Project acronym activeFly
Project Circuit mechanisms of self-movement estimation during walking
Researcher (PI) M Eugenia CHIAPPE
Host Institution (HI) FUNDACAO D. ANNA SOMMER CHAMPALIMAUD E DR. CARLOS MONTEZ CHAMPALIMAUD
Call Details Starting Grant (StG), LS5, ERC-2017-STG
Summary The brain evolves, develops, and operates in the context of animal movements. As a consequence, fundamental brain functions such as spatial perception and motor control critically depend on the precise knowledge of the ongoing body motion. An accurate internal estimate of self-movement is thought to emerge from sensorimotor integration; nonetheless, which circuits perform this internal estimation, and exactly how motor-sensory coordination is implemented within these circuits are basic questions that remain to be poorly understood. There is growing evidence suggesting that, during locomotion, motor-related and visual signals interact at early stages of visual processing. In mammals, however, it is not clear what the function of this interaction is. Recently, we have shown that a population of Drosophila optic-flow processing neurons —neurons that are sensitive to self-generated visual flow, receives convergent visual and walking-related signals to form a faithful representation of the fly’s walking movements. Leveraging from these results, and combining quantitative analysis of behavior with physiology, optogenetics, and modelling, we propose to investigate circuit mechanisms of self-movement estimation during walking. We will:1) use cell specific manipulations to identify what cells are necessary to generate the motor-related activity in the population of visual neurons, 2) record from the identified neurons and correlate their activity with specific locomotor parameters, and 3) perturb the activity of different cell-types within the identified circuits to test their role in the dynamics of the visual neurons, and on the fly’s walking behavior. These experiments will establish unprecedented causal relationships among neural activity, the formation of an internal representation, and locomotor control. The identified sensorimotor principles will establish a framework that can be tested in other scenarios or animal systems with implications both in health and disease.
Summary
The brain evolves, develops, and operates in the context of animal movements. As a consequence, fundamental brain functions such as spatial perception and motor control critically depend on the precise knowledge of the ongoing body motion. An accurate internal estimate of self-movement is thought to emerge from sensorimotor integration; nonetheless, which circuits perform this internal estimation, and exactly how motor-sensory coordination is implemented within these circuits are basic questions that remain to be poorly understood. There is growing evidence suggesting that, during locomotion, motor-related and visual signals interact at early stages of visual processing. In mammals, however, it is not clear what the function of this interaction is. Recently, we have shown that a population of Drosophila optic-flow processing neurons —neurons that are sensitive to self-generated visual flow, receives convergent visual and walking-related signals to form a faithful representation of the fly’s walking movements. Leveraging from these results, and combining quantitative analysis of behavior with physiology, optogenetics, and modelling, we propose to investigate circuit mechanisms of self-movement estimation during walking. We will:1) use cell specific manipulations to identify what cells are necessary to generate the motor-related activity in the population of visual neurons, 2) record from the identified neurons and correlate their activity with specific locomotor parameters, and 3) perturb the activity of different cell-types within the identified circuits to test their role in the dynamics of the visual neurons, and on the fly’s walking behavior. These experiments will establish unprecedented causal relationships among neural activity, the formation of an internal representation, and locomotor control. The identified sensorimotor principles will establish a framework that can be tested in other scenarios or animal systems with implications both in health and disease.
Max ERC Funding
1 500 000 €
Duration
Start date: 2017-11-01, End date: 2022-10-31
Project acronym AGRISCENTS
Project Scents and sensibility in agriculture: exploiting specificity in herbivore- and pathogen-induced plant volatiles for real-time crop monitoring
Researcher (PI) Theodoor Turlings
Host Institution (HI) UNIVERSITE DE NEUCHATEL
Call Details Advanced Grant (AdG), LS9, ERC-2017-ADG
Summary Plants typically release large quantities of volatiles in response to attack by herbivores or pathogens. I may claim to have contributed to various breakthroughs in this research field, including the discovery that the volatile blends induced by different attackers are astonishingly specific, resulting in characteristic, readily distinguishable odour blends. Using maize as our model plant, I wish to take several leaps forward in our understanding of this signal specificity and use this knowledge to develop sensors for the real-time detection of crop pests and diseases. For this, three interconnected work-packages will aim to:
• Develop chemical analytical techniques and statistical models to decipher the odorous vocabulary of plants, and to create a complete inventory of “odour-prints” for a wide range of herbivore-plant and pathogen-plant combinations, including simultaneous infestations.
• Develop and optimize nano-mechanical sensors for the detection of specific plant volatile mixtures. For this, we will initially adapt a prototype sensor that has been successfully developed for the detection of cancer-related volatiles in human breath.
• Genetically manipulate maize plants to release a unique blend of root-produced volatiles upon herbivory. For this, we will engineer gene cassettes that combine recently identified P450 (CYP) genes from poplar with inducible, root-specific promoters from maize. This will result in maize plants that, in response to pest attack, release easy-to-detect aldoximes and nitriles from their roots.
In short, by investigating and manipulating the specificity of inducible odour blends we will generate the necessary knowhow to develop a novel odour-detection device. The envisioned sensor technology will permit real-time monitoring of the pests and enable farmers to apply crop protection treatments at the right time and in the right place.
Summary
Plants typically release large quantities of volatiles in response to attack by herbivores or pathogens. I may claim to have contributed to various breakthroughs in this research field, including the discovery that the volatile blends induced by different attackers are astonishingly specific, resulting in characteristic, readily distinguishable odour blends. Using maize as our model plant, I wish to take several leaps forward in our understanding of this signal specificity and use this knowledge to develop sensors for the real-time detection of crop pests and diseases. For this, three interconnected work-packages will aim to:
• Develop chemical analytical techniques and statistical models to decipher the odorous vocabulary of plants, and to create a complete inventory of “odour-prints” for a wide range of herbivore-plant and pathogen-plant combinations, including simultaneous infestations.
• Develop and optimize nano-mechanical sensors for the detection of specific plant volatile mixtures. For this, we will initially adapt a prototype sensor that has been successfully developed for the detection of cancer-related volatiles in human breath.
• Genetically manipulate maize plants to release a unique blend of root-produced volatiles upon herbivory. For this, we will engineer gene cassettes that combine recently identified P450 (CYP) genes from poplar with inducible, root-specific promoters from maize. This will result in maize plants that, in response to pest attack, release easy-to-detect aldoximes and nitriles from their roots.
In short, by investigating and manipulating the specificity of inducible odour blends we will generate the necessary knowhow to develop a novel odour-detection device. The envisioned sensor technology will permit real-time monitoring of the pests and enable farmers to apply crop protection treatments at the right time and in the right place.
Max ERC Funding
2 498 086 €
Duration
Start date: 2018-09-01, End date: 2023-08-31
Project acronym BETLIV
Project Returning to a Better Place: The (Re)assessment of the ‘Good Life’ in Times of Crisis
Researcher (PI) Valerio SIMONI RIBA
Host Institution (HI) FONDATION POUR L INSTITUT DE HAUTES ETUDES INTERNATIONALES ET DU DEVELOPPEMENT
Call Details Starting Grant (StG), SH5, ERC-2017-STG
Summary What makes for a valuable and good life is a question that many people in the contemporary world ask themselves, yet it is one that social science research has seldom addressed. Only recently have scholars started undertaking inductive comparative research on different notions of the ‘good life’, highlighting socio-cultural variations and calling for a better understanding of the different imaginaries, aspirations and values that guide people in their quest for better living conditions. Research is still lacking, however, on how people themselves evaluate, compare, and put into perspective different visions of good living and their socio-cultural anchorage. This project addresses such questions from an anthropological perspective, proposing an innovative study of how ideals of the good life are articulated, (re)assessed, and related to specific places and contexts as a result of the experience of crisis and migration. The case studies chosen to operationalize these lines of enquiry focus on the phenomenon of return migration, and consist in an analysis of the imaginaries and experience of return by Ecuadorian and Cuban men and women who migrated to Spain, are dissatisfied with their life there, and envisage/carry out the project of going back to their countries of origin (Ecuador and Cuba respectively). The project’s ambition is to bring together and contribute to three main scholarly areas of enquiry: 1) the study of morality, ethics and what counts as ‘good life’, 2) the study of the field of economic practice, its definition, value regimes, and ‘crises’, and 3) the study of migratory aspirations, projects, and trajectories. A multi-sited endeavour, the research is designed in three subprojects carried out in Spain (PhD student), Ecuador (Post-Doc), and Cuba (PI), in which ethnographic methods will be used to provide the first empirically grounded study of the links between notions and experiences of crisis, return migration, and the (re)assessment of good living.
