Project acronym a SMILE
Project analyse Soluble + Membrane complexes with Improved LILBID Experiments
Researcher (PI) Nina Morgner
Host Institution (HI) JOHANN WOLFGANG GOETHE-UNIVERSITATFRANKFURT AM MAIN
Call Details Starting Grant (StG), PE4, ERC-2013-StG
Summary Crucial processes within cells depend on specific non-covalent interactions which mediate the assembly of proteins and other biomolecules. Deriving structural information to understand the function of these complex systems is the primary goal of Structural Biology.
In this application, the recently developed LILBID method (Laser Induced Liquid Bead Ion Desorption) will be optimized for investigation of macromolecular complexes with a mass accuracy two orders of magnitude better than in 1st generation spectrometers.
Controlled disassembly of the multiprotein complexes in the mass spectrometric analysis while keeping the 3D structure intact, will allow for the determination of complex stoichiometry and connectivity of the constituting proteins. Methods for such controlled disassembly will be developed in two separate units of the proposed LILBID spectrometer, in a collision chamber and in a laser dissociation chamber, enabling gas phase dissociation of protein complexes and removal of excess water/buffer molecules. As a third unit, a chamber allowing determination of ion mobility (IM) will be integrated to determine collisional cross sections (CCS). From CCS, unique information regarding the spatial arrangement of proteins in complexes or subcomplexes will then be obtainable from LILBID.
The proposed design of the new spectrometer will offer fundamentally new possibilities for the investigation of non-covalent RNA, soluble and membrane protein complexes, as well as broadening the applicability of non-covalent MS towards supercomplexes.
Summary
Crucial processes within cells depend on specific non-covalent interactions which mediate the assembly of proteins and other biomolecules. Deriving structural information to understand the function of these complex systems is the primary goal of Structural Biology.
In this application, the recently developed LILBID method (Laser Induced Liquid Bead Ion Desorption) will be optimized for investigation of macromolecular complexes with a mass accuracy two orders of magnitude better than in 1st generation spectrometers.
Controlled disassembly of the multiprotein complexes in the mass spectrometric analysis while keeping the 3D structure intact, will allow for the determination of complex stoichiometry and connectivity of the constituting proteins. Methods for such controlled disassembly will be developed in two separate units of the proposed LILBID spectrometer, in a collision chamber and in a laser dissociation chamber, enabling gas phase dissociation of protein complexes and removal of excess water/buffer molecules. As a third unit, a chamber allowing determination of ion mobility (IM) will be integrated to determine collisional cross sections (CCS). From CCS, unique information regarding the spatial arrangement of proteins in complexes or subcomplexes will then be obtainable from LILBID.
The proposed design of the new spectrometer will offer fundamentally new possibilities for the investigation of non-covalent RNA, soluble and membrane protein complexes, as well as broadening the applicability of non-covalent MS towards supercomplexes.
Max ERC Funding
1 264 477 €
Duration
Start date: 2014-02-01, End date: 2019-01-31
Project acronym AttentionCircuits
Project Modulation of neocortical microcircuits for attention
Researcher (PI) Johannes Jakob Letzkus
Host Institution (HI) MAX-PLANCK-GESELLSCHAFT ZUR FORDERUNG DER WISSENSCHAFTEN EV
Call Details Starting Grant (StG), LS5, ERC-2013-StG
Summary At every moment in time, the brain receives a vast amount of sensory information about the environment. This makes attention, the process by which we select currently relevant stimuli for processing and ignore irrelevant input, a fundamentally important brain function. Studies in primates have yielded a detailed description of how attention to a stimulus modifies the responses of neuronal ensembles in visual cortex, but how this modulation is produced mechanistically in the circuit is not well understood. Neuronal circuits comprise a large variety of neuron types, and to gain mechanistic insights, and to treat specific diseases of the nervous system, it is crucial to characterize the contribution of different identified cell types to information processing. Inhibition supplied by a small yet highly diverse set of interneurons controls all aspects of cortical function, and the central hypothesis of this proposal is that differential modulation of genetically-defined interneuron types is a key mechanism of attention in visual cortex. To identify the interneuron types underlying attentional modulation and to investigate how this, in turn, affects computations in the circuit we will use an innovative multidisciplinary approach combining genetic targeting in mice with cutting-edge in vivo 2-photon microscopy-based recordings and selective optogenetic manipulation of activity. Importantly, a key set of experiments will test whether the observed neuronal mechanisms are causally involved in attention at the level of behavior, the ultimate readout of the computations we are interested in. The expected results will provide a detailed, mechanistic dissection of the neuronal basis of attention. Beyond attention, selection of different functional states of the same hard-wired circuit by modulatory input is a fundamental, but poorly understood, phenomenon in the brain, and we predict that our insights will elucidate similar mechanisms in other brain areas and functional contexts.
