Project acronym BreakingBarriers
Project Targeting endothelial barriers to combat disease
Researcher (PI) Anne Eichmann
Host Institution (HI) INSTITUT NATIONAL DE LA SANTE ET DE LA RECHERCHE MEDICALE
Country France
Call Details Advanced Grant (AdG), LS4, ERC-2018-ADG
Summary Tissue homeostasis requires coordinated barrier function in blood and lymphatic vessels. Opening of junctions between endothelial cells (ECs) lining blood vessels leads to tissue fluid accumulation that is drained by lymphatic vessels. A pathological increase in blood vessel permeability or lack or malfunction of lymphatic vessels leads to edema and associated defects in macromolecule and immune cell clearance. Unbalanced barrier function between blood and lymphatic vessels contributes to neurodegeneration, chronic inflammation, and cardiovascular disease. In this proposal, we seek to gain mechanistic understanding into coordination of barrier function between blood and lymphatic vessels, how this process is altered in disease models and how it can be manipulated for therapeutic purposes. We will focus on two critical barriers with diametrically opposing functions, the blood-brain barrier (BBB) and the lymphatic capillary barrier (LCB). ECs of the BBB form very tight junctions that restrict paracellular access to the brain. In contrast, open junctions of the LCB ensure uptake of extravasated fluid, macromolecules and immune cells, as well as lipid in the gut. We have identified novel effectors of BBB and LCB junctions and will determine their role in adult homeostasis and in disease models. Mouse genetic gain and loss of function approaches in combination with histological, ultrastructural, functional and molecular analysis will determine mechanisms underlying formation of tissue specific EC barriers. Deliverables include in vivo validated targets that could be used for i) opening the BBB on demand for drug delivery into the brain, and ii) to lower plasma lipid uptake via interfering with the LCB, with implications for prevention of obesity, cardiovascular disease and inflammation. These pioneering studies promise to open up new opportunities for research and treatment of neurovascular and cardiovascular disease.
Summary
Tissue homeostasis requires coordinated barrier function in blood and lymphatic vessels. Opening of junctions between endothelial cells (ECs) lining blood vessels leads to tissue fluid accumulation that is drained by lymphatic vessels. A pathological increase in blood vessel permeability or lack or malfunction of lymphatic vessels leads to edema and associated defects in macromolecule and immune cell clearance. Unbalanced barrier function between blood and lymphatic vessels contributes to neurodegeneration, chronic inflammation, and cardiovascular disease. In this proposal, we seek to gain mechanistic understanding into coordination of barrier function between blood and lymphatic vessels, how this process is altered in disease models and how it can be manipulated for therapeutic purposes. We will focus on two critical barriers with diametrically opposing functions, the blood-brain barrier (BBB) and the lymphatic capillary barrier (LCB). ECs of the BBB form very tight junctions that restrict paracellular access to the brain. In contrast, open junctions of the LCB ensure uptake of extravasated fluid, macromolecules and immune cells, as well as lipid in the gut. We have identified novel effectors of BBB and LCB junctions and will determine their role in adult homeostasis and in disease models. Mouse genetic gain and loss of function approaches in combination with histological, ultrastructural, functional and molecular analysis will determine mechanisms underlying formation of tissue specific EC barriers. Deliverables include in vivo validated targets that could be used for i) opening the BBB on demand for drug delivery into the brain, and ii) to lower plasma lipid uptake via interfering with the LCB, with implications for prevention of obesity, cardiovascular disease and inflammation. These pioneering studies promise to open up new opportunities for research and treatment of neurovascular and cardiovascular disease.
