Project acronym 20SComplexity
Project An integrative approach to uncover the multilevel regulation of 20S proteasome degradation
Researcher (PI) Michal Sharon
Host Institution (HI) WEIZMANN INSTITUTE OF SCIENCE
Call Details Starting Grant (StG), LS1, ERC-2014-STG
Summary For many years, the ubiquitin-26S proteasome degradation pathway was considered the primary route for proteasomal degradation. However, it is now becoming clear that proteins can also be targeted for degradation by a ubiquitin-independent mechanism mediated by the core 20S proteasome itself. Although initially believed to be limited to rare exceptions, degradation by the 20S proteasome is now understood to have a wide range of substrates, many of which are key regulatory proteins. Despite its importance, little is known about the mechanisms that control 20S proteasomal degradation, unlike the extensive knowledge acquired over the years concerning degradation by the 26S proteasome. Our overall aim is to reveal the multiple regulatory levels that coordinate the 20S proteasome degradation route.
To achieve this goal we will carry out a comprehensive research program characterizing three distinct levels of 20S proteasome regulation:
Intra-molecular regulation- Revealing the intrinsic molecular switch that activates the latent 20S proteasome.
Inter-molecular regulation- Identifying novel proteins that bind the 20S proteasome to regulate its activity and characterizing their mechanism of function.
Cellular regulatory networks- Unraveling the cellular cues and multiple pathways that influence 20S proteasome activity using a novel systematic and unbiased screening approach.
Our experimental strategy involves the combination of biochemical approaches with native mass spectrometry, cross-linking and fluorescence measurements, complemented by cell biology analyses and high-throughput screening. Such a multidisciplinary approach, integrating in vitro and in vivo findings, will likely provide the much needed knowledge on the 20S proteasome degradation route. When completed, we anticipate that this work will be part of a new paradigm – no longer perceiving the 20S proteasome mediated degradation as a simple and passive event but rather a tightly regulated and coordinated process.
Summary
For many years, the ubiquitin-26S proteasome degradation pathway was considered the primary route for proteasomal degradation. However, it is now becoming clear that proteins can also be targeted for degradation by a ubiquitin-independent mechanism mediated by the core 20S proteasome itself. Although initially believed to be limited to rare exceptions, degradation by the 20S proteasome is now understood to have a wide range of substrates, many of which are key regulatory proteins. Despite its importance, little is known about the mechanisms that control 20S proteasomal degradation, unlike the extensive knowledge acquired over the years concerning degradation by the 26S proteasome. Our overall aim is to reveal the multiple regulatory levels that coordinate the 20S proteasome degradation route.
To achieve this goal we will carry out a comprehensive research program characterizing three distinct levels of 20S proteasome regulation:
Intra-molecular regulation- Revealing the intrinsic molecular switch that activates the latent 20S proteasome.
Inter-molecular regulation- Identifying novel proteins that bind the 20S proteasome to regulate its activity and characterizing their mechanism of function.
Cellular regulatory networks- Unraveling the cellular cues and multiple pathways that influence 20S proteasome activity using a novel systematic and unbiased screening approach.
Our experimental strategy involves the combination of biochemical approaches with native mass spectrometry, cross-linking and fluorescence measurements, complemented by cell biology analyses and high-throughput screening. Such a multidisciplinary approach, integrating in vitro and in vivo findings, will likely provide the much needed knowledge on the 20S proteasome degradation route. When completed, we anticipate that this work will be part of a new paradigm – no longer perceiving the 20S proteasome mediated degradation as a simple and passive event but rather a tightly regulated and coordinated process.
Max ERC Funding
1 500 000 €
Duration
Start date: 2015-04-01, End date: 2020-03-31
Project acronym ABACUS
Project Advancing Behavioral and Cognitive Understanding of Speech
Researcher (PI) Bart De Boer
Host Institution (HI) VRIJE UNIVERSITEIT BRUSSEL
Call Details Starting Grant (StG), SH4, ERC-2011-StG_20101124
Summary I intend to investigate what cognitive mechanisms give us combinatorial speech. Combinatorial speech is the ability to make new words using pre-existing speech sounds. Humans are the only apes that can do this, yet we do not know how our brains do it, nor how exactly we differ from other apes. Using new experimental techniques to study human behavior and new computational techniques to model human cognition, I will find out how we deal with combinatorial speech.
