Project acronym A-FRO
Project Actively Frozen - contextual modulation of freezing and its neuronal basis
Researcher (PI) Marta de Aragão Pacheco Moita
Host Institution (HI) FUNDACAO D. ANNA SOMMER CHAMPALIMAUD E DR. CARLOS MONTEZ CHAMPALIMAUD
Call Details Consolidator Grant (CoG), LS5, ERC-2018-COG
Summary When faced with a threat, an animal must decide whether to freeze, reducing its chances of being noticed, or to flee to the safety of a refuge. Animals from fish to primates choose between these two alternatives when confronted by an attacking predator, a choice that largely depends on the context in which the threat occurs. Recent work has made strides identifying the pre-motor circuits, and their inputs, which control freezing behavior in rodents, but how contextual information is integrated to guide this choice is still far from understood. We recently found that fruit flies in response to visual looming stimuli, simulating a large object on collision course, make rapid freeze/flee choices that depend on the social and spatial environment, and the fly’s internal state. Further, identification of looming detector neurons was recently reported and we identified the descending command neurons, DNp09, responsible for freezing in the fly. Knowing the sensory input and descending output for looming-evoked freezing, two environmental factors that modulate its expression, and using a genetically tractable system affording the use of large sample sizes, places us in an unique position to understand how a information about a threat is integrated with cues from the environment to guide the choice of whether to freeze (our goal). To assess how social information impinges on the circuit for freezing, we will examine the sensory inputs and neuromodulators that mediate this process, mapping their connections to DNp09 neurons (Aim 1). We ask whether learning is required for the spatial modulation of freezing, which cues flies are using to discriminate different places and which brain circuits mediate this process (Aim 2). Finally, we will study how activity of DNp09 neurons drives freezing (Aim 3). This project will provide a comprehensive understanding of the mechanism of freezing and its modulation by the environment, from single neurons to behaviour.
Summary
When faced with a threat, an animal must decide whether to freeze, reducing its chances of being noticed, or to flee to the safety of a refuge. Animals from fish to primates choose between these two alternatives when confronted by an attacking predator, a choice that largely depends on the context in which the threat occurs. Recent work has made strides identifying the pre-motor circuits, and their inputs, which control freezing behavior in rodents, but how contextual information is integrated to guide this choice is still far from understood. We recently found that fruit flies in response to visual looming stimuli, simulating a large object on collision course, make rapid freeze/flee choices that depend on the social and spatial environment, and the fly’s internal state. Further, identification of looming detector neurons was recently reported and we identified the descending command neurons, DNp09, responsible for freezing in the fly. Knowing the sensory input and descending output for looming-evoked freezing, two environmental factors that modulate its expression, and using a genetically tractable system affording the use of large sample sizes, places us in an unique position to understand how a information about a threat is integrated with cues from the environment to guide the choice of whether to freeze (our goal). To assess how social information impinges on the circuit for freezing, we will examine the sensory inputs and neuromodulators that mediate this process, mapping their connections to DNp09 neurons (Aim 1). We ask whether learning is required for the spatial modulation of freezing, which cues flies are using to discriminate different places and which brain circuits mediate this process (Aim 2). Finally, we will study how activity of DNp09 neurons drives freezing (Aim 3). This project will provide a comprehensive understanding of the mechanism of freezing and its modulation by the environment, from single neurons to behaviour.
Max ERC Funding
1 969 750 €
Duration
Start date: 2019-02-01, End date: 2024-01-31
Project acronym CapTherPV
Project Integration of Capacitor, Thermoelectric and PhotoVoltaic thin films for efficient energy conversion and storage
Researcher (PI) Isabel Maria Das Merces Ferreira
Host Institution (HI) NOVA ID FCT - ASSOCIACAO PARA A INOVACAO E DESENVOLVIMENTO DA FCT
Call Details Consolidator Grant (CoG), PE8, ERC-2014-CoG
Summary The possibility of having a unique device that converts thermal and photonics energy into electrical energy and simultaneously stores it, is something dreamed by the PI since the beginning of her research career. To achieve that goal, this project aims to gather, in a single substrate, solar cells with up-conversion nanoparticles, thermoelectrics and graphene super-capacitor, all made of thin films. These three main components will be developed separately and integrated sequentially. The innovation proposed is not limited to the integration of components, but rely in ground-breaking concepts: 1) thermoelectric elements based on thin film (TE-TF) oxides; 2) plasmonic nanoparticles for up conversion of near infrared radiation to visible emission in solar cells; 3) graphene super-capacitors; 4) integration and optimization of all components in a single CapTherPV device. This ambitious project will bring new insights at large area, low cost and flexible energy harvesting and comes from an old idea of combining energy conversion and storage that has been pursued by the PI. She started her career in amorphous silicon thin film solar cells, later she started the development of thin film batteries and more recently started a research line in thermoelectric films. If approved, this project will give financial support to consolidate the research being carried out and will give independence to the PI in terms of resources and creative think. More importantly, will facilitate the concretization of the dream that has been pursued with hard work.
