Project acronym BinCosmos
Project The Impact of Massive Binaries Through Cosmic Time
Researcher (PI) Selma DE MINK
Host Institution (HI) UNIVERSITEIT VAN AMSTERDAM
Call Details Starting Grant (StG), PE9, ERC-2016-STG
Summary Massive stars play many key roles in Astrophysics. As COSMIC ENGINES they transformed the pristine Universe left after the Big Bang into our modern Universe. We use massive stars, their explosions and products as COSMIC PROBES to study the conditions in the distant Universe and the extreme physics inaccessible at earth. Models of massive stars are thus widely applied. A central common assumption is that massive stars are non-rotating single objects, in stark contrast with new data. Recent studies show that majority (70% according to our data) will experience severe interaction with a companion (Sana, de Mink et al. Science 2012).
I propose to conduct the most ambitious and extensive exploration to date of the effects of binarity and rotation on the lives and fates of massive stars to (I) transform our understanding of the complex physical processes and how they operate in the vast parameter space and (II) explore the cosmological implications after calibrating and verifying the models. To achieve this ambitious objective I will use an innovative computational approach that combines the strength of two highly complementary codes and seek direct confrontation with observations to overcome the computational challenges that inhibited previous work.
This timely project will provide the urgent theory framework needed for interpretation and guiding of observing programs with the new facilities (JWST, LSST, aLIGO/VIRGO). Public release of the model grids and code will ensure wide impact of this project. I am in the unique position to successfully lead this project because of my (i) extensive experience modeling the complex physical processes, (ii) leading role in introducing large statistical simulations in the massive star community and (iii) direct involvement in surveys that will be used in this project.
Summary
Massive stars play many key roles in Astrophysics. As COSMIC ENGINES they transformed the pristine Universe left after the Big Bang into our modern Universe. We use massive stars, their explosions and products as COSMIC PROBES to study the conditions in the distant Universe and the extreme physics inaccessible at earth. Models of massive stars are thus widely applied. A central common assumption is that massive stars are non-rotating single objects, in stark contrast with new data. Recent studies show that majority (70% according to our data) will experience severe interaction with a companion (Sana, de Mink et al. Science 2012).
I propose to conduct the most ambitious and extensive exploration to date of the effects of binarity and rotation on the lives and fates of massive stars to (I) transform our understanding of the complex physical processes and how they operate in the vast parameter space and (II) explore the cosmological implications after calibrating and verifying the models. To achieve this ambitious objective I will use an innovative computational approach that combines the strength of two highly complementary codes and seek direct confrontation with observations to overcome the computational challenges that inhibited previous work.
This timely project will provide the urgent theory framework needed for interpretation and guiding of observing programs with the new facilities (JWST, LSST, aLIGO/VIRGO). Public release of the model grids and code will ensure wide impact of this project. I am in the unique position to successfully lead this project because of my (i) extensive experience modeling the complex physical processes, (ii) leading role in introducing large statistical simulations in the massive star community and (iii) direct involvement in surveys that will be used in this project.
Max ERC Funding
1 926 634 €
Duration
Start date: 2017-09-01, End date: 2022-08-31
Project acronym DELPHI
Project DELPHI: a framework to study Dark Matter and the emergence of galaxies in the epoch of reionization
Researcher (PI) Pratika DAYAL
Host Institution (HI) RIJKSUNIVERSITEIT GRONINGEN
Call Details Starting Grant (StG), PE9, ERC-2016-STG
Summary Our Universe started as a dark featureless sea of hydrogen, helium, and dark matter of unknown composition about 13 and a half billion years ago. The earliest galaxies lit up the Universe with pinpricks of light, ushering in the era of ‘cosmic dawn’. These galaxies represent the primary building blocks of all subsequent galaxies and the sources of the first (hydrogen ionizing) photons that could break apart the hydrogen atoms suffusing all of space starting the process of ‘cosmic reionization’. By virtue of being the smallest bound structures in the early Universe, these galaxies also provide an excellent testbed for models wherein Dark Matter is composed of warm, fast moving particles as opposed to the sluggish heavy particles used in the standard Cold Dark Matter paradigm.
Exploiting the power of the latest cosmological simulations as well as semi-analytic modelling rooted in first principles, DELPHI will build a coherent and predictive model to answer three of the key outstanding questions in physical cosmology:
- how did the interlinked processes of galaxy formation and reionization drive each other?
