Project acronym CABUM
Project An investigation of the mechanisms at the interaction between cavitation bubbles and contaminants
Researcher (PI) Matevz DULAR
Host Institution (HI) UNIVERZA V LJUBLJANI
Call Details Consolidator Grant (CoG), PE8, ERC-2017-COG
Summary A sudden decrease in pressure triggers the formation of vapour and gas bubbles inside a liquid medium (also called cavitation). This leads to many (key) engineering problems: material loss, noise and vibration of hydraulic machinery. On the other hand, cavitation is a potentially a useful phenomenon: the extreme conditions are increasingly used for a wide variety of applications such as surface cleaning, enhanced chemistry, and waste water treatment (bacteria eradication and virus inactivation).
Despite this significant progress a large gap persists between the understanding of the mechanisms that contribute to the effects of cavitation and its application. Although engineers are already commercializing devices that employ cavitation, we are still not able to answer the fundamental question: What precisely are the mechanisms how bubbles can clean, disinfect, kill bacteria and enhance chemical activity? The overall objective of the project is to understand and determine the fundamental physics of the interaction of cavitation bubbles with different contaminants. To address this issue, the CABUM project will investigate the physical background of cavitation from physical, biological and engineering perspective on three complexity scales: i) on single bubble level, ii) on organised and iii) on random bubble clusters, producing a progressive multidisciplinary synergetic effect.
The proposed synergetic approach builds on the PI's preliminary research and employs novel experimental and numerical methodologies, some of which have been developed by the PI and his research group, to explore the physics of cavitation behaviour in interaction with bacteria and viruses.
Understanding the fundamental physical background of cavitation in interaction with contaminants will have a ground-breaking implications in various scientific fields (engineering, chemistry and biology) and will, in the future, enable the exploitation of cavitation in water and soil treatment processes.
Summary
A sudden decrease in pressure triggers the formation of vapour and gas bubbles inside a liquid medium (also called cavitation). This leads to many (key) engineering problems: material loss, noise and vibration of hydraulic machinery. On the other hand, cavitation is a potentially a useful phenomenon: the extreme conditions are increasingly used for a wide variety of applications such as surface cleaning, enhanced chemistry, and waste water treatment (bacteria eradication and virus inactivation).
Despite this significant progress a large gap persists between the understanding of the mechanisms that contribute to the effects of cavitation and its application. Although engineers are already commercializing devices that employ cavitation, we are still not able to answer the fundamental question: What precisely are the mechanisms how bubbles can clean, disinfect, kill bacteria and enhance chemical activity? The overall objective of the project is to understand and determine the fundamental physics of the interaction of cavitation bubbles with different contaminants. To address this issue, the CABUM project will investigate the physical background of cavitation from physical, biological and engineering perspective on three complexity scales: i) on single bubble level, ii) on organised and iii) on random bubble clusters, producing a progressive multidisciplinary synergetic effect.
The proposed synergetic approach builds on the PI's preliminary research and employs novel experimental and numerical methodologies, some of which have been developed by the PI and his research group, to explore the physics of cavitation behaviour in interaction with bacteria and viruses.
Understanding the fundamental physical background of cavitation in interaction with contaminants will have a ground-breaking implications in various scientific fields (engineering, chemistry and biology) and will, in the future, enable the exploitation of cavitation in water and soil treatment processes.
Max ERC Funding
1 904 565 €
Duration
Start date: 2018-07-01, End date: 2023-06-30
Project acronym CoreSat
Project Dynamics of Earth’s core from multi-satellite observations
Researcher (PI) Christopher FINLAY
Host Institution (HI) DANMARKS TEKNISKE UNIVERSITET
Call Details Consolidator Grant (CoG), PE10, ERC-2017-COG
Summary Earth's magnetic field plays a fundamental role in our planetary habitat, controlling interactions between the Earth and the solar wind. Here, I propose to use magnetic observations, made simultaneously by multiple satellites, along with numerical models of outer core dynamics, to test whether convective processes can account for ongoing changes in the field. The geomagnetic field is generated by a dynamo process within the core converting kinetic energy of the moving liquid metal into magnetic energy. Yet observations show a region of persistently weak field in the South Atlantic that has grown in size in recent decades. Pinning down the core dynamics responsible for this behaviour is essential if we are to understand the detailed time-dependence of the geodynamo, and to forecast future field changes.
