Project acronym CIRCUITASSEMBLY
Project Development of functional organization of the visual circuits in mice
Researcher (PI) Keisuke Yonehara
Host Institution (HI) AARHUS UNIVERSITET
Country Denmark
Call Details Starting Grant (StG), LS5, ERC-2014-STG
Summary The key organizing principles that characterize neuronal systems include asymmetric, parallel, and topographic connectivity of the neural circuits. The main aim of my research is to elucidate the key principles underlying functional development of neural circuits by focusing on those organizing principles. I choose mouse visual system as my model since it contains all of these principles and provides sophisticated genetic tools to label and manipulate individual circuit components. My research is based on the central hypothesis that the mechanisms of brain development cannot be fully understood without first identifying individual functional cell types in adults, and then understanding how the functions of these cell types become established, using cell-type-specific molecular and synaptic mechanisms in developing animals. Recently, I have identified several transgenic mouse lines in which specific cell types in a visual center, the superior colliculus, are labeled with Cre recombinase in both developing and adult animals. Here I will take advantage of these mouse lines to ask fundamental questions about the functional development of neural circuits. First, how are distinct sensory features processed by the parallel topographic neuronal pathways, and how do they contribute to behavior? Second, what are the molecular and synaptic mechanisms that underlie developmental circuit plasticity for forming parallel topographic neuronal maps in the brain? Third, what are the molecular mechanisms that set up spatially asymmetric circuit connectivity without the need for sensory experience? I predict that my insights into the developmental mechanism of asymmetric, parallel, and topographic connectivity and circuit plasticity will be instructive when studying other brain circuits which contain similar organizing principles.
Summary
The key organizing principles that characterize neuronal systems include asymmetric, parallel, and topographic connectivity of the neural circuits. The main aim of my research is to elucidate the key principles underlying functional development of neural circuits by focusing on those organizing principles. I choose mouse visual system as my model since it contains all of these principles and provides sophisticated genetic tools to label and manipulate individual circuit components. My research is based on the central hypothesis that the mechanisms of brain development cannot be fully understood without first identifying individual functional cell types in adults, and then understanding how the functions of these cell types become established, using cell-type-specific molecular and synaptic mechanisms in developing animals. Recently, I have identified several transgenic mouse lines in which specific cell types in a visual center, the superior colliculus, are labeled with Cre recombinase in both developing and adult animals. Here I will take advantage of these mouse lines to ask fundamental questions about the functional development of neural circuits. First, how are distinct sensory features processed by the parallel topographic neuronal pathways, and how do they contribute to behavior? Second, what are the molecular and synaptic mechanisms that underlie developmental circuit plasticity for forming parallel topographic neuronal maps in the brain? Third, what are the molecular mechanisms that set up spatially asymmetric circuit connectivity without the need for sensory experience? I predict that my insights into the developmental mechanism of asymmetric, parallel, and topographic connectivity and circuit plasticity will be instructive when studying other brain circuits which contain similar organizing principles.
Max ERC Funding
1 500 000 €
Duration
Start date: 2015-04-01, End date: 2020-03-31
Project acronym CSUMECH
Project Cholesterol and Sugar Uptake Mechanisms
Researcher (PI) Bjoern Pedersen
Host Institution (HI) AARHUS UNIVERSITET
Country Denmark
Call Details Starting Grant (StG), LS1, ERC-2014-STG
Summary Cardiovascular disease, diabetes and cancer have a dramatic impact on modern society, and in great part are related to uptake of cholesterol and sugar. We still know surprisingly little about the molecular details of the processes that goes on in this essential part of human basic metabolism. This application addresses cholesterol and sugar transport and aim to elucidate the molecular mechanism of cholesterol and sugar uptake in humans. It moves the frontiers of the field by shifting the focus to in vitro work allowing hitherto untried structural and biochemical experiments to be performed.
Cholesterol uptake from the intestine is mediated by the membrane protein NPC1L1. Despite extensive research, the molecular mechanism of NPC1L1-dependent cholesterol uptake still remains largely unknown.
