Project acronym 3DEpi
Project Transgenerational epigenetic inheritance of chromatin states : the role of Polycomb and 3D chromosome architecture
Researcher (PI) Giacomo CAVALLI
Host Institution (HI) CENTRE NATIONAL DE LA RECHERCHE SCIENTIFIQUE CNRS
Country France
Call Details Advanced Grant (AdG), LS2, ERC-2017-ADG
Summary Epigenetic inheritance entails transmission of phenotypic traits not encoded in the DNA sequence and, in the most extreme case, Transgenerational Epigenetic Inheritance (TEI) involves transmission of memory through multiple generations. Very little is known on the mechanisms governing TEI and this is the subject of the present proposal. By transiently enhancing long-range chromatin interactions, we recently established isogenic Drosophila epilines that carry stable alternative epialleles, defined by differential levels of the Polycomb-dependent H3K27me3 mark. Furthermore, we extended our paradigm to natural phenotypes. These are ideal systems to study the role of Polycomb group (PcG) proteins and other components in regulating nuclear organization and epigenetic inheritance of chromatin states. The present project conjugates genetics, epigenomics, imaging and molecular biology to reach three critical aims.
Aim 1: Analysis of the molecular mechanisms regulating Polycomb-mediated TEI. We will identify the DNA, protein and RNA components that trigger and maintain transgenerational chromatin inheritance as well as their mechanisms of action.
Aim 2: Role of 3D genome organization in the regulation of TEI. We will analyze the developmental dynamics of TEI-inducing long-range chromatin interactions, identify chromatin components mediating 3D chromatin contacts and characterize their function in the TEI process.
Aim 3: Identification of a broader role of TEI during development. TEI might reflect a normal role of PcG components in the transmission of parental chromatin onto the next embryonic generation. We will explore this possibility by establishing other TEI paradigms and by relating TEI to the normal PcG function in these systems and in normal development.
This research program will unravel the biological significance and the molecular underpinnings of TEI and lead the way towards establishing this area of research into a consolidated scientific discipline.
Summary
Epigenetic inheritance entails transmission of phenotypic traits not encoded in the DNA sequence and, in the most extreme case, Transgenerational Epigenetic Inheritance (TEI) involves transmission of memory through multiple generations. Very little is known on the mechanisms governing TEI and this is the subject of the present proposal. By transiently enhancing long-range chromatin interactions, we recently established isogenic Drosophila epilines that carry stable alternative epialleles, defined by differential levels of the Polycomb-dependent H3K27me3 mark. Furthermore, we extended our paradigm to natural phenotypes. These are ideal systems to study the role of Polycomb group (PcG) proteins and other components in regulating nuclear organization and epigenetic inheritance of chromatin states. The present project conjugates genetics, epigenomics, imaging and molecular biology to reach three critical aims.
Aim 1: Analysis of the molecular mechanisms regulating Polycomb-mediated TEI. We will identify the DNA, protein and RNA components that trigger and maintain transgenerational chromatin inheritance as well as their mechanisms of action.
Aim 2: Role of 3D genome organization in the regulation of TEI. We will analyze the developmental dynamics of TEI-inducing long-range chromatin interactions, identify chromatin components mediating 3D chromatin contacts and characterize their function in the TEI process.
Aim 3: Identification of a broader role of TEI during development. TEI might reflect a normal role of PcG components in the transmission of parental chromatin onto the next embryonic generation. We will explore this possibility by establishing other TEI paradigms and by relating TEI to the normal PcG function in these systems and in normal development.
This research program will unravel the biological significance and the molecular underpinnings of TEI and lead the way towards establishing this area of research into a consolidated scientific discipline.
