Project acronym 2STEPPARKIN
Project A novel two-step model for neurodegeneration in Parkinson’s disease
Researcher (PI) Emi Nagoshi
Host Institution (HI) UNIVERSITE DE GENEVE
Call Details Starting Grant (StG), LS5, ERC-2012-StG_20111109
Summary Parkinson’s disease (PD) is the second most common neurodegenerative disorder primarily caused by the progressive loss of dopaminergic (DA) neurons in the substantia nigra (SN). Despite the advances in gene discovery associated with PD, the knowledge of the PD pathogenesis is largely limited to the involvement of these genes in the generic cell death pathways, and why degeneration is specific to DA neurons and why the degeneration is progressive remain enigmatic. Broad goal of our work is therefore to elucidate the mechanisms underlying specific and progressive DA neuron degeneration in PD. Our new Drosophila model of PD ⎯Fer2 gene loss-of-function mutation⎯ is unusually well suited to address these questions. Fer2 mutants exhibit specific and progressive death of brain DA neurons as well as severe locomotor defects and short life span. Strikingly, the death of DA neuron is initiated in a small cluster of Fer2-expressing DA neurons and subsequently propagates to Fer2-negative DA neurons. We therefore propose a novel two-step model of the neurodegeneration in PD: primary cell death occurs in a specific subset of dopamindegic neurons that are genetically defined, and subsequently the failure of the neuronal connectivity triggers and propagates secondary cell death to remaining DA neurons. In this research, we will test this hypothesis and investigate the underlying molecular mechanisms. This will be the first study to examine circuit-dependency in DA neuron degeneration. Our approach will use a combination of non-biased genomic techniques and candidate-based screening, in addition to the powerful Drosophila genetic toolbox. Furthermore, to test this hypothesis beyond the Drosophila model, we will establish new mouse models of PD that exhibit progressive DA neuron degeneration. Outcome of this research will likely revolutionize the understanding of PD pathogenesis and open an avenue toward the discovery of effective therapy strategies against PD.
Summary
Parkinson’s disease (PD) is the second most common neurodegenerative disorder primarily caused by the progressive loss of dopaminergic (DA) neurons in the substantia nigra (SN). Despite the advances in gene discovery associated with PD, the knowledge of the PD pathogenesis is largely limited to the involvement of these genes in the generic cell death pathways, and why degeneration is specific to DA neurons and why the degeneration is progressive remain enigmatic. Broad goal of our work is therefore to elucidate the mechanisms underlying specific and progressive DA neuron degeneration in PD. Our new Drosophila model of PD ⎯Fer2 gene loss-of-function mutation⎯ is unusually well suited to address these questions. Fer2 mutants exhibit specific and progressive death of brain DA neurons as well as severe locomotor defects and short life span. Strikingly, the death of DA neuron is initiated in a small cluster of Fer2-expressing DA neurons and subsequently propagates to Fer2-negative DA neurons. We therefore propose a novel two-step model of the neurodegeneration in PD: primary cell death occurs in a specific subset of dopamindegic neurons that are genetically defined, and subsequently the failure of the neuronal connectivity triggers and propagates secondary cell death to remaining DA neurons. In this research, we will test this hypothesis and investigate the underlying molecular mechanisms. This will be the first study to examine circuit-dependency in DA neuron degeneration. Our approach will use a combination of non-biased genomic techniques and candidate-based screening, in addition to the powerful Drosophila genetic toolbox. Furthermore, to test this hypothesis beyond the Drosophila model, we will establish new mouse models of PD that exhibit progressive DA neuron degeneration. Outcome of this research will likely revolutionize the understanding of PD pathogenesis and open an avenue toward the discovery of effective therapy strategies against PD.