Facilitated sugar transport in humans is made possible by sugar transporters called GLUTs and SWEETs, and every cell possesses these sugar transport systems. For all these uptake systems structural information is sorely lacking to address important mechanistic questions to help elucidate their molecular mechanism.
I will address this using a complementary set of methods founded in macromolecular crystallography and electron microscopy to determine the 3-dimensional structures of key players in these uptake systems. My unpublished preliminary results have established the feasibility of this approach. This will be followed up by biochemical characterization of the molecular mechanism in vitro and in silico.
This high risk/high reward membrane protein proposal could lead to a breakthrough in how we approach human biochemical pathways that are linked to trans-membrane transport. An improved understanding of cholesterol and sugar homeostasis has tremendous potential for improving general public health, and furthermore this proposal will help to uncover general principles of endocytotic uptake and facilitated diffusion systems at the molecular level.
Summary
Cardiovascular disease, diabetes and cancer have a dramatic impact on modern society, and in great part are related to uptake of cholesterol and sugar. We still know surprisingly little about the molecular details of the processes that goes on in this essential part of human basic metabolism. This application addresses cholesterol and sugar transport and aim to elucidate the molecular mechanism of cholesterol and sugar uptake in humans. It moves the frontiers of the field by shifting the focus to in vitro work allowing hitherto untried structural and biochemical experiments to be performed.
Cholesterol uptake from the intestine is mediated by the membrane protein NPC1L1. Despite extensive research, the molecular mechanism of NPC1L1-dependent cholesterol uptake still remains largely unknown.
Facilitated sugar transport in humans is made possible by sugar transporters called GLUTs and SWEETs, and every cell possesses these sugar transport systems. For all these uptake systems structural information is sorely lacking to address important mechanistic questions to help elucidate their molecular mechanism.
I will address this using a complementary set of methods founded in macromolecular crystallography and electron microscopy to determine the 3-dimensional structures of key players in these uptake systems. My unpublished preliminary results have established the feasibility of this approach. This will be followed up by biochemical characterization of the molecular mechanism in vitro and in silico.
This high risk/high reward membrane protein proposal could lead to a breakthrough in how we approach human biochemical pathways that are linked to trans-membrane transport. An improved understanding of cholesterol and sugar homeostasis has tremendous potential for improving general public health, and furthermore this proposal will help to uncover general principles of endocytotic uptake and facilitated diffusion systems at the molecular level.
Max ERC Funding
1 499 848 €
Duration
Start date: 2015-07-01, End date: 2020-12-31
Project acronym EUROHERIT
Project Legitimation of European cultural heritage and the dynamics of identity politics in the EU
Researcher (PI) Tuuli Kaarina Laehdesmaeki
Host Institution (HI) JYVASKYLAN YLIOPISTO
Country Finland
Call Details Starting Grant (StG), SH5, ERC-2014-STG
Summary The problematic of transnational cultural heritage has become topical in a new way in Europe with the utilization of the idea of heritage for political purposes in the EU policy. Since the turn of the century, the EU has launched or jointly administered several initiatives focusing on fostering the idea of a common European cultural heritage. The heritage initiatives are the EU’s ‘technologies of power’ aiming to legitimate and justify certain political ideas and ideologies, such as European-wide identity politics and the cultural integration in Europe. However, the politics, discourses, and practices of heritage—and of transnational heritage in particular—are often intertwined with contentions over its symbolical and factual ownership, meanings, and uses. The project investigates the EU as a new heritage agent and its heritage politics as an attempt to create a new trans-European heritage regime in Europe: How does the EU aim to create common European cultural heritage in a politically shaking and culturally diversified Europe, and what kind of explicit and implicit politics are included in its aims? The project will focus on the legitimation processes of European cultural heritage at different territorial levels and the power relations formed in the processes between diverse agencies. The academia still lacks a comparative empirical investigation on the politics and practices of trans-European cultural heritage and the theoretical discussion on the role of the EU in them. The project aims to respond to this lack with a broad comparative empirical research including cases from various parts of Europe, penetrating different territorial scales (local, regional, national, and the EU), and theorizing cultural heritage from a multisectional perspective (stressing its concurrent use in diverse societal domains and discourses). The project participates in a critical discussion on the current identity and integration politics and policies in the EU and Europe.
