Project acronym 3D-CAP
Project 3D micro-supercapacitors for embedded electronics
Researcher (PI) David Sarinn PECH
Host Institution (HI) CENTRE NATIONAL DE LA RECHERCHE SCIENTIFIQUE CNRS
Call Details Consolidator Grant (CoG), PE7, ERC-2017-COG
Summary The realization of high-performance micro-supercapacitors is currently a big challenge but the ineluctable applications requiring such miniaturized energy storage devices are continuously emerging, from wearable electronic gadgets to wireless sensor networks. Although they store less energy than micro-batteries, micro-supercapacitors can be charged and discharged very rapidly and exhibit a quasi-unlimited lifetime. The global scientific research is consequently largely focused on the improvement of their capacitance and energetic performances. However, to date, they are still far from being able to power sensors or electronic components.
Here I propose a 3D paradigm shift of micro-supercapacitor design to ensure increased energy storage capacities. Hydrous ruthenium dioxide (RuO2) is a pseudocapacitive material for supercapacitor electrode well-known for its high capacitance. A thin-film of ruthenium will be deposited by atomic layer deposition (ALD), followed by an electrochemical oxidation process, onto a high-surface-area 3D current collector prepared via an ingenious dynamic template built with hydrogen bubbles. The structural features of these 3D architectures will be controllably tailored by the processing methodologies. These electrodes will be combined with an innovative electrolyte in solid form (a protic ionogel) able to operate over an extended cell voltage. In a parallel investigation, we will develop a fundamental understanding of electrochemical reactions occurring at the nanoscale with a FIB-patterned (Focused Ion Beam) RuO2 nano-supercapacitor. The resulting 3D micro-supercapacitors should display extremely high power, long lifetime and – for the first time – energy densities competing or even exceeding that of micro-batteries. As a key achievement, prototypes will be designed using a new concept based on a self-adaptative micro-supercapacitors matrix, which arranges itself according to the global amount of energy stored.
Summary
The realization of high-performance micro-supercapacitors is currently a big challenge but the ineluctable applications requiring such miniaturized energy storage devices are continuously emerging, from wearable electronic gadgets to wireless sensor networks. Although they store less energy than micro-batteries, micro-supercapacitors can be charged and discharged very rapidly and exhibit a quasi-unlimited lifetime. The global scientific research is consequently largely focused on the improvement of their capacitance and energetic performances. However, to date, they are still far from being able to power sensors or electronic components.
Here I propose a 3D paradigm shift of micro-supercapacitor design to ensure increased energy storage capacities. Hydrous ruthenium dioxide (RuO2) is a pseudocapacitive material for supercapacitor electrode well-known for its high capacitance. A thin-film of ruthenium will be deposited by atomic layer deposition (ALD), followed by an electrochemical oxidation process, onto a high-surface-area 3D current collector prepared via an ingenious dynamic template built with hydrogen bubbles. The structural features of these 3D architectures will be controllably tailored by the processing methodologies. These electrodes will be combined with an innovative electrolyte in solid form (a protic ionogel) able to operate over an extended cell voltage. In a parallel investigation, we will develop a fundamental understanding of electrochemical reactions occurring at the nanoscale with a FIB-patterned (Focused Ion Beam) RuO2 nano-supercapacitor. The resulting 3D micro-supercapacitors should display extremely high power, long lifetime and – for the first time – energy densities competing or even exceeding that of micro-batteries. As a key achievement, prototypes will be designed using a new concept based on a self-adaptative micro-supercapacitors matrix, which arranges itself according to the global amount of energy stored.
