Project acronym 3D-REPAIR
Project Spatial organization of DNA repair within the nucleus
Researcher (PI) Evanthia Soutoglou
Host Institution (HI) CENTRE EUROPEEN DE RECHERCHE EN BIOLOGIE ET MEDECINE
Call Details Consolidator Grant (CoG), LS2, ERC-2015-CoG
Summary Faithful repair of double stranded DNA breaks (DSBs) is essential, as they are at the origin of genome instability, chromosomal translocations and cancer. Cells repair DSBs through different pathways, which can be faithful or mutagenic, and the balance between them at a given locus must be tightly regulated to preserve genome integrity. Although, much is known about DSB repair factors, how the choice between pathways is controlled within the nuclear environment is not understood. We have shown that nuclear architecture and non-random genome organization determine the frequency of chromosomal translocations and that pathway choice is dictated by the spatial organization of DNA in the nucleus. Nevertheless, what determines which pathway is activated in response to DSBs at specific genomic locations is not understood. Furthermore, the impact of 3D-genome folding on the kinetics and efficiency of DSB repair is completely unknown.
Here we aim to understand how nuclear compartmentalization, chromatin structure and genome organization impact on the efficiency of detection, signaling and repair of DSBs. We will unravel what determines the DNA repair specificity within distinct nuclear compartments using protein tethering, promiscuous biotinylation and quantitative proteomics. We will determine how DNA repair is orchestrated at different heterochromatin structures using a CRISPR/Cas9-based system that allows, for the first time robust induction of DSBs at specific heterochromatin compartments. Finally, we will investigate the role of 3D-genome folding in the kinetics of DNA repair and pathway choice using single nucleotide resolution DSB-mapping coupled to 3D-topological maps.
This proposal has significant implications for understanding the mechanisms controlling DNA repair within the nuclear environment and will reveal the regions of the genome that are susceptible to genomic instability and help us understand why certain mutations and translocations are recurrent in cancer
Summary
Faithful repair of double stranded DNA breaks (DSBs) is essential, as they are at the origin of genome instability, chromosomal translocations and cancer. Cells repair DSBs through different pathways, which can be faithful or mutagenic, and the balance between them at a given locus must be tightly regulated to preserve genome integrity. Although, much is known about DSB repair factors, how the choice between pathways is controlled within the nuclear environment is not understood. We have shown that nuclear architecture and non-random genome organization determine the frequency of chromosomal translocations and that pathway choice is dictated by the spatial organization of DNA in the nucleus. Nevertheless, what determines which pathway is activated in response to DSBs at specific genomic locations is not understood. Furthermore, the impact of 3D-genome folding on the kinetics and efficiency of DSB repair is completely unknown.
Here we aim to understand how nuclear compartmentalization, chromatin structure and genome organization impact on the efficiency of detection, signaling and repair of DSBs. We will unravel what determines the DNA repair specificity within distinct nuclear compartments using protein tethering, promiscuous biotinylation and quantitative proteomics. We will determine how DNA repair is orchestrated at different heterochromatin structures using a CRISPR/Cas9-based system that allows, for the first time robust induction of DSBs at specific heterochromatin compartments. Finally, we will investigate the role of 3D-genome folding in the kinetics of DNA repair and pathway choice using single nucleotide resolution DSB-mapping coupled to 3D-topological maps.