Summary
What makes for a valuable and good life is a question that many people in the contemporary world ask themselves, yet it is one that social science research has seldom addressed. Only recently have scholars started undertaking inductive comparative research on different notions of the ‘good life’, highlighting socio-cultural variations and calling for a better understanding of the different imaginaries, aspirations and values that guide people in their quest for better living conditions. Research is still lacking, however, on how people themselves evaluate, compare, and put into perspective different visions of good living and their socio-cultural anchorage. This project addresses such questions from an anthropological perspective, proposing an innovative study of how ideals of the good life are articulated, (re)assessed, and related to specific places and contexts as a result of the experience of crisis and migration. The case studies chosen to operationalize these lines of enquiry focus on the phenomenon of return migration, and consist in an analysis of the imaginaries and experience of return by Ecuadorian and Cuban men and women who migrated to Spain, are dissatisfied with their life there, and envisage/carry out the project of going back to their countries of origin (Ecuador and Cuba respectively). The project’s ambition is to bring together and contribute to three main scholarly areas of enquiry: 1) the study of morality, ethics and what counts as ‘good life’, 2) the study of the field of economic practice, its definition, value regimes, and ‘crises’, and 3) the study of migratory aspirations, projects, and trajectories. A multi-sited endeavour, the research is designed in three subprojects carried out in Spain (PhD student), Ecuador (Post-Doc), and Cuba (PI), in which ethnographic methods will be used to provide the first empirically grounded study of the links between notions and experiences of crisis, return migration, and the (re)assessment of good living.
Max ERC Funding
1 500 000 €
Duration
Start date: 2018-02-01, End date: 2023-01-31
Project acronym BioMeTRe
Project Biophysical mechanisms of long-range transcriptional regulation
Researcher (PI) Luca GIORGETTI
Host Institution (HI) FRIEDRICH MIESCHER INSTITUTE FOR BIOMEDICAL RESEARCH FONDATION
Call Details Starting Grant (StG), LS2, ERC-2017-STG
Summary In mammals, transcriptional control of many genes relies on cis-regulatory elements such as enhancers, which are often located tens to hundreds of kilobases away from their cognate promoters. Functional interactions between distal regulatory elements and target promoters require mutual physical proximity, which is linked to the three-dimensional structure of the chromatin fiber. Chromosome conformation capture studies revealed that chromosomes are partitioned into Topologically Associating Domains (TADs), sub-megabase domains of preferential physical interactions of the chromatin fiber. Genetic evidence showed that TAD boundaries restrict the genomic range of enhancer-promoter communication, and that interactions between regulatory sequences within TADs are further fine-tuned by smaller-scale structures. However, the mechanistic details of how physical interactions translate into transcriptional outputs are totally unknown. Here we propose to explore the biophysical mechanisms that link chromosome conformation and long-range transcriptional regulation using molecular biology, genetic engineering, single-cell experiments and physical modeling. We will measure chromosomal interactions in single cells and in time using a novel method that relies on an enzymatic process in vivo. Genetic engineering will be used to establish a cell system that allows quantitative measurement of how enhancer-promoter interactions relate to transcription at the population and single-cell levels, and to test the effects of perturbations without confounding effects. Finally, we will develop physical models of promoter operation in the presence of distal enhancers, which will be used to interpret the experimental data and formulate new testable predictions. With this integrated approach we aim at providing an entirely new layer of description of the general principles underlying transcriptional control, which could establish new paradigms for research in epigenetics and gene regulation.
Summary
In mammals, transcriptional control of many genes relies on cis-regulatory elements such as enhancers, which are often located tens to hundreds of kilobases away from their cognate promoters. Functional interactions between distal regulatory elements and target promoters require mutual physical proximity, which is linked to the three-dimensional structure of the chromatin fiber. Chromosome conformation capture studies revealed that chromosomes are partitioned into Topologically Associating Domains (TADs), sub-megabase domains of preferential physical interactions of the chromatin fiber. Genetic evidence showed that TAD boundaries restrict the genomic range of enhancer-promoter communication, and that interactions between regulatory sequences within TADs are further fine-tuned by smaller-scale structures. However, the mechanistic details of how physical interactions translate into transcriptional outputs are totally unknown. Here we propose to explore the biophysical mechanisms that link chromosome conformation and long-range transcriptional regulation using molecular biology, genetic engineering, single-cell experiments and physical modeling. We will measure chromosomal interactions in single cells and in time using a novel method that relies on an enzymatic process in vivo. Genetic engineering will be used to establish a cell system that allows quantitative measurement of how enhancer-promoter interactions relate to transcription at the population and single-cell levels, and to test the effects of perturbations without confounding effects. Finally, we will develop physical models of promoter operation in the presence of distal enhancers, which will be used to interpret the experimental data and formulate new testable predictions. With this integrated approach we aim at providing an entirely new layer of description of the general principles underlying transcriptional control, which could establish new paradigms for research in epigenetics and gene regulation.
Max ERC Funding
1 500 000 €
Duration
Start date: 2018-01-01, End date: 2022-12-31
Project acronym CERDEV
Project Transcriptional controls over cerebellar neuron differentiation and circuit assembly
Researcher (PI) Ludovic TELLEY
Host Institution (HI) UNIVERSITE DE LAUSANNE
Call Details Starting Grant (StG), LS5, ERC-2017-STG
Summary The cerebellum is a critical regulator of motor function, which acts to integrate ongoing body states, sensory inputs and desired outcomes to adjust motor output. This motor control is achieved by a relatively small number of neuron types receiving two main sources of inputs and forming a single output pathway, the axons of Purkinje cells. Although the cerebellum is one of the first structures of the brain to differentiate, it undergoes a prolonged differentiation period such that mature cellular and circuit configuration is achieved only late after birth. Despite the functional importance of this structure, the molecular mechanisms that control type-specific cerebellar neurons generation, differentiation, and circuit assembly are poorly understood and are the topic of the present study.
In my research program, I propose to investigate the transcriptional programs that control the generation of distinct subtypes of cerebellar neurons from progenitors, including Purkinje cells, granule cells and molecular layer interneurons (Work Package 1); the diversity of Purkinje cells across cerebellar regions (Work Package 2) and the postnatal differentiation and circuit integration of granule cells and molecular layer interneurons (Work Package 3). The general bases of the approach I propose consist in: i) specifically label cerebellar neuron progenitors and their progeny at sequential developmental time points pre- and post-natally using birthdate-based tagging, ii) FAC-sort these distinct cell types, iii) isolate these cells and identify their transcriptional signatures with single-cell resolution, iv) functionally interrogate top candidate genes and associated transcriptional programs using in vivo gain- and loss-of-function approaches. Together, these experiments aim at deciphering the cell-intrinsic processes controlling cerebellar circuit formation, towards a better understanding of the molecular mechanisms underlying cerebellar function and dysfunction.
Summary
The cerebellum is a critical regulator of motor function, which acts to integrate ongoing body states, sensory inputs and desired outcomes to adjust motor output. This motor control is achieved by a relatively small number of neuron types receiving two main sources of inputs and forming a single output pathway, the axons of Purkinje cells. Although the cerebellum is one of the first structures of the brain to differentiate, it undergoes a prolonged differentiation period such that mature cellular and circuit configuration is achieved only late after birth. Despite the functional importance of this structure, the molecular mechanisms that control type-specific cerebellar neurons generation, differentiation, and circuit assembly are poorly understood and are the topic of the present study.
In my research program, I propose to investigate the transcriptional programs that control the generation of distinct subtypes of cerebellar neurons from progenitors, including Purkinje cells, granule cells and molecular layer interneurons (Work Package 1); the diversity of Purkinje cells across cerebellar regions (Work Package 2) and the postnatal differentiation and circuit integration of granule cells and molecular layer interneurons (Work Package 3). The general bases of the approach I propose consist in: i) specifically label cerebellar neuron progenitors and their progeny at sequential developmental time points pre- and post-natally using birthdate-based tagging, ii) FAC-sort these distinct cell types, iii) isolate these cells and identify their transcriptional signatures with single-cell resolution, iv) functionally interrogate top candidate genes and associated transcriptional programs using in vivo gain- and loss-of-function approaches. Together, these experiments aim at deciphering the cell-intrinsic processes controlling cerebellar circuit formation, towards a better understanding of the molecular mechanisms underlying cerebellar function and dysfunction.