Summary
The possibility of having a unique device that converts thermal and photonics energy into electrical energy and simultaneously stores it, is something dreamed by the PI since the beginning of her research career. To achieve that goal, this project aims to gather, in a single substrate, solar cells with up-conversion nanoparticles, thermoelectrics and graphene super-capacitor, all made of thin films. These three main components will be developed separately and integrated sequentially. The innovation proposed is not limited to the integration of components, but rely in ground-breaking concepts: 1) thermoelectric elements based on thin film (TE-TF) oxides; 2) plasmonic nanoparticles for up conversion of near infrared radiation to visible emission in solar cells; 3) graphene super-capacitors; 4) integration and optimization of all components in a single CapTherPV device. This ambitious project will bring new insights at large area, low cost and flexible energy harvesting and comes from an old idea of combining energy conversion and storage that has been pursued by the PI. She started her career in amorphous silicon thin film solar cells, later she started the development of thin film batteries and more recently started a research line in thermoelectric films. If approved, this project will give financial support to consolidate the research being carried out and will give independence to the PI in terms of resources and creative think. More importantly, will facilitate the concretization of the dream that has been pursued with hard work.
Max ERC Funding
1 999 375 €
Duration
Start date: 2015-07-01, End date: 2020-06-30
Project acronym CELLFITNESS
Project Active Mechanisms of Cell Selection: From Cell Competition to Cell Fitness
Researcher (PI) Eduardo Moreno Lampaya
Host Institution (HI) FUNDACAO D. ANNA SOMMER CHAMPALIMAUD E DR. CARLOS MONTEZ CHAMPALIMAUD
Call Details Consolidator Grant (CoG), LS3, ERC-2013-CoG
Summary The molecular mechanisms that mediate cell competition, cell fitness and cell selection is gaining interest. With innovative approaches, molecules and ground-breaking hypothesis, this field of research can help understand several biological processes such as development, cancer and tissue degeneration. The project has 3 clear and ambitious objectives: 1. We propose to identify all the key genes mediating cell competition and their molecular mechanisms. In order to reach this objective we will use data from two whole genome screens in Drosophila where we have identified 7 key genes. By the end of this CoG grant, we should have no big gaps in our knowledge of how slow dividing cells are recognised and eliminated in Drosophila. 2. In addition, we will explore how general the cell competition pathways are and how they can impact biomedical research, with a focus in cancer and tissue degeneration. The interest in cancer is based on experiments in Drosophila and mice where we and others have found that an active process of cell selection determines tumour growth. Preliminary results suggest that the pathways identified do not only play important roles in the elimination of slow dividing cells, but also during cancer initiation and progression. 3. We will further explore the role of cell competition in neuronal selection, specially during neurodegeneration, development of the retina and adult brain regeneration in Drosophila. This proposal is of an interdisciplinary nature because it takes a basic cellular mechanism (the genetic pathways that select cells within tissues) and crosses boundaries between different fields of research: development, cancer, regeneration and tissue degeneration. In this ERC CoG proposal, we are committed to continue our efforts from basic science to biomedical approaches. The phenomena of cell competition and its participating genes have the potential to discover novel biomarkers and therapeutic strategies against cancer and tissue degeneration.