This proposal has significant implications for understanding the mechanisms controlling DNA repair within the nuclear environment and will reveal the regions of the genome that are susceptible to genomic instability and help us understand why certain mutations and translocations are recurrent in cancer
Max ERC Funding
1 999 750 €
Duration
Start date: 2017-03-01, End date: 2022-02-28
Project acronym ALS-Networks
Project Defining functional networks of genetic causes for ALS and related neurodegenerative disorders
Researcher (PI) Edor Kabashi
Host Institution (HI) INSTITUT NATIONAL DE LA SANTE ET DE LA RECHERCHE MEDICALE
Call Details Consolidator Grant (CoG), LS5, ERC-2015-CoG
Summary Brain and spinal cord diseases affect 38% of the European population and cost over 800 billion € annually; representing by far the largest health challenge. ALS is a prevalent neurological disease caused by motor neuron death with an invariably fatal outcome. I contributed to ALS research with the groundbreaking discovery of TDP-43 mutations, functionally characterized these mutations in the first vertebrate model and demonstrated a genetic interaction with another major ALS gene FUS. Emerging evidence indicates that four major causative factors in ALS, C9orf72, TDP-43, FUS & SQSTM1, genetically interact and could function in common cellular mechanisms. Here, I will develop zebrafish transgenic lines for all four genes, using state of the art genomic editing tools to combine simultaneous gene knockout and expression of the mutant alleles. Using these innovative disease models I will study the functional interactions amongst these four genes and their converging effect on key ALS pathogenic mechanisms: autophagy degradation, stress granule formation and RNA regulation. These studies will permit to pinpoint the molecular cascades that underlie ALS-related neurodegeneration. We will further expand the current ALS network by proposing and validating novel genetic interactors, which will be further screened for disease-causing variants and as pathological markers in patient samples. The power of zebrafish as a vertebrate model amenable to high-content phenotype-based screens will enable discovery of bioactive compounds that are neuroprotective in multiple animal models of disease. This project will increase the fundamental understanding of the relevance of C9orf72, TDP-43, FUS and SQSTM1 by developing animal models to characterize common pathophysiological mechanisms. Furthermore, I will uncover novel genetic, disease-related and pharmacological modifiers to extend the ALS network that will facilitate development of therapeutic strategies for neurodegenerative disorders
Summary
Brain and spinal cord diseases affect 38% of the European population and cost over 800 billion € annually; representing by far the largest health challenge. ALS is a prevalent neurological disease caused by motor neuron death with an invariably fatal outcome. I contributed to ALS research with the groundbreaking discovery of TDP-43 mutations, functionally characterized these mutations in the first vertebrate model and demonstrated a genetic interaction with another major ALS gene FUS. Emerging evidence indicates that four major causative factors in ALS, C9orf72, TDP-43, FUS & SQSTM1, genetically interact and could function in common cellular mechanisms. Here, I will develop zebrafish transgenic lines for all four genes, using state of the art genomic editing tools to combine simultaneous gene knockout and expression of the mutant alleles. Using these innovative disease models I will study the functional interactions amongst these four genes and their converging effect on key ALS pathogenic mechanisms: autophagy degradation, stress granule formation and RNA regulation. These studies will permit to pinpoint the molecular cascades that underlie ALS-related neurodegeneration. We will further expand the current ALS network by proposing and validating novel genetic interactors, which will be further screened for disease-causing variants and as pathological markers in patient samples. The power of zebrafish as a vertebrate model amenable to high-content phenotype-based screens will enable discovery of bioactive compounds that are neuroprotective in multiple animal models of disease. This project will increase the fundamental understanding of the relevance of C9orf72, TDP-43, FUS and SQSTM1 by developing animal models to characterize common pathophysiological mechanisms. Furthermore, I will uncover novel genetic, disease-related and pharmacological modifiers to extend the ALS network that will facilitate development of therapeutic strategies for neurodegenerative disorders
Max ERC Funding
2 000 000 €
Duration
Start date: 2017-04-01, End date: 2022-03-31
Project acronym AMSEL
Project Atomic Force Microscopy for Molecular Structure Elucidation
Researcher (PI) Leo Gross
Host Institution (HI) IBM RESEARCH GMBH
Call Details Consolidator Grant (CoG), PE4, ERC-2015-CoG
Summary Molecular structure elucidation is of great importance in synthetic chemistry, pharmacy, life sciences, energy and environmental sciences, and technology applications. To date structure elucidation by atomic force microscopy (AFM) has been demonstrated for a few, small and mainly planar molecules. In this project high-risk, high-impact scientific questions will be solved using structure elucidation with the AFM employing a novel tool and novel methodologies.
A combined low-temperature scanning tunneling microscope/atomic force microscope (LT-STM/AFM) with high throughput and in situ electrospray deposition method will be developed. Chemical resolution will be achieved by novel measurement techniques, in particular the usage of different and novel tip functionalizations and combination with Kelvin probe force microscopy. Elements will be identified using substructure recognition provided by a database that will be erected and by refined theory and simulations.