Summary
The problematic of transnational cultural heritage has become topical in a new way in Europe with the utilization of the idea of heritage for political purposes in the EU policy. Since the turn of the century, the EU has launched or jointly administered several initiatives focusing on fostering the idea of a common European cultural heritage. The heritage initiatives are the EU’s ‘technologies of power’ aiming to legitimate and justify certain political ideas and ideologies, such as European-wide identity politics and the cultural integration in Europe. However, the politics, discourses, and practices of heritage—and of transnational heritage in particular—are often intertwined with contentions over its symbolical and factual ownership, meanings, and uses. The project investigates the EU as a new heritage agent and its heritage politics as an attempt to create a new trans-European heritage regime in Europe: How does the EU aim to create common European cultural heritage in a politically shaking and culturally diversified Europe, and what kind of explicit and implicit politics are included in its aims? The project will focus on the legitimation processes of European cultural heritage at different territorial levels and the power relations formed in the processes between diverse agencies. The academia still lacks a comparative empirical investigation on the politics and practices of trans-European cultural heritage and the theoretical discussion on the role of the EU in them. The project aims to respond to this lack with a broad comparative empirical research including cases from various parts of Europe, penetrating different territorial scales (local, regional, national, and the EU), and theorizing cultural heritage from a multisectional perspective (stressing its concurrent use in diverse societal domains and discourses). The project participates in a critical discussion on the current identity and integration politics and policies in the EU and Europe.
Max ERC Funding
1 339 755 €
Duration
Start date: 2015-09-01, End date: 2020-08-31
Project acronym FLOWTONICS
Project Solid-state flow as a novel approach for the fabrication of photonic devices
Researcher (PI) Fabien Sorin
Host Institution (HI) ECOLE POLYTECHNIQUE FEDERALE DE LAUSANNE
Country Switzerland
Call Details Starting Grant (StG), PE5, ERC-2015-STG
Summary The development of advanced photon-based technologies offers exciting promises in fields of crucial importance for the development of sustainable societies such as energy and food management, security and health care. Innovative photonic devices will however reveal their true potential if we can deploy their functionalities not only on rigid wafers, but also over large-area, flexible and stretchable substrates. Indeed, providing energy harvesting, sensing, or stimulating abilities over windows, screens, food packages, wearable textiles, or even biological tissues will be invaluable technological breakthroughs. Today, however, conventional fabrication approaches remain difficult to scale to large area, and are not well adapted to the mechanical and topological requirements of non-rigid and curved substrates. In FLOWTONICS, we propose innovative materials processing approaches and device architectures to enable the simple and scalable fabrication of nano-structured photonic systems compatible with flexible and stretchable substrates. Our strategy is to direct the flow of optical materials through an innovative and thus far unexplored exploitation of the solid-state dewetting and thermal drawing processes. Our objectives are three-fold: (1) Study and demonstrate, for the first time, the strong potential of the dewetting of chalcogenide glasses layers for the fabrication of large area photonic devices; (2) Show that dewetting can also be exploited to realize photonic architectures onto engineered, nano-imprinted flexible and stretchable polymer substrates; (3) Demonstrate, for the first time, the use of the thermal drawing process as a novel tool to realize advanced flexible and stretchable photonic ribbons and fibers. These novel approaches can contribute to game-changing scientific and technological advances for the sustainable management of our resources and to meet our growing health care needs, putting Europe at the forefront of innovation in these crucial areas.