- what were the physical properties of early galaxies and how have they evolved through time to give rise to the galaxy properties we see today?
- what is the nature (mass) of the mysterious Dark Matter that makes up 80% of the matter content in the Universe?
The timescale of the ERC represents an excellent opportunity for progress on these fundamental questions: observations with cutting-edge instruments (e.g. the Hubble and Subaru telescopes) are providing the first tantalising glimpses of early galaxies assembling in an infant Universe, required to pin down theoretical models. The realistic results obtained by DELPHI will also be vital in determining survey strategies and exploiting synergies between forthcoming key state-of-the-art instruments such as the European-Extremely Large Telescope, the James Webb Space Telescope and the Square Kilometre Array.
Summary
Our Universe started as a dark featureless sea of hydrogen, helium, and dark matter of unknown composition about 13 and a half billion years ago. The earliest galaxies lit up the Universe with pinpricks of light, ushering in the era of ‘cosmic dawn’. These galaxies represent the primary building blocks of all subsequent galaxies and the sources of the first (hydrogen ionizing) photons that could break apart the hydrogen atoms suffusing all of space starting the process of ‘cosmic reionization’. By virtue of being the smallest bound structures in the early Universe, these galaxies also provide an excellent testbed for models wherein Dark Matter is composed of warm, fast moving particles as opposed to the sluggish heavy particles used in the standard Cold Dark Matter paradigm.
Exploiting the power of the latest cosmological simulations as well as semi-analytic modelling rooted in first principles, DELPHI will build a coherent and predictive model to answer three of the key outstanding questions in physical cosmology:
- how did the interlinked processes of galaxy formation and reionization drive each other?
- what were the physical properties of early galaxies and how have they evolved through time to give rise to the galaxy properties we see today?
- what is the nature (mass) of the mysterious Dark Matter that makes up 80% of the matter content in the Universe?
The timescale of the ERC represents an excellent opportunity for progress on these fundamental questions: observations with cutting-edge instruments (e.g. the Hubble and Subaru telescopes) are providing the first tantalising glimpses of early galaxies assembling in an infant Universe, required to pin down theoretical models. The realistic results obtained by DELPHI will also be vital in determining survey strategies and exploiting synergies between forthcoming key state-of-the-art instruments such as the European-Extremely Large Telescope, the James Webb Space Telescope and the Square Kilometre Array.
Max ERC Funding
1 500 000 €
Duration
Start date: 2017-03-01, End date: 2022-02-28
Project acronym DIVERSE-EXPECON
Project Discriminative preferences and fairness ideals in diverse societies: An ‘experimental economics’ approach
Researcher (PI) Sigrid SUETENS
Host Institution (HI) STICHTING KATHOLIEKE UNIVERSITEIT BRABANT
Call Details Consolidator Grant (CoG), SH1, ERC-2016-COG
Summary In economics, a distinction is made between statistical and taste-based discrimination (henceforth, TBD). Statistical discrimination refers to discrimination in a context with strategic uncertainty. Someone who is uncertain about the future behaviour of a person with a different ethnicity may rely on information about the different ethnic group to which this person belongs to form beliefs about the behaviour of that person. This may lead to discrimination. TBD refers to discrimination in a context without strategic uncertainty. It implies suffering a disutility when interacting with ‘different’ others. This project systematically studies TBD in ethnically diverse societies.
Identifying TBD is important because overcoming it requires different policies than overcoming statistical discrimination: they should deal with changing preferences of people rather than providing information about specific interaction partners. But identifying TBD is tricky. First, it is impossible to identify using uncontrolled empirical data because these data are characterised by strategic uncertainty. Second, people are generally reluctant to identify themselves as a discriminator. In the project, I study TBS using novel economic experiments that circumvent these problems.
The project consists of three main objectives. First, I investigate whether and how preferences of European natives in social interactions depend on others’ ethnicity. Are natives as altruistic, reciprocal, envious to immigrants as compared to other natives? Second, I study whether natives have different fairness ideals—what constitutes a fair distribution of resources from the perspective of an impartial spectator—when it comes to natives than when it comes to non-natives. Third, I analyse whether preferences and fairness ideals depend on exposure to diversity: do preferences and fairness ideals of natives change as contact with non-natives increases, and, if so, how?
