanding peptide bond formation should lead to novel insights into this universal essential process. Our studies are designed to provide unprecedentedly powerful new tools for minimizing pathogens resistance thus should be of immense therapeutic relevance & will open up new horizons for researchers seeking response to challenges of the increasing antibiotic resistance.
Summary
Multi-drug resistant phenotype formation creates global severe clinical threat among the most important challenges facing medicine today, dictating an urgent need for novel approaches. We aim to reveal the scope and mechanisms of resistance in pathogens, by studies that have not been pursued so far worldwide. In parallel we initiated innovative research towards understanding the ribosome origin, aiming at illuminating the transition from the primordial RNA world to the contemporary coded translation era, alongside exploring new targets and providing useful clues for antibiotics design. We base our interdisciplinary objectives on our discoveries originating from the ribosomes high resolution structures, the results of our pioneering efforts and subsequent perseverance.
By revealing unique properties of genuine pathogens that facilitate their exclusive resistance pathways,instead of depending solely on benign eubacterial models, we expect to gain matchless new insights. As no crystals of ribosomes from pathogens are available, we have initiated crystallographic studies, and present here preliminary results on two pathogenic life threatening bacteria, Staphylococcus aureus (associated with MRSA resistance) and Mycobacterium tuberculosis via Mycobacterium smegmatis that serve as its medical diagnostic tool. We also aim at experimentally defining the intra-ribosome region suggested by us to be a vestige of a prebiotic apparatus (proto-ribosome) by designing autonomous molecular entities with catalytic capabilities. Constructs the bind substrates have already been obtained. The expected enhancement in understanding peptide bond formation should lead to novel insights into this universal essential process. Our studies are designed to provide unprecedentedly powerful new tools for minimizing pathogens resistance thus should be of immense therapeutic relevance & will open up new horizons for researchers seeking response to challenges of the increasing antibiotic resistance.
Max ERC Funding
2 487 989 €
Duration
Start date: 2013-02-01, End date: 2018-01-31
Project acronym P75NTR
Project Understanding death-receptor signaling and physiology in the nervous system: A roadmap for the development of new treatments to neurodegenerative diseases and neurotrauma
Researcher (PI) Carlos Fernando Ibañez Moliner
Host Institution (HI) KAROLINSKA INSTITUTET
Call Details Advanced Grant (AdG), LS5, ERC-2013-ADG
Summary The aim of this proposal is to elucidate the molecular mechanisms and physiological relevance of death-receptor signaling in the nervous system and to harness this knowledge for the development of novel treatments to neurodegenerative diseases and neurotrauma. The main focus is on the p75 neurotrophin receptor (p75NTR), which is predominantly expressed in the developing nervous system and is highly induced upon different types of adult neural injury. Additional studies on other death receptors, such as DR6, are also described. p75NTR signaling can induce neuronal death, reduce axonal growth and decrease synaptic function, hence there is a good rationale for inhibiting p75NTR in neural injury and neurodegeneration. Recent discoveries from my laboratory have clarified the mechanism of p75NTR activation and provided new insights into the underlying logic of p75NTR signaling, paving the way for a genetic dissection of p75NTR function and physiology. These discoveries have open new avenues to elucidate the molecular mechanisms underlying ligand-specific responses and downstream signal propagation by death-receptors, unravel the physiological relevance of death-receptor signaling pathways in health and disease, and develop new strategies to block death-receptor activity in neural injury and neurodegeneration.
To drive progress in this research area it is proposed to: i) Elucidate the mechanisms by which p75NTR and other death receptors become activated by different ligands and elicit distinct, ligand-specific cellular responses; ii) Elucidate the mechanisms underlying the specificity and diversity of p75NTR signaling and decipher their underlying logic; iii) Elucidate the physiological significance of distinct p75NTR signaling pathways through genetic dissection in knock-in mice; iv) Harness this knowledge to identify and characterize novel p75NTR inhibitors.
This is research of a high-gain/high-risk nature, posed to open unique opportunities in research & development.