Summary
The development of advanced photon-based technologies offers exciting promises in fields of crucial importance for the development of sustainable societies such as energy and food management, security and health care. Innovative photonic devices will however reveal their true potential if we can deploy their functionalities not only on rigid wafers, but also over large-area, flexible and stretchable substrates. Indeed, providing energy harvesting, sensing, or stimulating abilities over windows, screens, food packages, wearable textiles, or even biological tissues will be invaluable technological breakthroughs. Today, however, conventional fabrication approaches remain difficult to scale to large area, and are not well adapted to the mechanical and topological requirements of non-rigid and curved substrates. In FLOWTONICS, we propose innovative materials processing approaches and device architectures to enable the simple and scalable fabrication of nano-structured photonic systems compatible with flexible and stretchable substrates. Our strategy is to direct the flow of optical materials through an innovative and thus far unexplored exploitation of the solid-state dewetting and thermal drawing processes. Our objectives are three-fold: (1) Study and demonstrate, for the first time, the strong potential of the dewetting of chalcogenide glasses layers for the fabrication of large area photonic devices; (2) Show that dewetting can also be exploited to realize photonic architectures onto engineered, nano-imprinted flexible and stretchable polymer substrates; (3) Demonstrate, for the first time, the use of the thermal drawing process as a novel tool to realize advanced flexible and stretchable photonic ribbons and fibers. These novel approaches can contribute to game-changing scientific and technological advances for the sustainable management of our resources and to meet our growing health care needs, putting Europe at the forefront of innovation in these crucial areas.
Max ERC Funding
1 499 585 €
Duration
Start date: 2016-02-01, End date: 2021-07-31
Project acronym HBMAP
Project Decoding, Mapping and Designing the Structural Complexity of Hydrogen-Bond Networks: from Water to Proteins to Polymers
Researcher (PI) Michele Ceriotti
Host Institution (HI) ECOLE POLYTECHNIQUE FEDERALE DE LAUSANNE
Country Switzerland
Call Details Starting Grant (StG), PE4, ERC-2015-STG
Summary Hydrogen bonds are ubiquitous and fundamental in nature, underpinning the behavior of systems as different as water, proteins and polymers. Much of this flexibility derives from their propensity to form complex topological networks, which can be strong enough to hold Kevlar together, or sufficiently labile to enable reversible structural transitions in allosteric proteins.
Simulations must treat the quantum nature of both electrons and protons to describe accurately the microscopic structure of H-bonded materials, but this wealth of data does not necessarily translate into deep physical understanding. Even the structure of a compound as essential as water is still the subject of intense debate, despite extensive investigations. Identifying recurring bonding patterns is essential to comprehend and manipulate the structural and dynamical properties of H-bonded systems.
Our objective is to develop and apply machine-learning techniques to atomistic simulations, and identify the design principles that govern the structure and properties of H-bonded compounds. Our strategy rests on three efforts: (1) recognition of recurring structural motifs with probabilistic data analysis; (2) coarse-grained mapping of the energetically accessible structural landscape by non-linear dimensionality reduction techniques; (3) acceleration of configuration sampling using these data-driven collective variables.
Identifying motifs and order parameters will be crucial to interpret simulations and experiments of growing complexity, and will enable computational design of H-bond networks. We will focus first on two objectives. (1) Rationalizing the structure of crystalline, amorphous and liquid water across its phase diagram, from ambient to astrophysical conditions, and its response to solutes, interfaces or confinement. (2) Enabling efficient simulation and structural design of polymers and proteins in non-biological contexts, targeting biomimetic materials and organic/inorganic interfaces.
Summary
Hydrogen bonds are ubiquitous and fundamental in nature, underpinning the behavior of systems as different as water, proteins and polymers. Much of this flexibility derives from their propensity to form complex topological networks, which can be strong enough to hold Kevlar together, or sufficiently labile to enable reversible structural transitions in allosteric proteins.
Simulations must treat the quantum nature of both electrons and protons to describe accurately the microscopic structure of H-bonded materials, but this wealth of data does not necessarily translate into deep physical understanding. Even the structure of a compound as essential as water is still the subject of intense debate, despite extensive investigations. Identifying recurring bonding patterns is essential to comprehend and manipulate the structural and dynamical properties of H-bonded systems.
Our objective is to develop and apply machine-learning techniques to atomistic simulations, and identify the design principles that govern the structure and properties of H-bonded compounds. Our strategy rests on three efforts: (1) recognition of recurring structural motifs with probabilistic data analysis; (2) coarse-grained mapping of the energetically accessible structural landscape by non-linear dimensionality reduction techniques; (3) acceleration of configuration sampling using these data-driven collective variables.