Max ERC Funding
1 673 438 €
Duration
Start date: 2018-04-01, End date: 2023-03-31
Project acronym ACAP
Project Acency Costs and Asset Pricing
Researcher (PI) Thomas Mariotti
Host Institution (HI) FONDATION JEAN-JACQUES LAFFONT,TOULOUSE SCIENCES ECONOMIQUES
Call Details Starting Grant (StG), SH1, ERC-2007-StG
Summary The main objective of this research project is to contribute at bridging the gap between the two main branches of financial theory, namely corporate finance and asset pricing. It is motivated by the conviction that these two aspects of financial activity should and can be analyzed within a unified framework. This research will borrow from these two approaches in order to construct theoretical models that allow one to analyze the design and issuance of financial securities, as well as the dynamics of their valuations. Unlike asset pricing, which takes as given the price of the fundamentals, the goal is to derive security price processes from a precise description of firm’s operations and internal frictions. Regarding the latter, and in line with traditional corporate finance theory, the analysis will emphasize the role of agency costs within the firm for the design of its securities. But the analysis will be pushed one step further by studying the impact of these agency costs on key financial variables such as stock and bond prices, leverage, book-to-market ratios, default risk, or the holding of liquidities by firms. One of the contributions of this research project is to show how these variables are interrelated when firms and investors agree upon optimal financial arrangements. The final objective is to derive a rich set of testable asset pricing implications that would eventually be brought to the data.
Summary
The main objective of this research project is to contribute at bridging the gap between the two main branches of financial theory, namely corporate finance and asset pricing. It is motivated by the conviction that these two aspects of financial activity should and can be analyzed within a unified framework. This research will borrow from these two approaches in order to construct theoretical models that allow one to analyze the design and issuance of financial securities, as well as the dynamics of their valuations. Unlike asset pricing, which takes as given the price of the fundamentals, the goal is to derive security price processes from a precise description of firm’s operations and internal frictions. Regarding the latter, and in line with traditional corporate finance theory, the analysis will emphasize the role of agency costs within the firm for the design of its securities. But the analysis will be pushed one step further by studying the impact of these agency costs on key financial variables such as stock and bond prices, leverage, book-to-market ratios, default risk, or the holding of liquidities by firms. One of the contributions of this research project is to show how these variables are interrelated when firms and investors agree upon optimal financial arrangements. The final objective is to derive a rich set of testable asset pricing implications that would eventually be brought to the data.
Max ERC Funding
1 000 000 €
Duration
Start date: 2008-11-01, End date: 2014-10-31
Project acronym Actanthrope
Project Computational Foundations of Anthropomorphic Action
Researcher (PI) Jean Paul Laumond
Host Institution (HI) CENTRE NATIONAL DE LA RECHERCHE SCIENTIFIQUE CNRS
Call Details Advanced Grant (AdG), PE7, ERC-2013-ADG
Summary Actanthrope intends to promote a neuro-robotics perspective to explore original models of anthropomorphic action. The project targets contributions to humanoid robot autonomy (for rescue and service robotics), to advanced human body simulation (for applications in ergonomics), and to a new theory of embodied intelligence (by promoting a motion-based semiotics of the human action).
Actions take place in the physical space while they originate in the –robot or human– sensory-motor space. Geometry is the core abstraction that makes the link between these spaces. Considering that the structure of actions inherits from that of the body, the underlying intuition is that actions can be segmented within discrete sub-spaces lying in the entire continuous posture space. Such sub-spaces are viewed as symbols bridging deliberative reasoning and reactive control. Actanthrope argues that geometric approaches to motion segmentation and generation as promising and innovative routes to explore embodied intelligence:
- Motion segmentation: what are the sub-manifolds that define the structure of a given action?
- Motion generation: among all the solution paths within a given sub-manifold, what is the underlying law that makes the selection?
In Robotics these questions are related to the competition between abstract symbol manipulation and physical signal processing. In Computational Neuroscience the questions refer to the quest of motion invariants. The ambition of the project is to promote a dual perspective: exploring the computational foundations of human action to make better robots, while simultaneously doing better robotics to better understand human action.
A unique “Anthropomorphic Action Factory” supports the methodology. It aims at attracting to a single lab, researchers with complementary know-how and solid mathematical background. All of them will benefit from unique equipments, while being stimulated by four challenges dealing with locomotion and manipulation actions.
Summary
Actanthrope intends to promote a neuro-robotics perspective to explore original models of anthropomorphic action. The project targets contributions to humanoid robot autonomy (for rescue and service robotics), to advanced human body simulation (for applications in ergonomics), and to a new theory of embodied intelligence (by promoting a motion-based semiotics of the human action).