Max ERC Funding
1 499 885 €
Duration
Start date: 2018-02-01, End date: 2023-01-31
Project acronym ChronosAntibiotics
Project Exploring the bacterial cell cycle to re-sensitize antibiotic-resistant bacteria
Researcher (PI) MARIANA LUISA TOMAS GOMES DE PINHO
Host Institution (HI) UNIVERSIDADE NOVA DE LISBOA
Call Details Consolidator Grant (CoG), LS6, ERC-2017-COG
Summary Over the next 35 years, antibiotic resistant bacteria are expected to kill more than 300 million people. The need to find alternative strategies for antimicrobial therapies remains a global challenge with several bottlenecks in the antibiotic discovery process. Using Staphylococcus aureus, the most common multidrug-resistant bacterium in the European Union and an excellent model organism for cell division in cocci, we propose:
(i) to find new pathways to re-sensitize resistant bacteria. Bacteria undergo major morphology changes during the cell cycle. We hypothesize that these changes generate windows of opportunity during which bacteria are more susceptible or more tolerant to the action of antibiotics. We will identify key regulators of the cell cycle in order to manipulate the duration of windows of opportunity for the action of existing antibiotics.
(ii) to develop new fluorescence-based reporters for whole-cell screenings of antimicrobial compounds with new modes of action, including compounds that arrest or delay the cell cycle; compounds that target non-essential pathways that are required for expression of resistance against existing antibiotics and therefore can be used as synergistic drugs for combination therapies; compounds that inhibit the production of virulence factors and compounds that revert persister states that are phenotypically resistant to antibiotics.
(iii) to unravel new modes of action of antibiotics by using the constructed reporter strains as powerful tools to learn how antibiotics act at the single cell level.
Over the past years, my group has become expert on the biology of S. aureus, has constructed powerful biological tools to study cell division and synthesis of the cell surface and has studied mechanisms of action of various antimicrobial compounds. We are therefore in a privileged position to quickly unravel the function of new players in the bacterial cell cycle and simultaneously contribute to accelerate antibiotic discovery.
Summary
Over the next 35 years, antibiotic resistant bacteria are expected to kill more than 300 million people. The need to find alternative strategies for antimicrobial therapies remains a global challenge with several bottlenecks in the antibiotic discovery process. Using Staphylococcus aureus, the most common multidrug-resistant bacterium in the European Union and an excellent model organism for cell division in cocci, we propose:
(i) to find new pathways to re-sensitize resistant bacteria. Bacteria undergo major morphology changes during the cell cycle. We hypothesize that these changes generate windows of opportunity during which bacteria are more susceptible or more tolerant to the action of antibiotics. We will identify key regulators of the cell cycle in order to manipulate the duration of windows of opportunity for the action of existing antibiotics.
(ii) to develop new fluorescence-based reporters for whole-cell screenings of antimicrobial compounds with new modes of action, including compounds that arrest or delay the cell cycle; compounds that target non-essential pathways that are required for expression of resistance against existing antibiotics and therefore can be used as synergistic drugs for combination therapies; compounds that inhibit the production of virulence factors and compounds that revert persister states that are phenotypically resistant to antibiotics.
(iii) to unravel new modes of action of antibiotics by using the constructed reporter strains as powerful tools to learn how antibiotics act at the single cell level.
Over the past years, my group has become expert on the biology of S. aureus, has constructed powerful biological tools to study cell division and synthesis of the cell surface and has studied mechanisms of action of various antimicrobial compounds. We are therefore in a privileged position to quickly unravel the function of new players in the bacterial cell cycle and simultaneously contribute to accelerate antibiotic discovery.
Max ERC Funding
2 533 500 €
Duration
Start date: 2018-03-01, End date: 2023-02-28
Project acronym CLLCLONE
Project Harnessing clonal evolution in chronic lymphocytic leukemia
Researcher (PI) Davide ROSSI
Host Institution (HI) FONDAZIONE PER L'ISTITUTO ONCOLOGICO DI RICERCA (IOR)
Call Details Consolidator Grant (CoG), LS7, ERC-2017-COG
Summary Chronic lymphocytic leukemia (CLL), the most common leukemia in adults, is addicted of interactions with the microenvironment. The B-cell receptor (BCR) is one of the most important surface molecules that CLL cells use to gain oncogenic signals from the microenvironment. The critical role of BCR signaling for the pathogenesis of CLL is supported by the therapeutic success of ibrutinib, a targeted agent that disrupts the BCR pathway. Beside microenvironment-promoted oncogenic signals, the biology of CLL is also driven by molecular lesions and clonal evolution, that mark CLL progression and treatment resistance. The interconnection between microenvironment-promoted oncogenic signals and clonal evolution has been postulated in CLL but never proven because of the lack of suitable ex vivo models. Ibrutinib allows the unprecedented opportunity of assessing the contribution of cell signaling to cancer clonal evolution directly in vivo in patients. The project working hypothesis is that mutation- and selection-driven clonal evolution is promoted by microenvironment-induced signals, including those propagated from the BCR. According to this hypothesis: i) BCR signaling inhibition due to ibrutinib should stop clonal evolution; while ii) acquisition of by-pass mechanisms that keep ongoing signaling should promote mutation and selection despite BCR inhibition, thus favoring CLL clonal evolution and ibrutinib resistance. In this scenario, the combination of ibrutinib with drugs that overcome by-pass mechanisms could prevent clonal evolution, thus improving treatment efficacy and patient outcome. In order to address our working hypothesis, we will take advantage of clinical trial and co-clinical trial samples to monitor signaling and clonal evolution under ibrutinib and ibrutinib-based combination treatments.
Summary
Chronic lymphocytic leukemia (CLL), the most common leukemia in adults, is addicted of interactions with the microenvironment. The B-cell receptor (BCR) is one of the most important surface molecules that CLL cells use to gain oncogenic signals from the microenvironment. The critical role of BCR signaling for the pathogenesis of CLL is supported by the therapeutic success of ibrutinib, a targeted agent that disrupts the BCR pathway. Beside microenvironment-promoted oncogenic signals, the biology of CLL is also driven by molecular lesions and clonal evolution, that mark CLL progression and treatment resistance. The interconnection between microenvironment-promoted oncogenic signals and clonal evolution has been postulated in CLL but never proven because of the lack of suitable ex vivo models. Ibrutinib allows the unprecedented opportunity of assessing the contribution of cell signaling to cancer clonal evolution directly in vivo in patients. The project working hypothesis is that mutation- and selection-driven clonal evolution is promoted by microenvironment-induced signals, including those propagated from the BCR. According to this hypothesis: i) BCR signaling inhibition due to ibrutinib should stop clonal evolution; while ii) acquisition of by-pass mechanisms that keep ongoing signaling should promote mutation and selection despite BCR inhibition, thus favoring CLL clonal evolution and ibrutinib resistance. In this scenario, the combination of ibrutinib with drugs that overcome by-pass mechanisms could prevent clonal evolution, thus improving treatment efficacy and patient outcome. In order to address our working hypothesis, we will take advantage of clinical trial and co-clinical trial samples to monitor signaling and clonal evolution under ibrutinib and ibrutinib-based combination treatments.
Max ERC Funding
1 940 000 €
Duration
Start date: 2018-07-01, End date: 2023-06-30
Project acronym DYCOCIRC
Project Basal ganglia circuit mechanisms underlying dynamic cognitive behavior
Researcher (PI) Joseph PATON
Host Institution (HI) FUNDACAO D. ANNA SOMMER CHAMPALIMAUD E DR. CARLOS MONTEZ CHAMPALIMAUD
Call Details Consolidator Grant (CoG), LS5, ERC-2017-COG
Summary You’re faced with a difficult choice. What do you do? Most people will, either explicitly or implicitly, weigh the possible consequences their decision. This involves an internal journey through possible events. Its these kinds of dynamic processes and their mapping onto behavior that characterize higher brain function. And yet, their very internal nature is both what makes them of critical interest and so difficult to study. Here, we propose to study a simple, well-controlled decision-making behavior wherein mice have to generate a dynamic, internal representation of elapsed time in order to make choices that result in reward. We focus on frontal cortico-basal ganglia circuits and their dopaminergic inputs that together are broadly implicated in cognition and involved in the production of this particular behavior. We have demonstrated previously that striatal population dynamics and dopamine neuron activity both correlate with and exert control over animals’ judgments. Having identified key signals at multiple stages of the BG circuit related to this decision in rats and mice, my laboratory is now uniquely poised to dissect the circuit mechanisms by which such signals are generated and transformed into actions. Specifically, we will 1) Measure activity of specific cell types at multiple stages of the BG as mice judge duration. 2) Image and manipulate the activity of DA neurons while recording from neural populations in the BG to determine the relationship between neuromodulatory input, neural dynamics, and behavior. 3) Relate the activity of cortico-striatal inputs to striatal responses during behavior to understand the computational and circuit bases of striatal activity. These experiments promise to unlock deep mysteries regarding how animals free themselves from the immediacy of the current moment, learning, planning, and choosing their path toward a safer, more fruitful, and satisfying existence.