Summary
In economics, a distinction is made between statistical and taste-based discrimination (henceforth, TBD). Statistical discrimination refers to discrimination in a context with strategic uncertainty. Someone who is uncertain about the future behaviour of a person with a different ethnicity may rely on information about the different ethnic group to which this person belongs to form beliefs about the behaviour of that person. This may lead to discrimination. TBD refers to discrimination in a context without strategic uncertainty. It implies suffering a disutility when interacting with ‘different’ others. This project systematically studies TBD in ethnically diverse societies.
Identifying TBD is important because overcoming it requires different policies than overcoming statistical discrimination: they should deal with changing preferences of people rather than providing information about specific interaction partners. But identifying TBD is tricky. First, it is impossible to identify using uncontrolled empirical data because these data are characterised by strategic uncertainty. Second, people are generally reluctant to identify themselves as a discriminator. In the project, I study TBS using novel economic experiments that circumvent these problems.
The project consists of three main objectives. First, I investigate whether and how preferences of European natives in social interactions depend on others’ ethnicity. Are natives as altruistic, reciprocal, envious to immigrants as compared to other natives? Second, I study whether natives have different fairness ideals—what constitutes a fair distribution of resources from the perspective of an impartial spectator—when it comes to natives than when it comes to non-natives. Third, I analyse whether preferences and fairness ideals depend on exposure to diversity: do preferences and fairness ideals of natives change as contact with non-natives increases, and, if so, how?
Max ERC Funding
1 499 046 €
Duration
Start date: 2018-01-01, End date: 2022-12-31
Project acronym IntScOmics
Project A single-cell genomics approach integrating gene expression, lineage, and physical interactions
Researcher (PI) Alexander VAN OUDENAARDEN
Host Institution (HI) KONINKLIJKE NEDERLANDSE AKADEMIE VAN WETENSCHAPPEN - KNAW
Call Details Advanced Grant (AdG), LS2, ERC-2016-ADG
Summary From populations of unicellular organisms to complex tissues, cell-to-cell variability in phenotypic traits seems to be universal. To study this heterogeneity and its biological consequences, researchers have used advanced microscopy-based approaches that provide exquisite spatial and temporal resolution, but these methods are typically limited to measuring a few properties in parallel. On the other hand, next generation sequencing technologies allow for massively parallel genome-wide approaches but have, until recently, relied on studying population averages obtained from pooling thousands to millions of cells, precluding genome-wide analysis of cell-to-cell variability. Very excitingly, in the last few years there has been a revolution in single-cell sequencing technologies allowing genome-wide quantification of mRNA and genomic DNA in thousands of individual cells leading to the convergence of genomics and single-cell biology. However, during this convergence the spatial and temporal information, easily accessed by microscopy-based approaches, is often lost in a single-cell sequencing experiment. The overarching goal of this proposal is to develop single-cell sequencing technology that retains important aspects of the spatial-temporal information. In particular I will focus on integrating single-cell transcriptome and epigenome measurements with the physical cell-to-cell interaction network (spatial information) and lineage information (temporal information). These tools will be utilized to (i) explore the division symmetry of intestinal stem cells in vivo; (ii) to reconstruct the cell lineage history during zebrafish regeneration; and (iii) to determine lineage relations and the physical cell-to-cell interaction network of progenitor cells in the murine bone marrow.
Summary
From populations of unicellular organisms to complex tissues, cell-to-cell variability in phenotypic traits seems to be universal. To study this heterogeneity and its biological consequences, researchers have used advanced microscopy-based approaches that provide exquisite spatial and temporal resolution, but these methods are typically limited to measuring a few properties in parallel. On the other hand, next generation sequencing technologies allow for massively parallel genome-wide approaches but have, until recently, relied on studying population averages obtained from pooling thousands to millions of cells, precluding genome-wide analysis of cell-to-cell variability. Very excitingly, in the last few years there has been a revolution in single-cell sequencing technologies allowing genome-wide quantification of mRNA and genomic DNA in thousands of individual cells leading to the convergence of genomics and single-cell biology. However, during this convergence the spatial and temporal information, easily accessed by microscopy-based approaches, is often lost in a single-cell sequencing experiment. The overarching goal of this proposal is to develop single-cell sequencing technology that retains important aspects of the spatial-temporal information. In particular I will focus on integrating single-cell transcriptome and epigenome measurements with the physical cell-to-cell interaction network (spatial information) and lineage information (temporal information). These tools will be utilized to (i) explore the division symmetry of intestinal stem cells in vivo; (ii) to reconstruct the cell lineage history during zebrafish regeneration; and (iii) to determine lineage relations and the physical cell-to-cell interaction network of progenitor cells in the murine bone marrow.