Actions take place in the physical space while they originate in the –robot or human– sensory-motor space. Geometry is the core abstraction that makes the link between these spaces. Considering that the structure of actions inherits from that of the body, the underlying intuition is that actions can be segmented within discrete sub-spaces lying in the entire continuous posture space. Such sub-spaces are viewed as symbols bridging deliberative reasoning and reactive control. Actanthrope argues that geometric approaches to motion segmentation and generation as promising and innovative routes to explore embodied intelligence:
- Motion segmentation: what are the sub-manifolds that define the structure of a given action?
- Motion generation: among all the solution paths within a given sub-manifold, what is the underlying law that makes the selection?
In Robotics these questions are related to the competition between abstract symbol manipulation and physical signal processing. In Computational Neuroscience the questions refer to the quest of motion invariants. The ambition of the project is to promote a dual perspective: exploring the computational foundations of human action to make better robots, while simultaneously doing better robotics to better understand human action.
A unique “Anthropomorphic Action Factory” supports the methodology. It aims at attracting to a single lab, researchers with complementary know-how and solid mathematical background. All of them will benefit from unique equipments, while being stimulated by four challenges dealing with locomotion and manipulation actions.
Max ERC Funding
2 500 000 €
Duration
Start date: 2014-01-01, End date: 2018-12-31
Project acronym AIME
Project An Inquiry into Modes of Existence
Researcher (PI) Bruno Latour
Host Institution (HI) FONDATION NATIONALE DES SCIENCES POLITIQUES
Call Details Advanced Grant (AdG), SH2, ERC-2010-AdG_20100407
Summary "AIME is an inquiry to make more precise what is lumped together into the confusing word ""modernization"". The work done in the field of science studies (STS) on the progress and practice of science and technology has had the consequence of deeply modifying the definition of ""modernity"", resulting into the provocative idea that ""we (meaning the Europeans) have never been modern"". This is, however only a negative definition. To obtain a positive rendering of the European current situation, it is necessary to start an inquiry in the complex and conflicting set of values that have been invented. This inquiry is possible only if there is a clear and shareable way to judge the differences in the set of truth-conditions that make up those conflicting sets of values. AIME offers a grammar of those differences based on the key notion of modes of existence. Then it builds a procedure and an instrument to test this grammar into a selected set of situations where the definitions of the differing modes of existence is redefined and renegotiated. The result is a set of shareable definitions of what modernization has been in practice. This is important just at the moment when Europe has lost its privileged status and needs to be able to present itself in a new ways to the other cultures and civilizations which are making up the world of globalization with very different views on what it is to modernize themselves."
Summary
"AIME is an inquiry to make more precise what is lumped together into the confusing word ""modernization"". The work done in the field of science studies (STS) on the progress and practice of science and technology has had the consequence of deeply modifying the definition of ""modernity"", resulting into the provocative idea that ""we (meaning the Europeans) have never been modern"". This is, however only a negative definition. To obtain a positive rendering of the European current situation, it is necessary to start an inquiry in the complex and conflicting set of values that have been invented. This inquiry is possible only if there is a clear and shareable way to judge the differences in the set of truth-conditions that make up those conflicting sets of values. AIME offers a grammar of those differences based on the key notion of modes of existence. Then it builds a procedure and an instrument to test this grammar into a selected set of situations where the definitions of the differing modes of existence is redefined and renegotiated. The result is a set of shareable definitions of what modernization has been in practice. This is important just at the moment when Europe has lost its privileged status and needs to be able to present itself in a new ways to the other cultures and civilizations which are making up the world of globalization with very different views on what it is to modernize themselves."
Max ERC Funding
1 334 720 €
Duration
Start date: 2011-09-01, End date: 2015-06-30
Project acronym ALFA
Project Shaping a European Scientific Scene : Alfonsine Astronomy
Researcher (PI) Matthieu Husson
Host Institution (HI) CENTRE NATIONAL DE LA RECHERCHE SCIENTIFIQUE CNRS
Call Details Consolidator Grant (CoG), SH6, ERC-2016-COG
Summary Alfonsine astronomy is arguably among the first European scientific achievements. It shaped a scene for actors like Regiomontanus or Copernicus. There is however little detailed historical analysis encompassing its development in its full breadth. ALFA addresses this issue by studying tables, instruments, mathematical and theoretical texts in a methodologically innovative way relying on approaches from the history of manuscript cultures, history of mathematics, and history of astronomy.