Max ERC Funding
2 499 969 €
Duration
Start date: 2019-07-01, End date: 2024-06-30
Project acronym ChloroMito
Project Chloroplast and Mitochondria interactions for microalgal acclimation
Researcher (PI) Giovanni Finazzi
Host Institution (HI) CENTRE NATIONAL DE LA RECHERCHE SCIENTIFIQUE CNRS
Country France
Call Details Advanced Grant (AdG), LS8, ERC-2018-ADG
Summary Photosynthesis emerged as an energy-harvesting process at least 3.5 billion years ago, first in anoxygenic bacteria and then in oxygen-producing organisms, which led to the evolution of complex life forms with oxygen-based metabolisms (e.g. humans). Oxygenic photosynthesis produces ATP and NADPH, and the correct balance between these energy-rich molecules allows assimilation of CO2 into organic matter. Although the mechanisms of ATP/NADPH synthesis are well understood, less is known about how CO2 assimilation was optimised. This process was essential to the successful phototrophic colonisation of land (by Plantae) and the oceans (by phytoplankton). Plants optimised CO2 assimilation using chloroplast-localised ATP-generating processes to control the ATP/NADPH ratio, but the strategies developed by phytoplankton are poorly understood. However, diatoms—ecologically successful ocean organisms—are known to control this ratio by exchanging energy between plastids and mitochondria. Is this mechanism a paradigm for optimisation of photosynthesis in the ocean? The ChloroMito project aims to first decipher the mechanism(s) behind plastid-mitochondria interactions. Thanks to a novel combination of whole-cell approaches, including (opto)genetics, cellular tomography and single-cell spectroscopy, we will identify the nature of the exchanges occurring in diatoms and assess their contribution to dynamic responses to environmental stimuli (light, temperature, nutrients). We will then assess conservation of this mechanism in ecologically relevant phytoplankton taxa, test its role in supporting different lifestyles (autotrophy, mixotrophy, photosymbiosis) encountered in the ocean, and track transitions between these different lifestyles as part of an unprecedented effort to visualise ocean dynamics. Overall, the ChloroMito project will alter our understanding of ocean photosynthesis, challenging textbook concepts which are often inferred from plant-based concepts
Summary
Photosynthesis emerged as an energy-harvesting process at least 3.5 billion years ago, first in anoxygenic bacteria and then in oxygen-producing organisms, which led to the evolution of complex life forms with oxygen-based metabolisms (e.g. humans). Oxygenic photosynthesis produces ATP and NADPH, and the correct balance between these energy-rich molecules allows assimilation of CO2 into organic matter. Although the mechanisms of ATP/NADPH synthesis are well understood, less is known about how CO2 assimilation was optimised. This process was essential to the successful phototrophic colonisation of land (by Plantae) and the oceans (by phytoplankton). Plants optimised CO2 assimilation using chloroplast-localised ATP-generating processes to control the ATP/NADPH ratio, but the strategies developed by phytoplankton are poorly understood. However, diatoms—ecologically successful ocean organisms—are known to control this ratio by exchanging energy between plastids and mitochondria. Is this mechanism a paradigm for optimisation of photosynthesis in the ocean? The ChloroMito project aims to first decipher the mechanism(s) behind plastid-mitochondria interactions. Thanks to a novel combination of whole-cell approaches, including (opto)genetics, cellular tomography and single-cell spectroscopy, we will identify the nature of the exchanges occurring in diatoms and assess their contribution to dynamic responses to environmental stimuli (light, temperature, nutrients). We will then assess conservation of this mechanism in ecologically relevant phytoplankton taxa, test its role in supporting different lifestyles (autotrophy, mixotrophy, photosymbiosis) encountered in the ocean, and track transitions between these different lifestyles as part of an unprecedented effort to visualise ocean dynamics. Overall, the ChloroMito project will alter our understanding of ocean photosynthesis, challenging textbook concepts which are often inferred from plant-based concepts
Max ERC Funding
2 498 207 €
Duration
Start date: 2020-01-01, End date: 2024-12-31
Project acronym COGNIBRAINS
Project Cognition in an Insect Brain
Researcher (PI) Martin GIURFA
Host Institution (HI) CENTRE NATIONAL DE LA RECHERCHE SCIENTIFIQUE CNRS
Country France
Call Details Advanced Grant (AdG), LS5, ERC-2018-ADG
Summary There is a common perception that larger brains mediate higher cognitive capacity. Social insects, however, demonstrate that sophisticated cognition is possible with miniature brains. Honeybees display higher-order learning such as categorization, non-linear discriminations, concept learning and numerosity, which are unique among insects. These capacities are mediated by a miniature brain with only 950 000 neurons. Despite extensive behavioral analyses, no study has attempted to elucidate the neural mechanisms underpinning the higher-order learning of bees. Our current breakthrough establishing virtual-reality protocols for tethered honeybees offers a unique opportunity to uncover the minimal circuits that mediate higher-order forms of cognitive processing in the brain of a behaving bee. We have recently shown that bees learn to solve elemental and non-elemental problems in this experimental context, which allows integrating behavioral, neurobiological and computational approaches to unravel the neural mechanisms underlying non-elemental learning in the honeybee. I will combine behavioral recordings of bees learning non-linear discriminations and relational rules in a virtual reality environment, with access to their brain via multi-photon calcium imaging and multielectrode recordings of neural populations. I will determine the neural circuits of elemental and non-elemental visual learning along the visual circuits of the bee brain, and the necessity and sufficiency of these circuits for these capacities via selective knockdown and rescuing via wavelength-selective multi-photon uncaging of neurotransmitters. Data will be fed into computational models to test hypotheses about minimal neural architectures for visual cognition, working towards whole-brain modeling. This project will expand the information available on the neurobiology of insect learning, and will provide the first integral characterization of the mechanisms underlying cognition in a miniature brain.