Summary
At every moment in time, the brain receives a vast amount of sensory information about the environment. This makes attention, the process by which we select currently relevant stimuli for processing and ignore irrelevant input, a fundamentally important brain function. Studies in primates have yielded a detailed description of how attention to a stimulus modifies the responses of neuronal ensembles in visual cortex, but how this modulation is produced mechanistically in the circuit is not well understood. Neuronal circuits comprise a large variety of neuron types, and to gain mechanistic insights, and to treat specific diseases of the nervous system, it is crucial to characterize the contribution of different identified cell types to information processing. Inhibition supplied by a small yet highly diverse set of interneurons controls all aspects of cortical function, and the central hypothesis of this proposal is that differential modulation of genetically-defined interneuron types is a key mechanism of attention in visual cortex. To identify the interneuron types underlying attentional modulation and to investigate how this, in turn, affects computations in the circuit we will use an innovative multidisciplinary approach combining genetic targeting in mice with cutting-edge in vivo 2-photon microscopy-based recordings and selective optogenetic manipulation of activity. Importantly, a key set of experiments will test whether the observed neuronal mechanisms are causally involved in attention at the level of behavior, the ultimate readout of the computations we are interested in. The expected results will provide a detailed, mechanistic dissection of the neuronal basis of attention. Beyond attention, selection of different functional states of the same hard-wired circuit by modulatory input is a fundamental, but poorly understood, phenomenon in the brain, and we predict that our insights will elucidate similar mechanisms in other brain areas and functional contexts.
Max ERC Funding
1 466 505 €
Duration
Start date: 2014-02-01, End date: 2019-01-31
Project acronym BeadsOnString
Project Beads on String Genomics: Experimental Toolbox for Unmasking Genetic / Epigenetic Variation in Genomic DNA and Chromatin
Researcher (PI) Yuval Ebenstein
Host Institution (HI) TEL AVIV UNIVERSITY
Call Details Starting Grant (StG), PE4, ERC-2013-StG
Summary Next generation sequencing (NGS) is revolutionizing all fields of biological research but it fails to extract the full range of information associated with genetic material and is lacking in its ability to resolve variations between genomes. The high degree of genome variation exhibited both on the population level as well as between genetically “identical” cells (even in the same organ) makes genetic and epigenetic analysis on the single cell and single genome level a necessity.
Chromosomes may be conceptually represented as a linear one-dimensional barcode. However, in contrast to a traditional binary barcode approach that considers only two possible bits of information (1 & 0), I will use colour and molecular structure to expand the variety of information represented in the barcode. Like colourful beads threaded on a string, where each bead represents a distinct type of observable, I will label each type of genomic information with a different chemical moiety thus expanding the repertoire of information that can be simultaneously measured. A major effort in this proposal is invested in the development of unique chemistries to enable this labelling.
I specifically address three types of genomic variation: Variations in genomic layout (including DNA repeats, structural and copy number variations), variations in the patterns of chemical DNA modifications (such as methylation of cytosine bases) and variations in the chromatin composition (including nucleosome and transcription factor distributions). I will use physical extension of long DNA molecules on surfaces and in nanofluidic channels to reveal this information visually in the form of a linear, fluorescent “barcode” that is read-out by advanced imaging techniques. Similarly, DNA molecules will be threaded through a nanopore where the sequential position of “bulky” molecular groups attached to the DNA may be inferred from temporal modulation of an ionic current measured across the pore.
Summary
Next generation sequencing (NGS) is revolutionizing all fields of biological research but it fails to extract the full range of information associated with genetic material and is lacking in its ability to resolve variations between genomes. The high degree of genome variation exhibited both on the population level as well as between genetically “identical” cells (even in the same organ) makes genetic and epigenetic analysis on the single cell and single genome level a necessity.