Global magnetic observations from the Swarm constellation mission, with three identical satellites now carrying out the most detailed ever survey of the geomagnetic field, provide an exciting opportunity to probe the dynamics of the core in exquisite detail. To exploit this wealth of data, it is urgent that contaminating magnetic sources in the lithosphere and ionosphere are better separated from the core-generated field. I propose to achieve this, and to test the hypothesis that core convection has controlled the recent field evolution in the South Atlantic, via three interlinked projects. First I will co-estimate separate models for the lithospheric and core fields, making use of prior information from crustal geology and dynamo theory. In parallel, I will develop a new scheme for isolating and removing the signature of polar ionospheric currents, better utilising ground-based data. Taking advantage of these improvements, data from Swarm and previous missions will be reprocessed and then assimilated into a purpose-built model of quasi-geostrophic core convection.
Summary
Earth's magnetic field plays a fundamental role in our planetary habitat, controlling interactions between the Earth and the solar wind. Here, I propose to use magnetic observations, made simultaneously by multiple satellites, along with numerical models of outer core dynamics, to test whether convective processes can account for ongoing changes in the field. The geomagnetic field is generated by a dynamo process within the core converting kinetic energy of the moving liquid metal into magnetic energy. Yet observations show a region of persistently weak field in the South Atlantic that has grown in size in recent decades. Pinning down the core dynamics responsible for this behaviour is essential if we are to understand the detailed time-dependence of the geodynamo, and to forecast future field changes.
Global magnetic observations from the Swarm constellation mission, with three identical satellites now carrying out the most detailed ever survey of the geomagnetic field, provide an exciting opportunity to probe the dynamics of the core in exquisite detail. To exploit this wealth of data, it is urgent that contaminating magnetic sources in the lithosphere and ionosphere are better separated from the core-generated field. I propose to achieve this, and to test the hypothesis that core convection has controlled the recent field evolution in the South Atlantic, via three interlinked projects. First I will co-estimate separate models for the lithospheric and core fields, making use of prior information from crustal geology and dynamo theory. In parallel, I will develop a new scheme for isolating and removing the signature of polar ionospheric currents, better utilising ground-based data. Taking advantage of these improvements, data from Swarm and previous missions will be reprocessed and then assimilated into a purpose-built model of quasi-geostrophic core convection.
Max ERC Funding
1 828 708 €
Duration
Start date: 2018-03-01, End date: 2023-02-28
Project acronym Ctrl-ImpAct
Project Control of impulsive action
Researcher (PI) Frederick Leon Julien VERBRUGGEN
Host Institution (HI) UNIVERSITEIT GENT
Call Details Consolidator Grant (CoG), SH4, ERC-2017-COG
Summary Adaptive behaviour is typically attributed to an executive-control system that allows people to regulate impulsive actions and to fulfil long-term goals instead. Failures to regulate impulsive actions have been associated with a variety of clinical and behavioural disorders. Therefore, establishing a good understanding of impulse-control mechanisms and how to improve them could be hugely beneficial for both individuals and society at large. Yet many fundamental questions remain unanswered. This stems from a narrow focus on reactive inhibitory control and well-practiced actions. To make significant progress, we need to develop new models that integrate different aspects of impulsive action and executive control. The proposed research program aims to answer five fundamental questions. (1) Can novel impulsive actions arise during task-preparation stages?; (2) What is the role of negative emotions in the origin and control of impulsive actions?; (3) How does learning modulate impulsive behaviour?; (4) When are impulsive actions (dys)functional?; and (5) How is variation in state impulsivity associated with trait impulsivity?
To answer these questions, we will use carefully designed behavioural paradigms, cognitive neuroscience techniques (TMS & EEG), physiological measures (e.g. facial EMG), and mathematical modelling of decision-making to specify the origin and control of impulsive actions. Our ultimate goal is to transform the impulsive action field by replacing the currently dominant ‘inhibitory control’ models of impulsive action with detailed multifaceted models that can explain impulsivity and control across time and space. Developing a new behavioural model of impulsive action will also contribute to a better understanding of the causes of individual differences in impulsivity and the many disorders associated with impulse-control deficits.