Summary
You’re faced with a difficult choice. What do you do? Most people will, either explicitly or implicitly, weigh the possible consequences their decision. This involves an internal journey through possible events. Its these kinds of dynamic processes and their mapping onto behavior that characterize higher brain function. And yet, their very internal nature is both what makes them of critical interest and so difficult to study. Here, we propose to study a simple, well-controlled decision-making behavior wherein mice have to generate a dynamic, internal representation of elapsed time in order to make choices that result in reward. We focus on frontal cortico-basal ganglia circuits and their dopaminergic inputs that together are broadly implicated in cognition and involved in the production of this particular behavior. We have demonstrated previously that striatal population dynamics and dopamine neuron activity both correlate with and exert control over animals’ judgments. Having identified key signals at multiple stages of the BG circuit related to this decision in rats and mice, my laboratory is now uniquely poised to dissect the circuit mechanisms by which such signals are generated and transformed into actions. Specifically, we will 1) Measure activity of specific cell types at multiple stages of the BG as mice judge duration. 2) Image and manipulate the activity of DA neurons while recording from neural populations in the BG to determine the relationship between neuromodulatory input, neural dynamics, and behavior. 3) Relate the activity of cortico-striatal inputs to striatal responses during behavior to understand the computational and circuit bases of striatal activity. These experiments promise to unlock deep mysteries regarding how animals free themselves from the immediacy of the current moment, learning, planning, and choosing their path toward a safer, more fruitful, and satisfying existence.
Max ERC Funding
2 000 000 €
Duration
Start date: 2018-04-01, End date: 2023-03-31
Project acronym Ecol of interactions
Project Developing the predictive ecology of plant-animal interactions across space and time
Researcher (PI) Catherine GRAHAM
Host Institution (HI) EIDGENOESSISCHE FORSCHUNGSANSTALT WSL
Call Details Advanced Grant (AdG), LS8, ERC-2017-ADG
Summary In the face of the alarming pace of recent environmental change we lack the tools to accurately predict how biodiversity and ecosystem services will respond. One key gap in knowledge that limits our predictive ability is uncertainty concerning how the biotic interactions will change. Developing a predictive science of species interactions requires integrating evolutionary, biogeographic and ecological mechanisms acting at different spatial and temporal scales. We will use a hierarchical cross-scale approach, combining phylogeography, network ecology, statistical modelling and experiments, to disentangle the mechanisms governing species richness and mutualistic interactions in tropical hummingbirds and their food plants. Hummingbirds and their food plants are an excellent model system because they are highly diverse, highly specialized, and logistically feasible to study. Our objectives are to (1) evaluate the influence of factors, such as trait-matching, environmental conditions and relatedness, on network structure; (2) quantify how and why interaction beta-diversity (i.e., reflecting the change in both species composition, and in interacting partners) changes across elevation gradients in each of three biogeographic regions with distinct evolutionary histories (mountain regions in Costa Rica, Ecuador, Brazil); (3) evaluate the importance of multiple factors, such as trait-matching, environmental conditions, relatedness and abundance, on species interactions and network structure; and (4) develop a predictive model of species interactions and evaluate its performance using cross-validation and experimentation. Together, these tasks will provide new insight into one of the central enigmas in ecology, namely, why species diversity and its interaction architecture change across space and time. We will also be able predict how species interactions will change from present to the future, which is essential for the conservation of biodiversity and ecosystem services.
Summary
In the face of the alarming pace of recent environmental change we lack the tools to accurately predict how biodiversity and ecosystem services will respond. One key gap in knowledge that limits our predictive ability is uncertainty concerning how the biotic interactions will change. Developing a predictive science of species interactions requires integrating evolutionary, biogeographic and ecological mechanisms acting at different spatial and temporal scales. We will use a hierarchical cross-scale approach, combining phylogeography, network ecology, statistical modelling and experiments, to disentangle the mechanisms governing species richness and mutualistic interactions in tropical hummingbirds and their food plants. Hummingbirds and their food plants are an excellent model system because they are highly diverse, highly specialized, and logistically feasible to study. Our objectives are to (1) evaluate the influence of factors, such as trait-matching, environmental conditions and relatedness, on network structure; (2) quantify how and why interaction beta-diversity (i.e., reflecting the change in both species composition, and in interacting partners) changes across elevation gradients in each of three biogeographic regions with distinct evolutionary histories (mountain regions in Costa Rica, Ecuador, Brazil); (3) evaluate the importance of multiple factors, such as trait-matching, environmental conditions, relatedness and abundance, on species interactions and network structure; and (4) develop a predictive model of species interactions and evaluate its performance using cross-validation and experimentation. Together, these tasks will provide new insight into one of the central enigmas in ecology, namely, why species diversity and its interaction architecture change across space and time. We will also be able predict how species interactions will change from present to the future, which is essential for the conservation of biodiversity and ecosystem services.
Max ERC Funding
2 499 930 €
Duration
Start date: 2018-10-01, End date: 2023-09-30
Project acronym ElectroGene
Project Electrogenetics – Shaping Electrogenetic Interfaces for Closed-Loop Voltage-Controlled Gene Expression
Researcher (PI) Martin Fussenegger
Host Institution (HI) EIDGENOESSISCHE TECHNISCHE HOCHSCHULE ZUERICH
Call Details Advanced Grant (AdG), LS9, ERC-2017-ADG
Summary Man and man-made electronic systems share the same ecosystem, and yet work radically differently. Human metabolism uses ion gradients across insulated membranes to simultaneously process slow analog chemical reactions and communicate information in multicellular systems via soluble/volatile molecular signals. By contrast, electronic systems use multicore central processing units to control the flow of electrons through insulated metal wires with gigahertz frequency and communicate information across networks via wired/wireless connections. With the advent of the internet of things, networks of interconnected electronic devices will reach the processing complexity of living systems, yet they remain largely incompatible with biological systems. Wearable electronics can profile physical parameters such as steps and heartbeat, and Google’s proposal to develop glucose-monitoring contact lenses has triggered a wave of interest in harnessing the full potential of bioelectronics for medical applications. Yet this vision remains limited to diagnostics. Capitalizing on our mind-controlled and smartphone-adjustable optogenetic drug-dosing devices, ElectroGene will establish the foundations of electrogenetics, the science of creating electro-genetic interfaces that enable direct two-way communication between electronic devices and living cells. ElectroGene consists of three pillars, (i) voltage-triggered gene expression, (ii) genetically programmed electronics and (iii) wireless-powered implants providing closed-loop bioelectronic control, which allow real-time monitoring of metabolic conditions (diagnosis), enable remote-controlled production and dosing of protein therapeutics by implanted designer cells (treatment), and manage closed-loop control between cells and electronics, thus linking diagnosis and therapy to block disease onset (prevention). ElectroGene design principles and devices will be validated in proof-of-concept preclinical studies for the treatment of diabetes.
Summary
Man and man-made electronic systems share the same ecosystem, and yet work radically differently. Human metabolism uses ion gradients across insulated membranes to simultaneously process slow analog chemical reactions and communicate information in multicellular systems via soluble/volatile molecular signals. By contrast, electronic systems use multicore central processing units to control the flow of electrons through insulated metal wires with gigahertz frequency and communicate information across networks via wired/wireless connections. With the advent of the internet of things, networks of interconnected electronic devices will reach the processing complexity of living systems, yet they remain largely incompatible with biological systems. Wearable electronics can profile physical parameters such as steps and heartbeat, and Google’s proposal to develop glucose-monitoring contact lenses has triggered a wave of interest in harnessing the full potential of bioelectronics for medical applications. Yet this vision remains limited to diagnostics. Capitalizing on our mind-controlled and smartphone-adjustable optogenetic drug-dosing devices, ElectroGene will establish the foundations of electrogenetics, the science of creating electro-genetic interfaces that enable direct two-way communication between electronic devices and living cells. ElectroGene consists of three pillars, (i) voltage-triggered gene expression, (ii) genetically programmed electronics and (iii) wireless-powered implants providing closed-loop bioelectronic control, which allow real-time monitoring of metabolic conditions (diagnosis), enable remote-controlled production and dosing of protein therapeutics by implanted designer cells (treatment), and manage closed-loop control between cells and electronics, thus linking diagnosis and therapy to block disease onset (prevention). ElectroGene design principles and devices will be validated in proof-of-concept preclinical studies for the treatment of diabetes.