Summary
The molecular mechanisms that mediate cell competition, cell fitness and cell selection is gaining interest. With innovative approaches, molecules and ground-breaking hypothesis, this field of research can help understand several biological processes such as development, cancer and tissue degeneration. The project has 3 clear and ambitious objectives: 1. We propose to identify all the key genes mediating cell competition and their molecular mechanisms. In order to reach this objective we will use data from two whole genome screens in Drosophila where we have identified 7 key genes. By the end of this CoG grant, we should have no big gaps in our knowledge of how slow dividing cells are recognised and eliminated in Drosophila. 2. In addition, we will explore how general the cell competition pathways are and how they can impact biomedical research, with a focus in cancer and tissue degeneration. The interest in cancer is based on experiments in Drosophila and mice where we and others have found that an active process of cell selection determines tumour growth. Preliminary results suggest that the pathways identified do not only play important roles in the elimination of slow dividing cells, but also during cancer initiation and progression. 3. We will further explore the role of cell competition in neuronal selection, specially during neurodegeneration, development of the retina and adult brain regeneration in Drosophila. This proposal is of an interdisciplinary nature because it takes a basic cellular mechanism (the genetic pathways that select cells within tissues) and crosses boundaries between different fields of research: development, cancer, regeneration and tissue degeneration. In this ERC CoG proposal, we are committed to continue our efforts from basic science to biomedical approaches. The phenomena of cell competition and its participating genes have the potential to discover novel biomarkers and therapeutic strategies against cancer and tissue degeneration.
Max ERC Funding
1 968 062 €
Duration
Start date: 2014-06-01, End date: 2019-05-31
Project acronym CentrioleBirthDeath
Project Mechanism of centriole inheritance and maintenance
Researcher (PI) Monica BETTENCOURT CARVALHO DIAS
Host Institution (HI) FUNDACAO CALOUSTE GULBENKIAN
Call Details Consolidator Grant (CoG), LS3, ERC-2015-CoG
Summary Centrioles assemble centrosomes and cilia/flagella, critical structures for cell division, polarity, motility and signalling, which are often deregulated in human disease. Centriole inheritance, in particular the preservation of their copy number and position in the cell is critical in many eukaryotes. I propose to investigate, in an integrative and quantitative way, how centrioles are formed in the right numbers at the right time and place, and how they are maintained to ensure their function and inheritance. We first ask how centrioles guide their own assembly position and centriole copy number. Our recent work highlighted several properties of the system, including positive and negative feedbacks and spatial cues. We explore critical hypotheses through a combination of biochemistry, quantitative live cell microscopy and computational modelling. We then ask how the centrosome and the cell cycle are both coordinated. We recently identified the triggering event in centriole biogenesis and how its regulation is akin to cell cycle control of DNA replication and centromere assembly. We will explore new hypotheses to understand how assembly time is coupled to the cell cycle. Lastly, we ask how centriole maintenance is regulated. By studying centriole disappearance in the female germline we uncovered that centrioles need to be actively maintained by their surrounding matrix. We propose to investigate how that matrix provides stability to the centrioles, whether this is differently regulated in different cell types and the possible consequences of its misregulation for the organism (infertility and ciliopathy-like symptoms). We will take advantage of several experimental systems (in silico, ex-vivo, flies and human cells), tailoring the assay to the question and allowing for comparisons across experimental systems to provide a deeper understanding of the process and its regulation.
Summary
Centrioles assemble centrosomes and cilia/flagella, critical structures for cell division, polarity, motility and signalling, which are often deregulated in human disease. Centriole inheritance, in particular the preservation of their copy number and position in the cell is critical in many eukaryotes. I propose to investigate, in an integrative and quantitative way, how centrioles are formed in the right numbers at the right time and place, and how they are maintained to ensure their function and inheritance. We first ask how centrioles guide their own assembly position and centriole copy number. Our recent work highlighted several properties of the system, including positive and negative feedbacks and spatial cues. We explore critical hypotheses through a combination of biochemistry, quantitative live cell microscopy and computational modelling. We then ask how the centrosome and the cell cycle are both coordinated. We recently identified the triggering event in centriole biogenesis and how its regulation is akin to cell cycle control of DNA replication and centromere assembly. We will explore new hypotheses to understand how assembly time is coupled to the cell cycle. Lastly, we ask how centriole maintenance is regulated. By studying centriole disappearance in the female germline we uncovered that centrioles need to be actively maintained by their surrounding matrix. We propose to investigate how that matrix provides stability to the centrioles, whether this is differently regulated in different cell types and the possible consequences of its misregulation for the organism (infertility and ciliopathy-like symptoms). We will take advantage of several experimental systems (in silico, ex-vivo, flies and human cells), tailoring the assay to the question and allowing for comparisons across experimental systems to provide a deeper understanding of the process and its regulation.