Summary
Adaptive behaviour is typically attributed to an executive-control system that allows people to regulate impulsive actions and to fulfil long-term goals instead. Failures to regulate impulsive actions have been associated with a variety of clinical and behavioural disorders. Therefore, establishing a good understanding of impulse-control mechanisms and how to improve them could be hugely beneficial for both individuals and society at large. Yet many fundamental questions remain unanswered. This stems from a narrow focus on reactive inhibitory control and well-practiced actions. To make significant progress, we need to develop new models that integrate different aspects of impulsive action and executive control. The proposed research program aims to answer five fundamental questions. (1) Can novel impulsive actions arise during task-preparation stages?; (2) What is the role of negative emotions in the origin and control of impulsive actions?; (3) How does learning modulate impulsive behaviour?; (4) When are impulsive actions (dys)functional?; and (5) How is variation in state impulsivity associated with trait impulsivity?
To answer these questions, we will use carefully designed behavioural paradigms, cognitive neuroscience techniques (TMS & EEG), physiological measures (e.g. facial EMG), and mathematical modelling of decision-making to specify the origin and control of impulsive actions. Our ultimate goal is to transform the impulsive action field by replacing the currently dominant ‘inhibitory control’ models of impulsive action with detailed multifaceted models that can explain impulsivity and control across time and space. Developing a new behavioural model of impulsive action will also contribute to a better understanding of the causes of individual differences in impulsivity and the many disorders associated with impulse-control deficits.
Max ERC Funding
1 998 438 €
Duration
Start date: 2018-06-01, End date: 2023-05-31
Project acronym CUREORCURSE
Project Non-elected politics.Cure or Curse for the Crisis of Representative Democracy?
Researcher (PI) Jean-Benoit PILET
Host Institution (HI) UNIVERSITE LIBRE DE BRUXELLES
Call Details Consolidator Grant (CoG), SH2, ERC-2017-COG
Summary Evidence of a growing disengagement of citizens from politics is multiplying. Electoral turnout reaches historically low levels. Anti-establishment and populist parties are on the rise. Fewer and fewer Europeans trust their representative institutions. In response, we have observed a multiplication of institutional reforms aimed at revitalizing representative democracy. Two in particular stand out: the delegation of some political decision-making powers to (1) selected citizens and to (2) selected experts. But there is a paradox in attempting to cure the crisis of representative democracy by introducing such reforms. In representative democracy, control over political decision-making is vested in elected representatives. Delegating political decision-making to selected experts/citizens is at odds with this definition. It empowers the non-elected. If these reforms show that politics could work without elected officials, could we really expect that citizens’ support for representative democracy would be boosted and that citizens would re-engage with representative politics? In that sense, would it be a cure for the crisis of representative democracy, or rather a curse? Our central hypothesis is that there is no universal and univocal healing (or harming) effect of non-elected politics on support for representative democracy. In order to verify it, I propose to collect data across Europe on three elements: (1) a detailed study of the preferences of Europeans on how democracy should work and on institutional reforms towards non-elected politics, (2) a comprehensive inventory of all actual cases of empowerment of citizens and experts implemented across Europe since 2000, and (3) an analysis of the impact of exposure to non-elected politics on citizens’ attitudes towards representative democracy. An innovative combination of online survey experiments and of panel surveys will be used to answer this topical research question with far-reaching societal implication.
Summary
Evidence of a growing disengagement of citizens from politics is multiplying. Electoral turnout reaches historically low levels. Anti-establishment and populist parties are on the rise. Fewer and fewer Europeans trust their representative institutions. In response, we have observed a multiplication of institutional reforms aimed at revitalizing representative democracy. Two in particular stand out: the delegation of some political decision-making powers to (1) selected citizens and to (2) selected experts. But there is a paradox in attempting to cure the crisis of representative democracy by introducing such reforms. In representative democracy, control over political decision-making is vested in elected representatives. Delegating political decision-making to selected experts/citizens is at odds with this definition. It empowers the non-elected. If these reforms show that politics could work without elected officials, could we really expect that citizens’ support for representative democracy would be boosted and that citizens would re-engage with representative politics? In that sense, would it be a cure for the crisis of representative democracy, or rather a curse? Our central hypothesis is that there is no universal and univocal healing (or harming) effect of non-elected politics on support for representative democracy. In order to verify it, I propose to collect data across Europe on three elements: (1) a detailed study of the preferences of Europeans on how democracy should work and on institutional reforms towards non-elected politics, (2) a comprehensive inventory of all actual cases of empowerment of citizens and experts implemented across Europe since 2000, and (3) an analysis of the impact of exposure to non-elected politics on citizens’ attitudes towards representative democracy. An innovative combination of online survey experiments and of panel surveys will be used to answer this topical research question with far-reaching societal implication.