The experimental part will study individual and cultural learning. Experimental cultural learning is a new technique that simulates cultural evolution in the laboratory. Two types of cultural learning will be used: iterated learning, which simulates language transfer across generations, and social coordination, which simulates emergence of norms in a language community. Using the two types of cultural learning together with individual learning experiments will help to zero in, from three angles, on how humans deal with combinatorial speech. In addition it will make a methodological contribution by comparing the strengths and weaknesses of the three methods.
The computer modeling part will formalize hypotheses about how our brains deal with combinatorial speech. Two models will be built: a high-level model that will establish the basic algorithms with which combinatorial speech is learned and reproduced, and a neural model that will establish in more detail how the algorithms are implemented in the brain. In addition, the models, through increasing understanding of how humans deal with speech, will help bridge the performance gap between human and computer speech recognition.
The project will advance science in four ways: it will provide insight into how our unique ability for using combinatorial speech works, it will tell us how this is implemented in the brain, it will extend the novel methodology of experimental cultural learning and it will create new computer models for dealing with human speech.
Summary
I intend to investigate what cognitive mechanisms give us combinatorial speech. Combinatorial speech is the ability to make new words using pre-existing speech sounds. Humans are the only apes that can do this, yet we do not know how our brains do it, nor how exactly we differ from other apes. Using new experimental techniques to study human behavior and new computational techniques to model human cognition, I will find out how we deal with combinatorial speech.
The experimental part will study individual and cultural learning. Experimental cultural learning is a new technique that simulates cultural evolution in the laboratory. Two types of cultural learning will be used: iterated learning, which simulates language transfer across generations, and social coordination, which simulates emergence of norms in a language community. Using the two types of cultural learning together with individual learning experiments will help to zero in, from three angles, on how humans deal with combinatorial speech. In addition it will make a methodological contribution by comparing the strengths and weaknesses of the three methods.
The computer modeling part will formalize hypotheses about how our brains deal with combinatorial speech. Two models will be built: a high-level model that will establish the basic algorithms with which combinatorial speech is learned and reproduced, and a neural model that will establish in more detail how the algorithms are implemented in the brain. In addition, the models, through increasing understanding of how humans deal with speech, will help bridge the performance gap between human and computer speech recognition.
The project will advance science in four ways: it will provide insight into how our unique ability for using combinatorial speech works, it will tell us how this is implemented in the brain, it will extend the novel methodology of experimental cultural learning and it will create new computer models for dealing with human speech.
Max ERC Funding
1 276 620 €
Duration
Start date: 2012-02-01, End date: 2017-01-31
Project acronym ABDESIGN
Project Computational design of novel protein function in antibodies
Researcher (PI) Sarel-Jacob Fleishman
Host Institution (HI) WEIZMANN INSTITUTE OF SCIENCE
Call Details Starting Grant (StG), LS1, ERC-2013-StG
Summary We propose to elucidate the structural design principles of naturally occurring antibody complementarity-determining regions (CDRs) and to computationally design novel antibody functions. Antibodies represent the most versatile known system for molecular recognition. Research has yielded many insights into antibody design principles and promising biotechnological and pharmaceutical applications. Still, our understanding of how CDRs encode specific loop conformations lags far behind our understanding of structure-function relationships in non-immunological scaffolds. Thus, design of antibodies from first principles has not been demonstrated. We propose a computational-experimental strategy to address this challenge. We will: (a) characterize the design principles and sequence elements that rigidify antibody CDRs. Natural antibody loops will be subjected to computational modeling, crystallography, and a combined in vitro evolution and deep-sequencing approach to isolate sequence features that rigidify loop backbones; (b) develop a novel computational-design strategy, which uses the >1000 solved structures of antibodies deposited in structure databases to realistically model CDRs and design them to recognize proteins that have not been co-crystallized with antibodies. For example, we will design novel antibodies targeting insulin, for which clinically useful diagnostics are needed. By accessing much larger sequence/structure spaces than are available to natural immune-system repertoires and experimental methods, computational antibody design could produce higher-specificity and higher-affinity binders, even to challenging targets; and (c) develop new strategies to program conformational change in CDRs, generating, e.g., the first allosteric antibodies. These will allow targeting, in principle, of any molecule, potentially revolutionizing how antibodies are generated for research and medicine, providing new insights on the design principles of protein functional sites.