Summary
The aim of this proposal is to elucidate the molecular mechanisms and physiological relevance of death-receptor signaling in the nervous system and to harness this knowledge for the development of novel treatments to neurodegenerative diseases and neurotrauma. The main focus is on the p75 neurotrophin receptor (p75NTR), which is predominantly expressed in the developing nervous system and is highly induced upon different types of adult neural injury. Additional studies on other death receptors, such as DR6, are also described. p75NTR signaling can induce neuronal death, reduce axonal growth and decrease synaptic function, hence there is a good rationale for inhibiting p75NTR in neural injury and neurodegeneration. Recent discoveries from my laboratory have clarified the mechanism of p75NTR activation and provided new insights into the underlying logic of p75NTR signaling, paving the way for a genetic dissection of p75NTR function and physiology. These discoveries have open new avenues to elucidate the molecular mechanisms underlying ligand-specific responses and downstream signal propagation by death-receptors, unravel the physiological relevance of death-receptor signaling pathways in health and disease, and develop new strategies to block death-receptor activity in neural injury and neurodegeneration.
To drive progress in this research area it is proposed to: i) Elucidate the mechanisms by which p75NTR and other death receptors become activated by different ligands and elicit distinct, ligand-specific cellular responses; ii) Elucidate the mechanisms underlying the specificity and diversity of p75NTR signaling and decipher their underlying logic; iii) Elucidate the physiological significance of distinct p75NTR signaling pathways through genetic dissection in knock-in mice; iv) Harness this knowledge to identify and characterize novel p75NTR inhibitors.
This is research of a high-gain/high-risk nature, posed to open unique opportunities in research & development.
Max ERC Funding
2 500 000 €
Duration
Start date: 2014-06-01, End date: 2019-05-31
Project acronym PainCells
Project Decomposition of pain into celltypes
Researcher (PI) Johan Patrik Ernfors
Host Institution (HI) KAROLINSKA INSTITUTET
Call Details Advanced Grant (AdG), LS5, ERC-2016-ADG
Summary Almost 20% of the population has an ongoing pain problem. Pain is caused by a complex recruitment of different types of sensory neurons with different response-profiles and hence, the integrated response of an assembly of different neuronal types results in pain. Due to technical limitations, a system-wide approach to resolve the complexity of cell types and their involvement in the development of pain has yet not been tried.
PainCells will first identify and classify sensory neuron types by single-cell RNA seq in rodent and non-human primate. Based on the new classification we will determine the cellular basis for transduction of somatic sensation by developing enabling technologies allowing an activity-based Cre-dependent permanent labeling and identification by RNA-seq the exact cell types and hence, also neuronal assemblies active during particular types of pain. These assemblies will thereafter be silenced, ablated or artificially activated to functionally determine the role of these circuits in pain disorders. This work will for the first time reveal the full complexity of different cell types engaged in particular types of pain and unravel by activity-based mouse genetics the role of that these play in pain disorders. Thus, PainCells will reveal system-wide principles of coding pain in the nervous system.
PainCells will also address the role of terminal glial cells in the skin. This ignored cell type has in preliminary results been shown to respond to and transmit painful stimuli to primary sensory neurons. We will ascertain the role of terminal glial cells in the skin as pain initiating cells and in pain disorders. The discovery that glial cells in addition to sensory neurons represent pain receptive cells should fundamentally change the pain field.
Overall, this proposal takes a new system-wide strategy in that will affect development of new pain managing drugs, a field that has made little clinical advance the past century.
Summary
Almost 20% of the population has an ongoing pain problem. Pain is caused by a complex recruitment of different types of sensory neurons with different response-profiles and hence, the integrated response of an assembly of different neuronal types results in pain. Due to technical limitations, a system-wide approach to resolve the complexity of cell types and their involvement in the development of pain has yet not been tried.