Summary
There is a common perception that larger brains mediate higher cognitive capacity. Social insects, however, demonstrate that sophisticated cognition is possible with miniature brains. Honeybees display higher-order learning such as categorization, non-linear discriminations, concept learning and numerosity, which are unique among insects. These capacities are mediated by a miniature brain with only 950 000 neurons. Despite extensive behavioral analyses, no study has attempted to elucidate the neural mechanisms underpinning the higher-order learning of bees. Our current breakthrough establishing virtual-reality protocols for tethered honeybees offers a unique opportunity to uncover the minimal circuits that mediate higher-order forms of cognitive processing in the brain of a behaving bee. We have recently shown that bees learn to solve elemental and non-elemental problems in this experimental context, which allows integrating behavioral, neurobiological and computational approaches to unravel the neural mechanisms underlying non-elemental learning in the honeybee. I will combine behavioral recordings of bees learning non-linear discriminations and relational rules in a virtual reality environment, with access to their brain via multi-photon calcium imaging and multielectrode recordings of neural populations. I will determine the neural circuits of elemental and non-elemental visual learning along the visual circuits of the bee brain, and the necessity and sufficiency of these circuits for these capacities via selective knockdown and rescuing via wavelength-selective multi-photon uncaging of neurotransmitters. Data will be fed into computational models to test hypotheses about minimal neural architectures for visual cognition, working towards whole-brain modeling. This project will expand the information available on the neurobiology of insect learning, and will provide the first integral characterization of the mechanisms underlying cognition in a miniature brain.
Max ERC Funding
2 145 339 €
Duration
Start date: 2020-06-01, End date: 2025-05-31
Project acronym DIATOMIC
Project Untangling eco-evolutionary impacts on diatom genomes over timescales relevant to current climate change
Researcher (PI) Christopher Paul BOWLER
Host Institution (HI) CENTRE NATIONAL DE LA RECHERCHE SCIENTIFIQUE CNRS
Country France
Call Details Advanced Grant (AdG), LS8, ERC-2018-ADG
Summary Diatoms are major contributors of primary production in the ocean and participate in carbon sequestration over geologically relevant timescales. As key components of the Earth’s carbon cycle and marine food webs we need to understand the eco-evolutionary underpinnings of their ecological success to forecast their fate in a future ocean impacted by anthropogenic change. Genomes and epigenomes from model diatoms, as well as hundreds of transcriptomes from multiple species, have revealed genetic and epigenetic processes regulating gene expression in response to changing environments. The Tara Oceans survey has in parallel generated resources to explore diatom abundance, diversity and gene expression in the world’s ocean in widely contrasting conditions. DIATOMIC will build on these resources to understand how evolutionary and ecological processes combine to influence diatom adaptations to their environment at unprecedented spatiotemporal scales. To examine these processes over timescales relevant to current climate change, DIATOMIC includes the pioneering exploration of ancient diatom DNA from the sub-seafloor to reveal the genetic and epigenetic bases of speciation and adaptation that have impacted their ecological success during the last 100,000 years, when Earth experienced major climatological events and an increase in anthropogenic impacts. As a model for exploring eco-evolutionary processes in the past and contemporary ocean we will focus primarily on Chaetoceros because this diatom genus is ancient, ubiquitous, abundant and contributes significantly to carbon export. Key findings will be additionally supported by lab-based studies using the diatom Phaeodactylum for which exemplar molecular tools exist. Specifically, the project will address:
1. What molecular features characterize genome evolution in diatoms?
2. Which processes determine diatom metapopulation structure?
3. What can ancient DNA tell us about diatom adaptations to environmental change in the past?
Summary
Diatoms are major contributors of primary production in the ocean and participate in carbon sequestration over geologically relevant timescales. As key components of the Earth’s carbon cycle and marine food webs we need to understand the eco-evolutionary underpinnings of their ecological success to forecast their fate in a future ocean impacted by anthropogenic change. Genomes and epigenomes from model diatoms, as well as hundreds of transcriptomes from multiple species, have revealed genetic and epigenetic processes regulating gene expression in response to changing environments. The Tara Oceans survey has in parallel generated resources to explore diatom abundance, diversity and gene expression in the world’s ocean in widely contrasting conditions. DIATOMIC will build on these resources to understand how evolutionary and ecological processes combine to influence diatom adaptations to their environment at unprecedented spatiotemporal scales. To examine these processes over timescales relevant to current climate change, DIATOMIC includes the pioneering exploration of ancient diatom DNA from the sub-seafloor to reveal the genetic and epigenetic bases of speciation and adaptation that have impacted their ecological success during the last 100,000 years, when Earth experienced major climatological events and an increase in anthropogenic impacts. As a model for exploring eco-evolutionary processes in the past and contemporary ocean we will focus primarily on Chaetoceros because this diatom genus is ancient, ubiquitous, abundant and contributes significantly to carbon export. Key findings will be additionally supported by lab-based studies using the diatom Phaeodactylum for which exemplar molecular tools exist. Specifically, the project will address:
1. What molecular features characterize genome evolution in diatoms?
2. Which processes determine diatom metapopulation structure?
3. What can ancient DNA tell us about diatom adaptations to environmental change in the past?
Max ERC Funding
2 495 753 €
Duration
Start date: 2019-11-01, End date: 2024-10-31
Project acronym EMERGE
Project Reconstructing the emergence of the Milky Way’s stellar population with Gaia, SDSS-V and JWST
Researcher (PI) Dan Maoz
Host Institution (HI) TEL AVIV UNIVERSITY
Country Israel
Call Details Advanced Grant (AdG), PE9, ERC-2018-ADG
Summary Understanding how the Milky Way arrived at its present state requires a large volume of precision measurements of our Galaxy’s current makeup, as well as an empirically based understanding of the main processes involved in the Galaxy’s evolution. Such data are now about to arrive in the flood of quality information from Gaia and SDSS-V. The demography of the stars and of the compact stellar remnants in our Galaxy, in terms of phase-space location, mass, age, metallicity, and multiplicity are data products that will come directly from these surveys. I propose to integrate this information into a comprehensive picture of the Milky Way’s present state. In parallel, I will build a Galactic chemical evolution model, with input parameters that are as empirically based as possible, that will reproduce and explain the observations. To get those input parameters, I will measure the rates of supernovae (SNe) in nearby galaxies (using data from past and ongoing surveys) and in high-redshift proto-clusters (by conducting a SN search with JWST), to bring into sharp focus the element yields of SNe and the distribution of delay times (the DTD) between star formation and SN explosion. These empirically determined SN metal-production parameters will be used to find the observationally based reconstruction of the Galaxy’s stellar formation history and chemical evolution that reproduces the observed present-day Milky Way stellar population. The population census of stellar multiplicity with Gaia+SDSS-V, and particularly of short-orbit compact-object binaries, will hark back to the rates and the element yields of the various types of SNe, revealing the connections between various progenitor systems, their explosions, and their rates. The plan, while ambitious, is feasible, thanks to the data from these truly game-changing observational projects. My team will perform all steps of the analysis and will combine the results to obtain the clearest picture of how our Galaxy came to be.
Summary
Understanding how the Milky Way arrived at its present state requires a large volume of precision measurements of our Galaxy’s current makeup, as well as an empirically based understanding of the main processes involved in the Galaxy’s evolution. Such data are now about to arrive in the flood of quality information from Gaia and SDSS-V. The demography of the stars and of the compact stellar remnants in our Galaxy, in terms of phase-space location, mass, age, metallicity, and multiplicity are data products that will come directly from these surveys. I propose to integrate this information into a comprehensive picture of the Milky Way’s present state. In parallel, I will build a Galactic chemical evolution model, with input parameters that are as empirically based as possible, that will reproduce and explain the observations. To get those input parameters, I will measure the rates of supernovae (SNe) in nearby galaxies (using data from past and ongoing surveys) and in high-redshift proto-clusters (by conducting a SN search with JWST), to bring into sharp focus the element yields of SNe and the distribution of delay times (the DTD) between star formation and SN explosion. These empirically determined SN metal-production parameters will be used to find the observationally based reconstruction of the Galaxy’s stellar formation history and chemical evolution that reproduces the observed present-day Milky Way stellar population. The population census of stellar multiplicity with Gaia+SDSS-V, and particularly of short-orbit compact-object binaries, will hark back to the rates and the element yields of the various types of SNe, revealing the connections between various progenitor systems, their explosions, and their rates. The plan, while ambitious, is feasible, thanks to the data from these truly game-changing observational projects. My team will perform all steps of the analysis and will combine the results to obtain the clearest picture of how our Galaxy came to be.
