Project acronym APOSITE
Project Apoptotic foci: composition, structure and dynamics
Researcher (PI) Ana GARCIA SAEZ
Host Institution (HI) UNIVERSITAET ZU KOELN
Country Germany
Call Details Consolidator Grant (CoG), LS3, ERC-2018-COG
Summary Apoptotic cell death is essential for development, immune function or tissue homeostasis, and it is often deregulated in disease. Mitochondrial outer membrane permeabilization (MOMP) is central for apoptosis execution and plays a key role in its inflammatory outcome. Knowing the architecture of the macromolecular machineries mediating MOMP is crucial for understanding their function and for the clinical use of apoptosis.
Our recent work reveals that Bax and Bak dimers form distinct line, arc and ring assemblies at specific apoptotic foci to mediate MOMP. However, the molecular structure and mechanisms controlling the spatiotemporal formation and range of action of the apoptotic foci are missing. To address this fundamental gap in our knowledge, we aim to unravel the composition, dynamics and structure of apoptotic foci and to understand how they are integrated to orchestrate function. We will reach this goal by building on our expertise in cell death and cutting-edge imaging and by developing a new analytical pipeline to:
1) Identify the composition of apoptotic foci using in situ proximity-dependent labeling and extraction of near-native Bax/Bak membrane complexes coupled to mass spectrometry.
2) Define their contribution to apoptosis and its immunogenicity and establish their assembly dynamics to correlate it with apoptosis progression by live cell imaging.
3) Determine the stoichiometry and structural organization of the apoptotic foci by combining single molecule fluorescence and advanced electron microscopies.
This multidisciplinary approach offers high chances to solve the long-standing question of how Bax and Bak mediate MOMP. APOSITE will provide textbook knowledge of the mitochondrial contribution to cell death and inflammation. The implementation of this new analytical framework will open novel research avenues in membrane and organelle biology. Ultimately, understanding of Bax and Bak structure/function will help develop apoptosis modulators for medicine.
Summary
Apoptotic cell death is essential for development, immune function or tissue homeostasis, and it is often deregulated in disease. Mitochondrial outer membrane permeabilization (MOMP) is central for apoptosis execution and plays a key role in its inflammatory outcome. Knowing the architecture of the macromolecular machineries mediating MOMP is crucial for understanding their function and for the clinical use of apoptosis.
Our recent work reveals that Bax and Bak dimers form distinct line, arc and ring assemblies at specific apoptotic foci to mediate MOMP. However, the molecular structure and mechanisms controlling the spatiotemporal formation and range of action of the apoptotic foci are missing. To address this fundamental gap in our knowledge, we aim to unravel the composition, dynamics and structure of apoptotic foci and to understand how they are integrated to orchestrate function. We will reach this goal by building on our expertise in cell death and cutting-edge imaging and by developing a new analytical pipeline to:
1) Identify the composition of apoptotic foci using in situ proximity-dependent labeling and extraction of near-native Bax/Bak membrane complexes coupled to mass spectrometry.
2) Define their contribution to apoptosis and its immunogenicity and establish their assembly dynamics to correlate it with apoptosis progression by live cell imaging.
3) Determine the stoichiometry and structural organization of the apoptotic foci by combining single molecule fluorescence and advanced electron microscopies.
This multidisciplinary approach offers high chances to solve the long-standing question of how Bax and Bak mediate MOMP. APOSITE will provide textbook knowledge of the mitochondrial contribution to cell death and inflammation. The implementation of this new analytical framework will open novel research avenues in membrane and organelle biology. Ultimately, understanding of Bax and Bak structure/function will help develop apoptosis modulators for medicine.
Max ERC Funding
2 000 000 €
Duration
Start date: 2019-04-01, End date: 2024-03-31
Project acronym ARCHAIC ADAPT
Project Admixture accelerated adaptation: signals from modern, ancient and archaic DNA.