ALFA integrates these approaches not only to benefit from different perspectives but also to build new questions from their interactions. For instance the analysis of mathematical practices in astral sciences manuscripts induces new ways to analyse the documents and to think about astronomical questions.
Relying on these approaches the main objectives of ALFA are thus to:
- Retrace the development of the corpus of Alfonsine texts from its origin in the second half of the 13th century to the end of the 15th century by following, on the manuscript level, the milieus fostering it;
- Analyse the Alfonsine astronomers’ practices, their relations to mathematics, to the natural world, to proofs and justification, their intellectual context and audiences;
- Build a meaningful narrative showing how astronomers in different milieus with diverse practices shaped, also from Arabic materials, an original scientific scene in Europe.
ALFA will shed new light on the intellectual history of the late medieval period as a whole and produce a better understanding of its relations to related scientific periods in Europe and beyond. It will also produce methodological breakthroughs impacting the ways history of knowledge is practiced outside the field of ancient and medieval sciences. Efforts will be devoted to bring these results not only to the relevant scholarly communities but also to a wider audience as a resource in the public debates around science, knowledge and culture.
Summary
Alfonsine astronomy is arguably among the first European scientific achievements. It shaped a scene for actors like Regiomontanus or Copernicus. There is however little detailed historical analysis encompassing its development in its full breadth. ALFA addresses this issue by studying tables, instruments, mathematical and theoretical texts in a methodologically innovative way relying on approaches from the history of manuscript cultures, history of mathematics, and history of astronomy.
ALFA integrates these approaches not only to benefit from different perspectives but also to build new questions from their interactions. For instance the analysis of mathematical practices in astral sciences manuscripts induces new ways to analyse the documents and to think about astronomical questions.
Relying on these approaches the main objectives of ALFA are thus to:
- Retrace the development of the corpus of Alfonsine texts from its origin in the second half of the 13th century to the end of the 15th century by following, on the manuscript level, the milieus fostering it;
- Analyse the Alfonsine astronomers’ practices, their relations to mathematics, to the natural world, to proofs and justification, their intellectual context and audiences;
- Build a meaningful narrative showing how astronomers in different milieus with diverse practices shaped, also from Arabic materials, an original scientific scene in Europe.
ALFA will shed new light on the intellectual history of the late medieval period as a whole and produce a better understanding of its relations to related scientific periods in Europe and beyond. It will also produce methodological breakthroughs impacting the ways history of knowledge is practiced outside the field of ancient and medieval sciences. Efforts will be devoted to bring these results not only to the relevant scholarly communities but also to a wider audience as a resource in the public debates around science, knowledge and culture.
Max ERC Funding
1 871 250 €
Duration
Start date: 2017-09-01, End date: 2022-08-31
Project acronym ANTIViR
Project Molecular mechanisms of interferon-induced antiviral restriction and signalling
Researcher (PI) Caroline GOUJON
Host Institution (HI) INSTITUT NATIONAL DE LA SANTE ET DE LA RECHERCHE MEDICALE
Call Details Starting Grant (StG), LS6, ERC-2017-STG
Summary Interferons (IFNs), which are signalling proteins produced by infected cells, are the first line of defence against viral infections. IFNs induce, in infected and neighbouring cells, the expression of hundreds of IFN-stimulated genes (ISGs). The ISGs in turn induce in cells a potent antiviral state, capable of preventing replication of most viruses, including Human Immunodeficiency Virus type 1 (HIV-1) and influenza A virus (FLUAV). Identifying the antiviral ISGs and understanding their mechanisms of action is therefore crucial to progress in the fight against viruses.
ISGs playing a role in the antiviral state have been identified, such as human MX1, a well-known antiviral factor able to restrict numerous viruses including FLUAV, and MX2, an HIV-1 inhibitor. Both proteins bind to viral components but their detailed mechanisms of action, as well as the consequences of restriction on the activation of the innate immune system, remain unclear. Moreover, our preliminary work shows that additional anti-HIV-1 and anti-FLUAV ISGs remain to identify.