Summary
We propose to elucidate the structural design principles of naturally occurring antibody complementarity-determining regions (CDRs) and to computationally design novel antibody functions. Antibodies represent the most versatile known system for molecular recognition. Research has yielded many insights into antibody design principles and promising biotechnological and pharmaceutical applications. Still, our understanding of how CDRs encode specific loop conformations lags far behind our understanding of structure-function relationships in non-immunological scaffolds. Thus, design of antibodies from first principles has not been demonstrated. We propose a computational-experimental strategy to address this challenge. We will: (a) characterize the design principles and sequence elements that rigidify antibody CDRs. Natural antibody loops will be subjected to computational modeling, crystallography, and a combined in vitro evolution and deep-sequencing approach to isolate sequence features that rigidify loop backbones; (b) develop a novel computational-design strategy, which uses the >1000 solved structures of antibodies deposited in structure databases to realistically model CDRs and design them to recognize proteins that have not been co-crystallized with antibodies. For example, we will design novel antibodies targeting insulin, for which clinically useful diagnostics are needed. By accessing much larger sequence/structure spaces than are available to natural immune-system repertoires and experimental methods, computational antibody design could produce higher-specificity and higher-affinity binders, even to challenging targets; and (c) develop new strategies to program conformational change in CDRs, generating, e.g., the first allosteric antibodies. These will allow targeting, in principle, of any molecule, potentially revolutionizing how antibodies are generated for research and medicine, providing new insights on the design principles of protein functional sites.
Max ERC Funding
1 499 930 €
Duration
Start date: 2013-09-01, End date: 2018-08-31
Project acronym AcetyLys
Project Unravelling the role of lysine acetylation in the regulation of glycolysis in cancer cells through the development of synthetic biology-based tools
Researcher (PI) Eyal Arbely
Host Institution (HI) BEN-GURION UNIVERSITY OF THE NEGEV
Call Details Starting Grant (StG), LS9, ERC-2015-STG
Summary Synthetic biology is an emerging discipline that offers powerful tools to control and manipulate fundamental processes in living matter. We propose to develop and apply such tools to modify the genetic code of cultured mammalian cells and bacteria with the aim to study the role of lysine acetylation in the regulation of metabolism and in cancer development. Thousands of lysine acetylation sites were recently discovered on non-histone proteins, suggesting that acetylation is a widespread and evolutionarily conserved post translational modification, similar in scope to phosphorylation and ubiquitination. Specifically, it has been found that most of the enzymes of metabolic processes—including glycolysis—are acetylated, implying that acetylation is key regulator of cellular metabolism in general and in glycolysis in particular. The regulation of metabolic pathways is of particular importance to cancer research, as misregulation of metabolic pathways, especially upregulation of glycolysis, is common to most transformed cells and is now considered a new hallmark of cancer. These data raise an immediate question: what is the role of acetylation in the regulation of glycolysis and in the metabolic reprogramming of cancer cells? While current methods rely on mutational analyses, we will genetically encode the incorporation of acetylated lysine and directly measure the functional role of each acetylation site in cancerous and non-cancerous cell lines. Using this methodology, we will study the structural and functional implications of all the acetylation sites in glycolytic enzymes. We will also decipher the mechanism by which acetylation is regulated by deacetylases and answer a long standing question – how 18 deacetylases recognise their substrates among thousands of acetylated proteins? The developed methodologies can be applied to a wide range of protein families known to be acetylated, thereby making this study relevant to diverse research fields.