Max ERC Funding
1 859 375 €
Duration
Start date: 2019-10-01, End date: 2024-09-30
Project acronym ImmUne
Project Towards identification of the unifying principles of vertebrate adaptive immunity
Researcher (PI) Thomas BOEHM
Host Institution (HI) MAX-PLANCK-GESELLSCHAFT ZUR FORDERUNG DER WISSENSCHAFTEN EV
Country Germany
Call Details Advanced Grant (AdG), LS6, ERC-2018-ADG
Summary About 500 million years ago, the two sister groups of vertebrates independently evolved alternative forms of adaptive immunity, representing a striking example of convergent evolution. Whereas the components and functions of the immune system in jawed vertebrates (ranging from sharks to humans) are well characterized, much remains to be learned about adaptive immunity in jawless vertebrates (lampreys and hagfishes). Up to now, progress in understanding immunity in jawless fishes was hampered by their complex life-cycle, long generation time, and the difficulty of raising fish in the laboratory for extended periods, particularly after in vitro fertilization. Based on our recent methodological advances in aquatic husbandry and successful CRISPR/Cas9-mediated genetic modification, we propose to conduct a large-scale analysis of cellular immunity in lampreys laying the foundations for the identification of the unifying principles of vertebrate immunity. Our experiments will address the development and characteristics of different T cell subsets, the molecular basis of antigen receptor assembly, and the function of the two principal T cell lineages during the immune response. We will also examine the structure and function of the stromal microenvironment in the lamprey thymus equivalent, which is considered to be the site of T cell development. A particular focus will be on the functional analysis of a recently discovered MHC-like locus in the context of T cell development, and in the essential self/nonself discrimination mechanism(s) at play during the immune response. We expect that the identification of common design principles of adaptive immunity in vertebrates will provide us with an unprecedented view on immune functions in humans, potentially guiding the development of novel strategies for the treatment of failing immunity in patients with immunodeficiency and/or autoimmunity.
Summary
About 500 million years ago, the two sister groups of vertebrates independently evolved alternative forms of adaptive immunity, representing a striking example of convergent evolution. Whereas the components and functions of the immune system in jawed vertebrates (ranging from sharks to humans) are well characterized, much remains to be learned about adaptive immunity in jawless vertebrates (lampreys and hagfishes). Up to now, progress in understanding immunity in jawless fishes was hampered by their complex life-cycle, long generation time, and the difficulty of raising fish in the laboratory for extended periods, particularly after in vitro fertilization. Based on our recent methodological advances in aquatic husbandry and successful CRISPR/Cas9-mediated genetic modification, we propose to conduct a large-scale analysis of cellular immunity in lampreys laying the foundations for the identification of the unifying principles of vertebrate immunity. Our experiments will address the development and characteristics of different T cell subsets, the molecular basis of antigen receptor assembly, and the function of the two principal T cell lineages during the immune response. We will also examine the structure and function of the stromal microenvironment in the lamprey thymus equivalent, which is considered to be the site of T cell development. A particular focus will be on the functional analysis of a recently discovered MHC-like locus in the context of T cell development, and in the essential self/nonself discrimination mechanism(s) at play during the immune response. We expect that the identification of common design principles of adaptive immunity in vertebrates will provide us with an unprecedented view on immune functions in humans, potentially guiding the development of novel strategies for the treatment of failing immunity in patients with immunodeficiency and/or autoimmunity.
Max ERC Funding
2 498 813 €
Duration
Start date: 2019-06-01, End date: 2024-05-31
Project acronym IMMUNOTHROMBOSIS
Project Cross-talk between platelets and immunity - implications for host homeostasis and defense
Researcher (PI) Steffen MASSBERG
Host Institution (HI) LUDWIG-MAXIMILIANS-UNIVERSITAET MUENCHEN
Country Germany
Call Details Advanced Grant (AdG), LS4, ERC-2018-ADG
Summary The overall aim of the IMMUNOTHROMBOSIS project is to clarify the mechanisms underlying the recently identified synergism between thrombosis and inflammation. Thrombus formation and inflammation are vital host responses that ensure homeostasis, but can also drive cardiovascular disease, including myocardial infarction and stroke, the major causes of death in Europe. My group and others discovered, that thrombosis and inflammation are not to be considered separate processes. They are tightly interrelated and synergize in immune defence, but also in inflammatory and thrombotic diseases in a process we termed immunothrombosis. Targeting this synergism has great potential to identify innovative and unconventional strategies to more specifically prevent undesired activation of thrombotic and inflammatory pathways. However, this requires a deeper mechanistic understanding of immunothrombosis. I recently identified two ground-breaking novel immunothrombotic principles: I discovered that platelets have the ability to migrate autonomously, which assists immune cells in fighting pathogens. Further, I revealed that immune cells play a central role in controlling the production of platelets from their megakaryocyte precursors. The physiological and pathophysiological relevance of both processes is unclear. This is the starting point and focus of the IMMUNOTHROMBOSIS project. My aim is to define how platelets use their ability to migrate to support immune cells in protection of vascular integrity (objective 1) and to identify the contribution of platelet migration to different cardiovascular diseases involving immunothrombotic tissue damage (objective 2). Finally, I will clarify how inflammatory responses feedback to the production of thrombotic effectors and dissect inflammatory mechanisms that control platelet production (objective 3). IMMUNOTHROMBOSIS will identify new options for specific prevention or treatment of thrombotic and inflammatory cardiovascular diseases.