In this context, this proposal seeks an ERC StG funding to explore 3 major aims: 1) unravelling the mechanisms of antiviral action of MX proteins, by taking advantage of their similar structure and engineered chimeric proteins, and by using functional genetic screens to identify their cofactors; 2) investigating the consequences of incoming virus recognition by MX proteins on innate immune signalling, by altering their expression in target cells and measuring the cell response in terms of gene induction and cytokine production; 3) identifying and characterizing new ISGs able to inhibit viral replication with a combination of powerful approaches, including a whole-genome CRISPR/Cas9 knock-out screen.
Overall, this proposal will provide a better understanding of the molecular mechanisms involved in the antiviral effect of IFN, and may guide future efforts to identify novel therapeutic targets against major pathogenic viruses.
Summary
Interferons (IFNs), which are signalling proteins produced by infected cells, are the first line of defence against viral infections. IFNs induce, in infected and neighbouring cells, the expression of hundreds of IFN-stimulated genes (ISGs). The ISGs in turn induce in cells a potent antiviral state, capable of preventing replication of most viruses, including Human Immunodeficiency Virus type 1 (HIV-1) and influenza A virus (FLUAV). Identifying the antiviral ISGs and understanding their mechanisms of action is therefore crucial to progress in the fight against viruses.
ISGs playing a role in the antiviral state have been identified, such as human MX1, a well-known antiviral factor able to restrict numerous viruses including FLUAV, and MX2, an HIV-1 inhibitor. Both proteins bind to viral components but their detailed mechanisms of action, as well as the consequences of restriction on the activation of the innate immune system, remain unclear. Moreover, our preliminary work shows that additional anti-HIV-1 and anti-FLUAV ISGs remain to identify.
In this context, this proposal seeks an ERC StG funding to explore 3 major aims: 1) unravelling the mechanisms of antiviral action of MX proteins, by taking advantage of their similar structure and engineered chimeric proteins, and by using functional genetic screens to identify their cofactors; 2) investigating the consequences of incoming virus recognition by MX proteins on innate immune signalling, by altering their expression in target cells and measuring the cell response in terms of gene induction and cytokine production; 3) identifying and characterizing new ISGs able to inhibit viral replication with a combination of powerful approaches, including a whole-genome CRISPR/Cas9 knock-out screen.
Overall, this proposal will provide a better understanding of the molecular mechanisms involved in the antiviral effect of IFN, and may guide future efforts to identify novel therapeutic targets against major pathogenic viruses.
Max ERC Funding
1 499 794 €
Duration
Start date: 2017-12-01, End date: 2022-11-30
Project acronym ANTIVIRALRNAI
Project RNAi-mediated viral immunity in insects
Researcher (PI) Maria-Carla Saleh
Host Institution (HI) INSTITUT PASTEUR
Call Details Starting Grant (StG), LS6, ERC-2009-StG
Summary RNA interference (RNAi) is a conserved sequence-specific, gene-silencing mechanism that is induced by double-stranded RNA (dsRNA). One of the functions of this pathway is the defense against parasitic nucleic acids: transposons and viruses. Previous results demonstrated that viral infections in Drosophila melanogaster are fought by an antiviral RNAi response and that components of the endocytic pathway are required for dsRNA entry to initiate the RNAi response. Recently we have shown that infected insect cells spread a systemic silencing signal that elicits a protective RNAi-dependent immunity throughout the organism. This suggests that the cell-autonomous RNAi response is insufficient to control a viral infection and that flies also rely on systemic immune response to fight against such infections. As a junior group leader, I will study the mechanisms that mediate the RNAi-based antiviral response in insects. By combining biochemical, cellular, molecular and genomic approaches, both in vivo and in cell culture, I will analyze the mechanisms underlying viral tropism, systemic propagation of the antiviral signal and the basis of the persistence of the antiviral state. Furthermore, I will examine whether the dsRNA-uptake pathway is conserved in mosquitoes and its relationship with viral immunity in that host. This comprehensive approach will tackle how this nucleic acid-based immunity works in insects to generate an anti-viral stage. A better understanding of the role of RNA silencing in insects during virus infection will allow the exploitation of this pathway for improvement of public health related problems such as arbovirus infection and disease.