Chromosomes may be conceptually represented as a linear one-dimensional barcode. However, in contrast to a traditional binary barcode approach that considers only two possible bits of information (1 & 0), I will use colour and molecular structure to expand the variety of information represented in the barcode. Like colourful beads threaded on a string, where each bead represents a distinct type of observable, I will label each type of genomic information with a different chemical moiety thus expanding the repertoire of information that can be simultaneously measured. A major effort in this proposal is invested in the development of unique chemistries to enable this labelling.
I specifically address three types of genomic variation: Variations in genomic layout (including DNA repeats, structural and copy number variations), variations in the patterns of chemical DNA modifications (such as methylation of cytosine bases) and variations in the chromatin composition (including nucleosome and transcription factor distributions). I will use physical extension of long DNA molecules on surfaces and in nanofluidic channels to reveal this information visually in the form of a linear, fluorescent “barcode” that is read-out by advanced imaging techniques. Similarly, DNA molecules will be threaded through a nanopore where the sequential position of “bulky” molecular groups attached to the DNA may be inferred from temporal modulation of an ionic current measured across the pore.
Max ERC Funding
1 627 600 €
Duration
Start date: 2013-10-01, End date: 2018-09-30
Project acronym BIOGRAPHENE
Project Sequencing biological molecules with graphene
Researcher (PI) Gregory Schneider
Host Institution (HI) UNIVERSITEIT LEIDEN
Call Details Starting Grant (StG), PE4, ERC-2013-StG
Summary Graphene – a one atom thin material – has the potential to act as a sensor, primarily the surface and the edges of graphene. This proposal aims at exploring new biosensing routes by exploiting the unique surface and edge chemistry of graphene.
Summary
Graphene – a one atom thin material – has the potential to act as a sensor, primarily the surface and the edges of graphene. This proposal aims at exploring new biosensing routes by exploiting the unique surface and edge chemistry of graphene.
Max ERC Funding
1 499 996 €
Duration
Start date: 2014-05-01, End date: 2019-04-30
Project acronym C.o.C.O.
Project Circuits of con-specific observation
Researcher (PI) Marta De Aragao Pacheco Moita
Host Institution (HI) FUNDACAO D. ANNA SOMMER CHAMPALIMAUD E DR. CARLOS MONTEZ CHAMPALIMAUD
Call Details Starting Grant (StG), LS5, ERC-2013-StG
Summary A great deal is known about the neural basis of associative fear learning. However, many animal species are able to use social cues to recognize threats, a defence mechanism that may be less costly than learning from self-experience. We have previously shown that rats perceive the cessation of movement-evoked sound as a signal of danger and its resumption as a signal of safety. To study transmission of fear between rats we assessed the behavior of an observer while witnessing a demonstrator rat display fear responses. With this paradigm we will take advantage of the accumulated knowledge on learned fear to investigate the neural mechanisms by which the social environment regulates defense behaviors. We will unravel the neural circuits involved in detecting the transition from movement-evoked sound to silence. Moreover, since observer rats previously exposed to shock display observational freezing, but naive observer rats do not, we will determine the mechanism by which prior experience contribute to observational freezing. To this end, we will focus on the amygdala, crucial for fear learning and expression, and its auditory inputs, combining immunohistochemistry, pharmacology and optogenetics. Finally, as the detection of and responses to threat are often inherently social, we will study these behaviors in the context of large groups of individuals. To circumvent the serious limitations in using large populations of rats, we will resort to a different model system. The fruit fly is the ideal model system, as it is both amenable to the search for the neural mechanism of behavior, while at the same time allowing the study of the behavior of large groups of individuals. We will develop behavioral tasks, where conditioned demonstrator flies signal danger to other naïve ones. These experiments unravel how the brain uses defense behaviors as signals of danger and how it contributes to defense mechanisms at the population level.