Max ERC Funding
2 500 000 €
Duration
Start date: 2018-01-01, End date: 2022-12-31
Project acronym Learn2Walk
Project Brain meets spine: the neural origin of toddler’s first steps
Researcher (PI) Nadia DOMINICI
Host Institution (HI) STICHTING VU
Call Details Starting Grant (StG), LS5, ERC-2016-STG
Summary A child’s first steps may be small, but they are a giant leap for its development. Children have an instinct to walk from the moment they are born – a 'stepping reflex' hardwired in their neural circuitry – but it typically takes about one year before they can start walking independently. In a pioneering work published on Science in 2011, I demonstrated that the coordinated muscle activation in neonate stepping is described by two basic activation patterns that are retained throughout development, and supplemented by two new ones that be-come manifest in toddlers.
These seminal findings triggered profound questions: Is the development of new patterns an emergent property, indicative of spontaneously changing cortico-muscular interaction? Does locomotor impairment change the spontaneous character of this emergent property into a gradual one? With the proposed research, I plan to answer these questions by studying the interplay between brain and muscular activity at the onset of independent walking.
The overarching aim is to characterize the emergence of independent walking in typically developing children and in children affected by cerebral palsy, and to identify an optimal rehabilitation strategy to promote normal walking in the latter. I plan to perform a combined analysis of brain and muscular activity in typically developing children, unraveling the detailed processes underlying the learning of walking. I will then elucidate the reorganization of cortical and cortico-muscular activity accompanying the altered development of walking in children with cerebral palsy. Finally, I will apply these results to the identification of optimal rehabilitation techniques for children with cerebral palsy.
It is my long-term ambition to exploit fundamental insights into neuro-motor control for promoting normal walking in children with locomotor impairments. The proposed project provides an exciting opportunity for me to realize this goal.
Summary
A child’s first steps may be small, but they are a giant leap for its development. Children have an instinct to walk from the moment they are born – a 'stepping reflex' hardwired in their neural circuitry – but it typically takes about one year before they can start walking independently. In a pioneering work published on Science in 2011, I demonstrated that the coordinated muscle activation in neonate stepping is described by two basic activation patterns that are retained throughout development, and supplemented by two new ones that be-come manifest in toddlers.
These seminal findings triggered profound questions: Is the development of new patterns an emergent property, indicative of spontaneously changing cortico-muscular interaction? Does locomotor impairment change the spontaneous character of this emergent property into a gradual one? With the proposed research, I plan to answer these questions by studying the interplay between brain and muscular activity at the onset of independent walking.
The overarching aim is to characterize the emergence of independent walking in typically developing children and in children affected by cerebral palsy, and to identify an optimal rehabilitation strategy to promote normal walking in the latter. I plan to perform a combined analysis of brain and muscular activity in typically developing children, unraveling the detailed processes underlying the learning of walking. I will then elucidate the reorganization of cortical and cortico-muscular activity accompanying the altered development of walking in children with cerebral palsy. Finally, I will apply these results to the identification of optimal rehabilitation techniques for children with cerebral palsy.
It is my long-term ambition to exploit fundamental insights into neuro-motor control for promoting normal walking in children with locomotor impairments. The proposed project provides an exciting opportunity for me to realize this goal.
Max ERC Funding
1 331 625 €
Duration
Start date: 2017-02-01, End date: 2022-01-31
Project acronym Mushroomics
Project Functional genomics in Schizophyllum commune: leveraging the diversity in this hypervariable fungus to understand mushroom development
Researcher (PI) Robin Arthur Ohm
Host Institution (HI) UNIVERSITEIT UTRECHT
Call Details Starting Grant (StG), LS2, ERC-2016-STG
Summary Mushrooms are the sexual reproductive structures of basidiomycetes. Much remains to be learned about the molecular regulation of mushroom development. Only a few genes have been implicated in this process, but their exact function remains unknown. Schizophyllum commune is a model system for mushroom-forming fungi. It was recently shown that this species shows the highest intraspecies DNA variability in eukaryotes with 150 SNPs per 1000 base pairs, yet they can still reproduce sexually. This hypervariabity is also illustrated by variability in the response to environmental factors that initiate mushroom development and by the differences in morphology within this species. I propose a functional genomics approach to elucidate the molecular genetics of mushroom development.