Summary
RNA interference (RNAi) is a conserved sequence-specific, gene-silencing mechanism that is induced by double-stranded RNA (dsRNA). One of the functions of this pathway is the defense against parasitic nucleic acids: transposons and viruses. Previous results demonstrated that viral infections in Drosophila melanogaster are fought by an antiviral RNAi response and that components of the endocytic pathway are required for dsRNA entry to initiate the RNAi response. Recently we have shown that infected insect cells spread a systemic silencing signal that elicits a protective RNAi-dependent immunity throughout the organism. This suggests that the cell-autonomous RNAi response is insufficient to control a viral infection and that flies also rely on systemic immune response to fight against such infections. As a junior group leader, I will study the mechanisms that mediate the RNAi-based antiviral response in insects. By combining biochemical, cellular, molecular and genomic approaches, both in vivo and in cell culture, I will analyze the mechanisms underlying viral tropism, systemic propagation of the antiviral signal and the basis of the persistence of the antiviral state. Furthermore, I will examine whether the dsRNA-uptake pathway is conserved in mosquitoes and its relationship with viral immunity in that host. This comprehensive approach will tackle how this nucleic acid-based immunity works in insects to generate an anti-viral stage. A better understanding of the role of RNA silencing in insects during virus infection will allow the exploitation of this pathway for improvement of public health related problems such as arbovirus infection and disease.
Max ERC Funding
1 900 000 €
Duration
Start date: 2009-10-01, End date: 2014-12-31
Project acronym B-response
Project Memory and innate-like B-cell subsets: deciphering a multi-layered B-cell response in mice and humans
Researcher (PI) Claude-Agnes REYNAUD
Host Institution (HI) INSTITUT NATIONAL DE LA SANTE ET DE LA RECHERCHE MEDICALE
Call Details Advanced Grant (AdG), LS6, ERC-2015-AdG
Summary B cells are the main actors of successful vaccines, and their protective capacity relies on several subsets with innate-like and memory properties that fulfill different effector functions. In the present project, we wish to develop approaches in both mice and humans, to confront the similarities and the differences of their B cell responses.
The three aims proposed are:
1) To study the different B cell subsets and TFH cells engaged in a memory response through the use of a new mouse reporter line allowing their irreversible labeling (inducible Cre recombinase under the control of the Bcl6 gene): this will be performed in different conditions of TH1 vs. TH2 polarization, as well as during a chronic viral infection, in which virus-specific antibodies have been shown to be required to control the disease (in collaboration with D. Pinschewer, Basel)
2) To study whether the lifelong persistence of B cell memory, as occurs for memory B cells against smallpox that we can obtain at high purity from aged donor's spleens, corresponds to a specific transcriptional program at the miRNA, lncRNA or mRNA level, as well as a specific cell homeostasis
3) To discriminate the specific effector function of human marginal zone and IgM memory B cells in, respectively, T-independent and T-dependent responses, as well as their specific differentiation/diversification pathway.
The general goal is to delineate the regulatory pathways leading to the activation and persistence of the different B cell subsets, allowing for a better understanding of the conditions leading to their pathological or beneficial mobilization.
Summary
B cells are the main actors of successful vaccines, and their protective capacity relies on several subsets with innate-like and memory properties that fulfill different effector functions. In the present project, we wish to develop approaches in both mice and humans, to confront the similarities and the differences of their B cell responses.
The three aims proposed are:
1) To study the different B cell subsets and TFH cells engaged in a memory response through the use of a new mouse reporter line allowing their irreversible labeling (inducible Cre recombinase under the control of the Bcl6 gene): this will be performed in different conditions of TH1 vs. TH2 polarization, as well as during a chronic viral infection, in which virus-specific antibodies have been shown to be required to control the disease (in collaboration with D. Pinschewer, Basel)
2) To study whether the lifelong persistence of B cell memory, as occurs for memory B cells against smallpox that we can obtain at high purity from aged donor's spleens, corresponds to a specific transcriptional program at the miRNA, lncRNA or mRNA level, as well as a specific cell homeostasis
3) To discriminate the specific effector function of human marginal zone and IgM memory B cells in, respectively, T-independent and T-dependent responses, as well as their specific differentiation/diversification pathway.