Identifying motifs and order parameters will be crucial to interpret simulations and experiments of growing complexity, and will enable computational design of H-bond networks. We will focus first on two objectives. (1) Rationalizing the structure of crystalline, amorphous and liquid water across its phase diagram, from ambient to astrophysical conditions, and its response to solutes, interfaces or confinement. (2) Enabling efficient simulation and structural design of polymers and proteins in non-biological contexts, targeting biomimetic materials and organic/inorganic interfaces.
Max ERC Funding
1 500 000 €
Duration
Start date: 2016-05-01, End date: 2021-04-30
Project acronym HOLDING-HANDS
Project Holding hands: cell-cell junctions in breast cancer metastasis and resistance to therapy
Researcher (PI) Nicola Aceto
Host Institution (HI) UNIVERSITAT BASEL
Country Switzerland
Call Details Starting Grant (StG), LS4, ERC-2015-STG
Summary Breast cancer is the most common cancer in women, resulting in as many as 500000 deaths per year worldwide. Patients with breast cancer die unequivocally because of the development of incurable distant metastases and not because of symptoms related to the primary site. Understanding the complex, yet fundamental mechanisms driving breast cancer metastasis is critical to develop therapies tailored to this disease.
The current understanding of how metastasis occurs is derived primarily from mouse models and largely dominated by the notion that single migratory cancer cells within the primary tumor can actively disseminate to distant sites and develop as metastatic deposits. Unexpectedly, our very recent study on patient blood samples has shown that cancer cell groupings, held together through strong cell-cell junctions, can break off the primary tumor and form a metastatic lesion up to 50 times more efficiently than single migratory cancer cells (Aceto et al, Cell, 2014). These findings lead to new open questions, yet highlight a previously unappreciated and targetable mechanism of cancer dissemination.
Our preliminary data suggest that, among all types of cell-cell junctions, desmosomes and tight junctions are involved in this process, and therefore represent unprecedented options for developing a metastasis-tailored therapy for breast cancer.
The two predominant goals of this proposal are: first, to define the role of specific desmosome (DSG2) and tight junction (CLDN3 and TJP2) components in the development of metastasis. Second, to address their involvement in cellular signaling and response to therapy. These studies will not only use our first-of-a-kind in vivo models developed from patients with breast cancer metastases, but also cross the boundaries between basic science and clinical applications.
Our research has the long-term ambition to lead to a novel class of therapeutic agents tailored to block cell-cell junctions and prevent metastatic spread of cancer.
Summary
Breast cancer is the most common cancer in women, resulting in as many as 500000 deaths per year worldwide. Patients with breast cancer die unequivocally because of the development of incurable distant metastases and not because of symptoms related to the primary site. Understanding the complex, yet fundamental mechanisms driving breast cancer metastasis is critical to develop therapies tailored to this disease.
The current understanding of how metastasis occurs is derived primarily from mouse models and largely dominated by the notion that single migratory cancer cells within the primary tumor can actively disseminate to distant sites and develop as metastatic deposits. Unexpectedly, our very recent study on patient blood samples has shown that cancer cell groupings, held together through strong cell-cell junctions, can break off the primary tumor and form a metastatic lesion up to 50 times more efficiently than single migratory cancer cells (Aceto et al, Cell, 2014). These findings lead to new open questions, yet highlight a previously unappreciated and targetable mechanism of cancer dissemination.
Our preliminary data suggest that, among all types of cell-cell junctions, desmosomes and tight junctions are involved in this process, and therefore represent unprecedented options for developing a metastasis-tailored therapy for breast cancer.
The two predominant goals of this proposal are: first, to define the role of specific desmosome (DSG2) and tight junction (CLDN3 and TJP2) components in the development of metastasis. Second, to address their involvement in cellular signaling and response to therapy. These studies will not only use our first-of-a-kind in vivo models developed from patients with breast cancer metastases, but also cross the boundaries between basic science and clinical applications.
Our research has the long-term ambition to lead to a novel class of therapeutic agents tailored to block cell-cell junctions and prevent metastatic spread of cancer.