Summary
Synthetic biology is an emerging discipline that offers powerful tools to control and manipulate fundamental processes in living matter. We propose to develop and apply such tools to modify the genetic code of cultured mammalian cells and bacteria with the aim to study the role of lysine acetylation in the regulation of metabolism and in cancer development. Thousands of lysine acetylation sites were recently discovered on non-histone proteins, suggesting that acetylation is a widespread and evolutionarily conserved post translational modification, similar in scope to phosphorylation and ubiquitination. Specifically, it has been found that most of the enzymes of metabolic processes—including glycolysis—are acetylated, implying that acetylation is key regulator of cellular metabolism in general and in glycolysis in particular. The regulation of metabolic pathways is of particular importance to cancer research, as misregulation of metabolic pathways, especially upregulation of glycolysis, is common to most transformed cells and is now considered a new hallmark of cancer. These data raise an immediate question: what is the role of acetylation in the regulation of glycolysis and in the metabolic reprogramming of cancer cells? While current methods rely on mutational analyses, we will genetically encode the incorporation of acetylated lysine and directly measure the functional role of each acetylation site in cancerous and non-cancerous cell lines. Using this methodology, we will study the structural and functional implications of all the acetylation sites in glycolytic enzymes. We will also decipher the mechanism by which acetylation is regulated by deacetylases and answer a long standing question – how 18 deacetylases recognise their substrates among thousands of acetylated proteins? The developed methodologies can be applied to a wide range of protein families known to be acetylated, thereby making this study relevant to diverse research fields.
Max ERC Funding
1 499 375 €
Duration
Start date: 2016-07-01, End date: 2021-06-30
Project acronym AfricanWomen
Project Women in Africa
Researcher (PI) catherine GUIRKINGER
Host Institution (HI) UNIVERSITE DE NAMUR ASBL
Call Details Starting Grant (StG), SH1, ERC-2017-STG
Summary Rates of domestic violence and the relative risk of premature death for women are higher in sub-Saharan Africa than in any other region. Yet we know remarkably little about the economic forces, incentives and constraints that drive discrimination against women in this region, making it hard to identify policy levers to address the problem. This project will help fill this gap.
I will investigate gender discrimination from two complementary perspectives. First, through the lens of economic history, I will investigate the forces driving trends in women’s relative well-being since slavery. To quantify the evolution of well-being of sub-Saharan women relative to men, I will use three types of historical data: anthropometric indicators (relative height), vital statistics (to compute numbers of missing women), and outcomes of formal and informal family law disputes. I will then investigate how major economic developments and changes in family laws differentially affected women’s welfare across ethnic groups with different norms on women’s roles and rights.
Second, using intra-household economic models, I will provide new insights into domestic violence and gender bias in access to crucial resources in present-day Africa. I will develop a new household model that incorporates gender identity and endogenous outside options to explore the relationship between women’s empowerment and the use of violence. Using the notion of strategic delegation, I will propose a new rationale for the separation of budgets often observed in African households and generate predictions of how improvements in women’s outside options affect welfare. Finally, with first hand data, I will investigate intra-household differences in nutrition and work effort in times of food shortage from the points of view of efficiency and equity. I will use activity trackers as an innovative means of collecting high quality data on work effort and thus overcome data limitations restricting the existing literature
Summary
Rates of domestic violence and the relative risk of premature death for women are higher in sub-Saharan Africa than in any other region. Yet we know remarkably little about the economic forces, incentives and constraints that drive discrimination against women in this region, making it hard to identify policy levers to address the problem. This project will help fill this gap.
I will investigate gender discrimination from two complementary perspectives. First, through the lens of economic history, I will investigate the forces driving trends in women’s relative well-being since slavery. To quantify the evolution of well-being of sub-Saharan women relative to men, I will use three types of historical data: anthropometric indicators (relative height), vital statistics (to compute numbers of missing women), and outcomes of formal and informal family law disputes. I will then investigate how major economic developments and changes in family laws differentially affected women’s welfare across ethnic groups with different norms on women’s roles and rights.