The general goal is to delineate the regulatory pathways leading to the activation and persistence of the different B cell subsets, allowing for a better understanding of the conditions leading to their pathological or beneficial mobilization.
Max ERC Funding
2 098 750 €
Duration
Start date: 2016-09-01, End date: 2021-08-31
Project acronym BacCellEpi
Project Bacterial, cellular and epigenetic factors that control enteropathogenicity
Researcher (PI) Pascale Cossart
Host Institution (HI) INSTITUT PASTEUR
Call Details Advanced Grant (AdG), LS6, ERC-2014-ADG
Summary Understanding the establishment and persistence of bacterial infections in the gut requires integrating an ensemble of factors including bacterial and host components and the presence of other microorganisms. We will capitalize on 25 years of studies on the bacterium Listeria monocytogenes used as a model, to focus on three objectives which will significantly increase our knowledge of the bacterium, of the cell biology of infection and of the epigenetic reprogramming upon infection.
Our aims are:
- at the bacterial level : to describe for the first time, the proteomic landscape of a bacterium during switch from saprophytism to virulence. We will use a proteogenomic approach together with ribosome profiling, to analyze the translation of the whole transcriptome after bacterial growth in several conditions, including in vivo, in order to barcode all the proteins which play a role in infection. This will open the way to assess the role of 1) small proteins; 2) internal translation initiation sites ; 3) the coupling of transcription and translation.
- at the host cell level : To decipher the molecular mechanisms underlying the dynamics and role in infection of host intracellular organelles, starting with mitochondria.
- At the host epigenetic level : To explore how the microbe reprograms host transcription and how tolerance to a commensal such as Akkermansia muciniphila differs from responsiveness to a pathogen insult, at the level of histones and mRNA modifications by studying 1) chromatin remodeling, in particular histones modifications during infection ; 2) modifications of the epitranscriptome during Listeria infection and colonization with Akkermansia ; 3) whether there is an epigenetic memory of infection and colonization.
This ambitious multidisciplinary project will not only generate new concepts in infection biology but also will unravel fundamental mechanisms in microbiology, cell biology, and epigenetics opening new avenues for further research.
Summary
Understanding the establishment and persistence of bacterial infections in the gut requires integrating an ensemble of factors including bacterial and host components and the presence of other microorganisms. We will capitalize on 25 years of studies on the bacterium Listeria monocytogenes used as a model, to focus on three objectives which will significantly increase our knowledge of the bacterium, of the cell biology of infection and of the epigenetic reprogramming upon infection.
Our aims are:
- at the bacterial level : to describe for the first time, the proteomic landscape of a bacterium during switch from saprophytism to virulence. We will use a proteogenomic approach together with ribosome profiling, to analyze the translation of the whole transcriptome after bacterial growth in several conditions, including in vivo, in order to barcode all the proteins which play a role in infection. This will open the way to assess the role of 1) small proteins; 2) internal translation initiation sites ; 3) the coupling of transcription and translation.
- at the host cell level : To decipher the molecular mechanisms underlying the dynamics and role in infection of host intracellular organelles, starting with mitochondria.
- At the host epigenetic level : To explore how the microbe reprograms host transcription and how tolerance to a commensal such as Akkermansia muciniphila differs from responsiveness to a pathogen insult, at the level of histones and mRNA modifications by studying 1) chromatin remodeling, in particular histones modifications during infection ; 2) modifications of the epitranscriptome during Listeria infection and colonization with Akkermansia ; 3) whether there is an epigenetic memory of infection and colonization.
This ambitious multidisciplinary project will not only generate new concepts in infection biology but also will unravel fundamental mechanisms in microbiology, cell biology, and epigenetics opening new avenues for further research.