Max ERC Funding
1 744 921 €
Duration
Start date: 2016-03-01, End date: 2021-02-28
Project acronym Immune Regulation
Project How Infection History Shapes the Immune System: Pathogen-induced Changes in Regulatory T Cells
Researcher (PI) Nicole Christine Joller
Host Institution (HI) UNIVERSITAT ZURICH
Country Switzerland
Call Details Starting Grant (StG), LS6, ERC-2015-STG
Summary Studying host-pathogen interactions by focusing on the interaction of a single pathogen with the host has defined our understanding of these events and the insights gained form the basis for the therapeutic and vaccination strategies we use today. However, people become infected with multiple pathogens throughout their lifetime, at times even simultaneously. Still, it is largely unknown how the immune response to one pathogen alters the body’s ability to respond to a second infectious agent or the susceptibility to autoimmunity or cancer. This project will address this question by focusing on infection-induced changes in regulatory T cells (Tregs) as they may lead to biased suppression and changes in the nature of subsequent immune responses.
Our efforts will focus on two areas: In a first part, we will use single cell RNA-Seq to address how infections shape the Treg compartment by defining the specialized Treg subsets generated during polarized infectious settings and analyzing how they interact with effector T cells. Based on the depth of information we expect to obtain from this approach, we envisage finding thus far unappreciated interactions and functions of Tregs in the course of an immune response. The second part will investigate how an altered Treg compartment, either through genetic modifications or infection-induced, affects disease susceptibility. In this context, we will also address stability and persistence of pathogen-induced changes in the Treg compartment. Collectively the proposed experiments will allow us to start addressing how preceding infections affect disease susceptibility. Deciphering how infection history shapes the Treg compartment and how this affects susceptibility to future challenges will lay the groundwork for addressing this question more broadly in the future and as such will likely have a transformative impact on the field.
Summary
Studying host-pathogen interactions by focusing on the interaction of a single pathogen with the host has defined our understanding of these events and the insights gained form the basis for the therapeutic and vaccination strategies we use today. However, people become infected with multiple pathogens throughout their lifetime, at times even simultaneously. Still, it is largely unknown how the immune response to one pathogen alters the body’s ability to respond to a second infectious agent or the susceptibility to autoimmunity or cancer. This project will address this question by focusing on infection-induced changes in regulatory T cells (Tregs) as they may lead to biased suppression and changes in the nature of subsequent immune responses.
Our efforts will focus on two areas: In a first part, we will use single cell RNA-Seq to address how infections shape the Treg compartment by defining the specialized Treg subsets generated during polarized infectious settings and analyzing how they interact with effector T cells. Based on the depth of information we expect to obtain from this approach, we envisage finding thus far unappreciated interactions and functions of Tregs in the course of an immune response. The second part will investigate how an altered Treg compartment, either through genetic modifications or infection-induced, affects disease susceptibility. In this context, we will also address stability and persistence of pathogen-induced changes in the Treg compartment. Collectively the proposed experiments will allow us to start addressing how preceding infections affect disease susceptibility. Deciphering how infection history shapes the Treg compartment and how this affects susceptibility to future challenges will lay the groundwork for addressing this question more broadly in the future and as such will likely have a transformative impact on the field.
Max ERC Funding
1 499 755 €
Duration
Start date: 2016-06-01, End date: 2022-05-31
Project acronym InterWiring
Project Wiring up the SomatoSensory Cortex
Researcher (PI) Theofanis Karayannis
Host Institution (HI) UNIVERSITAT ZURICH
Country Switzerland
Call Details Starting Grant (StG), LS5, ERC-2015-STG
Summary Understanding how the mammalian brain network acquires its ability during development to process information and interact with the environment is one of the fundamental challenges in modern biology.
The brain originates from a sheet of neural progenitors during embryogenesis but rapidly develops into distinct functional areas such as primary sensory and the highly associative cortices. Although all cortical areas consist of the same main neuronal elements, excitatory and inhibitory cells, their functions are markedly distinct. Unlike others, primary sensory cortical regions receive direct inputs from the environment through the respective thalamic nuclei starting at an early stage in development and are therefore likely to be shaped by incoming activity from sensory modalities. Despite the plethora of data on the arealization of the cortex by early signaling centers and the critical period plasticity mechanisms which take place after the basic elements of the circuit have been laid out, very little is known about the important period in between and how individual elements bind together to construct a functional circuit.