Summary
The overall aim of the IMMUNOTHROMBOSIS project is to clarify the mechanisms underlying the recently identified synergism between thrombosis and inflammation. Thrombus formation and inflammation are vital host responses that ensure homeostasis, but can also drive cardiovascular disease, including myocardial infarction and stroke, the major causes of death in Europe. My group and others discovered, that thrombosis and inflammation are not to be considered separate processes. They are tightly interrelated and synergize in immune defence, but also in inflammatory and thrombotic diseases in a process we termed immunothrombosis. Targeting this synergism has great potential to identify innovative and unconventional strategies to more specifically prevent undesired activation of thrombotic and inflammatory pathways. However, this requires a deeper mechanistic understanding of immunothrombosis. I recently identified two ground-breaking novel immunothrombotic principles: I discovered that platelets have the ability to migrate autonomously, which assists immune cells in fighting pathogens. Further, I revealed that immune cells play a central role in controlling the production of platelets from their megakaryocyte precursors. The physiological and pathophysiological relevance of both processes is unclear. This is the starting point and focus of the IMMUNOTHROMBOSIS project. My aim is to define how platelets use their ability to migrate to support immune cells in protection of vascular integrity (objective 1) and to identify the contribution of platelet migration to different cardiovascular diseases involving immunothrombotic tissue damage (objective 2). Finally, I will clarify how inflammatory responses feedback to the production of thrombotic effectors and dissect inflammatory mechanisms that control platelet production (objective 3). IMMUNOTHROMBOSIS will identify new options for specific prevention or treatment of thrombotic and inflammatory cardiovascular diseases.
Max ERC Funding
2 321 416 €
Duration
Start date: 2019-09-01, End date: 2024-08-31
Project acronym KissAndSpitRhoptry
Project Unravelling the secretion machinery for virulence factors in apicomplexan parasites
Researcher (PI) Maryse LEBRUN
Host Institution (HI) INSTITUT NATIONAL DE LA SANTE ET DE LA RECHERCHE MEDICALE
Country France
Call Details Advanced Grant (AdG), LS6, ERC-2018-ADG
Summary Apicomplexan are obligatory intracellular parasites. The ability of these parasites (Plasmodium, Toxoplasma) to cause disease depends on the coordinated secretion of specialized secretory organelles. The rhoptries are particularly important, because they act as the apicomplexan equivalent of bacterial secretion systems. They inject parasite proteins directly in the cytoplasm of host cells not only for invasion but also to hijack host functions crucial to establish and maintain infection. However, in contrast to bacteria where the secretion machinery has been resolved to atomic detail, how eukaryotic parasites secrete and inject rhoptry effectors into cells is an enigma. This proposal aims to dissect the mechanistic steps and the molecular components that assemble the rhoptry secretion machine.
Our aims are:
1- To explore the mechanisms that trigger rhoptry exocytosis upon binding of the parasite to the host cell.
2- To provide insights into fusion machinery of rhoptry with the parasite plasma membrane. Our model is based on the discovery that free-living Ciliates and intracellular Apicomplexa share an evolutionarily conserved blueprint for their fusion mechanism.
3- To test and expand our hypothesis that rhoptries deliver their content through a transient pore formed into the host cell membrane.
We will employ powerful experimental systems in Toxoplasma, Plasmodium and the Ciliate Tetrahymena, taking full advantage of the relative strength of each model. This comprehensive project will bring together comparative genomics, targeted and global genetics, biochemistry, high resolution imaging and electrophysiology.
This project answers a question of fundamental biological importance. How can a parasite sense the host cell and inject virulence factors to attain control? Understanding this mechanism will guide future efforts to disrupt parasite infection and will contribute to broader understanding of fascinating questions of membrane fusion and export processes.