We have a collection of 100 S. commune strains sampled world-wide. I propose to leverage the extraordinary diversity among these strains. I will identify genes that explain differences in mushroom morphology and in responses to environmental stimuli such as light and CO2. The genes/alleles responsible for these phenotypes will by mapped by genome sequencing followed by bulk segregant analysis.
Transcription factors (TFs) are expected to play an important role in regulation of mushroom development. Therefore I propose to systematically study TF function by generating a knock-down collection of all predicted 313 TFs. The phenotypes of the resulting strains will be analyzed and target genes of TFs will be identified by RNA-Seq and ChIP-Seq.
The genes identified by these strategies will subsequently be analyzed to determine their function. My initial results demonstrate the feasibility of this approach. The availability of the strain collection, the available molecular toolbox, and my strong expertise both in genomics and molecular biology of mushroom development will enable me to take a huge step forward in our understanding of mushroom development.
Summary
Mushrooms are the sexual reproductive structures of basidiomycetes. Much remains to be learned about the molecular regulation of mushroom development. Only a few genes have been implicated in this process, but their exact function remains unknown. Schizophyllum commune is a model system for mushroom-forming fungi. It was recently shown that this species shows the highest intraspecies DNA variability in eukaryotes with 150 SNPs per 1000 base pairs, yet they can still reproduce sexually. This hypervariabity is also illustrated by variability in the response to environmental factors that initiate mushroom development and by the differences in morphology within this species. I propose a functional genomics approach to elucidate the molecular genetics of mushroom development.
We have a collection of 100 S. commune strains sampled world-wide. I propose to leverage the extraordinary diversity among these strains. I will identify genes that explain differences in mushroom morphology and in responses to environmental stimuli such as light and CO2. The genes/alleles responsible for these phenotypes will by mapped by genome sequencing followed by bulk segregant analysis.
Transcription factors (TFs) are expected to play an important role in regulation of mushroom development. Therefore I propose to systematically study TF function by generating a knock-down collection of all predicted 313 TFs. The phenotypes of the resulting strains will be analyzed and target genes of TFs will be identified by RNA-Seq and ChIP-Seq.
The genes identified by these strategies will subsequently be analyzed to determine their function. My initial results demonstrate the feasibility of this approach. The availability of the strain collection, the available molecular toolbox, and my strong expertise both in genomics and molecular biology of mushroom development will enable me to take a huge step forward in our understanding of mushroom development.
Max ERC Funding
1 500 000 €
Duration
Start date: 2017-01-01, End date: 2021-12-31
Project acronym NANOGLU
Project Enlightening synaptic architecture: nanoscale segregation of glutamate receptor subtypes
Researcher (PI) Harold MAC GILLAVRY
Host Institution (HI) UNIVERSITEIT UTRECHT
Call Details Starting Grant (StG), LS5, ERC-2016-STG
Summary Efficient neuronal communication lies at the heart of all cognitive functions, and synaptic dysfunction underlies mental disorders such as autism. However, although over the past decades many components of synapses have been characterized, it is unknown how these constituents are assembled within synapses, and how this organization contributes to synapse function. The overall aim of this proposal is to understand how excitatory synapses are built to efficiently control neuronal function. Specifically, I aim to reveal the molecular organization that controls glutamate receptor positioning. While AMPA-type glutamate receptors concentrate in nano-domains within the synaptic core that directly apposes the presynaptic release site, metabotropic glutamate receptors accumulate in a distinct perisynaptic domain considerably further from the release site. Despite that this organization critically controls synaptic transmission and plasticity, we know little about the mechanisms that underlie the spatial and temporal segregation of glutamate receptor subtypes into these distinct subsynaptic domains. To address this, I developed single-molecule imaging tools, a powerful dimerization system to control receptor positioning, and physiological read-outs of synapse function.
In this proposal I will combine innovative experimental and computational approaches, integrating single-molecule imaging with optical and electrophysiological measurements of neuronal function to:
1) elucidate the organizational principles that underlie the nano-compartmentalization of glutamate receptors at synapses, and
2) understand how the spatial distribution of receptor subtypes contributes to neuronal functioning.
This project will reveal how nanoscale synapse organization contributes to neuronal circuit function, and will help understand how synaptic disruption contributes to neurological disease mechanisms.