PainCells will first identify and classify sensory neuron types by single-cell RNA seq in rodent and non-human primate. Based on the new classification we will determine the cellular basis for transduction of somatic sensation by developing enabling technologies allowing an activity-based Cre-dependent permanent labeling and identification by RNA-seq the exact cell types and hence, also neuronal assemblies active during particular types of pain. These assemblies will thereafter be silenced, ablated or artificially activated to functionally determine the role of these circuits in pain disorders. This work will for the first time reveal the full complexity of different cell types engaged in particular types of pain and unravel by activity-based mouse genetics the role of that these play in pain disorders. Thus, PainCells will reveal system-wide principles of coding pain in the nervous system.
PainCells will also address the role of terminal glial cells in the skin. This ignored cell type has in preliminary results been shown to respond to and transmit painful stimuli to primary sensory neurons. We will ascertain the role of terminal glial cells in the skin as pain initiating cells and in pain disorders. The discovery that glial cells in addition to sensory neurons represent pain receptive cells should fundamentally change the pain field.
Overall, this proposal takes a new system-wide strategy in that will affect development of new pain managing drugs, a field that has made little clinical advance the past century.
Max ERC Funding
2 443 953 €
Duration
Start date: 2017-08-01, End date: 2022-07-31
Project acronym PRISTINE-PD
Project Prion-like transmission of α-synuclein in Parkinson's disease
Researcher (PI) Patrik Brundin
Host Institution (HI) LUNDS UNIVERSITET
Call Details Advanced Grant (AdG), LS5, ERC-2010-AdG_20100317
Summary Protein misfolding is implicated as a pathogenetic mechanism in several neurodegenerative disorders, including Parkinson¿s disease (PD). In prion disease, the misfolded protein spreads between cells and acts as a ¿permissive template¿, causing protein in the recipient cell to misfold. In 2008 we reported that classical neuropathological changes gradually propagate from a PD patient¿s brain to a graft of healthy neurons, over one decade after surgery. These groundbreaking findings suggest that the protein ¿-synuclei may transfer between cells and propagate protein aggregation in a ¿prion-like¿ fashion in PD. This molecular disease mechanism might explain how protein aggregates gradually spread throughout the nervous system and promote progression of disease symptoms. This highly novel concept represents a hitherto poorly explored route of intercellular communication and might have far-reaching implications well beyond PD. Little is known about how various forms of ¿-synuclein are taken up; if they seed aggregation in the recipient cell; how they affect proteostasis in the recipient cells; if they are transported axonally; and, finally, whether they can cause spreading of PD-like pathology in the nervous system.
In a multidisciplinary project will now examine the molecular mechanisms underlying translocation of ¿-synuclein across a lipid membrane, from the outside to the inside of a cell; what the molecular and functional consequences are of importing ¿-synuclein; what the dynamics of ¿-synuclein transfer are in vivo; whether aggregates of misfolded ¿-synuclein can spread from one region of the nervous system to another; what genes influence the likelihood for ¿-synuclein transfer to take place; and, finally if small molecules that inhibit ¿-synuclein can be identified. Our studies will shed light on what appears to be a new principle for pathogenesis of neurodegenerative disorders and can open up avenues for new therapeutic strategies.
Summary
Protein misfolding is implicated as a pathogenetic mechanism in several neurodegenerative disorders, including Parkinson¿s disease (PD). In prion disease, the misfolded protein spreads between cells and acts as a ¿permissive template¿, causing protein in the recipient cell to misfold. In 2008 we reported that classical neuropathological changes gradually propagate from a PD patient¿s brain to a graft of healthy neurons, over one decade after surgery. These groundbreaking findings suggest that the protein ¿-synuclei may transfer between cells and propagate protein aggregation in a ¿prion-like¿ fashion in PD. This molecular disease mechanism might explain how protein aggregates gradually spread throughout the nervous system and promote progression of disease symptoms. This highly novel concept represents a hitherto poorly explored route of intercellular communication and might have far-reaching implications well beyond PD. Little is known about how various forms of ¿-synuclein are taken up; if they seed aggregation in the recipient cell; how they affect proteostasis in the recipient cells; if they are transported axonally; and, finally, whether they can cause spreading of PD-like pathology in the nervous system.