Second, using intra-household economic models, I will provide new insights into domestic violence and gender bias in access to crucial resources in present-day Africa. I will develop a new household model that incorporates gender identity and endogenous outside options to explore the relationship between women’s empowerment and the use of violence. Using the notion of strategic delegation, I will propose a new rationale for the separation of budgets often observed in African households and generate predictions of how improvements in women’s outside options affect welfare. Finally, with first hand data, I will investigate intra-household differences in nutrition and work effort in times of food shortage from the points of view of efficiency and equity. I will use activity trackers as an innovative means of collecting high quality data on work effort and thus overcome data limitations restricting the existing literature
Max ERC Funding
1 499 313 €
Duration
Start date: 2018-08-01, End date: 2023-07-31
Project acronym AIDA
Project Architectural design In Dialogue with dis-Ability Theoretical and methodological exploration of a multi-sensorial design approach in architecture
Researcher (PI) Ann Heylighen
Host Institution (HI) KATHOLIEKE UNIVERSITEIT LEUVEN
Call Details Starting Grant (StG), SH2, ERC-2007-StG
Summary This research project is based on the notion that, because of their specific interaction with space, people with particular dis-abilities are able to appreciate spatial qualities or detect misfits in the environment that most architects—or other designers—are not even aware of. This notion holds for sensory dis-abilities such as blindness or visual impairment, but also for mental dis-abilities like autism or Alzheimer’s dementia. The experiences and subsequent insights of these dis-abled people, so it is argued, represent a considerable knowledge resource that would complement and enrich the professional expertise of architects and designers in general. This argument forms the basis for a methodological and theoretical exploration of a multi-sensorial design approach in architecture. On the one hand, a series of retrospective case studies will be conducted to identify and describe the motives and elements that trigger or stimulate architects’ attention for the multi-sensorial spatial experiences of people with dis-abilities when designing spaces. On the other hand, the research project will investigate experimentally in real time to what extent design processes and products in architecture can be enriched by establishing a dialogue between the multi-sensorial ‘knowing-in-action’ of people with dis-abilities and the expertise of professional architects/designers. In this way, the research project aims to develop a more profound understanding of how the concept of Design for All can be realised in architectural practice. At least as important, however, is its contribution to innovation in architecture tout court. The research results are expected to give a powerful impulse to quality improvement of the built environment by stimulating and supporting the development of innovative design concepts.
Summary
This research project is based on the notion that, because of their specific interaction with space, people with particular dis-abilities are able to appreciate spatial qualities or detect misfits in the environment that most architects—or other designers—are not even aware of. This notion holds for sensory dis-abilities such as blindness or visual impairment, but also for mental dis-abilities like autism or Alzheimer’s dementia. The experiences and subsequent insights of these dis-abled people, so it is argued, represent a considerable knowledge resource that would complement and enrich the professional expertise of architects and designers in general. This argument forms the basis for a methodological and theoretical exploration of a multi-sensorial design approach in architecture. On the one hand, a series of retrospective case studies will be conducted to identify and describe the motives and elements that trigger or stimulate architects’ attention for the multi-sensorial spatial experiences of people with dis-abilities when designing spaces. On the other hand, the research project will investigate experimentally in real time to what extent design processes and products in architecture can be enriched by establishing a dialogue between the multi-sensorial ‘knowing-in-action’ of people with dis-abilities and the expertise of professional architects/designers. In this way, the research project aims to develop a more profound understanding of how the concept of Design for All can be realised in architectural practice. At least as important, however, is its contribution to innovation in architecture tout court. The research results are expected to give a powerful impulse to quality improvement of the built environment by stimulating and supporting the development of innovative design concepts.