Max ERC Funding
2 000 000 €
Duration
Start date: 2017-01-01, End date: 2021-12-31
Project acronym ChronosAntibiotics
Project Exploring the bacterial cell cycle to re-sensitize antibiotic-resistant bacteria
Researcher (PI) MARIANA LUISA TOMAS GOMES DE PINHO
Host Institution (HI) UNIVERSIDADE NOVA DE LISBOA
Call Details Consolidator Grant (CoG), LS6, ERC-2017-COG
Summary Over the next 35 years, antibiotic resistant bacteria are expected to kill more than 300 million people. The need to find alternative strategies for antimicrobial therapies remains a global challenge with several bottlenecks in the antibiotic discovery process. Using Staphylococcus aureus, the most common multidrug-resistant bacterium in the European Union and an excellent model organism for cell division in cocci, we propose:
(i) to find new pathways to re-sensitize resistant bacteria. Bacteria undergo major morphology changes during the cell cycle. We hypothesize that these changes generate windows of opportunity during which bacteria are more susceptible or more tolerant to the action of antibiotics. We will identify key regulators of the cell cycle in order to manipulate the duration of windows of opportunity for the action of existing antibiotics.
(ii) to develop new fluorescence-based reporters for whole-cell screenings of antimicrobial compounds with new modes of action, including compounds that arrest or delay the cell cycle; compounds that target non-essential pathways that are required for expression of resistance against existing antibiotics and therefore can be used as synergistic drugs for combination therapies; compounds that inhibit the production of virulence factors and compounds that revert persister states that are phenotypically resistant to antibiotics.
(iii) to unravel new modes of action of antibiotics by using the constructed reporter strains as powerful tools to learn how antibiotics act at the single cell level.
Over the past years, my group has become expert on the biology of S. aureus, has constructed powerful biological tools to study cell division and synthesis of the cell surface and has studied mechanisms of action of various antimicrobial compounds. We are therefore in a privileged position to quickly unravel the function of new players in the bacterial cell cycle and simultaneously contribute to accelerate antibiotic discovery.
Summary
Over the next 35 years, antibiotic resistant bacteria are expected to kill more than 300 million people. The need to find alternative strategies for antimicrobial therapies remains a global challenge with several bottlenecks in the antibiotic discovery process. Using Staphylococcus aureus, the most common multidrug-resistant bacterium in the European Union and an excellent model organism for cell division in cocci, we propose:
(i) to find new pathways to re-sensitize resistant bacteria. Bacteria undergo major morphology changes during the cell cycle. We hypothesize that these changes generate windows of opportunity during which bacteria are more susceptible or more tolerant to the action of antibiotics. We will identify key regulators of the cell cycle in order to manipulate the duration of windows of opportunity for the action of existing antibiotics.
(ii) to develop new fluorescence-based reporters for whole-cell screenings of antimicrobial compounds with new modes of action, including compounds that arrest or delay the cell cycle; compounds that target non-essential pathways that are required for expression of resistance against existing antibiotics and therefore can be used as synergistic drugs for combination therapies; compounds that inhibit the production of virulence factors and compounds that revert persister states that are phenotypically resistant to antibiotics.
(iii) to unravel new modes of action of antibiotics by using the constructed reporter strains as powerful tools to learn how antibiotics act at the single cell level.
Over the past years, my group has become expert on the biology of S. aureus, has constructed powerful biological tools to study cell division and synthesis of the cell surface and has studied mechanisms of action of various antimicrobial compounds. We are therefore in a privileged position to quickly unravel the function of new players in the bacterial cell cycle and simultaneously contribute to accelerate antibiotic discovery.