Max ERC Funding
1 518 960 €
Duration
Start date: 2013-06-01, End date: 2018-05-31
Project acronym ADAPTIVES
Project Algorithmic Development and Analysis of Pioneer Techniques for Imaging with waVES
Researcher (PI) Chrysoula Tsogka
Host Institution (HI) IDRYMA TECHNOLOGIAS KAI EREVNAS
Call Details Starting Grant (StG), PE1, ERC-2009-StG
Summary The proposed work concerns the theoretical and numerical development of robust and adaptive methodologies for broadband imaging in clutter. The word clutter expresses our uncertainty on the wave speed of the propagation medium. Our results are expected to have a strong impact in a wide range of applications, including underwater acoustics, exploration geophysics and ultrasound non-destructive testing. Our machinery is coherent interferometry (CINT), a state-of-the-art statistically stable imaging methodology, highly suitable for the development of imaging methods in clutter. We aim to extend CINT along two complementary directions: novel types of applications, and further mathematical and numerical development so as to assess and extend its range of applicability. CINT is designed for imaging with partially coherent array data recorded in richly scattering media. It uses statistical smoothing techniques to obtain results that are independent of the clutter realization. Quantifying the amount of smoothing needed is difficult, especially when there is no a priori knowledge about the propagation medium. We intend to address this question by coupling the imaging process with the estimation of the medium's large scale features. Our algorithms rely on the residual coherence in the data. When the coherent signal is too weak, the CINT results are unsatisfactory. We propose two ways for enhancing the resolution of CINT: filter the data prior to imaging (noise reduction) and waveform design (optimize the source distribution). Finally, we propose to extend the applicability of our imaging-in-clutter methodologies by investigating the possibility of utilizing ambient noise sources to perform passive sensor imaging, as well as by studying the imaging problem in random waveguides.
Summary
The proposed work concerns the theoretical and numerical development of robust and adaptive methodologies for broadband imaging in clutter. The word clutter expresses our uncertainty on the wave speed of the propagation medium. Our results are expected to have a strong impact in a wide range of applications, including underwater acoustics, exploration geophysics and ultrasound non-destructive testing. Our machinery is coherent interferometry (CINT), a state-of-the-art statistically stable imaging methodology, highly suitable for the development of imaging methods in clutter. We aim to extend CINT along two complementary directions: novel types of applications, and further mathematical and numerical development so as to assess and extend its range of applicability. CINT is designed for imaging with partially coherent array data recorded in richly scattering media. It uses statistical smoothing techniques to obtain results that are independent of the clutter realization. Quantifying the amount of smoothing needed is difficult, especially when there is no a priori knowledge about the propagation medium. We intend to address this question by coupling the imaging process with the estimation of the medium's large scale features. Our algorithms rely on the residual coherence in the data. When the coherent signal is too weak, the CINT results are unsatisfactory. We propose two ways for enhancing the resolution of CINT: filter the data prior to imaging (noise reduction) and waveform design (optimize the source distribution). Finally, we propose to extend the applicability of our imaging-in-clutter methodologies by investigating the possibility of utilizing ambient noise sources to perform passive sensor imaging, as well as by studying the imaging problem in random waveguides.
Max ERC Funding
690 000 €
Duration
Start date: 2010-06-01, End date: 2015-11-30
Project acronym ADIPODIF
Project Adipocyte Differentiation and Metabolic Functions in Obesity and Type 2 Diabetes
Researcher (PI) Christian Wolfrum
Host Institution (HI) EIDGENOESSISCHE TECHNISCHE HOCHSCHULE ZUERICH
Call Details Starting Grant (StG), LS6, ERC-2007-StG
Summary Obesity associated disorders such as T2D, hypertension and CVD, commonly referred to as the “metabolic syndrome”, are prevalent diseases of industrialized societies. Deranged adipose tissue proliferation and differentiation contribute significantly to the development of these metabolic disorders. Comparatively little however is known, about how these processes influence the development of metabolic disorders. Using a multidisciplinary approach, I plan to elucidate molecular mechanisms underlying the altered adipocyte differentiation and maturation in different models of obesity associated metabolic disorders. Special emphasis will be given to the analysis of gene expression, postranslational modifications and lipid molecular species composition. To achieve this goal, I am establishing several novel methods to isolate pure primary preadipocytes including a new animal model that will allow me to monitor preadipocytes, in vivo and track their cellular fate in the context of a complete organism. These systems will allow, for the first time to study preadipocyte biology, in an in vivo setting. By monitoring preadipocyte differentiation in vivo, I will also be able to answer the key questions regarding the development of preadipocytes and examine signals that induce or inhibit their differentiation. Using transplantation techniques, I will elucidate the genetic and environmental contributions to the progression of obesity and its associated metabolic disorders. Furthermore, these studies will integrate a lipidomics approach to systematically analyze lipid molecular species composition in different models of metabolic disorders. My studies will provide new insights into the mechanisms and dynamics underlying adipocyte differentiation and maturation, and relate them to metabolic disorders. Detailed knowledge of these mechanisms will facilitate development of novel therapeutic approaches for the treatment of obesity and associated metabolic disorders.