Max ERC Funding
1 195 385 €
Duration
Start date: 2008-05-01, End date: 2013-10-31
Project acronym ANXIETY & COGNITION
Project How anxiety transforms human cognition: an Affective Neuroscience perspective
Researcher (PI) Gilles Roger Charles Pourtois
Host Institution (HI) UNIVERSITEIT GENT
Call Details Starting Grant (StG), SH3, ERC-2007-StG
Summary Anxiety, a state of apprehension or fear, may provoke cognitive or behavioural disorders and eventually lead to serious medical illnesses. The high prevalence of anxiety disorders in our society sharply contrasts with the lack of clear factual knowledge about the corresponding brain mechanisms at the origin of this profound change in the appraisal of the environment. Little is known about how the psychopathological state of anxiety ultimately turns to a medical condition. The core of this proposal is to gain insight in the neural underpinnings of anxiety and disorders related to anxiety using modern human brain-imaging such as scalp EEG and fMRI. I propose to enlighten how anxiety transforms and shapes human cognition and what the neural correlates and time-course of this modulatory effect are. The primary innovation of this project is the systematic use scalp EEG and fMRI in human participants to better understand the neural mechanisms by which anxiety profoundly influences specific cognitive functions, in particular selective attention and decision-making. The goal of this proposal is to precisely determine the exact timing (using scalp EEG), location, size and extent (using fMRI) of anxiety-related modulations on selective attention and decision-making in the human brain. Here I propose to focus on these two specific processes, because they are likely to reveal selective effects of anxiety on human cognition and can thus serve as powerful models to better figure out how anxiety operates in the human brain. Another important aspect of this project is the fact I envision to help bridge the gap in Health Psychology between fundamental research and clinical practice by proposing alternative revalidation strategies for human adult subjects affected by anxiety-related disorders, which could directly exploit the neuro-scientific discoveries generated in this scientific project.
Summary
Anxiety, a state of apprehension or fear, may provoke cognitive or behavioural disorders and eventually lead to serious medical illnesses. The high prevalence of anxiety disorders in our society sharply contrasts with the lack of clear factual knowledge about the corresponding brain mechanisms at the origin of this profound change in the appraisal of the environment. Little is known about how the psychopathological state of anxiety ultimately turns to a medical condition. The core of this proposal is to gain insight in the neural underpinnings of anxiety and disorders related to anxiety using modern human brain-imaging such as scalp EEG and fMRI. I propose to enlighten how anxiety transforms and shapes human cognition and what the neural correlates and time-course of this modulatory effect are. The primary innovation of this project is the systematic use scalp EEG and fMRI in human participants to better understand the neural mechanisms by which anxiety profoundly influences specific cognitive functions, in particular selective attention and decision-making. The goal of this proposal is to precisely determine the exact timing (using scalp EEG), location, size and extent (using fMRI) of anxiety-related modulations on selective attention and decision-making in the human brain. Here I propose to focus on these two specific processes, because they are likely to reveal selective effects of anxiety on human cognition and can thus serve as powerful models to better figure out how anxiety operates in the human brain. Another important aspect of this project is the fact I envision to help bridge the gap in Health Psychology between fundamental research and clinical practice by proposing alternative revalidation strategies for human adult subjects affected by anxiety-related disorders, which could directly exploit the neuro-scientific discoveries generated in this scientific project.
Max ERC Funding
812 986 €
Duration
Start date: 2008-11-01, End date: 2013-10-31
Project acronym ARCHGLASS
Project Archaeometry and Archaeology of Ancient Glass Production as a Source for Ancient Technology and Trade of Raw Materials
Researcher (PI) Patrick Degryse
Host Institution (HI) KATHOLIEKE UNIVERSITEIT LEUVEN
Call Details Starting Grant (StG), SH6, ERC-2009-StG
Summary In this project, innovative techniques to reconstruct ancient economies are developed and new insights in the trade and processing of mineral raw materials are gained based on interdisciplinary archaeological and archaeometrical research. An innovative methodology for and a practical provenance database of the primary origin of natron glass from the Hellenistic-Roman world will be established. The project investigates both production and consumer sites of glass raw materials using both typo-chronological and archaeometrical (isotope geochemical) study of finished glass artefacts at consumer sites as well as mineralogical and chemical characterisation of raw glass and mineral resources at primary production sites. Suitable sand resources in the locations described by ancient authors will be identified through geological prospecting on the basis of literature review and field work. Sand and flux (natron) deposits will be mineralogically and geochemically characterised and compared to the results of the archaeological and geochemical investigations of the glass. Through integrated typo-chronological and archaeometrical analysis, the possible occurrence of primary production centres of raw glass outside the known locations in Syro-Palestine and Egypt, particularly in North-Africa, Italy, Spain and Gaul will be critically studied. In this way, historical, archaeological and archaeometrical data are combined, developing new interdisciplinary techniques for innovative archaeological interpretation of glass trade in the Hellenistic-Roman world.