Max ERC Funding
2 533 500 €
Duration
Start date: 2018-03-01, End date: 2023-02-28
Project acronym CODECHECK
Project CRACKING THE CODE BEHIND MITOTIC FIDELITY: the roles of tubulin post-translational modifications and a chromosome separation checkpoint
Researcher (PI) Helder Jose Martins Maiato
Host Institution (HI) INSTITUTO DE BIOLOGIA MOLECULAR E CELULAR-IBMC
Call Details Consolidator Grant (CoG), LS3, ERC-2015-CoG
Summary During the human lifetime 10000 trillion cell divisions take place to ensure tissue homeostasis and several vital functions in the organism. Mitosis is the process that ensures that dividing cells preserve the chromosome number of their progenitors, while deviation from this, a condition known as aneuploidy, represents the most common feature in human cancers. Here we will test two original concepts with strong implications for chromosome segregation fidelity. The first concept is based on the “tubulin code” hypothesis, which predicts that molecular motors “read” tubulin post-translational modifications on spindle microtubules. Our proof-of-concept experiments demonstrate that tubulin detyrosination works as a navigation system that guides chromosomes towards the cell equator. Thus, in addition to regulating the motors required for chromosome motion, the cell might regulate the tracks in which they move on. We will combine proteomic, super-resolution and live-cell microscopy, with in vitro reconstitutions, to perform a comprehensive survey of the tubulin code and the respective implications for motors involved in chromosome motion, mitotic spindle assembly and correction of kinetochore-microtubule attachments. The second concept is centered on the recently uncovered chromosome separation checkpoint mediated by a midzone-associated Aurora B gradient, which delays nuclear envelope reformation in response to incompletely separated chromosomes. We aim to identify Aurora B targets involved in the spatiotemporal regulation of the anaphase-telophase transition. We will establish powerful live-cell microscopy assays and a novel mammalian model system to dissect how this checkpoint allows the detection and correction of lagging/long chromosomes and DNA bridges that would otherwise contribute to genomic instability. Overall, this work will establish a paradigm shift in our understanding of how spatial information is conveyed to faithfully segregate chromosomes during mitosis.
Summary
During the human lifetime 10000 trillion cell divisions take place to ensure tissue homeostasis and several vital functions in the organism. Mitosis is the process that ensures that dividing cells preserve the chromosome number of their progenitors, while deviation from this, a condition known as aneuploidy, represents the most common feature in human cancers. Here we will test two original concepts with strong implications for chromosome segregation fidelity. The first concept is based on the “tubulin code” hypothesis, which predicts that molecular motors “read” tubulin post-translational modifications on spindle microtubules. Our proof-of-concept experiments demonstrate that tubulin detyrosination works as a navigation system that guides chromosomes towards the cell equator. Thus, in addition to regulating the motors required for chromosome motion, the cell might regulate the tracks in which they move on. We will combine proteomic, super-resolution and live-cell microscopy, with in vitro reconstitutions, to perform a comprehensive survey of the tubulin code and the respective implications for motors involved in chromosome motion, mitotic spindle assembly and correction of kinetochore-microtubule attachments. The second concept is centered on the recently uncovered chromosome separation checkpoint mediated by a midzone-associated Aurora B gradient, which delays nuclear envelope reformation in response to incompletely separated chromosomes. We aim to identify Aurora B targets involved in the spatiotemporal regulation of the anaphase-telophase transition. We will establish powerful live-cell microscopy assays and a novel mammalian model system to dissect how this checkpoint allows the detection and correction of lagging/long chromosomes and DNA bridges that would otherwise contribute to genomic instability. Overall, this work will establish a paradigm shift in our understanding of how spatial information is conveyed to faithfully segregate chromosomes during mitosis.
Max ERC Funding
2 323 468 €
Duration
Start date: 2016-07-01, End date: 2021-06-30
Project acronym COMPCON
Project Competition under (niche) construction
Researcher (PI) Sara NEWBERY RAPOSO DE MAGALHÃES
Host Institution (HI) FCIENCIAS.ID - ASSOCIACAO PARA A INVESTIGACAO E DESENVOLVIMENTO DE CIENCIAS
Call Details Consolidator Grant (CoG), LS8, ERC-2016-COG
Summary Interspecific competition is arguably the best interaction to address how individual trait variation and eco-evolutionary feedbacks shape species distributions and trait evolution, due to its indirect effects via the shared resource. However, a clear understanding of such feedbacks is only possible if each contributing factor can be manipulated independently. With COMPCON, we will address how individual variation, niche width, niche construction and the presence of competitors shape species distributions and trait evolution, using a system amenable to manipulation of all these variables. The system is composed of two spider mite species, Tetranychus urticae and T. ludeni, that up- and down-regulate plant defences (i.e., negative and positive niche construction, respectively). Tomato mutant plants with low defences will be used as an environment in which niche construction is not expressed. Furthermore, tomato plants will be grown under different cadmium concentrations, allowing quantitative variation of available niches. Using isogenic lines, we will measure individual variation in niche width, niche construction and competitive ability. Different combinations of lines will then be used to test key predictions of recent theory on how such variation affects coexistence with competitors. Subsequently, mite populations will evolve in environments with either one or more potential niches, in plants where niche construction is possible or not, and in presence or absence of competitors (coevolving or not). We will test how these selection pressures affect niche width, niche construction and competitive ability, as well as plant damage. Finally, we will re-derive isogenic lines from these treatments, to test how evolution under different scenarios affects individual variation in niche width.