Summary
Obesity associated disorders such as T2D, hypertension and CVD, commonly referred to as the “metabolic syndrome”, are prevalent diseases of industrialized societies. Deranged adipose tissue proliferation and differentiation contribute significantly to the development of these metabolic disorders. Comparatively little however is known, about how these processes influence the development of metabolic disorders. Using a multidisciplinary approach, I plan to elucidate molecular mechanisms underlying the altered adipocyte differentiation and maturation in different models of obesity associated metabolic disorders. Special emphasis will be given to the analysis of gene expression, postranslational modifications and lipid molecular species composition. To achieve this goal, I am establishing several novel methods to isolate pure primary preadipocytes including a new animal model that will allow me to monitor preadipocytes, in vivo and track their cellular fate in the context of a complete organism. These systems will allow, for the first time to study preadipocyte biology, in an in vivo setting. By monitoring preadipocyte differentiation in vivo, I will also be able to answer the key questions regarding the development of preadipocytes and examine signals that induce or inhibit their differentiation. Using transplantation techniques, I will elucidate the genetic and environmental contributions to the progression of obesity and its associated metabolic disorders. Furthermore, these studies will integrate a lipidomics approach to systematically analyze lipid molecular species composition in different models of metabolic disorders. My studies will provide new insights into the mechanisms and dynamics underlying adipocyte differentiation and maturation, and relate them to metabolic disorders. Detailed knowledge of these mechanisms will facilitate development of novel therapeutic approaches for the treatment of obesity and associated metabolic disorders.
Max ERC Funding
1 607 105 €
Duration
Start date: 2008-07-01, End date: 2013-06-30
Project acronym Amygdala Circuits
Project Amygdala Circuits for Appetitive Conditioning
Researcher (PI) Andreas Luthi
Host Institution (HI) FRIEDRICH MIESCHER INSTITUTE FOR BIOMEDICAL RESEARCH FONDATION
Call Details Advanced Grant (AdG), LS5, ERC-2014-ADG
Summary The project outlined here addresses the fundamental question how the brain encodes and controls behavior. While we have a reasonable understanding of the role of entire brain areas in such processes, and of mechanisms at the molecular and synaptic levels, there is a big gap in our knowledge of how behavior is controlled at the level of defined neuronal circuits.
In natural environments, chances for survival depend on learning about possible aversive and appetitive outcomes and on the appropriate behavioral responses. Most studies addressing the underlying mechanisms at the level of neuronal circuits have focused on aversive learning, such as in Pavlovian fear conditioning. Understanding how activity in defined neuronal circuits mediates appetitive learning, as well as how these circuitries are shared and interact with aversive learning circuits, is a central question in the neuroscience of learning and memory and the focus of this grant application.
Using a multidisciplinary approach in mice, combining behavioral, in vivo and in vitro electrophysiological, imaging, optogenetic and state-of-the-art viral circuit tracing techniques, we aim at dissecting the neuronal circuitry of appetitive Pavlovian conditioning with a focus on the amygdala, a key brain region important for both aversive and appetitive learning. Ultimately, elucidating these mechanisms at the level of defined neurons and circuits is fundamental not only for an understanding of memory processes in the brain in general, but also to inform a mechanistic approach to psychiatric conditions associated with amygdala dysfunction and dysregulated emotional responses including anxiety and mood disorders.
Summary
The project outlined here addresses the fundamental question how the brain encodes and controls behavior. While we have a reasonable understanding of the role of entire brain areas in such processes, and of mechanisms at the molecular and synaptic levels, there is a big gap in our knowledge of how behavior is controlled at the level of defined neuronal circuits.
In natural environments, chances for survival depend on learning about possible aversive and appetitive outcomes and on the appropriate behavioral responses. Most studies addressing the underlying mechanisms at the level of neuronal circuits have focused on aversive learning, such as in Pavlovian fear conditioning. Understanding how activity in defined neuronal circuits mediates appetitive learning, as well as how these circuitries are shared and interact with aversive learning circuits, is a central question in the neuroscience of learning and memory and the focus of this grant application.