Summary
A great deal is known about the neural basis of associative fear learning. However, many animal species are able to use social cues to recognize threats, a defence mechanism that may be less costly than learning from self-experience. We have previously shown that rats perceive the cessation of movement-evoked sound as a signal of danger and its resumption as a signal of safety. To study transmission of fear between rats we assessed the behavior of an observer while witnessing a demonstrator rat display fear responses. With this paradigm we will take advantage of the accumulated knowledge on learned fear to investigate the neural mechanisms by which the social environment regulates defense behaviors. We will unravel the neural circuits involved in detecting the transition from movement-evoked sound to silence. Moreover, since observer rats previously exposed to shock display observational freezing, but naive observer rats do not, we will determine the mechanism by which prior experience contribute to observational freezing. To this end, we will focus on the amygdala, crucial for fear learning and expression, and its auditory inputs, combining immunohistochemistry, pharmacology and optogenetics. Finally, as the detection of and responses to threat are often inherently social, we will study these behaviors in the context of large groups of individuals. To circumvent the serious limitations in using large populations of rats, we will resort to a different model system. The fruit fly is the ideal model system, as it is both amenable to the search for the neural mechanism of behavior, while at the same time allowing the study of the behavior of large groups of individuals. We will develop behavioral tasks, where conditioned demonstrator flies signal danger to other naïve ones. These experiments unravel how the brain uses defense behaviors as signals of danger and how it contributes to defense mechanisms at the population level.
Max ERC Funding
1 412 376 €
Duration
Start date: 2013-12-01, End date: 2018-11-30
Project acronym CANCERMETAB
Project Metabolic requirements for prostate cancer cell fitness
Researcher (PI) Arkaitz Carracedo Perez
Host Institution (HI) ASOCIACION CENTRO DE INVESTIGACION COOPERATIVA EN BIOCIENCIAS
Call Details Starting Grant (StG), LS4, ERC-2013-StG
Summary The actual view of cellular transformation and cancer progression supports the notion that cancer cells must undergo metabolic reprogramming in order to survive in a hostile environment. This field has experienced a renaissance in recent years, with the discovery of cancer genes regulating metabolic homeostasis, in turn being accepted as an emergent hallmark of cancer. Prostate cancer presents one of the highest incidences in men mostly in developed societies and exhibits a significant association with lifestyle environmental factors. Prostate cancer recurrence is thought to rely on a subpopulation of cancer cells with low-androgen requirements, high self-renewal potential and multidrug resistance, defined as cancer-initiating cells. However, whether this cancer cell fraction presents genuine metabolic properties that can be therapeutically relevant remains undefined. In CancerMetab, we aim to understand the potential benefit of monitoring and manipulating metabolism for prostate cancer prevention, detection and therapy. My group will carry out a multidisciplinary strategy, comprising cellular systems, genetic mouse models of prostate cancer, human epidemiological and clinical studies and bioinformatic analysis. The singularity of this proposal stems from the approach to the three key aspects that we propose to study. For prostate cancer prevention, we will use our faithful mouse model of prostate cancer to shed light on the contribution of obesity to prostate cancer. For prostate cancer detection, we will overcome the consistency issues of previously reported metabolic biomarkers by adding robustness to the human studies with mouse data integration. For prostate cancer therapy, we will focus on a cell population for which the metabolic requirements and the potential of targeting them for therapy have been overlooked to date, that is the prostate cancer-initiating cell compartment.
Summary
The actual view of cellular transformation and cancer progression supports the notion that cancer cells must undergo metabolic reprogramming in order to survive in a hostile environment. This field has experienced a renaissance in recent years, with the discovery of cancer genes regulating metabolic homeostasis, in turn being accepted as an emergent hallmark of cancer. Prostate cancer presents one of the highest incidences in men mostly in developed societies and exhibits a significant association with lifestyle environmental factors. Prostate cancer recurrence is thought to rely on a subpopulation of cancer cells with low-androgen requirements, high self-renewal potential and multidrug resistance, defined as cancer-initiating cells. However, whether this cancer cell fraction presents genuine metabolic properties that can be therapeutically relevant remains undefined. In CancerMetab, we aim to understand the potential benefit of monitoring and manipulating metabolism for prostate cancer prevention, detection and therapy. My group will carry out a multidisciplinary strategy, comprising cellular systems, genetic mouse models of prostate cancer, human epidemiological and clinical studies and bioinformatic analysis. The singularity of this proposal stems from the approach to the three key aspects that we propose to study. For prostate cancer prevention, we will use our faithful mouse model of prostate cancer to shed light on the contribution of obesity to prostate cancer. For prostate cancer detection, we will overcome the consistency issues of previously reported metabolic biomarkers by adding robustness to the human studies with mouse data integration. For prostate cancer therapy, we will focus on a cell population for which the metabolic requirements and the potential of targeting them for therapy have been overlooked to date, that is the prostate cancer-initiating cell compartment.