Max ERC Funding
2 500 000 €
Duration
Start date: 2018-11-01, End date: 2023-10-31
Project acronym ADAM
Project The Adaptive Auditory Mind
Researcher (PI) Shihab Shamma
Host Institution (HI) ECOLE NORMALE SUPERIEURE
Country France
Call Details Advanced Grant (AdG), SH4, ERC-2011-ADG_20110406
Summary Listening in realistic situations is an active process that engages perceptual and cognitive faculties, endowing speech with meaning, music with joy, and environmental sounds with emotion. Through hearing, humans and other animals navigate complex acoustic scenes, separate sound mixtures, and assess their behavioral relevance. These remarkable feats are currently beyond our understanding and exceed the capabilities of the most sophisticated audio engineering systems. The goal of the proposed research is to investigate experimentally a novel view of hearing, where active hearing emerges from a deep interplay between adaptive sensory processes and goal-directed cognition. Specifically, we shall explore the postulate that versatile perception is mediated by rapid-plasticity at the neuronal level. At the conjunction of sensory and cognitive processing, rapid-plasticity pervades all levels of auditory system, from the cochlea up to the auditory and prefrontal cortices. Exploiting fundamental statistical regularities of acoustics, it is what allows humans and other animal to deal so successfully with natural acoustic scenes where artificial systems fail. The project builds on the internationally recognized leadership of the PI in the fields of physiology and computational modeling, combined with the expertise of the Co-Investigator in psychophysics. Building on these highly complementary fields and several technical innovations, we hope to promote a novel view of auditory perception and cognition. We aim also to contribute significantly to translational research in the domain of signal processing for clinical hearing aids, given that many current limitations are not technological but rather conceptual. The project will finally result in the creation of laboratory facilities and an intellectual network unique in France and rare in all of Europe, combining cognitive, neural, and computational approaches to auditory neuroscience.
Summary
Listening in realistic situations is an active process that engages perceptual and cognitive faculties, endowing speech with meaning, music with joy, and environmental sounds with emotion. Through hearing, humans and other animals navigate complex acoustic scenes, separate sound mixtures, and assess their behavioral relevance. These remarkable feats are currently beyond our understanding and exceed the capabilities of the most sophisticated audio engineering systems. The goal of the proposed research is to investigate experimentally a novel view of hearing, where active hearing emerges from a deep interplay between adaptive sensory processes and goal-directed cognition. Specifically, we shall explore the postulate that versatile perception is mediated by rapid-plasticity at the neuronal level. At the conjunction of sensory and cognitive processing, rapid-plasticity pervades all levels of auditory system, from the cochlea up to the auditory and prefrontal cortices. Exploiting fundamental statistical regularities of acoustics, it is what allows humans and other animal to deal so successfully with natural acoustic scenes where artificial systems fail. The project builds on the internationally recognized leadership of the PI in the fields of physiology and computational modeling, combined with the expertise of the Co-Investigator in psychophysics. Building on these highly complementary fields and several technical innovations, we hope to promote a novel view of auditory perception and cognition. We aim also to contribute significantly to translational research in the domain of signal processing for clinical hearing aids, given that many current limitations are not technological but rather conceptual. The project will finally result in the creation of laboratory facilities and an intellectual network unique in France and rare in all of Europe, combining cognitive, neural, and computational approaches to auditory neuroscience.
Max ERC Funding
3 199 078 €
Duration
Start date: 2012-10-01, End date: 2018-09-30
Project acronym ADEQUATE
Project Advanced optoelectronic Devices with Enhanced QUAntum efficiency at THz frEquencies
Researcher (PI) Carlo Sirtori
Host Institution (HI) UNIVERSITE PARIS DIDEROT - PARIS 7
Country France
Call Details Advanced Grant (AdG), PE3, ERC-2009-AdG
Summary The aim of this project is the realisation of efficient mid-infrared and THz optoelectronic emitters. This work is motivated by the fact that the spontaneous emission in this frequency range is characterized by an extremely long lifetime when compared to non-radiative processes, giving rise to devices with very low quantum efficiency. To this end we want to develop hybrid light-matter systems, already well known in quantum optics, within optoelectronics devices, that will be driven by electrical injection. With this project we want to extend the field of optoelectronics by introducing some of the concepts of quantum optic, particularly the light-matter strong coupling, into semiconductor devices. More precisely this project aims at the implementation of novel optoelectronic emitters operating in the strong coupling regime between an intersubband excitation of a two-dimensional electron gas and a microcavity photonic mode. The quasiparticles issued from this coupling are called intersubband polaritons. The major difficulties and challenges of this project, do not lay in the observation of these quantum effects, but in their exploitation for a specific function, in particular an efficient electrical to optical conversion. To obtain efficient quantum emitters in the THz frequency range we will follow two different approaches: - In the first case we will try to exploit the additional characteristic time of the system introduced by the light-matter interaction in the strong (or ultra-strong) coupling regime. - The second approach will exploit the fact that, under certain conditions, intersubband polaritons have a bosonic character; as a consequence they can undergo stimulated scattering, giving rise to polaritons lasers as it has been shown for excitonic polaritons.