In a multidisciplinary project will now examine the molecular mechanisms underlying translocation of ¿-synuclein across a lipid membrane, from the outside to the inside of a cell; what the molecular and functional consequences are of importing ¿-synuclein; what the dynamics of ¿-synuclein transfer are in vivo; whether aggregates of misfolded ¿-synuclein can spread from one region of the nervous system to another; what genes influence the likelihood for ¿-synuclein transfer to take place; and, finally if small molecules that inhibit ¿-synuclein can be identified. Our studies will shed light on what appears to be a new principle for pathogenesis of neurodegenerative disorders and can open up avenues for new therapeutic strategies.
Max ERC Funding
2 499 998 €
Duration
Start date: 2011-06-01, End date: 2016-05-31
Project acronym RATLAND
Project Understanding Auditory Information Processing in Naturalistic Environments
Researcher (PI) Israel Nelken
Host Institution (HI) THE HEBREW UNIVERSITY OF JERUSALEM
Call Details Advanced Grant (AdG), LS5, ERC-2013-ADG
Summary Studies of sensory processing in awake mammals are often limited to simple perceptual decisions, such as detecting the differences between two similar stimuli. However, such sensory tasks are usually limited by peripheral information, and do not tap into the special processing capabilities of the cortex. I hypothesize that neuronal responses in auditory cortex represent ethologically-relevant quantities that optimally summarize knowledge about the current scene and that allow behaviourally-relevant predictions of its future development. In order to study the role of such mechanisms in controlling behaviour, it is necessary to develop new technological and methodological tools.
I will develop a semi-natural living environment for rats that will make it possible to train multiple animals to perform behavioural tasks while continuously recording the electrical activity of their brains. Neural activity will be recorded continuously using telemetry inside the environment, or periodically outside it with chronic imaging techniques. Brain activity will be manipulated with optogenetic techniques. This methodology will minimize human intervention, increasing the reproducibility of behavioral and electrophysiological data collection while reducing the number of animals used.
Various amount of information about the states of the environment will be communicated to the rats with sounds. I will apply a new theory that rigorously quantifies the balance between information and reward. The theory will make it possible to deduce what the rats believe about the environment from their behavior, and to correlate these beliefs with neural activity.
Hearing disorders are a major cause of reduction of quality of life, especially in the elderly population. Better understanding of auditory processing in real-world scenarios is a crucial step for the future development of better tools and therapies.
Summary
Studies of sensory processing in awake mammals are often limited to simple perceptual decisions, such as detecting the differences between two similar stimuli. However, such sensory tasks are usually limited by peripheral information, and do not tap into the special processing capabilities of the cortex. I hypothesize that neuronal responses in auditory cortex represent ethologically-relevant quantities that optimally summarize knowledge about the current scene and that allow behaviourally-relevant predictions of its future development. In order to study the role of such mechanisms in controlling behaviour, it is necessary to develop new technological and methodological tools.
I will develop a semi-natural living environment for rats that will make it possible to train multiple animals to perform behavioural tasks while continuously recording the electrical activity of their brains. Neural activity will be recorded continuously using telemetry inside the environment, or periodically outside it with chronic imaging techniques. Brain activity will be manipulated with optogenetic techniques. This methodology will minimize human intervention, increasing the reproducibility of behavioral and electrophysiological data collection while reducing the number of animals used.
Various amount of information about the states of the environment will be communicated to the rats with sounds. I will apply a new theory that rigorously quantifies the balance between information and reward. The theory will make it possible to deduce what the rats believe about the environment from their behavior, and to correlate these beliefs with neural activity.
Hearing disorders are a major cause of reduction of quality of life, especially in the elderly population. Better understanding of auditory processing in real-world scenarios is a crucial step for the future development of better tools and therapies.
Max ERC Funding
2 499 800 €
Duration
Start date: 2014-02-01, End date: 2019-01-31