Max ERC Funding
1 498 686 €
Duration
Start date: 2013-11-01, End date: 2019-10-31
Project acronym CeMoMagneto
Project The Cellular and Molecular Basis of Magnetoreception
Researcher (PI) David Anthony Keays
Host Institution (HI) FORSCHUNGSINSTITUT FUR MOLEKULARE PATHOLOGIE GESELLSCHAFT MBH
Call Details Starting Grant (StG), LS5, ERC-2013-StG
Summary Each year millions of animals undertake remarkable migratory journeys, across oceans and through hemispheres, guided by the Earth’s magnetic field. The cellular and molecular basis of this enigmatic sense, known as magnetoreception, remains an unsolved scientific mystery. One hypothesis that attempts to explain the basis of this sensory faculty is known as the magnetite theory of magnetoreception. It argues that magnetic information is transduced into a neuronal impulse by employing the iron oxide magnetite (Fe3O4). Current evidence indicates that pigeons employ a magnetoreceptor that is associated with the ophthalmic branch of the trigeminal nerve and the vestibular system, but the sensory cells remain undiscovered. The goal of this ambitious proposal is to discover the cells and molecules that mediate magnetoreception. This overall objective can be divided into three specific aims: (1) the identification of putative magnetoreceptive cells (PMCs); (2) the cellular characterisation of PMCs; and (3) the discovery and functional ablation of molecules specific to PMCs. In tackling these three aims this proposal adopts a reductionist mindset, employing and developing the latest imaging, subcellular, and molecular technologies.
Summary
Each year millions of animals undertake remarkable migratory journeys, across oceans and through hemispheres, guided by the Earth’s magnetic field. The cellular and molecular basis of this enigmatic sense, known as magnetoreception, remains an unsolved scientific mystery. One hypothesis that attempts to explain the basis of this sensory faculty is known as the magnetite theory of magnetoreception. It argues that magnetic information is transduced into a neuronal impulse by employing the iron oxide magnetite (Fe3O4). Current evidence indicates that pigeons employ a magnetoreceptor that is associated with the ophthalmic branch of the trigeminal nerve and the vestibular system, but the sensory cells remain undiscovered. The goal of this ambitious proposal is to discover the cells and molecules that mediate magnetoreception. This overall objective can be divided into three specific aims: (1) the identification of putative magnetoreceptive cells (PMCs); (2) the cellular characterisation of PMCs; and (3) the discovery and functional ablation of molecules specific to PMCs. In tackling these three aims this proposal adopts a reductionist mindset, employing and developing the latest imaging, subcellular, and molecular technologies.
Max ERC Funding
1 499 752 €
Duration
Start date: 2014-04-01, End date: 2019-03-31
Project acronym CHEMOSENSORYCIRCUITS
Project Function of Chemosensory Circuits
Researcher (PI) Emre Yaksi
Host Institution (HI) NORGES TEKNISK-NATURVITENSKAPELIGE UNIVERSITET NTNU
Call Details Starting Grant (StG), LS5, ERC-2013-StG
Summary Smell and taste are the least studied of all senses. Very little is known about chemosensory information processing beyond the level of receptor neurons. Every morning we enjoy our coffee thanks to our brains ability to combine and process multiple sensory modalities. Meanwhile, we can still review a document on our desk by adjusting the weights of numerous sensory inputs that constantly bombard our brains. Yet, the smell of our coffee may remind us that pleasant weekend breakfast through associative learning and memory. In the proposed project we will explore the function and the architecture of neural circuits that are involved in olfactory and gustatory information processing, namely habenula and brainstem. Moreover we will investigate the fundamental principles underlying multimodal sensory integration and the neural basis of behavior in these highly conserved brain areas.
To achieve these goals we will take an innovative approach by combining two-photon calcium imaging, optogenetics and electrophysiology with the expanding genetic toolbox of a small vertebrate, the zebrafish. This pioneering approach will enable us to design new types of experiments that were unthinkable only a few years ago. Using this unique combination of methods, we will monitor and perturb the activity of functionally distinct elements of habenular and brainstem circuits, in vivo. The habenula and brainstem are important in mediating stress/anxiety and eating habits respectively. Therefore, understanding the neural computations in these brain regions is important for comprehending the neural mechanisms underlying psychological conditions related to anxiety and eating disorders. We anticipate that our results will go beyond chemical senses and contribute new insights to the understanding of how brain circuits work and interact with the sensory world to shape neural activity and behavioral outputs of animals.