Max ERC Funding
1 147 500 €
Duration
Start date: 2015-10-01, End date: 2019-09-30
Project acronym BASILIC
Project Decoding at systems-level the crosstalk between the T cell antigen receptor, the CD28 costimulator and the PD-1 coinhibitor under physiological and pathological conditions.
Researcher (PI) Bernard MALISSEN
Host Institution (HI) CENTRE NATIONAL DE LA RECHERCHE SCIENTIFIQUE CNRS
Call Details Advanced Grant (AdG), LS6, ERC-2017-ADG
Summary Although the T cell antigen receptor (TCR) occupies a central place in T cell physiology, it does not work in isolation and the signals it triggers are tuned by receptors that convey positive (costimulators) and negative (coinhibitors) informations. We lack a satisfying comprehension of the way T cells integrate such multiple inputs to make informed decisions. The proteomics-based methodology we developed around the TCR places us in a favorable situation to decode at systems-level the crosstalk between the TCR, the CD28 costimulator and the PD-1 coinhibitor signaling pathways. The novelty of our approach stems from (1) its use of primary T cells, (2) its capacity to probe the architecture and dynamics of signalosomes resulting from T cell-antigen presenting cell encounters, (3) the attention we pay to the stoichiometry of the studied signalosomes, a key parameter largely ignored in previous studies, and (4) its multidisciplinary nature straddling molecular and organismal scales.
Our specific aims are:
Aim 1. To understand how the TCR and CD28 signaling pathways cooperate to achieve optimal T cell responses.
Aim 2. To determine whether CD28 is the sole target of the PD-1 coinhibitor.
Aim 3. To determine how under inflammatory conditions CD28 functions can be superseded by those of OX40, a costimulator of the TNFR superfamily.
Aim 4. To unveil how malfunctions of LAT, a key signaling hub used by the TCR, disrupt the TCR-CD28 crosstalk and result in unique pathogenic T cells that by becoming ‘autistic’ to TCR signals and addicted to CD28 signals lead to severe immunopathologies.
We think that combining genetic, epigenomics, proteomics, and computational approaches creates ideal experimental conditions to understand at system-levels how TCR, costimulatory, coinhibitory and inflammatory signals are integrated during T cell clonal expansion. Although of fundamental nature, our project should help understanding the harmful role PD-1 plays during anti-tumoral responses.
Summary
Although the T cell antigen receptor (TCR) occupies a central place in T cell physiology, it does not work in isolation and the signals it triggers are tuned by receptors that convey positive (costimulators) and negative (coinhibitors) informations. We lack a satisfying comprehension of the way T cells integrate such multiple inputs to make informed decisions. The proteomics-based methodology we developed around the TCR places us in a favorable situation to decode at systems-level the crosstalk between the TCR, the CD28 costimulator and the PD-1 coinhibitor signaling pathways. The novelty of our approach stems from (1) its use of primary T cells, (2) its capacity to probe the architecture and dynamics of signalosomes resulting from T cell-antigen presenting cell encounters, (3) the attention we pay to the stoichiometry of the studied signalosomes, a key parameter largely ignored in previous studies, and (4) its multidisciplinary nature straddling molecular and organismal scales.
Our specific aims are:
Aim 1. To understand how the TCR and CD28 signaling pathways cooperate to achieve optimal T cell responses.
Aim 2. To determine whether CD28 is the sole target of the PD-1 coinhibitor.
Aim 3. To determine how under inflammatory conditions CD28 functions can be superseded by those of OX40, a costimulator of the TNFR superfamily.
Aim 4. To unveil how malfunctions of LAT, a key signaling hub used by the TCR, disrupt the TCR-CD28 crosstalk and result in unique pathogenic T cells that by becoming ‘autistic’ to TCR signals and addicted to CD28 signals lead to severe immunopathologies.
We think that combining genetic, epigenomics, proteomics, and computational approaches creates ideal experimental conditions to understand at system-levels how TCR, costimulatory, coinhibitory and inflammatory signals are integrated during T cell clonal expansion. Although of fundamental nature, our project should help understanding the harmful role PD-1 plays during anti-tumoral responses.
Max ERC Funding
2 000 000 €
Duration
Start date: 2018-08-01, End date: 2022-07-31