The developed tools and techniques will be applied to molecules of increasing fragility, complexity, size, and three-dimensionality. In particular samples that are challenging to characterize with conventional methods will be studied. Complex molecular mixtures will be investigated molecule-by-molecule taking advantage of the single-molecule sensitivity. The absolute stereochemistry of molecules will be determined, resolving molecules with multiple stereocenters. The operation of single molecular machines as nanocars and molecular gears will be investigated. Reactive intermediates generated with atomic manipulation will be characterized and their on-surface reactivity will be studied by AFM.
Summary
Molecular structure elucidation is of great importance in synthetic chemistry, pharmacy, life sciences, energy and environmental sciences, and technology applications. To date structure elucidation by atomic force microscopy (AFM) has been demonstrated for a few, small and mainly planar molecules. In this project high-risk, high-impact scientific questions will be solved using structure elucidation with the AFM employing a novel tool and novel methodologies.
A combined low-temperature scanning tunneling microscope/atomic force microscope (LT-STM/AFM) with high throughput and in situ electrospray deposition method will be developed. Chemical resolution will be achieved by novel measurement techniques, in particular the usage of different and novel tip functionalizations and combination with Kelvin probe force microscopy. Elements will be identified using substructure recognition provided by a database that will be erected and by refined theory and simulations.
The developed tools and techniques will be applied to molecules of increasing fragility, complexity, size, and three-dimensionality. In particular samples that are challenging to characterize with conventional methods will be studied. Complex molecular mixtures will be investigated molecule-by-molecule taking advantage of the single-molecule sensitivity. The absolute stereochemistry of molecules will be determined, resolving molecules with multiple stereocenters. The operation of single molecular machines as nanocars and molecular gears will be investigated. Reactive intermediates generated with atomic manipulation will be characterized and their on-surface reactivity will be studied by AFM.
Max ERC Funding
2 000 000 €
Duration
Start date: 2016-06-01, End date: 2021-05-31
Project acronym ANGI
Project Adaptive significance of Non Genetic Inheritance
Researcher (PI) Benoit François Pujol
Host Institution (HI) CENTRE NATIONAL DE LA RECHERCHE SCIENTIFIQUE CNRS
Call Details Consolidator Grant (CoG), LS8, ERC-2015-CoG
Summary Our ability to predict adaptation and the response of populations to selection is limited. Solving this issue is a fundamental challenge of evolutionary ecology with implications for applied sciences such as conservation, and agronomy. Non genetic inheritance (NGI; e.g., ecological niche transmission) is suspected to play a foremost role in adaptive evolution but such hypothesis remains untested. Using quantitative genetics in wild plant populations, experimental evolution, and epigenetics, we will assess the role of NGI in the adaptive response to selection of plant populations. The ANGI project will follow the subsequent research program: (1) Using long-term survey data, we will measure natural selection in wild populations of Antirrhinum majus within its heterogeneous array of micro-habitats. We will calculate the fitness gain provided by multiple traits and stem elongation to plants growing in bushes where they compete for light. Stem elongation is known to depend on epigenetic variation. (2) Using a statistical approach that we developed, we will estimate the quantitative genetic and non genetic heritability of traits. (3) We will identify phenotypic changes caused by fitness that are based on genetic variation and NGI and assess their respective roles in adaptive evolution. (4) In controlled conditions, we will artificially select for increased stem elongation in clonal lineages, thereby excluding DNA variation. We will quantify the non genetic response to selection and test for a quantitative epigenetic signature of selection. (5) We will build on our results to generate an inclusive theory of genetic and non genetic natural selection. ANGI builds on a confirmed expertise in selection experiments, quantitative genetics and NGI. In addition, the availability of survey data provides a solid foundation for the achievement of this project. Our ambition is to shed light on original mechanisms underlying adaptation that are an alternative to genetic selection.