Summary
The aim of this project is the realisation of efficient mid-infrared and THz optoelectronic emitters. This work is motivated by the fact that the spontaneous emission in this frequency range is characterized by an extremely long lifetime when compared to non-radiative processes, giving rise to devices with very low quantum efficiency. To this end we want to develop hybrid light-matter systems, already well known in quantum optics, within optoelectronics devices, that will be driven by electrical injection. With this project we want to extend the field of optoelectronics by introducing some of the concepts of quantum optic, particularly the light-matter strong coupling, into semiconductor devices. More precisely this project aims at the implementation of novel optoelectronic emitters operating in the strong coupling regime between an intersubband excitation of a two-dimensional electron gas and a microcavity photonic mode. The quasiparticles issued from this coupling are called intersubband polaritons. The major difficulties and challenges of this project, do not lay in the observation of these quantum effects, but in their exploitation for a specific function, in particular an efficient electrical to optical conversion. To obtain efficient quantum emitters in the THz frequency range we will follow two different approaches: - In the first case we will try to exploit the additional characteristic time of the system introduced by the light-matter interaction in the strong (or ultra-strong) coupling regime. - The second approach will exploit the fact that, under certain conditions, intersubband polaritons have a bosonic character; as a consequence they can undergo stimulated scattering, giving rise to polaritons lasers as it has been shown for excitonic polaritons.
Max ERC Funding
1 761 000 €
Duration
Start date: 2010-05-01, End date: 2015-04-30
Project acronym ALLEGRO
Project Active large-scale learning for visual recognition
Researcher (PI) Cordelia Schmid
Host Institution (HI) INSTITUT NATIONAL DE RECHERCHE ENINFORMATIQUE ET AUTOMATIQUE
Country France
Call Details Advanced Grant (AdG), PE6, ERC-2012-ADG_20120216
Summary A massive and ever growing amount of digital image and video content
is available today, on sites such as
Flickr and YouTube, in audiovisual archives such as those of BBC and
INA, and in personal collections. In most cases, it comes with
additional information, such as text, audio or other metadata, that forms a
rather sparse and noisy, yet rich and diverse source of annotation,
ideally suited to emerging weakly supervised and active machine
learning technology. The ALLEGRO project will take visual recognition
to the next level by using this largely untapped source of data to
automatically learn visual models. The main research objective of
our project is the development of new algorithms and computer software
capable of autonomously exploring evolving data collections, selecting
the relevant information, and determining the visual models most
appropriate for different object, scene, and activity categories. An
emphasis will be put on learning visual models from video, a
particularly rich source of information, and on the representation of
human activities, one of today's most challenging problems in computer
vision. Although this project addresses fundamental research
issues, it is expected to result in significant advances in
high-impact applications that range from visual mining of the Web and
automated annotation and organization of family photo and video albums
to large-scale information retrieval in television archives.
Summary
A massive and ever growing amount of digital image and video content
is available today, on sites such as
Flickr and YouTube, in audiovisual archives such as those of BBC and
INA, and in personal collections. In most cases, it comes with
additional information, such as text, audio or other metadata, that forms a
rather sparse and noisy, yet rich and diverse source of annotation,
ideally suited to emerging weakly supervised and active machine
learning technology. The ALLEGRO project will take visual recognition
to the next level by using this largely untapped source of data to
automatically learn visual models. The main research objective of
our project is the development of new algorithms and computer software
capable of autonomously exploring evolving data collections, selecting
the relevant information, and determining the visual models most
appropriate for different object, scene, and activity categories. An
emphasis will be put on learning visual models from video, a
particularly rich source of information, and on the representation of
human activities, one of today's most challenging problems in computer
vision. Although this project addresses fundamental research
issues, it is expected to result in significant advances in
high-impact applications that range from visual mining of the Web and
automated annotation and organization of family photo and video albums
to large-scale information retrieval in television archives.