COMPCON will shed new light on the role of competition in shaping eco-evolutionary communities, with bearings on disciplines ranging from macro-ecology to evolutionary genetics
Summary
Interspecific competition is arguably the best interaction to address how individual trait variation and eco-evolutionary feedbacks shape species distributions and trait evolution, due to its indirect effects via the shared resource. However, a clear understanding of such feedbacks is only possible if each contributing factor can be manipulated independently. With COMPCON, we will address how individual variation, niche width, niche construction and the presence of competitors shape species distributions and trait evolution, using a system amenable to manipulation of all these variables. The system is composed of two spider mite species, Tetranychus urticae and T. ludeni, that up- and down-regulate plant defences (i.e., negative and positive niche construction, respectively). Tomato mutant plants with low defences will be used as an environment in which niche construction is not expressed. Furthermore, tomato plants will be grown under different cadmium concentrations, allowing quantitative variation of available niches. Using isogenic lines, we will measure individual variation in niche width, niche construction and competitive ability. Different combinations of lines will then be used to test key predictions of recent theory on how such variation affects coexistence with competitors. Subsequently, mite populations will evolve in environments with either one or more potential niches, in plants where niche construction is possible or not, and in presence or absence of competitors (coevolving or not). We will test how these selection pressures affect niche width, niche construction and competitive ability, as well as plant damage. Finally, we will re-derive isogenic lines from these treatments, to test how evolution under different scenarios affects individual variation in niche width.
COMPCON will shed new light on the role of competition in shaping eco-evolutionary communities, with bearings on disciplines ranging from macro-ecology to evolutionary genetics
Max ERC Funding
1 999 275 €
Duration
Start date: 2017-05-01, End date: 2022-04-30
Project acronym Des.solve
Project When solids become liquids: natural deep eutectic solvents for chemical process engineering
Researcher (PI) Ana Rita CRUZ DUARTE
Host Institution (HI) NOVA ID FCT - ASSOCIACAO PARA A INOVACAO E DESENVOLVIMENTO DA FCT
Call Details Consolidator Grant (CoG), PE8, ERC-2016-COG
Summary Sugars, aminoacids or organic acids are typically solid at room temperature. Nonetheless when combined at a particular molar fraction they present a high melting point depression, becoming liquids at room temperature. These are called Natural Deep Eutectic Solvents – NADES. NADES are envisaged to play a major role on different chemical engineering processes in the future. Nonetheless, there is a significant lack of knowledge on fundamental and basic research on NADES, which is hindering their industrial applications. For this reason it is important to extend the knowledge on these systems, boosting their application development. NADES applications go beyond chemical or materials engineering and cover a wide range of fields from biocatalysis, extraction, electrochemistry, carbon dioxide capture or biomedical applications. Des.solve encompasses four major themes of research: 1 – Development of NADES and therapeutic deep eutectic solvents – THEDES; 2 – Characterization of the obtained mixtures and computer simulation of NADES/THEDES properties; 3 – Phase behaviour of binary/ternary systems NADES/THEDES + carbon dioxide and thermodynamic modelling 4 – Application development. Starting from the development of novel NADES/THEDES which, by different characterization techniques, will be deeply studied and characterized, the essential raw-materials will be produced for the subsequent research activities. The envisaged research involves modelling and molecular simulations. Des.solve will be deeply engaged in application development, particularly in extraction, biocatalysis and pharmaceutical/biomedical applications. The knowledge that will be created in this proposal is expected not only to have a major impact in the scientific community, but also in society, economy and industry.