This proposal is aimed at bridging this gap in knowledge, by addressing the long-standing question of how genes and activity interact during development to establish the correct wiring of excitatory and inhibitory cells in cortical sensory areas.
As the primary role of inhibitory cells is to shape the flow of information transfer in the brain, they are well positioned to contribute significantly to the distinct modes of information processing performed in different cortical areas. Considering that dysfunction of cortical inhibitory circuits has been proposed as a major contributor to the etiology of neuropsychiatric-neurodevelopmental disorders, it is my hope that this approach will not only provide insights into the making of the healthy brain, but also into clinically relevant pathologies.
Summary
Understanding how the mammalian brain network acquires its ability during development to process information and interact with the environment is one of the fundamental challenges in modern biology.
The brain originates from a sheet of neural progenitors during embryogenesis but rapidly develops into distinct functional areas such as primary sensory and the highly associative cortices. Although all cortical areas consist of the same main neuronal elements, excitatory and inhibitory cells, their functions are markedly distinct. Unlike others, primary sensory cortical regions receive direct inputs from the environment through the respective thalamic nuclei starting at an early stage in development and are therefore likely to be shaped by incoming activity from sensory modalities. Despite the plethora of data on the arealization of the cortex by early signaling centers and the critical period plasticity mechanisms which take place after the basic elements of the circuit have been laid out, very little is known about the important period in between and how individual elements bind together to construct a functional circuit.
This proposal is aimed at bridging this gap in knowledge, by addressing the long-standing question of how genes and activity interact during development to establish the correct wiring of excitatory and inhibitory cells in cortical sensory areas.
As the primary role of inhibitory cells is to shape the flow of information transfer in the brain, they are well positioned to contribute significantly to the distinct modes of information processing performed in different cortical areas. Considering that dysfunction of cortical inhibitory circuits has been proposed as a major contributor to the etiology of neuropsychiatric-neurodevelopmental disorders, it is my hope that this approach will not only provide insights into the making of the healthy brain, but also into clinically relevant pathologies.
Max ERC Funding
1 970 000 €
Duration
Start date: 2016-11-01, End date: 2022-04-30
Project acronym LimitMDR
Project Utilizing evolutionary interactions to limit multidrug resistance
Researcher (PI) Morten Otto Alexander Sommer
Host Institution (HI) DANMARKS TEKNISKE UNIVERSITET
Country Denmark
Call Details Starting Grant (StG), LS2, ERC-2014-STG
Summary Drug resistance is limiting our ability to treat most infectious diseases and forms of cancer. Indeed this relentless evolution is the major driver of treatment failure for diseases that are responsible for over half of the global disease related mortality. Yet, the underlying principles that guide this evolutionary response are poorly understood, in particular with regards to understanding the impact of multidrug treatment.
LimitMDR will characterize evolutionary trajectories leading to multidrug resistance in response to individual and combination drug treatment through the execution of large-scale adaptive evolution experiment with two bacterial pathogens followed by genome sequencing and phenotyping. This effort will enable testing of contrasting hypotheses regarding the evolution of multidrug resistance in response to combination treatment.
We will characterize the cause-and-effect of resistance and sensitivity mutations identified in our global data set and map comprehensive fitness landscapes of mutations accumulated during drug resistance evolution to understand the evolutionary dynamics underlying resistance evolution. To accomplish these bold goals we shall develop novel multiplexed methodologies enabling unprecedented scale of construction and phenotypic testing of identified mutations. While genetic epistasis is considered of key importance to resistance evolution most studies focus on mutations within an individual gene. Through the development of a novel experimental approach we shall elucidate complex epistatic interaction networks between mutations accumulated during resistance evolution.
Finally, we will conduct mechanistic studies to uncover the mechanisms of collateral sensitivity. These studies will shed light on this underappreciated phenomenon, which is of critical relevance to drug discovery and the evolution of drug resistance. In conclusion LimitMDR will develop groundbreaking novel methodologies and scientific insights that will c
Summary
Drug resistance is limiting our ability to treat most infectious diseases and forms of cancer. Indeed this relentless evolution is the major driver of treatment failure for diseases that are responsible for over half of the global disease related mortality. Yet, the underlying principles that guide this evolutionary response are poorly understood, in particular with regards to understanding the impact of multidrug treatment.