Max ERC Funding
2 493 322 €
Duration
Start date: 2013-04-01, End date: 2019-03-31
Project acronym AnoPath
Project Genetics of mosquito resistance to pathogens
Researcher (PI) Kenneth Du Souchet Vernick
Host Institution (HI) INSTITUT PASTEUR
Country France
Call Details Advanced Grant (AdG), LS2, ERC-2012-ADG_20120314
Summary Malaria parasite infection in humans has been called “the strongest known force for evolutionary selection in the recent history of the human genome”, and I hypothesize that a similar statement may apply to the mosquito vector, which is the definitive host of the malaria parasite. We previously discovered efficient malaria-resistance mechanisms in natural populations of the African malaria vector, Anopheles gambiae. Aim 1 of the proposed project will implement a novel genetic mapping design to systematically survey the mosquito population for common and rare genetic variants of strong effect against the human malaria parasite, Plasmodium falciparum. A product of the mapping design will be living mosquito families carrying the resistance loci. Aim 2 will use the segregating families to functionally dissect the underlying molecular mechanisms controlled by the loci, including determination of the pathogen specificity spectra of the host-defense traits. Aim 3 targets arbovirus transmission, where Anopheles mosquitoes transmit human malaria but not arboviruses such as Dengue and Chikungunya, even though the two mosquitoes bite the same people and are exposed to the same pathogens, often in malaria-arbovirus co-infections. We will use deep-sequencing to detect processing of the arbovirus dsRNA intermediates of replication produced by the RNAi pathway of the mosquitoes. The results will reveal important new information about differences in the efficiency and quality of the RNAi response between mosquitoes, which is likely to underlie at least part of the host specificity of arbovirus transmission. The 3 Aims will make significant contributions to understanding malaria and arbovirus transmission, major global public health problems, will aid the development of a next generation of vector surveillance and control tools, and will produce a definitive description of the major genetic factors influencing host-pathogen interactions in mosquito immunity.
Summary
Malaria parasite infection in humans has been called “the strongest known force for evolutionary selection in the recent history of the human genome”, and I hypothesize that a similar statement may apply to the mosquito vector, which is the definitive host of the malaria parasite. We previously discovered efficient malaria-resistance mechanisms in natural populations of the African malaria vector, Anopheles gambiae. Aim 1 of the proposed project will implement a novel genetic mapping design to systematically survey the mosquito population for common and rare genetic variants of strong effect against the human malaria parasite, Plasmodium falciparum. A product of the mapping design will be living mosquito families carrying the resistance loci. Aim 2 will use the segregating families to functionally dissect the underlying molecular mechanisms controlled by the loci, including determination of the pathogen specificity spectra of the host-defense traits. Aim 3 targets arbovirus transmission, where Anopheles mosquitoes transmit human malaria but not arboviruses such as Dengue and Chikungunya, even though the two mosquitoes bite the same people and are exposed to the same pathogens, often in malaria-arbovirus co-infections. We will use deep-sequencing to detect processing of the arbovirus dsRNA intermediates of replication produced by the RNAi pathway of the mosquitoes. The results will reveal important new information about differences in the efficiency and quality of the RNAi response between mosquitoes, which is likely to underlie at least part of the host specificity of arbovirus transmission. The 3 Aims will make significant contributions to understanding malaria and arbovirus transmission, major global public health problems, will aid the development of a next generation of vector surveillance and control tools, and will produce a definitive description of the major genetic factors influencing host-pathogen interactions in mosquito immunity.
Max ERC Funding
2 307 800 €
Duration
Start date: 2013-03-01, End date: 2018-02-28
Project acronym ARPEMA
Project Anionic redox processes: A transformational approach for advanced energy materials
Researcher (PI) Jean-Marie Tarascon
Host Institution (HI) COLLEGE DE FRANCE
Country France
Call Details Advanced Grant (AdG), PE5, ERC-2014-ADG
Summary Redox chemistry provides the fundamental basis for numerous energy-related electrochemical devices, among which Li-ion batteries (LIB) have become the premier energy storage technology for portable electronics and vehicle electrification. Throughout its history, LIB technology has relied on cationic redox reactions as the sole source of energy storage capacity. This is no longer true. In 2013 we demonstrated that Li-driven reversible formation of (O2)n peroxo-groups in new layered oxides led to extraordinary increases in energy storage capacity. This finding, which is receiving worldwide attention, represents a transformational approach for creating advanced energy materials for not only energy storage, but also water splitting applications as both involve peroxo species. However, as is often the case with new discoveries, the fundamental science at work needs to be rationalized and understood. Specifically, what are the mechanisms for ion and electron transport in these Li-driven anionic redox reactions?