Summary
Smell and taste are the least studied of all senses. Very little is known about chemosensory information processing beyond the level of receptor neurons. Every morning we enjoy our coffee thanks to our brains ability to combine and process multiple sensory modalities. Meanwhile, we can still review a document on our desk by adjusting the weights of numerous sensory inputs that constantly bombard our brains. Yet, the smell of our coffee may remind us that pleasant weekend breakfast through associative learning and memory. In the proposed project we will explore the function and the architecture of neural circuits that are involved in olfactory and gustatory information processing, namely habenula and brainstem. Moreover we will investigate the fundamental principles underlying multimodal sensory integration and the neural basis of behavior in these highly conserved brain areas.
To achieve these goals we will take an innovative approach by combining two-photon calcium imaging, optogenetics and electrophysiology with the expanding genetic toolbox of a small vertebrate, the zebrafish. This pioneering approach will enable us to design new types of experiments that were unthinkable only a few years ago. Using this unique combination of methods, we will monitor and perturb the activity of functionally distinct elements of habenular and brainstem circuits, in vivo. The habenula and brainstem are important in mediating stress/anxiety and eating habits respectively. Therefore, understanding the neural computations in these brain regions is important for comprehending the neural mechanisms underlying psychological conditions related to anxiety and eating disorders. We anticipate that our results will go beyond chemical senses and contribute new insights to the understanding of how brain circuits work and interact with the sensory world to shape neural activity and behavioral outputs of animals.
Max ERC Funding
1 499 471 €
Duration
Start date: 2014-04-01, End date: 2019-03-31
Project acronym ChromatinTargets
Project Systematic in-vivo analysis of chromatin-associated targets in leukemia
Researcher (PI) Johannes Zuber
Host Institution (HI) FORSCHUNGSINSTITUT FUR MOLEKULARE PATHOLOGIE GESELLSCHAFT MBH
Call Details Starting Grant (StG), LS4, ERC-2013-StG
Summary Recent advances in genome sequencing illustrate the complexity, heterogeneity and plasticity of cancer genomes. In leukemia - a group of blood cancers affecting 300,000 new patients every year – we know over 100 driver mutations. This genetic complexity poses a daunting challenge for the development of targeted therapies and highlights the urgent need for evaluating them in combination. One gene class that has recently emerged as highly promising target space are chromatin regulators, which maintain aberrant cell fate programs in leukemia. The dependency on altered chromatin states is thought to provide great therapeutic opportunities, since epigenetic aberrations are reversible and controlled by a machinery that is amenable to drug modulation. However, the precise mechanisms underlying these dependencies and the most effective and safe targets to exploit them therapeutically remain unknown.
Here we propose an innovative approach combining genetically engineered leukemia mouse models and advanced in-vivo RNAi technologies to explore chromatin-associated vulnerabilities at an unprecedented level of depth. Following a first screen in MLL-AF9;Nras-driven AML, which led to the discovery of BRD4 as a promising therapeutic target, we aim to (1) construct a knockdown-validated shRNA library targeting 520 chromatin regulators and use it to comparatively probe chromatin-associated dependencies in diverse leukemia subtypes; (2) explore the mechanistic basis of response and resistance to suppression of BRD4 and new chromatin-associated targets; and (3) pioneer a system for multiplexed combinatorial RNAi screening and use it to identify synergies between established and new chromatin-associated targets. We envision that this ERC-funded project will generate a comprehensive functional-genetic dataset that will greatly complement ongoing genome and epigenome profiling studies and ultimately guide the development of targeted therapies for leukemia and, potentially, other cancers.
Summary
Recent advances in genome sequencing illustrate the complexity, heterogeneity and plasticity of cancer genomes. In leukemia - a group of blood cancers affecting 300,000 new patients every year – we know over 100 driver mutations. This genetic complexity poses a daunting challenge for the development of targeted therapies and highlights the urgent need for evaluating them in combination. One gene class that has recently emerged as highly promising target space are chromatin regulators, which maintain aberrant cell fate programs in leukemia. The dependency on altered chromatin states is thought to provide great therapeutic opportunities, since epigenetic aberrations are reversible and controlled by a machinery that is amenable to drug modulation. However, the precise mechanisms underlying these dependencies and the most effective and safe targets to exploit them therapeutically remain unknown.