Max ERC Funding
1 981 589 €
Duration
Start date: 2018-09-01, End date: 2023-08-31
Project acronym DEFEAT
Project DiseasE-FreE social life without Antibiotics resisTance
Researcher (PI) Michael THOMAS-POULSEN
Host Institution (HI) KOBENHAVNS UNIVERSITET
Call Details Consolidator Grant (CoG), LS8, ERC-2017-COG
Summary The application of antimicrobial compounds produced by hosts or defensive symbionts to counter the effects of diseases has been identified in a number of organisms, but despite extensive studies on their presence, we know essentially nothing about why antimicrobials do not trigger rampant resistance evolution in target parasites. In stark contrast to virtually any other organism, fungus-farming termites have evolved a sophisticated agricultural symbiosis that pre-dates human farming by 30 million years without suffering from specialised diseases. I will capitalise on recent pioneering work in my group on proximate evidence for antimicrobial defences in the termites, their fungal crops, and their complex gut bacterial communities, by proposing to develop the farming symbiosis as a major model to test three novel concepts that may account for the evasion of resistance evolution. First, the antimicrobial compounds may have properties and evolve in ways that preclude resistance evolution in pathogens. Second, resistance is only possible towards individual compounds and not natural antimicrobial cocktails. Third, pathogens can only successfully invade and proliferate if they bypass several consecutive lines of defence, analogous to the six hallmarks of metazoan defence against cancer development. Addressing these concepts will allow fundamental insights into the remarkable success of complementary symbiont contributions to defence, and they will clarify the forces of multilevel natural selection that have allowed long-lived insect societies to evolve sustainability. Documenting and understanding these disease management principles is fundamentally important for several branches of evolutionary biology, and strategically important for adjusting human practices for future antimicrobial stewardship.
Summary
The application of antimicrobial compounds produced by hosts or defensive symbionts to counter the effects of diseases has been identified in a number of organisms, but despite extensive studies on their presence, we know essentially nothing about why antimicrobials do not trigger rampant resistance evolution in target parasites. In stark contrast to virtually any other organism, fungus-farming termites have evolved a sophisticated agricultural symbiosis that pre-dates human farming by 30 million years without suffering from specialised diseases. I will capitalise on recent pioneering work in my group on proximate evidence for antimicrobial defences in the termites, their fungal crops, and their complex gut bacterial communities, by proposing to develop the farming symbiosis as a major model to test three novel concepts that may account for the evasion of resistance evolution. First, the antimicrobial compounds may have properties and evolve in ways that preclude resistance evolution in pathogens. Second, resistance is only possible towards individual compounds and not natural antimicrobial cocktails. Third, pathogens can only successfully invade and proliferate if they bypass several consecutive lines of defence, analogous to the six hallmarks of metazoan defence against cancer development. Addressing these concepts will allow fundamental insights into the remarkable success of complementary symbiont contributions to defence, and they will clarify the forces of multilevel natural selection that have allowed long-lived insect societies to evolve sustainability. Documenting and understanding these disease management principles is fundamentally important for several branches of evolutionary biology, and strategically important for adjusting human practices for future antimicrobial stewardship.
Max ERC Funding
1 998 809 €
Duration
Start date: 2018-06-01, End date: 2023-05-31
Project acronym FRECOM
Project Nonlinear-Distortion Free Communication over the Optical Fibre Channel
Researcher (PI) Darko ZIBAR
Host Institution (HI) DANMARKS TEKNISKE UNIVERSITET
Call Details Consolidator Grant (CoG), PE7, ERC-2017-COG
Summary Motivation
The enormous growth in the Internet of Things and server farms for cloud services has increased the strain on the optical communication infrastructure. By 2025, our society will require data rates that are physically impossible to implement using current state-of-the-art optical communication technologies. This is because fibre-optic communication systems are rapidly approaching their fundamental capacity limits imposed by the Kerr nonlinearity of the fibre. Nonlinear distortion limits the ability to transport and detect the information stream. This is a very critical problem for increasing the data rates of any optical fibre communication system.