Researcher (PI) Emilia HUERTA-SANCHEZ
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 Starting Grant (StG), LS8, ERC-2018-STG
Summary With the advent of new sequencing technologies, population geneticists now have access to more data than ever before. We have access to thousands of human genomes from a diverse set of populations around the globe, and, thanks to advances in DNA extraction and library preparation, we now are beginning to have access to ancient DNA sequence data. These data have greatly improved our knowledge of human history, human adaptation to different environments and human disease. Genome-wide studies have highlighted many genes or genomic loci that may play a role in adaptive or disease related phenotypes of biological importance.
With these collections of modern and ancient sequence data we want to answer a key evolutionary question: how do human adaptations arise? We strongly believe that the state-of-the-art methodologies for uncovering signatures of adaptation are blind to potential modes of adaptation because they are lacking two critical components – more complete integration of multiple population haplotype data (including archaic, ancient and modern samples), and an account of population interactions that facilitate adaptation.
Therefore I plan to develop new methods to detect shared selective events across populations by creating novel statistical summaries, and to detect admixture-facilitated adaptation which we believe is likely a common mode of natural selection. We will apply these tools to new datasets to characterize the interplay of natural selection, archaic and modern admixture in populations in the Americas and make a comparative analysis of modern and ancient European samples to understand the origin and changing profile of adaptive archaic alleles. As a result our work will reveal evolutionary processes that have played an important role in human evolution and disease.
Summary
With the advent of new sequencing technologies, population geneticists now have access to more data than ever before. We have access to thousands of human genomes from a diverse set of populations around the globe, and, thanks to advances in DNA extraction and library preparation, we now are beginning to have access to ancient DNA sequence data. These data have greatly improved our knowledge of human history, human adaptation to different environments and human disease. Genome-wide studies have highlighted many genes or genomic loci that may play a role in adaptive or disease related phenotypes of biological importance.
With these collections of modern and ancient sequence data we want to answer a key evolutionary question: how do human adaptations arise? We strongly believe that the state-of-the-art methodologies for uncovering signatures of adaptation are blind to potential modes of adaptation because they are lacking two critical components – more complete integration of multiple population haplotype data (including archaic, ancient and modern samples), and an account of population interactions that facilitate adaptation.
Therefore I plan to develop new methods to detect shared selective events across populations by creating novel statistical summaries, and to detect admixture-facilitated adaptation which we believe is likely a common mode of natural selection. We will apply these tools to new datasets to characterize the interplay of natural selection, archaic and modern admixture in populations in the Americas and make a comparative analysis of modern and ancient European samples to understand the origin and changing profile of adaptive archaic alleles. As a result our work will reveal evolutionary processes that have played an important role in human evolution and disease.
Max ERC Funding
1 500 000 €
Duration
Start date: 2020-12-01, End date: 2025-11-30
Project acronym ASTROFLOW
Project The influence of stellar outflows on exoplanetary mass loss
Researcher (PI) Aline VIDOTTO
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 Consolidator Grant (CoG), PE9, ERC-2018-COG
Summary ASTROFLOW aims to make ground-breaking progress in our physical understanding of exoplanetary mass loss, by quantifying the influence of stellar outflows on atmospheric escape of close-in exoplanets. Escape plays a key role in planetary evolution, population, and potential to develop life. Stellar irradiation and outflows affect planetary mass loss: irradiation heats planetary atmospheres, which inflate and more likely escape; outflows cause pressure confinement around otherwise freely escaping atmospheres. This external pressure can increase, reduce or even suppress escape rates; its effects on exoplanetary mass loss remain largely unexplored due to the complexity of such interactions. I will fill this knowledge gap by developing a novel modelling framework of atmospheric escape that will, for the first time, consider the effects of realistic stellar outflows on exoplanetary mass loss. My expertise in stellar wind theory and 3D magnetohydrodynamic simulations is crucial for producing the next-generation models of planetary escape. My framework will consist of state-of-the-art, time-dependent, 3D simulations of stellar outflows (Method 1), which will be coupled to novel 3D simulations of atmospheric escape (Method 2). My models will account for the major underlying physical processes of mass loss. With this, I will determine the response of planetary mass loss to realistic stellar particle, magnetic and radiation environments and will characterise the physical conditions of the escaping material. I will compute how its extinction varies during transit and compare synthetic line profiles to atmospheric escape observations from, eg, Hubble and our NASA cubesat CUTE. Strong synergy with upcoming observations (JWST, TESS, SPIRou, CARMENES) also exists. Determining the lifetime of planetary atmospheres is essential to understanding populations of exoplanets. ASTROFLOW’s work will be the foundation for future research of how exoplanets evolve under mass-loss processes.