Summary
Sugars, aminoacids or organic acids are typically solid at room temperature. Nonetheless when combined at a particular molar fraction they present a high melting point depression, becoming liquids at room temperature. These are called Natural Deep Eutectic Solvents – NADES. NADES are envisaged to play a major role on different chemical engineering processes in the future. Nonetheless, there is a significant lack of knowledge on fundamental and basic research on NADES, which is hindering their industrial applications. For this reason it is important to extend the knowledge on these systems, boosting their application development. NADES applications go beyond chemical or materials engineering and cover a wide range of fields from biocatalysis, extraction, electrochemistry, carbon dioxide capture or biomedical applications. Des.solve encompasses four major themes of research: 1 – Development of NADES and therapeutic deep eutectic solvents – THEDES; 2 – Characterization of the obtained mixtures and computer simulation of NADES/THEDES properties; 3 – Phase behaviour of binary/ternary systems NADES/THEDES + carbon dioxide and thermodynamic modelling 4 – Application development. Starting from the development of novel NADES/THEDES which, by different characterization techniques, will be deeply studied and characterized, the essential raw-materials will be produced for the subsequent research activities. The envisaged research involves modelling and molecular simulations. Des.solve will be deeply engaged in application development, particularly in extraction, biocatalysis and pharmaceutical/biomedical applications. The knowledge that will be created in this proposal is expected not only to have a major impact in the scientific community, but also in society, economy and industry.
Max ERC Funding
1 877 006 €
Duration
Start date: 2017-03-01, End date: 2022-02-28
Project acronym DevoTed_miR
Project MicroRNA determinants of the balance between effector and regulatory T cells in vivo
Researcher (PI) Bruno Miguel De Carvalho e Silva Santos
Host Institution (HI) INSTITUTO DE MEDICINA MOLECULAR JOAO LOBO ANTUNES
Call Details Consolidator Grant (CoG), LS6, ERC-2014-CoG
Summary T lymphocytes display potent pro- or anti-inflammatory properties, which typically associate with distinct effector (Teff) versus regulatory (Treg) cell subsets. Based on published and our preliminary data showing a major impact of microRNAs on T cell differentiation and (auto)immune pathology, my proposal aims to dissect the miRNA networks that control the balance between Teff and Treg subsets in vivo, in various experimental models of infection and autoimmunity.
We will focus on three critical mediators of T cell functions: interferon-gamma (IFN-g) and interleukin-17A (IL-17), highly pro-inflammatory Teff cytokines; and Foxp3, the transcription factor that confers Treg suppressive properties. To track the activity of these key genes, we will generate a new Ifng/ Il17/ Foxp3 triple reporter mouse, from which we will isolate Teff and Treg subsets to determine their genome-wide miRNA profiles and specific signatures in vivo. We will investigate both natural (thymic-derived and present in naïve mice) and induced (in the periphery upon challenge) Teff and Treg subsets, as they make distinct contributions to the immune response. We will identify miRNAs selectively expressed in Teff (Ifng+ or Il17+) versus Treg (Foxp3+) subsets of various lineages (CD4+, CD8+, gamma-delta or NKT) in each in vivo model; assess whether they are induced during thymic development or upon peripheral activation; and determine the robustness of subset-specific miRNA profiles across various in vivo challenges.
We will then use loss- and gain-of-function strategies to define the individual miRNAs that impact Teff or Treg differentiation and disease pathogenesis; dissect the external cues and intracellular mechanisms that regulate miRNA expression; and identify the mRNA networks controlled by key miRNAs in Teff and Treg differentiation. I expect this project to provide major conceptual and experimental advances towards manipulating miRNAs either to boost immunity or to treat autoimmunity.
Summary
T lymphocytes display potent pro- or anti-inflammatory properties, which typically associate with distinct effector (Teff) versus regulatory (Treg) cell subsets. Based on published and our preliminary data showing a major impact of microRNAs on T cell differentiation and (auto)immune pathology, my proposal aims to dissect the miRNA networks that control the balance between Teff and Treg subsets in vivo, in various experimental models of infection and autoimmunity.
We will focus on three critical mediators of T cell functions: interferon-gamma (IFN-g) and interleukin-17A (IL-17), highly pro-inflammatory Teff cytokines; and Foxp3, the transcription factor that confers Treg suppressive properties. To track the activity of these key genes, we will generate a new Ifng/ Il17/ Foxp3 triple reporter mouse, from which we will isolate Teff and Treg subsets to determine their genome-wide miRNA profiles and specific signatures in vivo. We will investigate both natural (thymic-derived and present in naïve mice) and induced (in the periphery upon challenge) Teff and Treg subsets, as they make distinct contributions to the immune response. We will identify miRNAs selectively expressed in Teff (Ifng+ or Il17+) versus Treg (Foxp3+) subsets of various lineages (CD4+, CD8+, gamma-delta or NKT) in each in vivo model; assess whether they are induced during thymic development or upon peripheral activation; and determine the robustness of subset-specific miRNA profiles across various in vivo challenges.