Proposed research
The only physical quantities not affected by the nonlinearity are eigenvalues, associated with the optical fibre propagation equation. Eigenvalues are thereby ideal candidates for information transport. The concept of eigenvalues is derived under the assumption that the fibre is lossless and that there is no noise in the system which is not strictly correct. Therefore, novel methodologies and concepts for the design of a noise mitigating receiver and a noise robust transmitter are needed to reap the full benefits of optical communication systems employing eigenvalues. This proposal will develop such strategies. This will be achieved by combining, for the first time, the fields of nonlinear optics, optical communication and nonlinear digital signal processing. The results from the project will be verified experimentally, and will form the basis for a new generation of commercial optical communication systems.
Preliminary results
Our proof-of-concept results demonstrate, for the first time, that noise can be handled by employing novel receiver concepts. An order of magnitude improvement compared to the state-of-the-art is demonstrated.
Environment
The research will be carried out in close cooperation with leading groups at Stanford University and Technical University of Munich.
Summary
Motivation
The enormous growth in the Internet of Things and server farms for cloud services has increased the strain on the optical communication infrastructure. By 2025, our society will require data rates that are physically impossible to implement using current state-of-the-art optical communication technologies. This is because fibre-optic communication systems are rapidly approaching their fundamental capacity limits imposed by the Kerr nonlinearity of the fibre. Nonlinear distortion limits the ability to transport and detect the information stream. This is a very critical problem for increasing the data rates of any optical fibre communication system.
Proposed research
The only physical quantities not affected by the nonlinearity are eigenvalues, associated with the optical fibre propagation equation. Eigenvalues are thereby ideal candidates for information transport. The concept of eigenvalues is derived under the assumption that the fibre is lossless and that there is no noise in the system which is not strictly correct. Therefore, novel methodologies and concepts for the design of a noise mitigating receiver and a noise robust transmitter are needed to reap the full benefits of optical communication systems employing eigenvalues. This proposal will develop such strategies. This will be achieved by combining, for the first time, the fields of nonlinear optics, optical communication and nonlinear digital signal processing. The results from the project will be verified experimentally, and will form the basis for a new generation of commercial optical communication systems.
Preliminary results
Our proof-of-concept results demonstrate, for the first time, that noise can be handled by employing novel receiver concepts. An order of magnitude improvement compared to the state-of-the-art is demonstrated.
Environment
The research will be carried out in close cooperation with leading groups at Stanford University and Technical University of Munich.
Max ERC Funding
2 000 000 €
Duration
Start date: 2018-03-01, End date: 2023-02-28
Project acronym GENOMIA
Project Genomic Modifiers of Inherited Aortapathy
Researcher (PI) Bart Leo LOEYS
Host Institution (HI) UNIVERSITEIT ANTWERPEN
Call Details Consolidator Grant (CoG), LS4, ERC-2017-COG
Summary Thoracic aortic aneurysm and dissection (TAAD) is an important cause of morbidity and mortality in the western world. As 20% of all affected individuals have a positive family history, the genetic contribution to the development of TAAD is significant. Over the last decade dozens of genes were identified underlying syndromic and non-syndromic forms of TAAD. Although mutations in these disease culprits do not yet explain all cases, their identification and functional characterization were essential in deciphering three key aortic aneurysm/dissection patho-mechanisms: disturbed extracellular matrix homeostasis, dysregulated TGFbeta signaling and altered aortic smooth muscle cell contractility. Owing to the recent advent of next-generation sequencing technologies, I anticipate that the identification of additional genetic TAAD causes will remain quite straightforward in the coming years. Importantly, in many syndromic and non-syndromic families, significant non-penetrance and both inter- and intra-familial clinical variation are observed. So, although the primary genetic underlying mutation is identical in all these family members, the clinical spectrum varies widely from completely asymptomatic to sudden death due to aortic dissection at young age. The precise mechanisms underlying this variability remain largely elusive. Consequently, a better understanding of the functional effects of the primary mutation is highly needed and the identification of genetic variation that modifies these effects is becoming increasingly important. In this project, I carefully selected four different innovative strategies to discover mother nature’s own modifying capabilities in human and mouse aortopathy. The identification of these genetic modifiers will advance the knowledge significantly beyond the current understanding, individualize current treatment protocols to deliver true precision medicine and offer promising new leads to novel therapeutic strategies.