Summary
ASTROFLOW aims to make ground-breaking progress in our physical understanding of exoplanetary mass loss, by quantifying the influence of stellar outflows on atmospheric escape of close-in exoplanets. Escape plays a key role in planetary evolution, population, and potential to develop life. Stellar irradiation and outflows affect planetary mass loss: irradiation heats planetary atmospheres, which inflate and more likely escape; outflows cause pressure confinement around otherwise freely escaping atmospheres. This external pressure can increase, reduce or even suppress escape rates; its effects on exoplanetary mass loss remain largely unexplored due to the complexity of such interactions. I will fill this knowledge gap by developing a novel modelling framework of atmospheric escape that will, for the first time, consider the effects of realistic stellar outflows on exoplanetary mass loss. My expertise in stellar wind theory and 3D magnetohydrodynamic simulations is crucial for producing the next-generation models of planetary escape. My framework will consist of state-of-the-art, time-dependent, 3D simulations of stellar outflows (Method 1), which will be coupled to novel 3D simulations of atmospheric escape (Method 2). My models will account for the major underlying physical processes of mass loss. With this, I will determine the response of planetary mass loss to realistic stellar particle, magnetic and radiation environments and will characterise the physical conditions of the escaping material. I will compute how its extinction varies during transit and compare synthetic line profiles to atmospheric escape observations from, eg, Hubble and our NASA cubesat CUTE. Strong synergy with upcoming observations (JWST, TESS, SPIRou, CARMENES) also exists. Determining the lifetime of planetary atmospheres is essential to understanding populations of exoplanets. ASTROFLOW’s work will be the foundation for future research of how exoplanets evolve under mass-loss processes.
Max ERC Funding
1 999 956 €
Duration
Start date: 2019-09-01, End date: 2024-08-31
Project acronym BactRNA
Project Bacterial small RNAs networks unravelling novel features of transcription and translation
Researcher (PI) Maude Audrey Guillier
Host Institution (HI) CENTRE NATIONAL DE LA RECHERCHE SCIENTIFIQUE CNRS
Country France
Call Details Consolidator Grant (CoG), LS2, ERC-2018-COG
Summary Regulation of gene expression plays a key role in the ability of bacteria to rapidly adapt to changing environments and to colonize extremely diverse habitats. The relatively recent discovery of a plethora of small regulatory RNAs and the beginning of their characterization has unravelled new aspects of bacterial gene expression. First, the expression of many bacterial genes responds to a complex network of both transcriptional and post-transcriptional regulators. However, the properties of the resulting regulatory circuits on the dynamics of gene expression and in the bacterial adaptive response have been poorly addressed so far. In a first part of this project, we will tackle this question by characterizing the circuits that are formed between two widespread classes of bacterial regulators, the sRNAs and the two-component systems, which act at the post-transcriptional and the transcriptional level, respectively. The study of sRNAs also led to major breakthroughs regarding the basic mechanisms of gene expression. In particular, we recently showed that repressor sRNAs can target activating stem-loop structures located within the coding region of mRNAs that promote translation initiation, in striking contrast with the previously recognized inhibitory role of mRNA structures in translation. The second objective of this project is thus to draw an unprecedented map of non-canonical translation initiation events and their regulation by sRNAs.
Overall, this project will greatly improve our understanding of how bacteria can so rapidly and successfully adapt to many different environments, and in the long term, provide clues towards the development of anti-bacterial strategies.