Summary
Our ability to predict adaptation and the response of populations to selection is limited. Solving this issue is a fundamental challenge of evolutionary ecology with implications for applied sciences such as conservation, and agronomy. Non genetic inheritance (NGI; e.g., ecological niche transmission) is suspected to play a foremost role in adaptive evolution but such hypothesis remains untested. Using quantitative genetics in wild plant populations, experimental evolution, and epigenetics, we will assess the role of NGI in the adaptive response to selection of plant populations. The ANGI project will follow the subsequent research program: (1) Using long-term survey data, we will measure natural selection in wild populations of Antirrhinum majus within its heterogeneous array of micro-habitats. We will calculate the fitness gain provided by multiple traits and stem elongation to plants growing in bushes where they compete for light. Stem elongation is known to depend on epigenetic variation. (2) Using a statistical approach that we developed, we will estimate the quantitative genetic and non genetic heritability of traits. (3) We will identify phenotypic changes caused by fitness that are based on genetic variation and NGI and assess their respective roles in adaptive evolution. (4) In controlled conditions, we will artificially select for increased stem elongation in clonal lineages, thereby excluding DNA variation. We will quantify the non genetic response to selection and test for a quantitative epigenetic signature of selection. (5) We will build on our results to generate an inclusive theory of genetic and non genetic natural selection. ANGI builds on a confirmed expertise in selection experiments, quantitative genetics and NGI. In addition, the availability of survey data provides a solid foundation for the achievement of this project. Our ambition is to shed light on original mechanisms underlying adaptation that are an alternative to genetic selection.
Max ERC Funding
1 999 970 €
Duration
Start date: 2016-03-01, End date: 2021-02-28
Project acronym Antibodyomics
Project Vaccine profiling and immunodiagnostic discovery by high-throughput antibody repertoire analysis
Researcher (PI) Sai Tota Reddy
Host Institution (HI) EIDGENOESSISCHE TECHNISCHE HOCHSCHULE ZUERICH
Call Details Starting Grant (StG), LS7, ERC-2015-STG
Summary Vaccines and immunodiagnostics have been vital for public health and medicine, however a quantitative molecular understanding of vaccine-induced antibody responses is lacking. Antibody research is currently going through a big-data driven revolution, largely due to progress in next-generation sequencing (NGS) and bioinformatic analysis of antibody repertoires. A main advantage of high-throughput antibody repertoire analysis is that it provides a wealth of quantitative information not possible with other classical methods of antibody analysis (i.e., serum titers); this information includes: clonal distribution and diversity, somatic hypermutation patterns, and lineage tracing. In preliminary work my group has established standardized methods for antibody repertoire NGS, including an experimental-bioinformatic pipeline for error and bias correction that enables highly accurate repertoire sequencing and analysis. The overall goal of this proposal will be to apply high-throughput antibody repertoire analysis for quantitative vaccine profiling and discovery of next-generation immunodiagnostics. Using mouse subunit vaccination as our model system, we will answer for the first time, a fundamental biological question within the context of antibody responses - what is the link between genotype (antibody repertoire) and phenotype (serum antibodies)? We will expand upon this approach for improved rational vaccine design by quantitatively determining the impact of a comprehensive set of subunit vaccination parameters on complete antibody landscapes. Finally, we will develop advanced bioinformatic methods to discover immunodiagnostics based on antibody repertoire sequences. In summary, this proposal lays the foundation for fundamentally new approaches in the quantitative analysis of antibody responses, which long-term will promote the development of next-generation vaccines and immunodiagnostics.
Summary
Vaccines and immunodiagnostics have been vital for public health and medicine, however a quantitative molecular understanding of vaccine-induced antibody responses is lacking. Antibody research is currently going through a big-data driven revolution, largely due to progress in next-generation sequencing (NGS) and bioinformatic analysis of antibody repertoires. A main advantage of high-throughput antibody repertoire analysis is that it provides a wealth of quantitative information not possible with other classical methods of antibody analysis (i.e., serum titers); this information includes: clonal distribution and diversity, somatic hypermutation patterns, and lineage tracing. In preliminary work my group has established standardized methods for antibody repertoire NGS, including an experimental-bioinformatic pipeline for error and bias correction that enables highly accurate repertoire sequencing and analysis. The overall goal of this proposal will be to apply high-throughput antibody repertoire analysis for quantitative vaccine profiling and discovery of next-generation immunodiagnostics. Using mouse subunit vaccination as our model system, we will answer for the first time, a fundamental biological question within the context of antibody responses - what is the link between genotype (antibody repertoire) and phenotype (serum antibodies)? We will expand upon this approach for improved rational vaccine design by quantitatively determining the impact of a comprehensive set of subunit vaccination parameters on complete antibody landscapes. Finally, we will develop advanced bioinformatic methods to discover immunodiagnostics based on antibody repertoire sequences. In summary, this proposal lays the foundation for fundamentally new approaches in the quantitative analysis of antibody responses, which long-term will promote the development of next-generation vaccines and immunodiagnostics.