Summary
Thoracic aortic aneurysm and dissection (TAAD) is an important cause of morbidity and mortality in the western world. As 20% of all affected individuals have a positive family history, the genetic contribution to the development of TAAD is significant. Over the last decade dozens of genes were identified underlying syndromic and non-syndromic forms of TAAD. Although mutations in these disease culprits do not yet explain all cases, their identification and functional characterization were essential in deciphering three key aortic aneurysm/dissection patho-mechanisms: disturbed extracellular matrix homeostasis, dysregulated TGFbeta signaling and altered aortic smooth muscle cell contractility. Owing to the recent advent of next-generation sequencing technologies, I anticipate that the identification of additional genetic TAAD causes will remain quite straightforward in the coming years. Importantly, in many syndromic and non-syndromic families, significant non-penetrance and both inter- and intra-familial clinical variation are observed. So, although the primary genetic underlying mutation is identical in all these family members, the clinical spectrum varies widely from completely asymptomatic to sudden death due to aortic dissection at young age. The precise mechanisms underlying this variability remain largely elusive. Consequently, a better understanding of the functional effects of the primary mutation is highly needed and the identification of genetic variation that modifies these effects is becoming increasingly important. In this project, I carefully selected four different innovative strategies to discover mother nature’s own modifying capabilities in human and mouse aortopathy. The identification of these genetic modifiers will advance the knowledge significantly beyond the current understanding, individualize current treatment protocols to deliver true precision medicine and offer promising new leads to novel therapeutic strategies.
Max ERC Funding
1 987 860 €
Duration
Start date: 2019-01-01, End date: 2023-12-31
Project acronym GlycoSkin
Project Dissection of Glycan Function by Engineered Tissue Models
Researcher (PI) Hans Heugh Wandall
Host Institution (HI) KOBENHAVNS UNIVERSITET
Call Details Consolidator Grant (CoG), LS1, ERC-2017-COG
Summary Glycans decorate most proteins, cover cell membranes, and represent one of the four building blocks of life, together with nucleic acids, lipids, and amino acids. Yet, our understanding of how glycans influence the life of cells and organisms is limited, and only few functions have been molecularly dissected. Glycans present a huge structural diversity with species and cell- type specificity that underlie specific biological functions. However, more than half a century of research has been severely hampered by the complexity and technical difficulties with analyzing glycans. While, the glycome (all glycans in a cell or organism) is a difficult entry point for discovery, the glycogenome (all genes involved in glycosylation) in contrast is a feasible entry point, because most of the genes controlling glycosylation are now known, and there are fewer technical barriers especially with the emergence of gene editing technologies.
Our research group has pioneered the “glycogenome entry” to functional glycomics using gene editing to simplify glycosylation in cells. My research group has pioneered a next generation approach using organotypic tissue models in combination with sophisticated mass spectrometry to decipher glycan functions. The tissue model has provided the first evidence that aberrant glycosylation in cancer directly induce oncogenic features, and that glycosylation of Herpes virus is essential for viral propagation. In this proposal, I will use step-by-step genetic deconstruction of glycosylation capacities in organotypic tissue models for broad discovery and dissection of specific structure-function relationships driving normal epithelial formation, transformation and interaction with the microbiome. Specifically, I will address:
1. How glycosylation affect and shape epithelial homeostasis and transformation
2. How regulation of glycosylation fine-tunes protein functions
3. How glycans influence host-pathogen interactions in “real” epithelial tissue models
Summary
Glycans decorate most proteins, cover cell membranes, and represent one of the four building blocks of life, together with nucleic acids, lipids, and amino acids. Yet, our understanding of how glycans influence the life of cells and organisms is limited, and only few functions have been molecularly dissected. Glycans present a huge structural diversity with species and cell- type specificity that underlie specific biological functions. However, more than half a century of research has been severely hampered by the complexity and technical difficulties with analyzing glycans. While, the glycome (all glycans in a cell or organism) is a difficult entry point for discovery, the glycogenome (all genes involved in glycosylation) in contrast is a feasible entry point, because most of the genes controlling glycosylation are now known, and there are fewer technical barriers especially with the emergence of gene editing technologies.