Summary
Efficient neuronal communication lies at the heart of all cognitive functions, and synaptic dysfunction underlies mental disorders such as autism. However, although over the past decades many components of synapses have been characterized, it is unknown how these constituents are assembled within synapses, and how this organization contributes to synapse function. The overall aim of this proposal is to understand how excitatory synapses are built to efficiently control neuronal function. Specifically, I aim to reveal the molecular organization that controls glutamate receptor positioning. While AMPA-type glutamate receptors concentrate in nano-domains within the synaptic core that directly apposes the presynaptic release site, metabotropic glutamate receptors accumulate in a distinct perisynaptic domain considerably further from the release site. Despite that this organization critically controls synaptic transmission and plasticity, we know little about the mechanisms that underlie the spatial and temporal segregation of glutamate receptor subtypes into these distinct subsynaptic domains. To address this, I developed single-molecule imaging tools, a powerful dimerization system to control receptor positioning, and physiological read-outs of synapse function.
In this proposal I will combine innovative experimental and computational approaches, integrating single-molecule imaging with optical and electrophysiological measurements of neuronal function to:
1) elucidate the organizational principles that underlie the nano-compartmentalization of glutamate receptors at synapses, and
2) understand how the spatial distribution of receptor subtypes contributes to neuronal functioning.
This project will reveal how nanoscale synapse organization contributes to neuronal circuit function, and will help understand how synaptic disruption contributes to neurological disease mechanisms.
Max ERC Funding
1 500 000 €
Duration
Start date: 2017-04-01, End date: 2022-03-31
Project acronym PRIMATE-TE-IMPACT
Project Mapping the retrotransposon-mediated layer of neuronal gene regulation in the human genome
Researcher (PI) Frank Michael Johannes JACOBS
Host Institution (HI) UNIVERSITEIT VAN AMSTERDAM
Call Details Starting Grant (StG), LS2, ERC-2016-STG
Summary Throughout evolution, the human genome has been attacked by retrotransposons, parasitic DNA elements that spread through our genome by a copy-paste activity. I previously showed that SVA elements, the youngest class of retrotransposons in our genome, harbour a strong gene-regulatory potential which is normally repressed by KRAB zinc finger protein ZNF91 (Jacobs et al., 2014, Nature). However, for reasons unknown, repression of retrotransposons is much less efficient in the human brain, resulting in activation of the enhancer potential of SVA elements spread throughout the human genome. The importance of these SVA insertions for the evolution of human neuronal gene-regulatory networks, and how many genes have come to depend on SVA's regulatory influence, remains elusive. In this research program, I will use ‘cortical organoids’; three-dimensional brain tissues derived from human and primate stem cells, to investigate how recent SVA insertions have impacted human neuronal gene expression. Furthermore, I will investigate how changes of the epigenetic landscape in neurons affect the activity of retrotransposons in our genome and the influence they have on nearby neuronal genes. Finally, I will explore the possibility that loss of epigenetic silencing of retrotransposons is responsible for dysregulation of genes associated with neurological diseases. Preliminary findings suggest a potential role for retrotransposons in susceptibility loci for Alzheimer's and Parkinson's disease. Finding further support for this in the current research program, will form the basis of a novel concept which explains how changes in the epigenetic landscape can uncover a dormant genetic predisposition to disease.
Summary
Throughout evolution, the human genome has been attacked by retrotransposons, parasitic DNA elements that spread through our genome by a copy-paste activity. I previously showed that SVA elements, the youngest class of retrotransposons in our genome, harbour a strong gene-regulatory potential which is normally repressed by KRAB zinc finger protein ZNF91 (Jacobs et al., 2014, Nature). However, for reasons unknown, repression of retrotransposons is much less efficient in the human brain, resulting in activation of the enhancer potential of SVA elements spread throughout the human genome. The importance of these SVA insertions for the evolution of human neuronal gene-regulatory networks, and how many genes have come to depend on SVA's regulatory influence, remains elusive. In this research program, I will use ‘cortical organoids’; three-dimensional brain tissues derived from human and primate stem cells, to investigate how recent SVA insertions have impacted human neuronal gene expression. Furthermore, I will investigate how changes of the epigenetic landscape in neurons affect the activity of retrotransposons in our genome and the influence they have on nearby neuronal genes. Finally, I will explore the possibility that loss of epigenetic silencing of retrotransposons is responsible for dysregulation of genes associated with neurological diseases. Preliminary findings suggest a potential role for retrotransposons in susceptibility loci for Alzheimer's and Parkinson's disease. Finding further support for this in the current research program, will form the basis of a novel concept which explains how changes in the epigenetic landscape can uncover a dormant genetic predisposition to disease.