Summary
Regulation of gene expression plays a key role in the ability of bacteria to rapidly adapt to changing environments and to colonize extremely diverse habitats. The relatively recent discovery of a plethora of small regulatory RNAs and the beginning of their characterization has unravelled new aspects of bacterial gene expression. First, the expression of many bacterial genes responds to a complex network of both transcriptional and post-transcriptional regulators. However, the properties of the resulting regulatory circuits on the dynamics of gene expression and in the bacterial adaptive response have been poorly addressed so far. In a first part of this project, we will tackle this question by characterizing the circuits that are formed between two widespread classes of bacterial regulators, the sRNAs and the two-component systems, which act at the post-transcriptional and the transcriptional level, respectively. The study of sRNAs also led to major breakthroughs regarding the basic mechanisms of gene expression. In particular, we recently showed that repressor sRNAs can target activating stem-loop structures located within the coding region of mRNAs that promote translation initiation, in striking contrast with the previously recognized inhibitory role of mRNA structures in translation. The second objective of this project is thus to draw an unprecedented map of non-canonical translation initiation events and their regulation by sRNAs.
Overall, this project will greatly improve our understanding of how bacteria can so rapidly and successfully adapt to many different environments, and in the long term, provide clues towards the development of anti-bacterial strategies.
Max ERC Funding
1 999 754 €
Duration
Start date: 2019-09-01, End date: 2024-08-31
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 ChromoSOMe
Project Canonical and Non-canonical modes of Chromosome Segregation in Oocyte Meiosis
Researcher (PI) Julien Dumont
Host Institution (HI) CENTRE NATIONAL DE LA RECHERCHE SCIENTIFIQUE CNRS
Country France
Call Details Consolidator Grant (CoG), LS3, ERC-2018-COG
Summary Cell division is crucial for the development of complex organisms, for the homeostasis of tissues, and for the reproductive capacity of individuals. While most somatic cells are diploid and proliferate through mitosis, multiplication of sexually reproducing species relies on haploid gametes that are generated through a specialized cell division process called meiosis. To achieve this reduction in ploidy, two rounds of chromosome segregation follow a single phase of genome replication. Inaccuracy in this process leads to gametes that carry an incorrect number of chromosomes and to aneuploid embryos after fertilization. In their vast majority, these are non-viable and lead to spontaneous abortion: defective meiotic division is therefore a major obstacle in achieving reproduction. However, the key principles that drive this process are still poorly understood, one main reason being the diversity of the molecular scenarios that have been adopted across evolution to regulate oocyte chromosome segregation.
To dissect the key components of oocyte meiotic chromosome segregation, we propose to carry out a multi-disciplinary approach, combining several nematode species with the use of high-resolution live and electron microscopy, cutting edge genomic and proteomic technologies, and biochemistry coupled to in silico modeling. In Work Package 1 (WP1), we will analyze the molecular mechanisms controlling the self-assembly of the chromosome segregation machinery -the meiotic spindle- in the oocyte. WP2 will focus on defining how chromosome segregation is achieved in oocytes with non-canonical kinetochore geometry. WP3 aims at analyzing meiotic divisions in parthenogenetic nematodes with specific meiotic constraints, such as centrosomal oogenesis and unichromosomal genomes. By considering the wealth of mechanisms that can drive chromosome segregation in oocytes, this project will provide decisive steps towards understanding the essential and universal features of female meiosis.
Summary
Cell division is crucial for the development of complex organisms, for the homeostasis of tissues, and for the reproductive capacity of individuals. While most somatic cells are diploid and proliferate through mitosis, multiplication of sexually reproducing species relies on haploid gametes that are generated through a specialized cell division process called meiosis. To achieve this reduction in ploidy, two rounds of chromosome segregation follow a single phase of genome replication. Inaccuracy in this process leads to gametes that carry an incorrect number of chromosomes and to aneuploid embryos after fertilization. In their vast majority, these are non-viable and lead to spontaneous abortion: defective meiotic division is therefore a major obstacle in achieving reproduction. However, the key principles that drive this process are still poorly understood, one main reason being the diversity of the molecular scenarios that have been adopted across evolution to regulate oocyte chromosome segregation.