Max ERC Funding
1 492 586 €
Duration
Start date: 2016-06-01, End date: 2021-05-31
Project acronym ARTIVISM
Project Art and Activism : Creativity and Performance as Subversive Forms of Political Expression in Super-Diverse Cities
Researcher (PI) Monika Salzbrunn
Host Institution (HI) UNIVERSITE DE LAUSANNE
Call Details Consolidator Grant (CoG), SH5, ERC-2015-CoG
Summary ARTIVISM aims at exploring new artistic forms of political expression under difficult, precarious and/or oppressive conditions. It asks how social actors create belonging and multiple forms of resistance when they use art in activism or activism in art. What kind of alliances do these two forms of social practices generate in super-diverse places, in times of crisis and in precarious situations? Thus, ARTIVISM seeks to understand how social actors engage artistically in order to bring about social, economic and political change. Going beyond former research in urban and migration studies, and beyond the anthropology of art, ARTIVISM focuses on a broad range of artistic tools, styles and means of expression, namely festive events and parades, cartoons and comics and street art. By articulating performance studies, street anthropology and the sociology of celebration with migration and diversity studies, the project challenges former concepts, which took stable social groups for granted and reified them with ethnic lenses. The applied methodology considerably renews the field by bringing together event-, actor- and condition-centred approaches and a multi-sensory framework. Besides its multidisciplinary design, the ground-breaking nature of ARTIVISM lies in the application of the core concepts of performativity and liminality, as well as in an examination of the way to advance and refine these concepts and to create new analytical tools to respond to recent social phenomena. We have developed and tested innovative methods that respond to a postmodern type of fluid and temporary social action: audio-visual ethnography, urban event ethnography, street ethnography, field-crossing, and sensory ethnography (apprenticeship). Therefore, ARTIVISM develops new methods and theories in order to introduce a multi-faceted trans-disciplinary approach to the study of an emerging field of social transformations that is of challenging significance to the social sciences.
Summary
ARTIVISM aims at exploring new artistic forms of political expression under difficult, precarious and/or oppressive conditions. It asks how social actors create belonging and multiple forms of resistance when they use art in activism or activism in art. What kind of alliances do these two forms of social practices generate in super-diverse places, in times of crisis and in precarious situations? Thus, ARTIVISM seeks to understand how social actors engage artistically in order to bring about social, economic and political change. Going beyond former research in urban and migration studies, and beyond the anthropology of art, ARTIVISM focuses on a broad range of artistic tools, styles and means of expression, namely festive events and parades, cartoons and comics and street art. By articulating performance studies, street anthropology and the sociology of celebration with migration and diversity studies, the project challenges former concepts, which took stable social groups for granted and reified them with ethnic lenses. The applied methodology considerably renews the field by bringing together event-, actor- and condition-centred approaches and a multi-sensory framework. Besides its multidisciplinary design, the ground-breaking nature of ARTIVISM lies in the application of the core concepts of performativity and liminality, as well as in an examination of the way to advance and refine these concepts and to create new analytical tools to respond to recent social phenomena. We have developed and tested innovative methods that respond to a postmodern type of fluid and temporary social action: audio-visual ethnography, urban event ethnography, street ethnography, field-crossing, and sensory ethnography (apprenticeship). Therefore, ARTIVISM develops new methods and theories in order to introduce a multi-faceted trans-disciplinary approach to the study of an emerging field of social transformations that is of challenging significance to the social sciences.
Max ERC Funding
1 999 287 €
Duration
Start date: 2016-09-01, End date: 2021-08-31
Project acronym AstroWireSyn
Project Wiring synaptic circuits with astroglial connexins: mechanisms, dynamics and impact for critical period plasticity
Researcher (PI) Nathalie Rouach
Host Institution (HI) COLLEGE DE FRANCE
Call Details Consolidator Grant (CoG), LS5, ERC-2015-CoG
Summary Brain information processing is commonly thought to be a neuronal performance. However recent data point to a key role of astrocytes in brain development, activity and pathology. Indeed astrocytes are now viewed as crucial elements of the brain circuitry that control synapse formation, maturation, activity and elimination. How do astrocytes exert such control is matter of intense research, as they are now known to participate in critical developmental periods as well as in psychiatric disorders involving synapse alterations. Thus unraveling how astrocytes control synaptic circuit formation and maturation is crucial, not only for our understanding of brain development, but also for identifying novel therapeutic targets.