Summary
In this project, innovative techniques to reconstruct ancient economies are developed and new insights in the trade and processing of mineral raw materials are gained based on interdisciplinary archaeological and archaeometrical research. An innovative methodology for and a practical provenance database of the primary origin of natron glass from the Hellenistic-Roman world will be established. The project investigates both production and consumer sites of glass raw materials using both typo-chronological and archaeometrical (isotope geochemical) study of finished glass artefacts at consumer sites as well as mineralogical and chemical characterisation of raw glass and mineral resources at primary production sites. Suitable sand resources in the locations described by ancient authors will be identified through geological prospecting on the basis of literature review and field work. Sand and flux (natron) deposits will be mineralogically and geochemically characterised and compared to the results of the archaeological and geochemical investigations of the glass. Through integrated typo-chronological and archaeometrical analysis, the possible occurrence of primary production centres of raw glass outside the known locations in Syro-Palestine and Egypt, particularly in North-Africa, Italy, Spain and Gaul will be critically studied. In this way, historical, archaeological and archaeometrical data are combined, developing new interdisciplinary techniques for innovative archaeological interpretation of glass trade in the Hellenistic-Roman world.
Max ERC Funding
954 960 €
Duration
Start date: 2009-11-01, End date: 2014-10-31
Project acronym ARISE
Project The Ecology of Antibiotic Resistance
Researcher (PI) Roy Kishony
Host Institution (HI) TECHNION - ISRAEL INSTITUTE OF TECHNOLOGY
Call Details Starting Grant (StG), LS8, ERC-2011-StG_20101109
Summary Main goal. We aim to understand the puzzling coexistence of antibiotic-resistant and antibiotic-sensitive species in natural soil environments, using novel quantitative experimental techniques and mathematical analysis. The ecological insights gained will be translated into novel treatment strategies for combating antibiotic resistance.
Background. Microbial soil ecosystems comprise communities of species interacting through copious secretion of antibiotics and other chemicals. Defence mechanisms, i.e. resistance to antibiotics, are ubiquitous in these wild communities. However, in sharp contrast to clinical settings, resistance does not take over the population. Our hypothesis is that the ecological setting provides natural mechanisms that keep antibiotic resistance in check. We are motivated by our recent finding that specific antibiotic combinations can generate selection against resistance and that soil microbial strains produce compounds that directly target antibiotic resistant mechanisms.
Approaches. We will: (1) Isolate natural bacterial species from individual grains of soil, characterize their ability to produce and resist antibiotics and identify the spatial scale for correlations between resistance and production. (2) Systematically measure interactions between species and identify interaction patterns enriched in co-existing communities derived from the same grain of soil. (3) Introducing fluorescently-labelled resistant and sensitive strains into natural soil, we will measure the fitness cost and benefit of antibiotic resistance in situ and identify natural compounds that select against resistance. (4) Test whether such “selection-inverting” compounds can slow evolution of resistance to antibiotics in continuous culture experiments.
Conclusions. These findings will provide insights into the ecological processes that keep antibiotic resistance in check, and will suggest novel antimicrobial treatment strategies.
Summary
Main goal. We aim to understand the puzzling coexistence of antibiotic-resistant and antibiotic-sensitive species in natural soil environments, using novel quantitative experimental techniques and mathematical analysis. The ecological insights gained will be translated into novel treatment strategies for combating antibiotic resistance.