To address these seminal questions and to widen the spectrum of materials (transition metal and anion) showing anionic redox chemistry, we propose a comprehensive research program that combines experimental and computational methods. The experimental methods include structural and electrochemical analyses (both ex-situ and in-situ), and computational modeling will be based on first-principles DFT for identifying the fundamental processes that enable anionic redox activity. The knowledge gained from these studies, in combination with our expertise in inorganic synthesis, will enable us to design a new generation of Li-ion battery materials that exhibit substantial increases (20 -30%) in energy storage capacity, with additional impacts on the development of Na-ion batteries and the design of water splitting catalysts, with the feasibility to surpass current water splitting efficiencies via novel (O2)n-based electrocatalysts.
Summary
Redox chemistry provides the fundamental basis for numerous energy-related electrochemical devices, among which Li-ion batteries (LIB) have become the premier energy storage technology for portable electronics and vehicle electrification. Throughout its history, LIB technology has relied on cationic redox reactions as the sole source of energy storage capacity. This is no longer true. In 2013 we demonstrated that Li-driven reversible formation of (O2)n peroxo-groups in new layered oxides led to extraordinary increases in energy storage capacity. This finding, which is receiving worldwide attention, represents a transformational approach for creating advanced energy materials for not only energy storage, but also water splitting applications as both involve peroxo species. However, as is often the case with new discoveries, the fundamental science at work needs to be rationalized and understood. Specifically, what are the mechanisms for ion and electron transport in these Li-driven anionic redox reactions?
To address these seminal questions and to widen the spectrum of materials (transition metal and anion) showing anionic redox chemistry, we propose a comprehensive research program that combines experimental and computational methods. The experimental methods include structural and electrochemical analyses (both ex-situ and in-situ), and computational modeling will be based on first-principles DFT for identifying the fundamental processes that enable anionic redox activity. The knowledge gained from these studies, in combination with our expertise in inorganic synthesis, will enable us to design a new generation of Li-ion battery materials that exhibit substantial increases (20 -30%) in energy storage capacity, with additional impacts on the development of Na-ion batteries and the design of water splitting catalysts, with the feasibility to surpass current water splitting efficiencies via novel (O2)n-based electrocatalysts.
Max ERC Funding
2 249 196 €
Duration
Start date: 2015-10-01, End date: 2021-03-31
Project acronym BOOTPHON
Project A computational approach to early language bootstrapping
Researcher (PI) Emmanuel Dupoux
Host Institution (HI) ECOLE DES HAUTES ETUDES EN SCIENCES SOCIALES
Country France
Call Details Advanced Grant (AdG), SH4, ERC-2011-ADG_20110406
Summary "During their first year of life, infants become attuned to the phonemes, words and phonological rules of their language, with little or no adult supervision. After 30 years of accumulated experimental results, we are still lacking an account for the puzzling fact that these 3 interdependent components of language are acquired not sequentially, but in parallel. Drawing tools from Machine Learning and Automatic Speech Recognition, we construct a model of this early process, test it on 2 large spontaneous speech databases (Japanese, French and Dutch) and test its predictions in infants using behavioral, EEGs and fNIRS techniques.
1. Coding. We study different ways of defining coding features for speech, from fine-grained to coarse grained, in view of the automatic discovery of a hierarchy of linguistic units. We compare this with a systematic study of the units of speech coding as they unfold in 6, 9 and 12 month old infants..
2. Lexicon. Infants recognize some words before they know the phonemes of their language; we modify existing word segmentation algorithms so they can work on raw speech. We test the unique prediction that infants start with a large lexicon that’s quite different from the adult one.
3. Rules. Phonemes are produced as overlapping, coarticulated gestures. To untangle these context effects, we use a predictive model of coarticulation in auditory space and invert it. We test when and how infants perform reverse coarticulation.