Max ERC Funding
1 500 000 €
Duration
Start date: 2017-08-01, End date: 2022-07-31
Project acronym Secret Surface
Project The cell surface tetraspanin web drives tumour development and alters metabolic signalling
Researcher (PI) Annemiek van Spriel
Host Institution (HI) STICHTING KATHOLIEKE UNIVERSITEIT
Call Details Consolidator Grant (CoG), LS4, ERC-2016-COG
Summary Cancer development is characterized by uncontrolled proliferation, cell survival and metabolic reprogramming. Tumour cells are surrounded by a fluid-mosaic membrane that contains tetraspanins (Tspans) which are evolutionary conserved proteins important in the formation of multiprotein complexes at the cell surface (‘tetraspanin web’). Increasing evidence indicates that Tspans are involved in cancer, still the architecture of the Tspan web in native tumour membranes and its (patho)physiological functions have not been resolved. Based on my preliminary data, I hypothesize that tumour cells contain a disrupted Tspan web in which Tspan interactions are modified leading to aberrant metabolic signalling and tumour development. This is supported by my discovery that loss of Tspan CD37 leads to spontaneous lymphomagenesis due to activation of the Akt survival pathway. The overall aim of Secret Surface is to unravel the composition, physiological functions and molecular mechanisms of the Tspan web on tumour development and clinical outcome. To achieve this, I will focus on studying lymphomas using a multidisciplinary approach: I. Detailed analyses of Tspan web composition in lymphoma to select clinically relevant Tspans (high-throughput tissue microarray technology, multispectral imaging). II. Resolve the endogenous Tspan web on lymphoma cells (super-resolution microscopy), and generation and analysis of lymphoma cells that have a complete deficiency of multiple Tspans (CRISPR/Cas9 technology). III. Decipher molecular mechanisms underlying Tspan web function in lymphoma cells (membrane organization, membrane-proximal signalling, metabolic reprogramming). With my unique toolbox of Tspan knock-outs coupled to advanced microscopy and metabolic studies, I expect that Secret Surface will lead to a new concept in cellular physiology in which cell surface organization by the Tspan web drives tumour development, which may open new horizons for the generation of new cancer therapies.
Summary
Cancer development is characterized by uncontrolled proliferation, cell survival and metabolic reprogramming. Tumour cells are surrounded by a fluid-mosaic membrane that contains tetraspanins (Tspans) which are evolutionary conserved proteins important in the formation of multiprotein complexes at the cell surface (‘tetraspanin web’). Increasing evidence indicates that Tspans are involved in cancer, still the architecture of the Tspan web in native tumour membranes and its (patho)physiological functions have not been resolved. Based on my preliminary data, I hypothesize that tumour cells contain a disrupted Tspan web in which Tspan interactions are modified leading to aberrant metabolic signalling and tumour development. This is supported by my discovery that loss of Tspan CD37 leads to spontaneous lymphomagenesis due to activation of the Akt survival pathway. The overall aim of Secret Surface is to unravel the composition, physiological functions and molecular mechanisms of the Tspan web on tumour development and clinical outcome. To achieve this, I will focus on studying lymphomas using a multidisciplinary approach: I. Detailed analyses of Tspan web composition in lymphoma to select clinically relevant Tspans (high-throughput tissue microarray technology, multispectral imaging). II. Resolve the endogenous Tspan web on lymphoma cells (super-resolution microscopy), and generation and analysis of lymphoma cells that have a complete deficiency of multiple Tspans (CRISPR/Cas9 technology). III. Decipher molecular mechanisms underlying Tspan web function in lymphoma cells (membrane organization, membrane-proximal signalling, metabolic reprogramming). With my unique toolbox of Tspan knock-outs coupled to advanced microscopy and metabolic studies, I expect that Secret Surface will lead to a new concept in cellular physiology in which cell surface organization by the Tspan web drives tumour development, which may open new horizons for the generation of new cancer therapies.
Max ERC Funding
2 000 000 €
Duration
Start date: 2017-10-01, End date: 2022-09-30