Max ERC Funding
2 500 000 €
Duration
Start date: 2018-11-01, End date: 2023-10-31
Project acronym ENTRAINER
Project Enhancing brain function and cognition via artificial entrainment of neural oscillations
Researcher (PI) Rafael POLANIA
Host Institution (HI) EIDGENOESSISCHE TECHNISCHE HOCHSCHULE ZUERICH
Call Details Starting Grant (StG), LS5, ERC-2017-STG
Summary Neural oscillations are ubiquitous in the human brain and have been implicated in diverse cognitive functions to support both neural communication and plasticity. Their functional relevance is further supported by a large number of studies linking various cognitive deficits (e.g., attention deficit hyperactivity disorder, ADHD) with abnormal neural oscillations. However, this field of research faces two important problems: First, there is only correlative, but no causal evidence linking cognitive deficits to abnormal neural oscillations in humans. Second, there is virtually no theory-driven mechanistic approach that generates insights into how oscillations within and across neural networks are linked to human behavior. In this project, I propose to take decisive steps to provide a long-needed neurophysiological characterization—via (1) computational modelling, (2) electrophysiological measures, and (3) novel non-invasive manipulations of cortical rhythms—on how neural oscillations contribute to two types of cognitive processes that are fundamental for many aspects of human behavior: attention and short-term memory. I will go a step further by demonstrating that it is possible to augment performance in these cognitive functions with the design of non-invasive brain stimulation protocols individually tailored to the theory-driven neurocomputational characterizations and electrophysiological signatures of each individual. This will result in the applied goal of deriving new neuro-computational assays that can detect deviant network interactions causally related to cognitive functions, which is key for then renormalizing those functions in neuropsychological conditions such as ADHD. Thus, if successful, my proposed work will ultimately result in novel, low-cost, and painless non-invasive neural interventions for a wide range of neuropsychological disorders tied to abnormal neural oscillations.
Summary
Neural oscillations are ubiquitous in the human brain and have been implicated in diverse cognitive functions to support both neural communication and plasticity. Their functional relevance is further supported by a large number of studies linking various cognitive deficits (e.g., attention deficit hyperactivity disorder, ADHD) with abnormal neural oscillations. However, this field of research faces two important problems: First, there is only correlative, but no causal evidence linking cognitive deficits to abnormal neural oscillations in humans. Second, there is virtually no theory-driven mechanistic approach that generates insights into how oscillations within and across neural networks are linked to human behavior. In this project, I propose to take decisive steps to provide a long-needed neurophysiological characterization—via (1) computational modelling, (2) electrophysiological measures, and (3) novel non-invasive manipulations of cortical rhythms—on how neural oscillations contribute to two types of cognitive processes that are fundamental for many aspects of human behavior: attention and short-term memory. I will go a step further by demonstrating that it is possible to augment performance in these cognitive functions with the design of non-invasive brain stimulation protocols individually tailored to the theory-driven neurocomputational characterizations and electrophysiological signatures of each individual. This will result in the applied goal of deriving new neuro-computational assays that can detect deviant network interactions causally related to cognitive functions, which is key for then renormalizing those functions in neuropsychological conditions such as ADHD. Thus, if successful, my proposed work will ultimately result in novel, low-cost, and painless non-invasive neural interventions for a wide range of neuropsychological disorders tied to abnormal neural oscillations.
Max ERC Funding
1 497 104 €
Duration
Start date: 2018-02-01, End date: 2023-01-31
Project acronym FatTryp
Project Exploring the hidden life of African trypanosomes: parasite fat tropism and implications for disease
Researcher (PI) Luisa FIGUEIREDO
Host Institution (HI) INSTITUTO DE MEDICINA MOLECULAR JOAO LOBO ANTUNES
Call Details Consolidator Grant (CoG), LS6, ERC-2017-COG
Summary Background: The study of protozoan pathogens has been extensively explored often motivated to find suitable targets for new intervention strategies. However these studies have been mostly limited to those life-cycle stages that can be cultivated in vitro. Using a mouse model of African trypanosomiasis, we have recently discovered that the adipose tissue (fat) is a major reservoir for the extracellular protozoan Trypanosoma brucei and that, within this environment, parasites become phenotypically different from those in the blood. Our study exposed novel biology of the T. brucei life cycle, yet it remains unknown how parasites adapt to the fat and how parasite fat tropism affects disease.
Our first aim is to determine the molecular and cellular mechanisms underlying T. brucei fat tropism. We will perform a genetic screen in mice to identify key parasite genes required for establishing and maintaining chronic infection in the fat. Together with the information of the transcriptome and proteome, we will identify the mechanistic steps underlying parasite tissue-adaptation.
Our second aim is to identify the consequences of T. brucei fat tropism for the host and the importance for disease. We will first investigate if parasites can egress from the fat. We will also determine if parasites induce lipid breakdown in the host, leading to loss of fat mass. Finally, we will measure the impact of fat tropism in general traits of disease, including host survival and transmission potential.
Impact: This project represents a completely novel research avenue built on recent work from my laboratory. By uncovering fundamental aspects of the biology of T. brucei, we will also improve the understanding of clinically relevant features of African trypanosomiasis, including relapses and weight loss. In addition, since parasite fat tropism has also been observed in malaria and Chagas’ disease, our findings will help elucidate disease mechanisms relevant to other infectious diseases.
Summary
Background: The study of protozoan pathogens has been extensively explored often motivated to find suitable targets for new intervention strategies. However these studies have been mostly limited to those life-cycle stages that can be cultivated in vitro. Using a mouse model of African trypanosomiasis, we have recently discovered that the adipose tissue (fat) is a major reservoir for the extracellular protozoan Trypanosoma brucei and that, within this environment, parasites become phenotypically different from those in the blood. Our study exposed novel biology of the T. brucei life cycle, yet it remains unknown how parasites adapt to the fat and how parasite fat tropism affects disease.
Our first aim is to determine the molecular and cellular mechanisms underlying T. brucei fat tropism. We will perform a genetic screen in mice to identify key parasite genes required for establishing and maintaining chronic infection in the fat. Together with the information of the transcriptome and proteome, we will identify the mechanistic steps underlying parasite tissue-adaptation.
Our second aim is to identify the consequences of T. brucei fat tropism for the host and the importance for disease. We will first investigate if parasites can egress from the fat. We will also determine if parasites induce lipid breakdown in the host, leading to loss of fat mass. Finally, we will measure the impact of fat tropism in general traits of disease, including host survival and transmission potential.
Impact: This project represents a completely novel research avenue built on recent work from my laboratory. By uncovering fundamental aspects of the biology of T. brucei, we will also improve the understanding of clinically relevant features of African trypanosomiasis, including relapses and weight loss. In addition, since parasite fat tropism has also been observed in malaria and Chagas’ disease, our findings will help elucidate disease mechanisms relevant to other infectious diseases.
Max ERC Funding
2 000 000 €
Duration
Start date: 2018-08-01, End date: 2023-07-31
Project acronym Global Horizons
Project Global Horizons in Pre-Modern Art
Researcher (PI) Beate FRICKE
Host Institution (HI) UNIVERSITAET BERN
Call Details Consolidator Grant (CoG), SH5, ERC-2017-COG
Summary The horizon is the line that seems to separate earth from sky, the line that divides all visible categories into two categories: those that intersect the earth’s surface and those that do not. The horizon is key to the experience of space; it defines our perspective on the visible world. The GLOBAL HORIZONS project will investigate the historical meanings and functions of the horizon in visual and intellectual cultures of the pre-Modern world on a global scale. Examining how pre-Modern cultures conceived of the horizon opens a crucial line of inquiry into understanding the many different ways in which humans have conceived of the relationship between an invisible cosmos and the visible world.
Non-western art history is rarely taught at European institutions although countless important works of Non-Western art are kept in museum collections all across Europe. Including non-western concepts of pictorial space is key to the project, however, for Eurocentric models of art history have generally privileged the rise of the linear perspective. This framing has limited our understanding of the horizon’s complex rhetorical, visual and epistemological roles.
The project’s specific question connects a variety of objects and epistemological categories, such as panel painting, manuscript illumination, profane und religious objects, cartography, travel accounts, and cosmological treaties. The applied methodological approaches will range from art history, visual studies and cultural anthropology. They will also draw upon interdisciplinary expertise, such as technologies of art production, history of science and philosophy. The project thus makes an important contribution to global art history, a highly innovative area in which only very few pre-modern topics have been addressed. It is the ultimate goal of GLOBAL HORIZONS is to suggest a new history of representation in Western medieval art.