Summary
Apicomplexan are obligatory intracellular parasites. The ability of these parasites (Plasmodium, Toxoplasma) to cause disease depends on the coordinated secretion of specialized secretory organelles. The rhoptries are particularly important, because they act as the apicomplexan equivalent of bacterial secretion systems. They inject parasite proteins directly in the cytoplasm of host cells not only for invasion but also to hijack host functions crucial to establish and maintain infection. However, in contrast to bacteria where the secretion machinery has been resolved to atomic detail, how eukaryotic parasites secrete and inject rhoptry effectors into cells is an enigma. This proposal aims to dissect the mechanistic steps and the molecular components that assemble the rhoptry secretion machine.
Our aims are:
1- To explore the mechanisms that trigger rhoptry exocytosis upon binding of the parasite to the host cell.
2- To provide insights into fusion machinery of rhoptry with the parasite plasma membrane. Our model is based on the discovery that free-living Ciliates and intracellular Apicomplexa share an evolutionarily conserved blueprint for their fusion mechanism.
3- To test and expand our hypothesis that rhoptries deliver their content through a transient pore formed into the host cell membrane.
We will employ powerful experimental systems in Toxoplasma, Plasmodium and the Ciliate Tetrahymena, taking full advantage of the relative strength of each model. This comprehensive project will bring together comparative genomics, targeted and global genetics, biochemistry, high resolution imaging and electrophysiology.
This project answers a question of fundamental biological importance. How can a parasite sense the host cell and inject virulence factors to attain control? Understanding this mechanism will guide future efforts to disrupt parasite infection and will contribute to broader understanding of fascinating questions of membrane fusion and export processes.
Max ERC Funding
2 496 210 €
Duration
Start date: 2020-10-01, End date: 2025-09-30
Project acronym Mars through time
Project Modeling the past climates of planet Mars to understand its geology, its habitability and its evolution
Researcher (PI) Francois FORGET
Host Institution (HI) CENTRE NATIONAL DE LA RECHERCHE SCIENTIFIQUE CNRS
Country France
Call Details Advanced Grant (AdG), PE9, ERC-2018-ADG
Summary Over the past decades, the robotic exploration of the planet Mars has produced a wealth of geological observations. They show that Mars has not always been the desert planet of today. It has seen eras conducive to rivers and lakes, ice ages, and even periods with a collapsed atmosphere. These different epochs are the reason why Mars remains the objective of space agencies, as they evoke the possibility of past habitability and spectacular climate changes.
Yet, in spite of all the data, the climatic processes that have shaped Mars’ surface through time remain largely unknown. What happened on Mars? Was the Red Planet suitable for life? What explains its evolution?
The objective of this project is to develop numerical models to simulate the past environments of Mars.A completely new “Mars Evolution Model” will be created by asynchronously coupling hydrology, glacial flows and ground ice models with a new generation 3D Global Climate Model (GCM). This GCM will be derived from the one that we have previously designed to simulate present day Mars. We will radically update it using new technologies to represent the details of the surface as well as all the processes that affected Mars when its environment evolved because of the oscillations of its orbit and obliquity, during changes in the atmospheric composition, or through events like meteoritic impacts or volcanic eruptions. Notably, we will highlight the last ten millions years that have been recorded in the polar layered deposits, whose formation will be simulated for the first time realistically.
These new tools will address numerous enigmas found in Mars sciences. They will also offer a new platform to study specific processes such as the atmospheric escape through time or the chemical alteration of the soil. Furthermore, the project will test our capacity to model planetary environments and climate changes, as well as provide lessons on the evolution of terrestrial planets and the possibility of life elsewhere.
Summary
Over the past decades, the robotic exploration of the planet Mars has produced a wealth of geological observations. They show that Mars has not always been the desert planet of today. It has seen eras conducive to rivers and lakes, ice ages, and even periods with a collapsed atmosphere. These different epochs are the reason why Mars remains the objective of space agencies, as they evoke the possibility of past habitability and spectacular climate changes.
Yet, in spite of all the data, the climatic processes that have shaped Mars’ surface through time remain largely unknown. What happened on Mars? Was the Red Planet suitable for life? What explains its evolution?
The objective of this project is to develop numerical models to simulate the past environments of Mars.A completely new “Mars Evolution Model” will be created by asynchronously coupling hydrology, glacial flows and ground ice models with a new generation 3D Global Climate Model (GCM). This GCM will be derived from the one that we have previously designed to simulate present day Mars. We will radically update it using new technologies to represent the details of the surface as well as all the processes that affected Mars when its environment evolved because of the oscillations of its orbit and obliquity, during changes in the atmospheric composition, or through events like meteoritic impacts or volcanic eruptions. Notably, we will highlight the last ten millions years that have been recorded in the polar layered deposits, whose formation will be simulated for the first time realistically.