We recently found that connexin 30 (Cx30), an astroglial gap junction subunit expressed postnatally, tunes synaptic activity via an unprecedented non-channel function setting the proximity of glial processes to synaptic clefts, essential for synaptic glutamate clearance efficacy. Our work not only reveals Cx30 as a key determinant of glial synapse coverage, but also extends the classical model of neuroglial interactions in which astrocytes are generally considered as extrasynaptic elements indirectly regulating neurotransmission. Yet the molecular mechanisms involved in such control, its dynamic regulation by activity and impact in a native developmental context are unknown. We will now address these important questions, focusing on the involvement of this novel astroglial function in wiring developing synaptic circuits.
Thus using a multidisciplinary approach we will investigate:
1) the molecular and cellular mechanisms underlying Cx30 regulation of synaptic function
2) the activity-dependent dynamics of Cx30 function at synapses
3) a role for Cx30 in wiring synaptic circuits during critical developmental periods
This ambitious project will provide essential knowledge on the molecular mechanisms underlying astroglial control of synaptic circuits.
Summary
Brain information processing is commonly thought to be a neuronal performance. However recent data point to a key role of astrocytes in brain development, activity and pathology. Indeed astrocytes are now viewed as crucial elements of the brain circuitry that control synapse formation, maturation, activity and elimination. How do astrocytes exert such control is matter of intense research, as they are now known to participate in critical developmental periods as well as in psychiatric disorders involving synapse alterations. Thus unraveling how astrocytes control synaptic circuit formation and maturation is crucial, not only for our understanding of brain development, but also for identifying novel therapeutic targets.
We recently found that connexin 30 (Cx30), an astroglial gap junction subunit expressed postnatally, tunes synaptic activity via an unprecedented non-channel function setting the proximity of glial processes to synaptic clefts, essential for synaptic glutamate clearance efficacy. Our work not only reveals Cx30 as a key determinant of glial synapse coverage, but also extends the classical model of neuroglial interactions in which astrocytes are generally considered as extrasynaptic elements indirectly regulating neurotransmission. Yet the molecular mechanisms involved in such control, its dynamic regulation by activity and impact in a native developmental context are unknown. We will now address these important questions, focusing on the involvement of this novel astroglial function in wiring developing synaptic circuits.
Thus using a multidisciplinary approach we will investigate:
1) the molecular and cellular mechanisms underlying Cx30 regulation of synaptic function
2) the activity-dependent dynamics of Cx30 function at synapses
3) a role for Cx30 in wiring synaptic circuits during critical developmental periods
This ambitious project will provide essential knowledge on the molecular mechanisms underlying astroglial control of synaptic circuits.
Max ERC Funding
2 000 000 €
Duration
Start date: 2016-10-01, End date: 2021-09-30
Project acronym B-response
Project Memory and innate-like B-cell subsets: deciphering a multi-layered B-cell response in mice and humans
Researcher (PI) Claude-Agnes REYNAUD
Host Institution (HI) INSTITUT NATIONAL DE LA SANTE ET DE LA RECHERCHE MEDICALE
Call Details Advanced Grant (AdG), LS6, ERC-2015-AdG
Summary B cells are the main actors of successful vaccines, and their protective capacity relies on several subsets with innate-like and memory properties that fulfill different effector functions. In the present project, we wish to develop approaches in both mice and humans, to confront the similarities and the differences of their B cell responses.
The three aims proposed are:
1) To study the different B cell subsets and TFH cells engaged in a memory response through the use of a new mouse reporter line allowing their irreversible labeling (inducible Cre recombinase under the control of the Bcl6 gene): this will be performed in different conditions of TH1 vs. TH2 polarization, as well as during a chronic viral infection, in which virus-specific antibodies have been shown to be required to control the disease (in collaboration with D. Pinschewer, Basel)
2) To study whether the lifelong persistence of B cell memory, as occurs for memory B cells against smallpox that we can obtain at high purity from aged donor's spleens, corresponds to a specific transcriptional program at the miRNA, lncRNA or mRNA level, as well as a specific cell homeostasis
3) To discriminate the specific effector function of human marginal zone and IgM memory B cells in, respectively, T-independent and T-dependent responses, as well as their specific differentiation/diversification pathway.