Summary
The horizon is the line that seems to separate earth from sky, the line that divides all visible categories into two categories: those that intersect the earth’s surface and those that do not. The horizon is key to the experience of space; it defines our perspective on the visible world. The GLOBAL HORIZONS project will investigate the historical meanings and functions of the horizon in visual and intellectual cultures of the pre-Modern world on a global scale. Examining how pre-Modern cultures conceived of the horizon opens a crucial line of inquiry into understanding the many different ways in which humans have conceived of the relationship between an invisible cosmos and the visible world.
Non-western art history is rarely taught at European institutions although countless important works of Non-Western art are kept in museum collections all across Europe. Including non-western concepts of pictorial space is key to the project, however, for Eurocentric models of art history have generally privileged the rise of the linear perspective. This framing has limited our understanding of the horizon’s complex rhetorical, visual and epistemological roles.
The project’s specific question connects a variety of objects and epistemological categories, such as panel painting, manuscript illumination, profane und religious objects, cartography, travel accounts, and cosmological treaties. The applied methodological approaches will range from art history, visual studies and cultural anthropology. They will also draw upon interdisciplinary expertise, such as technologies of art production, history of science and philosophy. The project thus makes an important contribution to global art history, a highly innovative area in which only very few pre-modern topics have been addressed. It is the ultimate goal of GLOBAL HORIZONS is to suggest a new history of representation in Western medieval art.
Max ERC Funding
1 904 188 €
Duration
Start date: 2018-09-01, End date: 2023-08-31
Project acronym InflamCellDeath
Project Mechanism and function of gasdermin-induced inflammatory cell death
Researcher (PI) Petr BROZ
Host Institution (HI) UNIVERSITE DE LAUSANNE
Call Details Consolidator Grant (CoG), LS6, ERC-2017-COG
Summary Pyroptosis is a lytic pro-inflammatory type of programmed cell death that is induced by inflammatory caspases, a family of proteases that control the innate immune response to infection, injury or noxious substances. Inflammatory caspases are activated within so-called inflammasomes, cytosolic signalling platforms that are assembled by pattern recognition receptors upon the detection of pathogen- or host-derived danger signals. Pyroptosis is essential for antimicrobial host defense, but also promotes the concomitant release of inflammatory danger signals and leaderless cytokines that is detrimental during chronic inflammatory disease.
Recently it was found that pyroptosis is caused by the cleavage of a single caspase substrate called gasdermin-D. This cleavage generates a cytotoxic N-terminal fragment of gasdermin-D that targets the plasma membrane, where it forms large permeability pores and thus causes pyroptotic cell death. Gasdermin-D is only one member of the larger gasdermin protein family, an emerging group of cell death effectors that share its pore-forming cytotoxic activity and that appear to be major regulators of inflammatory necrotic cell death.
The main goal of this proposal is to comprehensively characterize the function of gasdermins in anti-microbial host defense, to investigate the consequences of gasdermin-D pore formation to the host cell and to elucidate the pathways that regulate gasdermin activation. My objectives are:
1) to define the role of gasdermin-D in inflammasome-dependent anti-bacterial host defense
2) to study the role of membrane repair in restricting gasdermin-D-induced membrane
3) to characterize the function and regulation of other gasdermin family members during infection
By characterizing the mechanism and function of gasdermin-induced cell death in host-defense and inflammation this project may contribute to the development of novel therapies for infectious as well as inflammatory diseases.
Summary
Pyroptosis is a lytic pro-inflammatory type of programmed cell death that is induced by inflammatory caspases, a family of proteases that control the innate immune response to infection, injury or noxious substances. Inflammatory caspases are activated within so-called inflammasomes, cytosolic signalling platforms that are assembled by pattern recognition receptors upon the detection of pathogen- or host-derived danger signals. Pyroptosis is essential for antimicrobial host defense, but also promotes the concomitant release of inflammatory danger signals and leaderless cytokines that is detrimental during chronic inflammatory disease.
Recently it was found that pyroptosis is caused by the cleavage of a single caspase substrate called gasdermin-D. This cleavage generates a cytotoxic N-terminal fragment of gasdermin-D that targets the plasma membrane, where it forms large permeability pores and thus causes pyroptotic cell death. Gasdermin-D is only one member of the larger gasdermin protein family, an emerging group of cell death effectors that share its pore-forming cytotoxic activity and that appear to be major regulators of inflammatory necrotic cell death.
The main goal of this proposal is to comprehensively characterize the function of gasdermins in anti-microbial host defense, to investigate the consequences of gasdermin-D pore formation to the host cell and to elucidate the pathways that regulate gasdermin activation. My objectives are:
1) to define the role of gasdermin-D in inflammasome-dependent anti-bacterial host defense
2) to study the role of membrane repair in restricting gasdermin-D-induced membrane
3) to characterize the function and regulation of other gasdermin family members during infection
By characterizing the mechanism and function of gasdermin-induced cell death in host-defense and inflammation this project may contribute to the development of novel therapies for infectious as well as inflammatory diseases.
Max ERC Funding
1 999 176 €
Duration
Start date: 2018-03-01, End date: 2023-02-28
Project acronym INPHORS
Project Intracellular phosphate reception and signaling: A novel homeostatic system with roles for an orphan organelle?
Researcher (PI) Andreas MAYER
Host Institution (HI) UNIVERSITE DE LAUSANNE
Call Details Advanced Grant (AdG), LS3, ERC-2017-ADG
Summary Cells face a phosphate challenge. Growth requires a minimal concentration of this limiting resource because intracellular phosphate (Pi) is a compound of nucleic acids and modifies most cellular proteins. At the same time, cytosolic Pi may not rise much, because elevated cytosolic Pi can stall metabolism. It reduces the free energy that nucleotide triphosphate hydrolysis can provide to drive energetically unfavorable reactions.
I will undertake a pioneering study to elucidate how cells strike this critical balance. We will identify a novel pathway for intracellular phosphate reception and signaling (INPHORS) and explore the role of acidocalcisomes in it. These studies may identify a key function of these very poorly understood organelles, provide one reason for their evolutionary conservation and elucidate a novel homeostatic system of critical importance for cellular metabolism.
We recently provided first hints that a dedicated pathway for sensing and signaling intracellular Pi might exist, which regulates multiple systems for import, export and acidocalcisomal storage of Pi, such that cytosolic Pi homeostasis is guaranteed 1. Yeast cells will serve as an powerful model system for exploring this pathway and its physiological relevance. Yeast Pi transport and storage proteins are known. Furthermore, we can establish cell-free in vitro systems that reconstitute Pi-regulated transport and storage processes, providing an excellent basis for identifying signaling complexes and studying their dynamics.
We will (A) generate novel tools to uncouple, individually manipulate and measure key parameters for the INPHORS pathway; (B) identify its components, study their interactions and regulation; (C) elucidate how acidocalcisomes are targeted by INPHORS and how they contribute to Pi homeostasis; (D) study the crosstalk between INPHORS and Pi-regulated transcriptional responses; (E) test the relevance of INPHORS for Pi homeostasis in mammalian cells.
Summary
Cells face a phosphate challenge. Growth requires a minimal concentration of this limiting resource because intracellular phosphate (Pi) is a compound of nucleic acids and modifies most cellular proteins. At the same time, cytosolic Pi may not rise much, because elevated cytosolic Pi can stall metabolism. It reduces the free energy that nucleotide triphosphate hydrolysis can provide to drive energetically unfavorable reactions.
I will undertake a pioneering study to elucidate how cells strike this critical balance. We will identify a novel pathway for intracellular phosphate reception and signaling (INPHORS) and explore the role of acidocalcisomes in it. These studies may identify a key function of these very poorly understood organelles, provide one reason for their evolutionary conservation and elucidate a novel homeostatic system of critical importance for cellular metabolism.
We recently provided first hints that a dedicated pathway for sensing and signaling intracellular Pi might exist, which regulates multiple systems for import, export and acidocalcisomal storage of Pi, such that cytosolic Pi homeostasis is guaranteed 1. Yeast cells will serve as an powerful model system for exploring this pathway and its physiological relevance. Yeast Pi transport and storage proteins are known. Furthermore, we can establish cell-free in vitro systems that reconstitute Pi-regulated transport and storage processes, providing an excellent basis for identifying signaling complexes and studying their dynamics.