Using a multidisciplinary approach in mice, combining behavioral, in vivo and in vitro electrophysiological, imaging, optogenetic and state-of-the-art viral circuit tracing techniques, we aim at dissecting the neuronal circuitry of appetitive Pavlovian conditioning with a focus on the amygdala, a key brain region important for both aversive and appetitive learning. Ultimately, elucidating these mechanisms at the level of defined neurons and circuits is fundamental not only for an understanding of memory processes in the brain in general, but also to inform a mechanistic approach to psychiatric conditions associated with amygdala dysfunction and dysregulated emotional responses including anxiety and mood disorders.
Max ERC Funding
2 497 200 €
Duration
Start date: 2016-01-01, End date: 2020-12-31
Project acronym astromnesis
Project The language of astrocytes: multilevel analysis to understand astrocyte communication and its role in memory-related brain operations and in cognitive behavior
Researcher (PI) Andrea Volterra
Host Institution (HI) UNIVERSITE DE LAUSANNE
Call Details Advanced Grant (AdG), LS5, ERC-2013-ADG
Summary In the 90s, two landmark observations brought to a paradigm shift about the role of astrocytes in brain function: 1) astrocytes respond to signals coming from other cells with transient Ca2+ elevations; 2) Ca2+ transients in astrocytes trigger release of neuroactive and vasoactive agents. Since then, many modulatory astrocytic actions and mechanisms were described, forming a complex - partly contradictory - picture, in which the exact roles and modes of astrocyte action remain ill defined. Our project wants to bring light into the “language of astrocytes”, i.e. into how they communicate with neurons and, ultimately, address their role in brain computations and cognitive behavior. To this end we will perform 4 complementary levels of analysis using highly innovative methodologies in order to obtain unprecedented results. We will study: 1) the subcellular organization of astrocytes underlying local microdomain communications by use of correlative light-electron microscopy; 2) the way individual astrocytes integrate inputs and control synaptic ensembles using 3D two-photon imaging, genetically-encoded Ca2+ indicators, optogenetics and electrophysiology; 3) the contribution of astrocyte ensembles to behavior-relevant circuit operations using miniaturized microscopes capturing neuronal/astrocytic population dynamics in freely-moving mice during memory tests; 4) the contribution of astrocytic signalling mechanisms to cognitive behavior using a set of new mouse lines with conditional, astrocyte-specific genetic modification of signalling pathways. We expect that this combination of groundbreaking ideas, innovative technologies and multilevel analysis makes our project highly attractive to the neuroscience community at large, bridging aspects of molecular, cellular, systems and behavioral neuroscience, with the goal of leading from a provocative hypothesis to the conclusive demonstration of whether and how “the language of astrocytes” participates in memory and cognition.
Summary
In the 90s, two landmark observations brought to a paradigm shift about the role of astrocytes in brain function: 1) astrocytes respond to signals coming from other cells with transient Ca2+ elevations; 2) Ca2+ transients in astrocytes trigger release of neuroactive and vasoactive agents. Since then, many modulatory astrocytic actions and mechanisms were described, forming a complex - partly contradictory - picture, in which the exact roles and modes of astrocyte action remain ill defined. Our project wants to bring light into the “language of astrocytes”, i.e. into how they communicate with neurons and, ultimately, address their role in brain computations and cognitive behavior. To this end we will perform 4 complementary levels of analysis using highly innovative methodologies in order to obtain unprecedented results. We will study: 1) the subcellular organization of astrocytes underlying local microdomain communications by use of correlative light-electron microscopy; 2) the way individual astrocytes integrate inputs and control synaptic ensembles using 3D two-photon imaging, genetically-encoded Ca2+ indicators, optogenetics and electrophysiology; 3) the contribution of astrocyte ensembles to behavior-relevant circuit operations using miniaturized microscopes capturing neuronal/astrocytic population dynamics in freely-moving mice during memory tests; 4) the contribution of astrocytic signalling mechanisms to cognitive behavior using a set of new mouse lines with conditional, astrocyte-specific genetic modification of signalling pathways. We expect that this combination of groundbreaking ideas, innovative technologies and multilevel analysis makes our project highly attractive to the neuroscience community at large, bridging aspects of molecular, cellular, systems and behavioral neuroscience, with the goal of leading from a provocative hypothesis to the conclusive demonstration of whether and how “the language of astrocytes” participates in memory and cognition.