The general goal is to delineate the regulatory pathways leading to the activation and persistence of the different B cell subsets, allowing for a better understanding of the conditions leading to their pathological or beneficial mobilization.
Summary
B cells are the main actors of successful vaccines, and their protective capacity relies on several subsets with innate-like and memory properties that fulfill different effector functions. In the present project, we wish to develop approaches in both mice and humans, to confront the similarities and the differences of their B cell responses.
The three aims proposed are:
1) To study the different B cell subsets and TFH cells engaged in a memory response through the use of a new mouse reporter line allowing their irreversible labeling (inducible Cre recombinase under the control of the Bcl6 gene): this will be performed in different conditions of TH1 vs. TH2 polarization, as well as during a chronic viral infection, in which virus-specific antibodies have been shown to be required to control the disease (in collaboration with D. Pinschewer, Basel)
2) To study whether the lifelong persistence of B cell memory, as occurs for memory B cells against smallpox that we can obtain at high purity from aged donor's spleens, corresponds to a specific transcriptional program at the miRNA, lncRNA or mRNA level, as well as a specific cell homeostasis
3) To discriminate the specific effector function of human marginal zone and IgM memory B cells in, respectively, T-independent and T-dependent responses, as well as their specific differentiation/diversification pathway.
The general goal is to delineate the regulatory pathways leading to the activation and persistence of the different B cell subsets, allowing for a better understanding of the conditions leading to their pathological or beneficial mobilization.
Max ERC Funding
2 098 750 €
Duration
Start date: 2016-09-01, End date: 2021-08-31
Project acronym Babylearn
Project Neural mechanisms of learning in the infant brain : from Statistics to Rules and Symbols
Researcher (PI) Ghislaine, Marie-Therese, Aline DEHAENE-LAMBERTZ
Host Institution (HI) COMMISSARIAT A L ENERGIE ATOMIQUE ET AUX ENERGIES ALTERNATIVES
Call Details Advanced Grant (AdG), SH4, ERC-2015-AdG
Summary Infant is the most powerful learner: He learns in a few months to master language, complex social interactions, etc. Powerful statistical algorithms, simultaneously acting at the different levels of functional hierarchies have been proposed to explain learning. I propose here that two other elements are crucial. The first is the particular human cerebral architecture that constrains statistical computations. The second is the human’s ability to access a rich symbolic system. I have planned 6 work packages using the complementary information offered by non-invasive brain-imaging techniques (EEG, MRI and optical topography) to understand the neural bases of infant statistical computations and symbolic competence from 6 months of gestation up until the end of the first year of life.
WP1 studies from which preterm age, statistical inferences can be demonstrated using hierarchical auditory oddball paradigms.
WP2 investigates the consequences of a different pre-term environment (in-utero versus ex-utero) on the early statistical computations in the visual and auditory domains and their consequences on the ongoing brain activity along the first year of life.
WP3 explores the neural bases of how infants infer word meaning and word category, and in particular the role of the left perisylvian areas and of their particular connectivity.
WP4 questions infant symbolic competency. I propose several criteria (generalization, bidirectionality, use of algebraic rules and of logical operations) tested in successive experiments to clarify infant symbolic abilities during the first semester of life.
WP5-6 are transversal to WP1-4: WP5 uses MRI to obtain accurate functional localization and maturational markers correlated with functional results. In WP6, we develop new tools to combine and analyse multimodal brain images.
With this proposal, I hope to clarify the specificities of a neural functional architecture that are critical for human learning from the onset of cortical circuits.
Summary
Infant is the most powerful learner: He learns in a few months to master language, complex social interactions, etc. Powerful statistical algorithms, simultaneously acting at the different levels of functional hierarchies have been proposed to explain learning. I propose here that two other elements are crucial. The first is the particular human cerebral architecture that constrains statistical computations. The second is the human’s ability to access a rich symbolic system. I have planned 6 work packages using the complementary information offered by non-invasive brain-imaging techniques (EEG, MRI and optical topography) to understand the neural bases of infant statistical computations and symbolic competence from 6 months of gestation up until the end of the first year of life.
WP1 studies from which preterm age, statistical inferences can be demonstrated using hierarchical auditory oddball paradigms.