Our research group has pioneered the “glycogenome entry” to functional glycomics using gene editing to simplify glycosylation in cells. My research group has pioneered a next generation approach using organotypic tissue models in combination with sophisticated mass spectrometry to decipher glycan functions. The tissue model has provided the first evidence that aberrant glycosylation in cancer directly induce oncogenic features, and that glycosylation of Herpes virus is essential for viral propagation. In this proposal, I will use step-by-step genetic deconstruction of glycosylation capacities in organotypic tissue models for broad discovery and dissection of specific structure-function relationships driving normal epithelial formation, transformation and interaction with the microbiome. Specifically, I will address:
1. How glycosylation affect and shape epithelial homeostasis and transformation
2. How regulation of glycosylation fine-tunes protein functions
3. How glycans influence host-pathogen interactions in “real” epithelial tissue models
Max ERC Funding
1 995 199 €
Duration
Start date: 2018-03-01, End date: 2023-02-28
Project acronym ImmunoFit
Project Harnessing tumor metabolism to overcome immunosupression
Researcher (PI) Massimiliano MAZZONE
Host Institution (HI) VIB
Call Details Consolidator Grant (CoG), LS4, ERC-2017-COG
Summary Anti-cancer immunotherapy has provided patients with a promising treatment. Yet, it has also unveiled that the immunosuppressive tumor microenvironment (TME) hampers the efficiency of this therapeutic option and limits its success. The concept that metabolism is able to shape the immune response has gained general acceptance. Nonetheless, little is known on how the metabolic crosstalk between different tumor compartments contributes to the harsh TME and ultimately impairs T cell fitness within the tumor.
This proposal aims to decipher which metabolic changes in the TME impede proper anti-tumor immunity. Starting from the meta-analysis of public human datasets, corroborated by metabolomics and transcriptomics data from several mouse tumors, we ranked clinically relevant and altered metabolic pathways that correlate with resistance to immunotherapy. Using a CRISPR/Cas9 platform for their functional in vivo selection, we want to identify cancer cell intrinsic metabolic mediators and, indirectly, distinguish those belonging specifically to the stroma. By means of genetic tools and small molecules, we will modify promising metabolic pathways in cancer cells and stromal cells (particularly in tumor-associated macrophages) to harness tumor immunosuppression. In a mirroring approach, we will apply a similar screening tool on cytotoxic T cells to identify metabolic targets that enhance their fitness under adverse growth conditions. This will allow us to manipulate T cells ex vivo and to therapeutically intervene via adoptive T cell transfer. By analyzing the metabolic network and crosstalk within the tumor, this project will shed light on how metabolism contributes to the immunosuppressive TME and T cell maladaptation. The overall goal is to identify druggable metabolic targets that i) reinforce the intrinsic anti-tumor immune response by breaking immunosuppression and ii) promote T cell function in immunotherapeutic settings by rewiring either the TME or the T cell itself.
Summary
Anti-cancer immunotherapy has provided patients with a promising treatment. Yet, it has also unveiled that the immunosuppressive tumor microenvironment (TME) hampers the efficiency of this therapeutic option and limits its success. The concept that metabolism is able to shape the immune response has gained general acceptance. Nonetheless, little is known on how the metabolic crosstalk between different tumor compartments contributes to the harsh TME and ultimately impairs T cell fitness within the tumor.