To dissect the key components of oocyte meiotic chromosome segregation, we propose to carry out a multi-disciplinary approach, combining several nematode species with the use of high-resolution live and electron microscopy, cutting edge genomic and proteomic technologies, and biochemistry coupled to in silico modeling. In Work Package 1 (WP1), we will analyze the molecular mechanisms controlling the self-assembly of the chromosome segregation machinery -the meiotic spindle- in the oocyte. WP2 will focus on defining how chromosome segregation is achieved in oocytes with non-canonical kinetochore geometry. WP3 aims at analyzing meiotic divisions in parthenogenetic nematodes with specific meiotic constraints, such as centrosomal oogenesis and unichromosomal genomes. By considering the wealth of mechanisms that can drive chromosome segregation in oocytes, this project will provide decisive steps towards understanding the essential and universal features of female meiosis.
Max ERC Funding
1 561 563 €
Duration
Start date: 2020-01-01, End date: 2024-12-31
Project acronym CiliaTubulinCode
Project Self-organization of the cilium: the role of the tubulin code
Researcher (PI) Gaia PIGINO
Host Institution (HI) MAX-PLANCK-GESELLSCHAFT ZUR FORDERUNG DER WISSENSCHAFTEN EV
Country Germany
Call Details Consolidator Grant (CoG), LS1, ERC-2018-COG
Summary This project aims at understanding of the role of the tubulin code for self-organization of complex microtubule based structures. Cilia turn out to be the ideal structures for the proposed research.
A cilium is a sophisticated cellular machine that self-organizes from many protein complexes. It plays motility, sensory, and signaling roles in most eukaryotic cells, and its malfunction causes pathologies. The assembly of the cilium requires intraflagellar transport (IFT), a specialized bidirectional motility process that is mediated by adaptor proteins and direction specific molecular motors. Work from my lab shows that anterograde and retrograde IFT make exclusive use of the B-tubules and A-tubules, respectively. This insight answered a long standing question and shows that functional differentiation of tubules exists and is important for IFT.
Tubulin post-translational modifications (PTMs) contribute to a tubulin code, making microtubules suitable for specific functions. Mutation of tubulin-PTM enzymes can have dramatic effects on cilia function and assembly. However, we do not understand of the role of tubulin-PTMs in cilia. Therefore, I propose to address the hypotheses that the tubulin code contributes to regulating bidirectional IFT motility, and more generally, that the tubulin code is a key player in structuring complex cellular assembly processes in space and time.
This proposal aims at (i) understanding if tubulin-PTMs are necessary and/or sufficient to regulate the bidirectionality of IFT (ii) examining how the tubulin code regulates the assembly of cilia and (iii) generating a high-resolution atlas of tubulin-PTMs and their respective enzymes.
We will combine advanced techniques encompassing state-of-the-art cryo-electron tomography, biochemical imaging, fluorescent microscopy, and in vitro assays to achieve molecular and structural understanding of the role of the tubulin code in the self-organization of cilia and of microtubule based cellular structures.
Summary
This project aims at understanding of the role of the tubulin code for self-organization of complex microtubule based structures. Cilia turn out to be the ideal structures for the proposed research.
A cilium is a sophisticated cellular machine that self-organizes from many protein complexes. It plays motility, sensory, and signaling roles in most eukaryotic cells, and its malfunction causes pathologies. The assembly of the cilium requires intraflagellar transport (IFT), a specialized bidirectional motility process that is mediated by adaptor proteins and direction specific molecular motors. Work from my lab shows that anterograde and retrograde IFT make exclusive use of the B-tubules and A-tubules, respectively. This insight answered a long standing question and shows that functional differentiation of tubules exists and is important for IFT.
Tubulin post-translational modifications (PTMs) contribute to a tubulin code, making microtubules suitable for specific functions. Mutation of tubulin-PTM enzymes can have dramatic effects on cilia function and assembly. However, we do not understand of the role of tubulin-PTMs in cilia. Therefore, I propose to address the hypotheses that the tubulin code contributes to regulating bidirectional IFT motility, and more generally, that the tubulin code is a key player in structuring complex cellular assembly processes in space and time.