We will (A) generate novel tools to uncouple, individually manipulate and measure key parameters for the INPHORS pathway; (B) identify its components, study their interactions and regulation; (C) elucidate how acidocalcisomes are targeted by INPHORS and how they contribute to Pi homeostasis; (D) study the crosstalk between INPHORS and Pi-regulated transcriptional responses; (E) test the relevance of INPHORS for Pi homeostasis in mammalian cells.
Max ERC Funding
2 499 998 €
Duration
Start date: 2018-09-01, End date: 2023-08-31
Project acronym NEUROFISH
Project Whole-brain circuits controlling visuomotor behavior
Researcher (PI) Michael Brian ORGER
Host Institution (HI) FUNDACAO D. ANNA SOMMER CHAMPALIMAUD E DR. CARLOS MONTEZ CHAMPALIMAUD
Call Details Consolidator Grant (CoG), LS5, ERC-2017-COG
Summary Understanding how our brains extract relevant features of sensory input to select and guide appropriate actions is a fundamental goal of neuroscience. Yet even relatively simple sensorimotor reflexes can depend on activity within complex networks of neurons that are distributed across the brain, presenting a challenge for traditional neuroscience approaches.
Our recent work has demonstrated the capacity to image neural activity with single cell resolution throughout the small transparent brain of behaving zebrafish. Here we will trace, from sensory input to motor output, the neural circuits that allow zebrafish to select and execute distinct swimming patterns in response to varying visual input. Through comprehensive whole-brain functional imaging in combination with optical and genetic circuit tracing, we aim to determine the principles on which these sensorimotor circuits are organised and reveal how activity dynamics unfold throughout the whole brain during behaviour.
We will take a systematic approach to this problem, based on a thorough quantitative analysis of swim kinematics and the sensory stimuli that drive them. We will: 1) Use whole-brain functional imaging of genetically defined neural populations to reveal the neural circuit organization and activity dynamics during visuomotor behaviour. 2) Establish how motor commands are encoded at the single-cell and population level by brainstem reticulospinal neurons, through imaging and ablation studies and 3) Systematically map the functional organisation of retinal inputs into the brain.
Taken together, these experiments will provide an unprecedented, single-cell resolution view of the organization of complete circuits that transform retinal inputs to motor outputs in the vertebrate brain.
Summary
Understanding how our brains extract relevant features of sensory input to select and guide appropriate actions is a fundamental goal of neuroscience. Yet even relatively simple sensorimotor reflexes can depend on activity within complex networks of neurons that are distributed across the brain, presenting a challenge for traditional neuroscience approaches.
Our recent work has demonstrated the capacity to image neural activity with single cell resolution throughout the small transparent brain of behaving zebrafish. Here we will trace, from sensory input to motor output, the neural circuits that allow zebrafish to select and execute distinct swimming patterns in response to varying visual input. Through comprehensive whole-brain functional imaging in combination with optical and genetic circuit tracing, we aim to determine the principles on which these sensorimotor circuits are organised and reveal how activity dynamics unfold throughout the whole brain during behaviour.
We will take a systematic approach to this problem, based on a thorough quantitative analysis of swim kinematics and the sensory stimuli that drive them. We will: 1) Use whole-brain functional imaging of genetically defined neural populations to reveal the neural circuit organization and activity dynamics during visuomotor behaviour. 2) Establish how motor commands are encoded at the single-cell and population level by brainstem reticulospinal neurons, through imaging and ablation studies and 3) Systematically map the functional organisation of retinal inputs into the brain.
Taken together, these experiments will provide an unprecedented, single-cell resolution view of the organization of complete circuits that transform retinal inputs to motor outputs in the vertebrate brain.
Max ERC Funding
1 694 063 €
Duration
Start date: 2018-02-01, End date: 2023-01-31
Project acronym NeuroStemCircuit
Project Neural Circuit Regulation of Adult Brain Stem Cells
Researcher (PI) Fiona DOETSCH
Host Institution (HI) UNIVERSITAT BASEL
Call Details Advanced Grant (AdG), LS5, ERC-2017-ADG
Summary In the adult mammalian brain, neural stem cells (NSCs) residing in the ventricular-subventricular zone (V-SVZ), give rise to new olfactory bulb neurons and glia throughout life. Adult V-SVZ NSC are highly heterogeneous. Stem cells co-exist in quiescent and activated states and reside in regionally-distinct V-SVZ domains and produce different subtypes of olfactory bulb neurons and glia. However, whether this heterogeneity is due to intrinsic fate commitment or whether it is dynamically responsive to external changes is still debated. Moreover, the mechanisms that modulate the balance between activation and dormancy are largely unknown. It is emerging that physiological states modulate V-SVZ cell behaviour and impact adult neurogenesis. We propose to investigate whether physiologically distinct states result in the recruitment of regionally distinct pools of adult V-SVZ neural stem cells. In Aim 1, we will map the domains of stem cell activation and cell types generated in different states in male and female mice. In Aim 2, we will perform large-scale single cell sequencing to decode stem cell heterogeneity and develop novel fate mapping strategies to selectively target different stem cell populations. We will also define the connectivity of different populations of interneuron subtypes. In Aim 3, we will define how the choroid plexus and long- range innervation differentially affect V-SVZ stem cell recruitment in different states using approaches to manipulate neural circuit activity. Together these experiments will provide a conceptual breakthrough into illuminating the logic of adult neural stem cell heterogeneity, and how regionally distinct adult neural stem cells integrate long-range signals from remote brain areas to respond to signals for on-demand neurogenesis or gliogenesis.
Summary
In the adult mammalian brain, neural stem cells (NSCs) residing in the ventricular-subventricular zone (V-SVZ), give rise to new olfactory bulb neurons and glia throughout life. Adult V-SVZ NSC are highly heterogeneous. Stem cells co-exist in quiescent and activated states and reside in regionally-distinct V-SVZ domains and produce different subtypes of olfactory bulb neurons and glia. However, whether this heterogeneity is due to intrinsic fate commitment or whether it is dynamically responsive to external changes is still debated. Moreover, the mechanisms that modulate the balance between activation and dormancy are largely unknown. It is emerging that physiological states modulate V-SVZ cell behaviour and impact adult neurogenesis. We propose to investigate whether physiologically distinct states result in the recruitment of regionally distinct pools of adult V-SVZ neural stem cells. In Aim 1, we will map the domains of stem cell activation and cell types generated in different states in male and female mice. In Aim 2, we will perform large-scale single cell sequencing to decode stem cell heterogeneity and develop novel fate mapping strategies to selectively target different stem cell populations. We will also define the connectivity of different populations of interneuron subtypes. In Aim 3, we will define how the choroid plexus and long- range innervation differentially affect V-SVZ stem cell recruitment in different states using approaches to manipulate neural circuit activity. Together these experiments will provide a conceptual breakthrough into illuminating the logic of adult neural stem cell heterogeneity, and how regionally distinct adult neural stem cells integrate long-range signals from remote brain areas to respond to signals for on-demand neurogenesis or gliogenesis.
Max ERC Funding
2 499 833 €
Duration
Start date: 2018-10-01, End date: 2023-09-30
Project acronym NucleolusChromatin
Project Analysis of the nucleolus in genome organization and function
Researcher (PI) Raffaella SANTORO
Host Institution (HI) UNIVERSITAT ZURICH
Call Details Advanced Grant (AdG), LS2, ERC-2017-ADG
Summary In eukaryotic cells, the higher-order organization of genomes is functionally important to ensure correct execution of gene expression programs. For instance, as cells differentiate into specialized cell types, chromosomes undergo diverse structural and organizational changes that affect gene expression and other cellular functions. However, how this process is achieved is still poorly understood. The elucidation of the mechanisms that control the spatial architecture of the genome and its contribution to gene regulation is a key open issue in molecular biology, relevant for physiological and pathological processes.
Increasing evidence indicated that large-scale folding of chromatin may affect gene expression by locating genes to specific nuclear subcompartments that are either stimulatory or inhibitory to transcription. Nuclear periphery (NP) and nucleolus are two important nuclear landmarks where repressive chromatin domains are often located. The interaction of chromosomes with NP and nucleolus is thought to contribute to a basal chromosome architecture and genome function. However, while the role of NP in genome organization has been well documented, the function of the nucleolus remains yet elusive.
To fully understand how genome organization regulates chromatin and gene expression states, it is necessary to obtain a comprehensive functional map of genome compartmentalization. However, so far, only domains associating with NP (LADs) have been identified and characterized while nucleolar-associated domains (NADs) remained under-investigated. The aim of this project is to fill this gap by developing methods to identify and characterize NADs and analyse the role of the nucleolus in genome organization, moving toward the obtainment of a comprehensive functional map of genome compartmentalization for each cell state and providing novel insights into basic principles of genome organization and its role in gene expression and cell function that yet remain elusive.