Max ERC Funding
2 513 896 €
Duration
Start date: 2014-02-01, End date: 2019-01-31
Project acronym AXPLAST
Project Deep brain imaging of cellular mechanisms of sensory processing and learning
Researcher (PI) Jan GRUNDEMANN
Host Institution (HI) UNIVERSITAT BASEL
Call Details Starting Grant (StG), LS5, ERC-2018-STG
Summary Learning and memory are the basis of our behaviour and mental well-being. Understanding the mechanisms of structural and cellular plasticity in defined neuronal circuits in vivo will be crucial to elucidate principles of circuit-specific memory formation and their relation to changes in neuronal ensemble dynamics.
Structural plasticity studies were technically limited to cortex, excluding deep brain areas like the amygdala, and mainly focussed on the input site (dendritic spines), whilst the plasticity of the axon initial segment (AIS), a neuron’s site of output generation, was so far not studied in vivo. Length and location of the AIS are plastic and strongly affects a neurons spike output. However, it remains unknown if AIS plasticity regulates neuronal activity upon learning in vivo.
We will combine viral expression of AIS live markers and genetically-encoded Ca2+-sensors with novel deep brain imaging techniques via gradient index (GRIN) lenses to investigate how AIS location and length are regulated upon associative learning in amygdala circuits in vivo. Two-photon time-lapse imaging of the AIS of amygdala neurons upon fear conditioning will help us to track learning-driven AIS location dynamics. Next, we will combine miniature microscope imaging of neuronal activity in freely moving animals with two-photon imaging to link AIS location, length and plasticity to the intrinsic activity as well as learning-related response plasticity of amygdala neurons during fear learning and extinction in vivo. Finally, we will test if AIS plasticity is a general cellular plasticity mechanisms in brain areas afferent to the amygdala, e.g. thalamus.
Using a combination of two-photon and miniature microscopy imaging to map structural dynamics of defined neural circuits in the amygdala and its thalamic input areas will provide fundamental insights into the cellular mechanisms underlying sensory processing upon learning and relate network level plasticity with the cellular level.
Summary
Learning and memory are the basis of our behaviour and mental well-being. Understanding the mechanisms of structural and cellular plasticity in defined neuronal circuits in vivo will be crucial to elucidate principles of circuit-specific memory formation and their relation to changes in neuronal ensemble dynamics.
Structural plasticity studies were technically limited to cortex, excluding deep brain areas like the amygdala, and mainly focussed on the input site (dendritic spines), whilst the plasticity of the axon initial segment (AIS), a neuron’s site of output generation, was so far not studied in vivo. Length and location of the AIS are plastic and strongly affects a neurons spike output. However, it remains unknown if AIS plasticity regulates neuronal activity upon learning in vivo.
We will combine viral expression of AIS live markers and genetically-encoded Ca2+-sensors with novel deep brain imaging techniques via gradient index (GRIN) lenses to investigate how AIS location and length are regulated upon associative learning in amygdala circuits in vivo. Two-photon time-lapse imaging of the AIS of amygdala neurons upon fear conditioning will help us to track learning-driven AIS location dynamics. Next, we will combine miniature microscope imaging of neuronal activity in freely moving animals with two-photon imaging to link AIS location, length and plasticity to the intrinsic activity as well as learning-related response plasticity of amygdala neurons during fear learning and extinction in vivo. Finally, we will test if AIS plasticity is a general cellular plasticity mechanisms in brain areas afferent to the amygdala, e.g. thalamus.
Using a combination of two-photon and miniature microscopy imaging to map structural dynamics of defined neural circuits in the amygdala and its thalamic input areas will provide fundamental insights into the cellular mechanisms underlying sensory processing upon learning and relate network level plasticity with the cellular level.