These new tools will address numerous enigmas found in Mars sciences. They will also offer a new platform to study specific processes such as the atmospheric escape through time or the chemical alteration of the soil. Furthermore, the project will test our capacity to model planetary environments and climate changes, as well as provide lessons on the evolution of terrestrial planets and the possibility of life elsewhere.
Max ERC Funding
2 493 836 €
Duration
Start date: 2019-10-01, End date: 2024-09-30
Project acronym Metabinnate
Project Metabolic crosstalk in the regulation of inflammation
Researcher (PI) Luke O'NEILL
Host Institution (HI) THE PROVOST, FELLOWS, FOUNDATION SCHOLARS & THE OTHER MEMBERS OF BOARD OF THE COLLEGE OF THE HOLY & UNDIVIDED TRINITY OF QUEEN ELIZABETH NEAR DUBLIN
Country Ireland
Call Details Advanced Grant (AdG), LS6, ERC-2018-ADG
Summary The study of the molecular basis to the immune response has for decades concerned receptors and the signalling pathways they activate which lead to immune cell activation. Recently metabolic changes have also been shown to couple to immune effector responses. A shift in appreciation of the role of metabolites beyond energy metabolism and biosynthetic processes has emerged. We have been examining the role of three metabolites in macrophages. We have evidence that two of these, malonyl-CoA and 2-hydroxyglutarate (2-HG) are pro-inflammatory, whilst the third, itaconate, has profound anti-inflammatory effects. In many ways, they mirror cytokines, with malonyl-CoA and 2-HG being akin to pro-inflammatory cytokines, whilst itaconate resembles anti-inflammatory cytokines. The specificity and breadth of the role of these metabolites in macrophages will be mapped in this proposal. For malonyl-CoA we have evidence that it regulates GAPDH, IRG1/CAD (which synthesises itaconate) and the key cytokine IL-1beta. For 2-HG, we will examine the production and actions of its 2 enantiomers, D-2-HG and L-2-HG, focusing on their effect on HIF1alpha and epigenetic regulation. For itaconate we have evidence for a role in Type I interferon modulation, antigen presentation, inflammasome regulation and GAPDH and LDHA (which can produce 2-HG) activities. We also have evidence that OXGR1 is the receptor for itaconate. All of these aspects will be explored in detail. Critically we will also determine the relationship between these metabolites since we have evidence for cross-talk. Their dynamic regulation is likely to be a key aspect of how metabolic reprogramming controls macrophage function. Our studies point to a major shift in our understanding of how intracellular metabolic changes lead to inflammation. The overall aim is therefore to elucidate how metabolic reprogramming controls inflammatory macrophage activation, which may lead to new therapeutic targets for inflammatory diseases.
Summary
The study of the molecular basis to the immune response has for decades concerned receptors and the signalling pathways they activate which lead to immune cell activation. Recently metabolic changes have also been shown to couple to immune effector responses. A shift in appreciation of the role of metabolites beyond energy metabolism and biosynthetic processes has emerged. We have been examining the role of three metabolites in macrophages. We have evidence that two of these, malonyl-CoA and 2-hydroxyglutarate (2-HG) are pro-inflammatory, whilst the third, itaconate, has profound anti-inflammatory effects. In many ways, they mirror cytokines, with malonyl-CoA and 2-HG being akin to pro-inflammatory cytokines, whilst itaconate resembles anti-inflammatory cytokines. The specificity and breadth of the role of these metabolites in macrophages will be mapped in this proposal. For malonyl-CoA we have evidence that it regulates GAPDH, IRG1/CAD (which synthesises itaconate) and the key cytokine IL-1beta. For 2-HG, we will examine the production and actions of its 2 enantiomers, D-2-HG and L-2-HG, focusing on their effect on HIF1alpha and epigenetic regulation. For itaconate we have evidence for a role in Type I interferon modulation, antigen presentation, inflammasome regulation and GAPDH and LDHA (which can produce 2-HG) activities. We also have evidence that OXGR1 is the receptor for itaconate. All of these aspects will be explored in detail. Critically we will also determine the relationship between these metabolites since we have evidence for cross-talk. Their dynamic regulation is likely to be a key aspect of how metabolic reprogramming controls macrophage function. Our studies point to a major shift in our understanding of how intracellular metabolic changes lead to inflammation. The overall aim is therefore to elucidate how metabolic reprogramming controls inflammatory macrophage activation, which may lead to new therapeutic targets for inflammatory diseases.
Max ERC Funding
2 484 858 €
Duration
Start date: 2019-06-01, End date: 2024-05-31