Summary
In eukaryotic cells, the higher-order organization of genomes is functionally important to ensure correct execution of gene expression programs. For instance, as cells differentiate into specialized cell types, chromosomes undergo diverse structural and organizational changes that affect gene expression and other cellular functions. However, how this process is achieved is still poorly understood. The elucidation of the mechanisms that control the spatial architecture of the genome and its contribution to gene regulation is a key open issue in molecular biology, relevant for physiological and pathological processes.
Increasing evidence indicated that large-scale folding of chromatin may affect gene expression by locating genes to specific nuclear subcompartments that are either stimulatory or inhibitory to transcription. Nuclear periphery (NP) and nucleolus are two important nuclear landmarks where repressive chromatin domains are often located. The interaction of chromosomes with NP and nucleolus is thought to contribute to a basal chromosome architecture and genome function. However, while the role of NP in genome organization has been well documented, the function of the nucleolus remains yet elusive.
To fully understand how genome organization regulates chromatin and gene expression states, it is necessary to obtain a comprehensive functional map of genome compartmentalization. However, so far, only domains associating with NP (LADs) have been identified and characterized while nucleolar-associated domains (NADs) remained under-investigated. The aim of this project is to fill this gap by developing methods to identify and characterize NADs and analyse the role of the nucleolus in genome organization, moving toward the obtainment of a comprehensive functional map of genome compartmentalization for each cell state and providing novel insights into basic principles of genome organization and its role in gene expression and cell function that yet remain elusive.
Max ERC Funding
2 500 000 €
Duration
Start date: 2018-09-01, End date: 2023-08-31
Project acronym PneumoCaTChER
Project The role of cell-to-cell variability in pneumococcal virulence and antibiotic resistance
Researcher (PI) Jan-Willem VEENING
Host Institution (HI) UNIVERSITE DE LAUSANNE
Call Details Consolidator Grant (CoG), LS6, ERC-2017-COG
Summary Within clonal bacterial populations not all cells exhibit the same phenotype, even though they grow in the same environment. The molecular sources contributing to phenotypic variation are diverse and can originate from noise in gene expression to heterogeneity in growth rates or cell cycle state. Phenotypic variation helps pathogenic bacteria to elude the host immune response or resist antibiotic pressure. Vice versa, there is cell-to-cell variability in the host’s response towards pathogens that can be exploited by bacteria. How the combined cellular heterogeneity of both host and microbe contribute to infection outcome is poorly understood. The role of phenotypic variation on antibiotic resistance development is also unclear.
Recently, we developed novel single cell imaging systems as well as genetic engineering and screening platforms for application to the important opportunistic human pathogen Streptococcus pneumoniae. In addition, we generated a dual-transcriptomics overview of pneumococcal infection of human lung epithelial cells and setup collaborations to perform several infection models. This now places us in an excellent position to investigate the mechanisms and the importance of single cell behaviour for pneumococcal virulence and antibiotic resistance.
The driving hypothesis of this application is that the combined heterogeneity of host cells and pneumococci influences infection and antibiotic therapy outcome. To test this, we will use innovative approaches for infection biology by combining synthetic biology and quantitative single cell biology including single cell RNA-seq, CRISPRi, engineered bistable switches and microfluidics. We will reveal the molecular mechanisms underlying cell-to-cell variability and its importance in virulence and antibiotic resistance.
Insights obtained in this project will lead to a better understanding of phenotypic variation and might result in new treatment strategies for pneumococcal infections.
Summary
Within clonal bacterial populations not all cells exhibit the same phenotype, even though they grow in the same environment. The molecular sources contributing to phenotypic variation are diverse and can originate from noise in gene expression to heterogeneity in growth rates or cell cycle state. Phenotypic variation helps pathogenic bacteria to elude the host immune response or resist antibiotic pressure. Vice versa, there is cell-to-cell variability in the host’s response towards pathogens that can be exploited by bacteria. How the combined cellular heterogeneity of both host and microbe contribute to infection outcome is poorly understood. The role of phenotypic variation on antibiotic resistance development is also unclear.
Recently, we developed novel single cell imaging systems as well as genetic engineering and screening platforms for application to the important opportunistic human pathogen Streptococcus pneumoniae. In addition, we generated a dual-transcriptomics overview of pneumococcal infection of human lung epithelial cells and setup collaborations to perform several infection models. This now places us in an excellent position to investigate the mechanisms and the importance of single cell behaviour for pneumococcal virulence and antibiotic resistance.
The driving hypothesis of this application is that the combined heterogeneity of host cells and pneumococci influences infection and antibiotic therapy outcome. To test this, we will use innovative approaches for infection biology by combining synthetic biology and quantitative single cell biology including single cell RNA-seq, CRISPRi, engineered bistable switches and microfluidics. We will reveal the molecular mechanisms underlying cell-to-cell variability and its importance in virulence and antibiotic resistance.
Insights obtained in this project will lead to a better understanding of phenotypic variation and might result in new treatment strategies for pneumococcal infections.
Max ERC Funding
1 999 735 €
Duration
Start date: 2018-11-01, End date: 2023-10-31
Project acronym StemCellHabitat
Project Metabolic and Timed Control of Stem Cell Fate in the Developing Animal
Researcher (PI) Catarina DE CERTIMA FERNANDES HOMEM
Host Institution (HI) UNIVERSIDADE NOVA DE LISBOA
Call Details Starting Grant (StG), LS3, ERC-2017-STG
Summary Stem cell (SC) proliferation during development requires tight spatial and temporal regulation to ensure correct cell number and right cell types are formed at the proper positions. Currently very little is known about how SCs are regulated during development. Specifically, it is unclear how SC waves of proliferation are regulated and how the fate of their progeny changes during development. In addition, it has recently become evident that metabolism provides additional complexity in cell fate regulation, highlighting the need for integrating metabolic information across physiological levels.
This project will answer the question of how the combination of metabolic state and temporal cues (animal developmental stage) regulate SC fate. I will use Drosophila melanogaster, an animal complex enough to be similar to higher eukaryotes and yet simple enough to dissect the mechanistic details of cell regulation and its impact on the organism. Drosophila neural stem cells, the neuroblasts (NB), are a fantastic model of temporally and metabolically regulated cells. NB lineage fate changes with time, directing the generation of a stereotypical set of neurons, after which they disappear. I have previously found that metabolism is an important regulator of NB cell cycle exit, which occurs in response to an increase in levels of oxidative phosphorylation.
Using a multidisciplinary approach combining genetics, cell type/age sorting, multi-omics analysis, fixed and 3D-live NB imaging and metabolite dynamics, I propose an integrative approach to investigate how NBs are regulated in the developing animal. First I will dissect the mechanisms by which metabolism regulates NB fate. Second, I will investigate how metabolism contributes to NB unlimited proliferation and brain tumors. Finally, we will address how temporal transcription factors and hormones dynamically affect cell fate decisions during development.
Summary
Stem cell (SC) proliferation during development requires tight spatial and temporal regulation to ensure correct cell number and right cell types are formed at the proper positions. Currently very little is known about how SCs are regulated during development. Specifically, it is unclear how SC waves of proliferation are regulated and how the fate of their progeny changes during development. In addition, it has recently become evident that metabolism provides additional complexity in cell fate regulation, highlighting the need for integrating metabolic information across physiological levels.
This project will answer the question of how the combination of metabolic state and temporal cues (animal developmental stage) regulate SC fate. I will use Drosophila melanogaster, an animal complex enough to be similar to higher eukaryotes and yet simple enough to dissect the mechanistic details of cell regulation and its impact on the organism. Drosophila neural stem cells, the neuroblasts (NB), are a fantastic model of temporally and metabolically regulated cells. NB lineage fate changes with time, directing the generation of a stereotypical set of neurons, after which they disappear. I have previously found that metabolism is an important regulator of NB cell cycle exit, which occurs in response to an increase in levels of oxidative phosphorylation.
Using a multidisciplinary approach combining genetics, cell type/age sorting, multi-omics analysis, fixed and 3D-live NB imaging and metabolite dynamics, I propose an integrative approach to investigate how NBs are regulated in the developing animal. First I will dissect the mechanisms by which metabolism regulates NB fate. Second, I will investigate how metabolism contributes to NB unlimited proliferation and brain tumors. Finally, we will address how temporal transcription factors and hormones dynamically affect cell fate decisions during development.
Max ERC Funding
1 697 493 €
Duration
Start date: 2018-02-01, End date: 2023-01-31