Max ERC Funding
1 475 475 €
Duration
Start date: 2018-12-01, End date: 2023-11-30
Project acronym BRAINCOMPATH
Project Mesoscale Brain Dynamics: Computing with Neuronal Pathways
Researcher (PI) Fritjof Helmchen
Host Institution (HI) UNIVERSITAT ZURICH
Call Details Advanced Grant (AdG), LS5, ERC-2014-ADG
Summary Brain computations rely on proper signal flow through the complex network of connected brain regions. Despite a wealth of anatomical and functional data – from microscopic to macroscopic scale – we still poorly understand the principles of how signal flow is routed through neuronal networks to generate appropriate behavior. Brain dynamics on the 'mesoscopic' scale, the intermediate level where local microcircuits communicate via axonal pathways, has remained a particular blind spot of research as it has been difficult to access under in vivo conditions. Here, I propose to tackle the mesoscopic level of brain dynamics both experimentally and theoretically, adopting a fresh perspective centered on neuronal pathway dynamics. Experimentally, we will utilize and further advance state-of-the-art genetic and optical techniques to create a toolbox for measuring and manipulating signal flow in pathway networks across a broad range of temporal scales. In particular, we will improve fiber-optic based methods for probing the activity of either individual or multiple neuronal pathways with high specificity. Using these tools we will set out to reveal mesoscopic brain dynamics across relevant cortical and subcortical regions in awake, behaving mice. Specifically, we will investigate sensorimotor learning for a reward-based texture discrimination task and rapid sensorimotor control during skilled locomotion. Moreover, by combining fiber-optic methods with two-photon microscopy and fMRI, respectively, we will start linking the meso-level to the micro- and macro-levels. Throughout the project, experiments will be complemented by computational approaches to analyse data, model pathway dynamics, and conceptualize a formal theory of mesoscopic dynamics. This project may transform the field by bridging the hierarchical brain levels and opening significant new avenues to assess physiological as well as pathological signal flow in the brain.
Summary
Brain computations rely on proper signal flow through the complex network of connected brain regions. Despite a wealth of anatomical and functional data – from microscopic to macroscopic scale – we still poorly understand the principles of how signal flow is routed through neuronal networks to generate appropriate behavior. Brain dynamics on the 'mesoscopic' scale, the intermediate level where local microcircuits communicate via axonal pathways, has remained a particular blind spot of research as it has been difficult to access under in vivo conditions. Here, I propose to tackle the mesoscopic level of brain dynamics both experimentally and theoretically, adopting a fresh perspective centered on neuronal pathway dynamics. Experimentally, we will utilize and further advance state-of-the-art genetic and optical techniques to create a toolbox for measuring and manipulating signal flow in pathway networks across a broad range of temporal scales. In particular, we will improve fiber-optic based methods for probing the activity of either individual or multiple neuronal pathways with high specificity. Using these tools we will set out to reveal mesoscopic brain dynamics across relevant cortical and subcortical regions in awake, behaving mice. Specifically, we will investigate sensorimotor learning for a reward-based texture discrimination task and rapid sensorimotor control during skilled locomotion. Moreover, by combining fiber-optic methods with two-photon microscopy and fMRI, respectively, we will start linking the meso-level to the micro- and macro-levels. Throughout the project, experiments will be complemented by computational approaches to analyse data, model pathway dynamics, and conceptualize a formal theory of mesoscopic dynamics. This project may transform the field by bridging the hierarchical brain levels and opening significant new avenues to assess physiological as well as pathological signal flow in the brain.
Max ERC Funding
2 498 915 €
Duration
Start date: 2016-02-01, End date: 2021-01-31
Project acronym BRIDGES
Project Bridging Non-Equilibrium Problems: From the Fourier Law to Gene Expression
Researcher (PI) Jean-Pierre Eckmann
Host Institution (HI) UNIVERSITE DE GENEVE
Call Details Advanced Grant (AdG), PE1, ERC-2011-ADG_20110209
Summary My goal is to study several important open mathematical problems in non-equilibrium (NEQ) systems and to build a bridge between these problems and NEQ aspects of soft sciences, in particular biological questions. Traffic on this bridge is going to be two-way, the mathematics carrying a long history as a language of science towards the soft sciences, and the soft sciences fruitfully asking new questions and building new paradigms for mathematical research.
Out-of-equilibrium systems pose several fascinating problems: The Fourier law which says that resistance of a wire is proportional to its length is still presenting hard problems for research, and even the existence and the convergence to a NEQ steady state are continuously posing new puzzles, as do questions of smoothness and correlations of such states. These will be addressed with stochastic differential equations, and with particlescatterer systems, both canonical and grand-canonical. The latter are extensions of the well-known Lorentz gas and the study of hyperbolic billiards.
Another field where NEQ plays an important role is the study of glassy systems. They were studied with molecular dynamics (MD) but I have used a topological variant, which mimics astonishingly well what happens in MD simulations. The aim is to extend this to 3 dimensions, where new problems appear.