We will then use loss- and gain-of-function strategies to define the individual miRNAs that impact Teff or Treg differentiation and disease pathogenesis; dissect the external cues and intracellular mechanisms that regulate miRNA expression; and identify the mRNA networks controlled by key miRNAs in Teff and Treg differentiation. I expect this project to provide major conceptual and experimental advances towards manipulating miRNAs either to boost immunity or to treat autoimmunity.
Max ERC Funding
2 000 000 €
Duration
Start date: 2015-07-01, End date: 2020-06-30
Project acronym DYCOCIRC
Project Basal ganglia circuit mechanisms underlying dynamic cognitive behavior
Researcher (PI) Joseph PATON
Host Institution (HI) FUNDACAO D. ANNA SOMMER CHAMPALIMAUD E DR. CARLOS MONTEZ CHAMPALIMAUD
Call Details Consolidator Grant (CoG), LS5, ERC-2017-COG
Summary You’re faced with a difficult choice. What do you do? Most people will, either explicitly or implicitly, weigh the possible consequences their decision. This involves an internal journey through possible events. Its these kinds of dynamic processes and their mapping onto behavior that characterize higher brain function. And yet, their very internal nature is both what makes them of critical interest and so difficult to study. Here, we propose to study a simple, well-controlled decision-making behavior wherein mice have to generate a dynamic, internal representation of elapsed time in order to make choices that result in reward. We focus on frontal cortico-basal ganglia circuits and their dopaminergic inputs that together are broadly implicated in cognition and involved in the production of this particular behavior. We have demonstrated previously that striatal population dynamics and dopamine neuron activity both correlate with and exert control over animals’ judgments. Having identified key signals at multiple stages of the BG circuit related to this decision in rats and mice, my laboratory is now uniquely poised to dissect the circuit mechanisms by which such signals are generated and transformed into actions. Specifically, we will 1) Measure activity of specific cell types at multiple stages of the BG as mice judge duration. 2) Image and manipulate the activity of DA neurons while recording from neural populations in the BG to determine the relationship between neuromodulatory input, neural dynamics, and behavior. 3) Relate the activity of cortico-striatal inputs to striatal responses during behavior to understand the computational and circuit bases of striatal activity. These experiments promise to unlock deep mysteries regarding how animals free themselves from the immediacy of the current moment, learning, planning, and choosing their path toward a safer, more fruitful, and satisfying existence.
Summary
You’re faced with a difficult choice. What do you do? Most people will, either explicitly or implicitly, weigh the possible consequences their decision. This involves an internal journey through possible events. Its these kinds of dynamic processes and their mapping onto behavior that characterize higher brain function. And yet, their very internal nature is both what makes them of critical interest and so difficult to study. Here, we propose to study a simple, well-controlled decision-making behavior wherein mice have to generate a dynamic, internal representation of elapsed time in order to make choices that result in reward. We focus on frontal cortico-basal ganglia circuits and their dopaminergic inputs that together are broadly implicated in cognition and involved in the production of this particular behavior. We have demonstrated previously that striatal population dynamics and dopamine neuron activity both correlate with and exert control over animals’ judgments. Having identified key signals at multiple stages of the BG circuit related to this decision in rats and mice, my laboratory is now uniquely poised to dissect the circuit mechanisms by which such signals are generated and transformed into actions. Specifically, we will 1) Measure activity of specific cell types at multiple stages of the BG as mice judge duration. 2) Image and manipulate the activity of DA neurons while recording from neural populations in the BG to determine the relationship between neuromodulatory input, neural dynamics, and behavior. 3) Relate the activity of cortico-striatal inputs to striatal responses during behavior to understand the computational and circuit bases of striatal activity. These experiments promise to unlock deep mysteries regarding how animals free themselves from the immediacy of the current moment, learning, planning, and choosing their path toward a safer, more fruitful, and satisfying existence.
Max ERC Funding
2 000 000 €
Duration
Start date: 2018-04-01, End date: 2023-03-31