WP2 investigates the consequences of a different pre-term environment (in-utero versus ex-utero) on the early statistical computations in the visual and auditory domains and their consequences on the ongoing brain activity along the first year of life.
WP3 explores the neural bases of how infants infer word meaning and word category, and in particular the role of the left perisylvian areas and of their particular connectivity.
WP4 questions infant symbolic competency. I propose several criteria (generalization, bidirectionality, use of algebraic rules and of logical operations) tested in successive experiments to clarify infant symbolic abilities during the first semester of life.
WP5-6 are transversal to WP1-4: WP5 uses MRI to obtain accurate functional localization and maturational markers correlated with functional results. In WP6, we develop new tools to combine and analyse multimodal brain images.
With this proposal, I hope to clarify the specificities of a neural functional architecture that are critical for human learning from the onset of cortical circuits.
Max ERC Funding
2 554 924 €
Duration
Start date: 2016-09-01, End date: 2021-08-31
Project acronym BactInd
Project Bacterial cooperation at the individual cell level
Researcher (PI) Rolf Kümmerli
Host Institution (HI) UNIVERSITAT ZURICH
Call Details Consolidator Grant (CoG), LS8, ERC-2015-CoG
Summary All levels of life entail cooperation and conflict. Genes cooperate to build up a functional genome, which can yet be undermined by selfish genetic elements. Humans and animals cooperate to build up societies, which can yet be subverted by cheats. There is a long-standing interest among biologists to comprehend the tug-of-war between cooperation and conflict. Recently, research on bacteria was successful in identifying key factors that can tip the balance in favour or against cooperation. Bacteria cooperate through the formation of protective biofilms, cell-to-cell communication, and the secretion of shareable public goods. However, the advantage of bacteria being fast replicating units, easily cultivatable in high numbers, is also their disadvantage: they are small and imperceptible, such that measures of cooperation typically rely on averaged responses across millions of cells. Thus, we still know very little about bacterial cooperation at the biological relevant scale: the individual cell level. Here, I present research using the secretion of public goods in the opportunistic human pathogen Pseudomonas aeruginosa, to tackle this issue. I will explore new dimensions of bacterial cooperation by asking whether bacteria engage in collective-decision making to find optimal group-level solutions; whether bacteria show division of labour to split up work efficiently; and whether bacteria can distinguish between trustworthy and cheating partners. The proposed research will make two significant contributions. First, it will reveal whether bacteria engage in complex forms of cooperation (collective decision-making, division of labour, partner recognition), which have traditionally been associated with higher organisms. Second, it will provide insights into the evolutionary stability of cooperation – key knowledge for designing therapies that interfere with virulence-inducing public goods in infections, and the design of stable public-good based remediation processes.
Summary
All levels of life entail cooperation and conflict. Genes cooperate to build up a functional genome, which can yet be undermined by selfish genetic elements. Humans and animals cooperate to build up societies, which can yet be subverted by cheats. There is a long-standing interest among biologists to comprehend the tug-of-war between cooperation and conflict. Recently, research on bacteria was successful in identifying key factors that can tip the balance in favour or against cooperation. Bacteria cooperate through the formation of protective biofilms, cell-to-cell communication, and the secretion of shareable public goods. However, the advantage of bacteria being fast replicating units, easily cultivatable in high numbers, is also their disadvantage: they are small and imperceptible, such that measures of cooperation typically rely on averaged responses across millions of cells. Thus, we still know very little about bacterial cooperation at the biological relevant scale: the individual cell level. Here, I present research using the secretion of public goods in the opportunistic human pathogen Pseudomonas aeruginosa, to tackle this issue. I will explore new dimensions of bacterial cooperation by asking whether bacteria engage in collective-decision making to find optimal group-level solutions; whether bacteria show division of labour to split up work efficiently; and whether bacteria can distinguish between trustworthy and cheating partners. The proposed research will make two significant contributions. First, it will reveal whether bacteria engage in complex forms of cooperation (collective decision-making, division of labour, partner recognition), which have traditionally been associated with higher organisms. Second, it will provide insights into the evolutionary stability of cooperation – key knowledge for designing therapies that interfere with virulence-inducing public goods in infections, and the design of stable public-good based remediation processes.
Max ERC Funding
1 994 981 €
Duration
Start date: 2016-09-01, End date: 2021-08-31