Finally, I will apply the NEQ studies to biological systems: How a system copes with the varying environment,adapting in this way to a novel type of NEQ. I will study networks of communication among neurons,which are like random graphs with the additional property of being embedded, and the arrangement of genes on chromosomes in such a way as to optimize the adaptation to the different cell types which must be produced using the same genetic information.
I will answer such questions with students and collaborators, who will specialize in the subprojects but will interact with my help across the common bridge.
Summary
My goal is to study several important open mathematical problems in non-equilibrium (NEQ) systems and to build a bridge between these problems and NEQ aspects of soft sciences, in particular biological questions. Traffic on this bridge is going to be two-way, the mathematics carrying a long history as a language of science towards the soft sciences, and the soft sciences fruitfully asking new questions and building new paradigms for mathematical research.
Out-of-equilibrium systems pose several fascinating problems: The Fourier law which says that resistance of a wire is proportional to its length is still presenting hard problems for research, and even the existence and the convergence to a NEQ steady state are continuously posing new puzzles, as do questions of smoothness and correlations of such states. These will be addressed with stochastic differential equations, and with particlescatterer systems, both canonical and grand-canonical. The latter are extensions of the well-known Lorentz gas and the study of hyperbolic billiards.
Another field where NEQ plays an important role is the study of glassy systems. They were studied with molecular dynamics (MD) but I have used a topological variant, which mimics astonishingly well what happens in MD simulations. The aim is to extend this to 3 dimensions, where new problems appear.
Finally, I will apply the NEQ studies to biological systems: How a system copes with the varying environment,adapting in this way to a novel type of NEQ. I will study networks of communication among neurons,which are like random graphs with the additional property of being embedded, and the arrangement of genes on chromosomes in such a way as to optimize the adaptation to the different cell types which must be produced using the same genetic information.
I will answer such questions with students and collaborators, who will specialize in the subprojects but will interact with my help across the common bridge.
Max ERC Funding
2 135 385 €
Duration
Start date: 2012-04-01, End date: 2017-07-31
Project acronym BROADimmune
Project Structural, genetic and functional analyses of broadly neutralizing antibodies against human pathogens
Researcher (PI) Antonio Lanzavecchia
Host Institution (HI) FONDAZIONE PER L ISTITUTO DI RICERCA IN BIOMEDICINA
Call Details Advanced Grant (AdG), LS6, ERC-2014-ADG
Summary The overall goal of this project is to understand the molecular mechanisms that lead to the generation of potent and broadly neutralizing antibodies against medically relevant pathogens, and to identify the factors that limit their production in response to infection or vaccination with current vaccines. We will use high-throughput cellular screens to isolate from immune donors clonally related antibodies to different sites of influenza hemagglutinin, which will be fully characterized and sequenced in order to reconstruct their developmental pathways. Using this approach, we will ask fundamental questions with regards to the role of somatic mutations in affinity maturation and intraclonal diversification, which in some cases may lead to the generation of autoantibodies. We will combine crystallography and long time-scale molecular dynamics simulation to understand how mutations can increase affinity and broaden antibody specificity. By mapping the B and T cell response to all sites and conformations of influenza hemagglutinin, we will uncover the factors, such as insufficient T cell help or the instability of the pre-fusion hemagglutinin, that may limit the generation of broadly neutralizing antibodies. We will also perform a broad analysis of the antibody response to erythrocytes infected by P. falciparum to identify conserved epitopes on the parasite and to unravel the role of an enigmatic V gene that appears to be involved in response to blood-stage parasites. The hypotheses tested are strongly supported by preliminary observations from our own laboratory. While these studies will contribute to our understanding of B cell biology, the results obtained will also have translational implications for the development of potent and broad-spectrum antibodies, for the definition of correlates of protection, and for improving vaccine design.