This proposal aims at (i) understanding if tubulin-PTMs are necessary and/or sufficient to regulate the bidirectionality of IFT (ii) examining how the tubulin code regulates the assembly of cilia and (iii) generating a high-resolution atlas of tubulin-PTMs and their respective enzymes.
We will combine advanced techniques encompassing state-of-the-art cryo-electron tomography, biochemical imaging, fluorescent microscopy, and in vitro assays to achieve molecular and structural understanding of the role of the tubulin code in the self-organization of cilia and of microtubule based cellular structures.
Max ERC Funding
1 986 406 €
Duration
Start date: 2019-03-01, End date: 2024-02-29
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 COLLEXISM
Project Collisional excitation of interstellar molecules: towards reactive systems
Researcher (PI) Francois LIQUE
Host Institution (HI) UNIVERSITE LE HAVRE NORMANDIE
Country France
Call Details Consolidator Grant (CoG), PE9, ERC-2018-COG
Summary Accurate determination of physical conditions of interstellar molecular clouds is a crucial step to better understand the life cycle of the interstellar matter and particularly the formation of stars and planets as well as the synthesis of organic molecules that may lead to emergence of life in the universe. A key parameter for the determination of these conditions from interstellar spectra is the calculation of accurate collisional rate coefficients of interstellar molecules with the most abundant species (H, He, H2 and e-). Whereas the knowledge of collisional processes has reached a certain level of maturity for collisions involving non-reactive molecules, very few reliable data exist for collisions involving reactive radicals and ions. The computation of such data is a real challenge since inelastic and reactive processes compete during collisions. In this project, we plan to overcome this complex problem and to provide collisional data for these radicals and ions in order to derive as much information as possible from the molecular spectra collected by current telescopes. As it is hardly possible to consider both collisional and reactive processes simultaneously, we will set up a new methodology based on quantum approach that allows obtaining accurate data. We will focus on molecular hydrides that are good candidates because of both their astrophysical importance and their quantum accessibility. We will carry out the determination of interaction potentials using quantum chemistry ab initio methods while the treatment of the dynamics of the nuclei will primarily be done using quantum time-independent reactive and non-reactive approaches. When exact quantum calculations will not be usable, innovative statistical quantum mechanical methods will also be explored. The new data will then be used in radiative transfer models and the predictions will be finally compared to observations in order to derive the abundances of reactive radicals with unprecedented accuracy.
Summary
Accurate determination of physical conditions of interstellar molecular clouds is a crucial step to better understand the life cycle of the interstellar matter and particularly the formation of stars and planets as well as the synthesis of organic molecules that may lead to emergence of life in the universe. A key parameter for the determination of these conditions from interstellar spectra is the calculation of accurate collisional rate coefficients of interstellar molecules with the most abundant species (H, He, H2 and e-). Whereas the knowledge of collisional processes has reached a certain level of maturity for collisions involving non-reactive molecules, very few reliable data exist for collisions involving reactive radicals and ions. The computation of such data is a real challenge since inelastic and reactive processes compete during collisions. In this project, we plan to overcome this complex problem and to provide collisional data for these radicals and ions in order to derive as much information as possible from the molecular spectra collected by current telescopes. As it is hardly possible to consider both collisional and reactive processes simultaneously, we will set up a new methodology based on quantum approach that allows obtaining accurate data. We will focus on molecular hydrides that are good candidates because of both their astrophysical importance and their quantum accessibility. We will carry out the determination of interaction potentials using quantum chemistry ab initio methods while the treatment of the dynamics of the nuclei will primarily be done using quantum time-independent reactive and non-reactive approaches. When exact quantum calculations will not be usable, innovative statistical quantum mechanical methods will also be explored. The new data will then be used in radiative transfer models and the predictions will be finally compared to observations in order to derive the abundances of reactive radicals with unprecedented accuracy.
Max ERC Funding
1 802 625 €
Duration
Start date: 2019-07-01, End date: 2024-06-30