4. Integration. The above subprojects provide only an initial bootstrapping into approximate phonemes, words, and contextual rules. We show how to iteratively integrate these approximate representations to derive better ones. The outcome will be numerically assessed on an adult directed and infant directed speech database, and compared to those of to state-of-the-art supervized phoneme recognizers. The predictions will be tested in infants learning artificial languages and in a longitudinal study."
Summary
"During their first year of life, infants become attuned to the phonemes, words and phonological rules of their language, with little or no adult supervision. After 30 years of accumulated experimental results, we are still lacking an account for the puzzling fact that these 3 interdependent components of language are acquired not sequentially, but in parallel. Drawing tools from Machine Learning and Automatic Speech Recognition, we construct a model of this early process, test it on 2 large spontaneous speech databases (Japanese, French and Dutch) and test its predictions in infants using behavioral, EEGs and fNIRS techniques.
1. Coding. We study different ways of defining coding features for speech, from fine-grained to coarse grained, in view of the automatic discovery of a hierarchy of linguistic units. We compare this with a systematic study of the units of speech coding as they unfold in 6, 9 and 12 month old infants..
2. Lexicon. Infants recognize some words before they know the phonemes of their language; we modify existing word segmentation algorithms so they can work on raw speech. We test the unique prediction that infants start with a large lexicon that’s quite different from the adult one.
3. Rules. Phonemes are produced as overlapping, coarticulated gestures. To untangle these context effects, we use a predictive model of coarticulation in auditory space and invert it. We test when and how infants perform reverse coarticulation.
4. Integration. The above subprojects provide only an initial bootstrapping into approximate phonemes, words, and contextual rules. We show how to iteratively integrate these approximate representations to derive better ones. The outcome will be numerically assessed on an adult directed and infant directed speech database, and compared to those of to state-of-the-art supervized phoneme recognizers. The predictions will be tested in infants learning artificial languages and in a longitudinal study."
Max ERC Funding
2 194 557 €
Duration
Start date: 2012-11-01, End date: 2017-10-31
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 CCC
Project Context, Content, and Compositionality
Researcher (PI) Francois Recanati
Host Institution (HI) CENTRE NATIONAL DE LA RECHERCHE SCIENTIFIQUE CNRS
Country France
Call Details Advanced Grant (AdG), SH4, ERC-2008-AdG
Summary Over the past fifteen years, I have argued that the effects of context on content go well beyond what is standardly acknowledged in semantics. This view is sometimes referred to as Contextualism or (more technically) Truth-Conditional Pragmatics (TCP). The key idea is that the effects of context on content need not be traceable to the linguistic material in the uttered sentence. Some effects are due to the linguistic material (e.g. to context-sensitive words or morphemes which trigger the search for contextual values), but others result from top-down or free pragmatic processes that take place not because the linguistic material demands it, but because the literal meaning of the sentence requires adjustment or elaboration ( modulation ) in order to determine a contextually admissible content for the speaker s utterance. In the literature, one often finds arguments to the effect that, if Contextualism is right, then systematic semantics becomes impossible. More precisely, the claim that is often made is that TCP is incompatible with the Principle of Compositionality, upon which any systematic semantics must be based. The aim of this project is to defend Contextualism/TCP by demonstrating that it is not incompatible with the project of constructing a systematic, compositional semantics for natural language. This demonstration is of importance given the current predicament in the philosophy of language. We are, as it were, caught in a dilemma : formal semanticists provide compelling arguments that natural language must be compositional, but contextualists offer no less compelling arguments to the effect that « sense modulation is essential to speech, because we use a (mor or less) fixed stock of lexemes to talk about an indefinite variety of things, situations, and experiences » (Recanati 2004 : 131). What are we to do, if modulation is incompatible with compositionality? Our aim is to show that it is not, and thereby to dissolve the alleged dilemma.