This proposal aims to decipher which metabolic changes in the TME impede proper anti-tumor immunity. Starting from the meta-analysis of public human datasets, corroborated by metabolomics and transcriptomics data from several mouse tumors, we ranked clinically relevant and altered metabolic pathways that correlate with resistance to immunotherapy. Using a CRISPR/Cas9 platform for their functional in vivo selection, we want to identify cancer cell intrinsic metabolic mediators and, indirectly, distinguish those belonging specifically to the stroma. By means of genetic tools and small molecules, we will modify promising metabolic pathways in cancer cells and stromal cells (particularly in tumor-associated macrophages) to harness tumor immunosuppression. In a mirroring approach, we will apply a similar screening tool on cytotoxic T cells to identify metabolic targets that enhance their fitness under adverse growth conditions. This will allow us to manipulate T cells ex vivo and to therapeutically intervene via adoptive T cell transfer. By analyzing the metabolic network and crosstalk within the tumor, this project will shed light on how metabolism contributes to the immunosuppressive TME and T cell maladaptation. The overall goal is to identify druggable metabolic targets that i) reinforce the intrinsic anti-tumor immune response by breaking immunosuppression and ii) promote T cell function in immunotherapeutic settings by rewiring either the TME or the T cell itself.
Max ERC Funding
1 999 721 €
Duration
Start date: 2018-07-01, End date: 2023-06-30
Project acronym INSITE
Project Development and use of an integrated in silico-in vitro mesofluidics system for tissue engineering
Researcher (PI) Liesbet Laura J GERIS
Host Institution (HI) UNIVERSITE DE LIEGE
Call Details Consolidator Grant (CoG), PE8, ERC-2017-COG
Summary Tissue Engineering (TE) refers to the branch of medicine that aims to replace or regenerate functional tissue or organs using man-made living implants. As the field is moving towards more complex TE constructs with sophisticated functionalities, there is a lack of dedicated in vitro devices that allow testing the response of the complex construct as a whole, prior to implantation. Additionally, the knowledge accumulated from mechanistic and empirical in vitro and in vivo studies is often underused in the development of novel constructs due to a lack of integration of all the data in a single, in silico, platform.
The INSITE project aims to address both challenges by developing a new mesofluidics set-up for in vitro testing of TE constructs and by developing dedicated multiscale and multiphysics models that aggregate the available data and use these to design complex constructs and proper mesofluidics settings for in vitro testing. The combination of these in silico and in vitro approaches will lead to an integrated knowledge-rich mesofluidics system that provides an in vivo-like time-varying in vitro environment. The system will emulate the in vivo environment present at the (early) stages of bone regeneration including the vascularization process and the innate immune response. A proof of concept will be delivered for complex TE constructs for large bone defects and infected fractures.
To realize this project, the applicant can draw on her well-published track record and extensive network in the fields of in silico medicine and skeletal TE. If successful, INSITE will generate a shift from in vivo to in vitro work and hence a transformation of the classical R&D pipeline. Using this system will allow for a maximum of relevant in vitro research prior to the in vivo phase, which is highly needed in academia and industry with the increasing ethical (3R), financial and regulatory constraints.
Summary
Tissue Engineering (TE) refers to the branch of medicine that aims to replace or regenerate functional tissue or organs using man-made living implants. As the field is moving towards more complex TE constructs with sophisticated functionalities, there is a lack of dedicated in vitro devices that allow testing the response of the complex construct as a whole, prior to implantation. Additionally, the knowledge accumulated from mechanistic and empirical in vitro and in vivo studies is often underused in the development of novel constructs due to a lack of integration of all the data in a single, in silico, platform.
The INSITE project aims to address both challenges by developing a new mesofluidics set-up for in vitro testing of TE constructs and by developing dedicated multiscale and multiphysics models that aggregate the available data and use these to design complex constructs and proper mesofluidics settings for in vitro testing. The combination of these in silico and in vitro approaches will lead to an integrated knowledge-rich mesofluidics system that provides an in vivo-like time-varying in vitro environment. The system will emulate the in vivo environment present at the (early) stages of bone regeneration including the vascularization process and the innate immune response. A proof of concept will be delivered for complex TE constructs for large bone defects and infected fractures.
To realize this project, the applicant can draw on her well-published track record and extensive network in the fields of in silico medicine and skeletal TE. If successful, INSITE will generate a shift from in vivo to in vitro work and hence a transformation of the classical R&D pipeline. Using this system will allow for a maximum of relevant in vitro research prior to the in vivo phase, which is highly needed in academia and industry with the increasing ethical (3R), financial and regulatory constraints.
Max ERC Funding
2 161 750 €
Duration
Start date: 2018-09-01, End date: 2023-08-31