Here we propose an innovative approach combining genetically engineered leukemia mouse models and advanced in-vivo RNAi technologies to explore chromatin-associated vulnerabilities at an unprecedented level of depth. Following a first screen in MLL-AF9;Nras-driven AML, which led to the discovery of BRD4 as a promising therapeutic target, we aim to (1) construct a knockdown-validated shRNA library targeting 520 chromatin regulators and use it to comparatively probe chromatin-associated dependencies in diverse leukemia subtypes; (2) explore the mechanistic basis of response and resistance to suppression of BRD4 and new chromatin-associated targets; and (3) pioneer a system for multiplexed combinatorial RNAi screening and use it to identify synergies between established and new chromatin-associated targets. We envision that this ERC-funded project will generate a comprehensive functional-genetic dataset that will greatly complement ongoing genome and epigenome profiling studies and ultimately guide the development of targeted therapies for leukemia and, potentially, other cancers.
Max ERC Funding
1 498 985 €
Duration
Start date: 2014-01-01, End date: 2018-12-31
Project acronym COGOPTO
Project The role of parvalbumin interneurons in cognition and behavior
Researcher (PI) Eva Marie Carlen
Host Institution (HI) KAROLINSKA INSTITUTET
Call Details Starting Grant (StG), LS5, ERC-2013-StG
Summary Cognition is a collective term for complex but sophisticated mental processes such as attention, learning, social interaction, language production, decision making and other executive functions. For normal brain function, these higher-order functions need to be aptly regulated and controlled, and the physiology and cellular substrates for cognitive functions are under intense investigation. The loss of cognitive control is intricately related to pathological states such as schizophrenia, depression, attention deficit hyperactive disorder and addiction.
Synchronized neural activity can be observed when the brain performs several important functions, including cognitive processes. As an example, gamma activity (30-80 Hz) predicts the allocation of attention and theta activity (4-12 Hz) is tightly linked to memory processes. A large body of work indicates that the integrity of local and global neural synchrony is mediated by interneuron networks and actuated by the balance of different neuromodulators.
However, much knowledge is still needed on the functional role interneurons play in cognitive processes, i.e. how the interneurons contribute to local and global network processes subserving cognition, and ultimately play a role in behavior. In addition, we need to understand how neuro-modulators, such as dopamine, regulate interneuron function.
The proposed project aims to functionally determine the specific role the parvalbumin interneurons and the neuromodulator dopamine in aspects of cognition, and in behavior. In addition, we ask the question if cognition can be enhanced.
We are employing a true multidisciplinary approach where brain activity is recorded in conjunctions with optogenetic manipulations of parvalbumin interneurons in animals performing cognitive tasks. In one set of experiments knock-down of dopamine receptors specifically in parvalbumin interneurons is employed to probe how this neuromodulator regulate network functions.
Summary
Cognition is a collective term for complex but sophisticated mental processes such as attention, learning, social interaction, language production, decision making and other executive functions. For normal brain function, these higher-order functions need to be aptly regulated and controlled, and the physiology and cellular substrates for cognitive functions are under intense investigation. The loss of cognitive control is intricately related to pathological states such as schizophrenia, depression, attention deficit hyperactive disorder and addiction.
Synchronized neural activity can be observed when the brain performs several important functions, including cognitive processes. As an example, gamma activity (30-80 Hz) predicts the allocation of attention and theta activity (4-12 Hz) is tightly linked to memory processes. A large body of work indicates that the integrity of local and global neural synchrony is mediated by interneuron networks and actuated by the balance of different neuromodulators.
However, much knowledge is still needed on the functional role interneurons play in cognitive processes, i.e. how the interneurons contribute to local and global network processes subserving cognition, and ultimately play a role in behavior. In addition, we need to understand how neuro-modulators, such as dopamine, regulate interneuron function.
The proposed project aims to functionally determine the specific role the parvalbumin interneurons and the neuromodulator dopamine in aspects of cognition, and in behavior. In addition, we ask the question if cognition can be enhanced.
We are employing a true multidisciplinary approach where brain activity is recorded in conjunctions with optogenetic manipulations of parvalbumin interneurons in animals performing cognitive tasks. In one set of experiments knock-down of dopamine receptors specifically in parvalbumin interneurons is employed to probe how this neuromodulator regulate network functions.
Max ERC Funding
1 400 000 €
Duration
Start date: 2014-02-01, End date: 2019-01-31