Summary
Over the past fifteen years, I have argued that the effects of context on content go well beyond what is standardly acknowledged in semantics. This view is sometimes referred to as Contextualism or (more technically) Truth-Conditional Pragmatics (TCP). The key idea is that the effects of context on content need not be traceable to the linguistic material in the uttered sentence. Some effects are due to the linguistic material (e.g. to context-sensitive words or morphemes which trigger the search for contextual values), but others result from top-down or free pragmatic processes that take place not because the linguistic material demands it, but because the literal meaning of the sentence requires adjustment or elaboration ( modulation ) in order to determine a contextually admissible content for the speaker s utterance. In the literature, one often finds arguments to the effect that, if Contextualism is right, then systematic semantics becomes impossible. More precisely, the claim that is often made is that TCP is incompatible with the Principle of Compositionality, upon which any systematic semantics must be based. The aim of this project is to defend Contextualism/TCP by demonstrating that it is not incompatible with the project of constructing a systematic, compositional semantics for natural language. This demonstration is of importance given the current predicament in the philosophy of language. We are, as it were, caught in a dilemma : formal semanticists provide compelling arguments that natural language must be compositional, but contextualists offer no less compelling arguments to the effect that « sense modulation is essential to speech, because we use a (mor or less) fixed stock of lexemes to talk about an indefinite variety of things, situations, and experiences » (Recanati 2004 : 131). What are we to do, if modulation is incompatible with compositionality? Our aim is to show that it is not, and thereby to dissolve the alleged dilemma.
Max ERC Funding
1 144 706 €
Duration
Start date: 2009-01-01, End date: 2013-12-31
Project acronym CELLO
Project From Cells to Organs on Chips: Development of an Integrative Microfluidic Platform
Researcher (PI) Jean-Louis Viovy
Host Institution (HI) INSTITUT CURIE
Country France
Call Details Advanced Grant (AdG), PE3, ERC-2012-ADG_20120216
Summary We shall develop a microfluidic and microsystems toolbox allowing the construction and study of complex cellular assemblies (“tissue or organ mimics on chip”), in a highly controlled and parallelized way. This platform will allow the selection of specific cells from one or several populations, their deterministic positioning and/or connection relative to each other, yielding functional assemblies with a degree of complexity, determinism and physiological realism unavailable to current in vitro systems We shall in particular develop “semi-3D” architectures, reproducing the local 3D arrangement of tissues, but presenting at mesoscale a planar and periodic arrangement facilitating high resolution stimulation and recording. This will provide biologists and clinicians with new experimental models able to bridge the gap between current in vitro systems, in which cells can be observed in parallel at high resolution, but lack the highly ordered architecture present in living systems, and in vivo models, in which observation and stimulation means are more limited. This development will follow a functional approach, and gather competences and concepts from micr-nano-systems, surface science, hydrodynamics, soft matter and biology. We shall validate it on three specific applications, the sorting and study of circulating tumour cells for understanding metastases, the creation of “miniguts”, artificial intestinal tissue, for applications in developmental biology and cancerogenesis, and the in vitro construction of active and connected neuron arrays, for studying the molecular mechanisms of Alzheimer, and signal processing by neuron networks. This platform will also open new routes for drug testing, replacing animal models and reducing the health and economic risk of clinical tests, developmental biology , stem cells research. and regenerative medicine.
Summary
We shall develop a microfluidic and microsystems toolbox allowing the construction and study of complex cellular assemblies (“tissue or organ mimics on chip”), in a highly controlled and parallelized way. This platform will allow the selection of specific cells from one or several populations, their deterministic positioning and/or connection relative to each other, yielding functional assemblies with a degree of complexity, determinism and physiological realism unavailable to current in vitro systems We shall in particular develop “semi-3D” architectures, reproducing the local 3D arrangement of tissues, but presenting at mesoscale a planar and periodic arrangement facilitating high resolution stimulation and recording. This will provide biologists and clinicians with new experimental models able to bridge the gap between current in vitro systems, in which cells can be observed in parallel at high resolution, but lack the highly ordered architecture present in living systems, and in vivo models, in which observation and stimulation means are more limited. This development will follow a functional approach, and gather competences and concepts from micr-nano-systems, surface science, hydrodynamics, soft matter and biology. We shall validate it on three specific applications, the sorting and study of circulating tumour cells for understanding metastases, the creation of “miniguts”, artificial intestinal tissue, for applications in developmental biology and cancerogenesis, and the in vitro construction of active and connected neuron arrays, for studying the molecular mechanisms of Alzheimer, and signal processing by neuron networks. This platform will also open new routes for drug testing, replacing animal models and reducing the health and economic risk of clinical tests, developmental biology , stem cells research. and regenerative medicine.
Max ERC Funding
2 260 000 €
Duration
Start date: 2013-07-01, End date: 2018-06-30