Summary
The overall goal of this project is to understand the molecular mechanisms that lead to the generation of potent and broadly neutralizing antibodies against medically relevant pathogens, and to identify the factors that limit their production in response to infection or vaccination with current vaccines. We will use high-throughput cellular screens to isolate from immune donors clonally related antibodies to different sites of influenza hemagglutinin, which will be fully characterized and sequenced in order to reconstruct their developmental pathways. Using this approach, we will ask fundamental questions with regards to the role of somatic mutations in affinity maturation and intraclonal diversification, which in some cases may lead to the generation of autoantibodies. We will combine crystallography and long time-scale molecular dynamics simulation to understand how mutations can increase affinity and broaden antibody specificity. By mapping the B and T cell response to all sites and conformations of influenza hemagglutinin, we will uncover the factors, such as insufficient T cell help or the instability of the pre-fusion hemagglutinin, that may limit the generation of broadly neutralizing antibodies. We will also perform a broad analysis of the antibody response to erythrocytes infected by P. falciparum to identify conserved epitopes on the parasite and to unravel the role of an enigmatic V gene that appears to be involved in response to blood-stage parasites. The hypotheses tested are strongly supported by preliminary observations from our own laboratory. While these studies will contribute to our understanding of B cell biology, the results obtained will also have translational implications for the development of potent and broad-spectrum antibodies, for the definition of correlates of protection, and for improving vaccine design.
Max ERC Funding
1 867 500 €
Duration
Start date: 2015-10-01, End date: 2020-09-30
Project acronym CausalStats
Project Statistics, Prediction and Causality for Large-Scale Data
Researcher (PI) Peter Lukas Bühlmann
Host Institution (HI) EIDGENOESSISCHE TECHNISCHE HOCHSCHULE ZUERICH
Call Details Advanced Grant (AdG), PE1, ERC-2017-ADG
Summary Understanding cause-effect relationships between variables is of great interest in many fields of science. However, causal inference from data is much more ambitious and difficult than inferring (undirected) measures of association such as correlations, partial correlations or multivariate regression coefficients, mainly because of fundamental identifiability
problems. A main objective of the proposal is to exploit advantages from large-scale heterogeneous data for causal inference where heterogeneity arises from different experimental conditions or different unknown sub-populations. A key idea is to consider invariance or stability across different experimental conditions of certain conditional probability distributions: the invariants correspond on the one hand to (properly defined) causal variables which are of main interest in causality; andon the other hand, they correspond to the features for constructing powerful predictions for new scenarios which are unobserved in the data (new probability distributions). This opens novel perspectives: causal inference
can be phrased as a prediction problem of a certain kind, and vice versa, new prediction methods which work well across different scenarios (unobserved in the data) should be based on or regularized towards causal variables. Fundamental identifiability limits will become weaker with increased degree of heterogeneity, as we expect in large-scale data. The topic is essentially unexplored, yet it opens new avenues for causal inference, structural equation and graphical modeling, and robust prediction based on large-scale complex data. We will develop mathematical theory, statistical methodology and efficient algorithms; and we will also work and collaborate on major application problems such as inferring causal effects (i.e., total intervention effects) from gene knock-out or RNA interference perturbation experiments, genome-wide association studies and novel prediction tasks in economics.
Summary
Understanding cause-effect relationships between variables is of great interest in many fields of science. However, causal inference from data is much more ambitious and difficult than inferring (undirected) measures of association such as correlations, partial correlations or multivariate regression coefficients, mainly because of fundamental identifiability
problems. A main objective of the proposal is to exploit advantages from large-scale heterogeneous data for causal inference where heterogeneity arises from different experimental conditions or different unknown sub-populations. A key idea is to consider invariance or stability across different experimental conditions of certain conditional probability distributions: the invariants correspond on the one hand to (properly defined) causal variables which are of main interest in causality; andon the other hand, they correspond to the features for constructing powerful predictions for new scenarios which are unobserved in the data (new probability distributions). This opens novel perspectives: causal inference
can be phrased as a prediction problem of a certain kind, and vice versa, new prediction methods which work well across different scenarios (unobserved in the data) should be based on or regularized towards causal variables. Fundamental identifiability limits will become weaker with increased degree of heterogeneity, as we expect in large-scale data. The topic is essentially unexplored, yet it opens new avenues for causal inference, structural equation and graphical modeling, and robust prediction based on large-scale complex data. We will develop mathematical theory, statistical methodology and efficient algorithms; and we will also work and collaborate on major application problems such as inferring causal effects (i.e., total intervention effects) from gene knock-out or RNA interference perturbation experiments, genome-wide association studies and novel prediction tasks in economics.
Max ERC Funding
2 184 375 €
Duration
Start date: 2018-10-01, End date: 2023-09-30