LimitMDR will characterize evolutionary trajectories leading to multidrug resistance in response to individual and combination drug treatment through the execution of large-scale adaptive evolution experiment with two bacterial pathogens followed by genome sequencing and phenotyping. This effort will enable testing of contrasting hypotheses regarding the evolution of multidrug resistance in response to combination treatment.
We will characterize the cause-and-effect of resistance and sensitivity mutations identified in our global data set and map comprehensive fitness landscapes of mutations accumulated during drug resistance evolution to understand the evolutionary dynamics underlying resistance evolution. To accomplish these bold goals we shall develop novel multiplexed methodologies enabling unprecedented scale of construction and phenotypic testing of identified mutations. While genetic epistasis is considered of key importance to resistance evolution most studies focus on mutations within an individual gene. Through the development of a novel experimental approach we shall elucidate complex epistatic interaction networks between mutations accumulated during resistance evolution.
Finally, we will conduct mechanistic studies to uncover the mechanisms of collateral sensitivity. These studies will shed light on this underappreciated phenomenon, which is of critical relevance to drug discovery and the evolution of drug resistance. In conclusion LimitMDR will develop groundbreaking novel methodologies and scientific insights that will c
Max ERC Funding
1 492 453 €
Duration
Start date: 2015-05-01, End date: 2020-04-30
Project acronym NanoSCAN
Project Developing multi-modality nanomedicines for targeted annotation of oncogenic signaling pathways
Researcher (PI) Jason Philip Holland
Host Institution (HI) UNIVERSITAT ZURICH
Country Switzerland
Call Details Starting Grant (StG), LS7, ERC-2015-STG
Summary Spatial and temporal changes in the underlying biochemistry of cancer control disease progression and response/resistance to treatment. Developing methods to detect changes in oncogenic signaling at an early stage is vital to further our understanding of cancer, and will advance the next generation of anti-cancer therapies. Nanomedicine is the medical application of nanotechnology to diagnose or treat disease. In light of the recent introduction of tools like Positron Emission Tomography/Magnetic Resonance Imaging (PET/MRI) scanners, there is now a new opportunity to develop hybrid imaging protocols that can simultaneously take advantage of the functional and anatomic information available from PET/MRI to address changes in oncogenic signaling pathways. The work outlined in this interdisciplinary ERC Project is designed to advance new chemistry and imaging methods to measure changes in oncogenic signaling in various cancers before, during and after treatment using PET/MRI. The long-term goals are to expand the scope and utility of radiolabelled nanomedicines as dual-modality PET/MRI probes for detecting changes in oncogenic signaling in various cancers and develop efficient methods for translating new technologies to the clinic. Successful completion of this ERC Project has the potential to transform personalised clinical management of cancer patients via advanced PET/MRI detection of oncogenic signaling processes.
Summary
Spatial and temporal changes in the underlying biochemistry of cancer control disease progression and response/resistance to treatment. Developing methods to detect changes in oncogenic signaling at an early stage is vital to further our understanding of cancer, and will advance the next generation of anti-cancer therapies. Nanomedicine is the medical application of nanotechnology to diagnose or treat disease. In light of the recent introduction of tools like Positron Emission Tomography/Magnetic Resonance Imaging (PET/MRI) scanners, there is now a new opportunity to develop hybrid imaging protocols that can simultaneously take advantage of the functional and anatomic information available from PET/MRI to address changes in oncogenic signaling pathways. The work outlined in this interdisciplinary ERC Project is designed to advance new chemistry and imaging methods to measure changes in oncogenic signaling in various cancers before, during and after treatment using PET/MRI. The long-term goals are to expand the scope and utility of radiolabelled nanomedicines as dual-modality PET/MRI probes for detecting changes in oncogenic signaling in various cancers and develop efficient methods for translating new technologies to the clinic. Successful completion of this ERC Project has the potential to transform personalised clinical management of cancer patients via advanced PET/MRI detection of oncogenic signaling processes.
Max ERC Funding
1 700 000 €
Duration
Start date: 2016-09-01, End date: 2022-01-31