Background. Microbial soil ecosystems comprise communities of species interacting through copious secretion of antibiotics and other chemicals. Defence mechanisms, i.e. resistance to antibiotics, are ubiquitous in these wild communities. However, in sharp contrast to clinical settings, resistance does not take over the population. Our hypothesis is that the ecological setting provides natural mechanisms that keep antibiotic resistance in check. We are motivated by our recent finding that specific antibiotic combinations can generate selection against resistance and that soil microbial strains produce compounds that directly target antibiotic resistant mechanisms.
Approaches. We will: (1) Isolate natural bacterial species from individual grains of soil, characterize their ability to produce and resist antibiotics and identify the spatial scale for correlations between resistance and production. (2) Systematically measure interactions between species and identify interaction patterns enriched in co-existing communities derived from the same grain of soil. (3) Introducing fluorescently-labelled resistant and sensitive strains into natural soil, we will measure the fitness cost and benefit of antibiotic resistance in situ and identify natural compounds that select against resistance. (4) Test whether such “selection-inverting” compounds can slow evolution of resistance to antibiotics in continuous culture experiments.
Conclusions. These findings will provide insights into the ecological processes that keep antibiotic resistance in check, and will suggest novel antimicrobial treatment strategies.
Max ERC Funding
1 900 000 €
Duration
Start date: 2012-09-01, End date: 2018-08-31
Project acronym BACTERIAL SPORES
Project Investigating the Nature of Bacterial Spores
Researcher (PI) Sigal Ben-Yehuda
Host Institution (HI) THE HEBREW UNIVERSITY OF JERUSALEM
Call Details Starting Grant (StG), LS3, ERC-2007-StG
Summary When triggered by nutrient limitation, the Gram-positive bacterium Bacillus subtilis and its relatives enter a pathway of cellular differentiation culminating in the formation of a dormant cell type called a spore, the most resilient cell type known. Bacterial spores can survive for long periods of time and are able to endure extremes of heat, radiation and chemical assault. Remarkably, dormant spores can rapidly convert back to actively growing cells by a process called germination. Consequently, spore forming bacteria, including dangerous pathogens, (such as C. botulinum and B. anthracis) are highly resistant to antibacterial treatments and difficult to eradicate. Despite significant advances in our understanding of the process of spore formation, little is known about the nature of the mature spore. It is unrevealed how dormancy is maintained within the spore and how it is ceased, as the organization and the dynamics of the spore macromolecules remain obscure. The unusual biochemical and biophysical characteristics of the dormant spore make it a challenging biological system to investigate using conventional methods, and thus set the need to develop innovative approaches to study spore biology. We propose to explore the nature of spores by using B. subtilis as a primary experimental system. We intend to: (1) define the architecture of the spore chromosome, (2) track the complexity and fate of mRNA and protein molecules during sporulation, dormancy and germination, (3) revisit the basic notion of the spore dormancy (is it metabolically inert?), (4) compare the characteristics of bacilli spores from diverse ecophysiological groups, (5) investigate the features of spores belonging to distant bacterial genera, (6) generate an integrative database that categorizes the molecular features of spores. Our study will provide original insights and introduce novel concepts to the field of spore biology and may help devise innovative ways to combat spore forming pathogens.
Summary
When triggered by nutrient limitation, the Gram-positive bacterium Bacillus subtilis and its relatives enter a pathway of cellular differentiation culminating in the formation of a dormant cell type called a spore, the most resilient cell type known. Bacterial spores can survive for long periods of time and are able to endure extremes of heat, radiation and chemical assault. Remarkably, dormant spores can rapidly convert back to actively growing cells by a process called germination. Consequently, spore forming bacteria, including dangerous pathogens, (such as C. botulinum and B. anthracis) are highly resistant to antibacterial treatments and difficult to eradicate. Despite significant advances in our understanding of the process of spore formation, little is known about the nature of the mature spore. It is unrevealed how dormancy is maintained within the spore and how it is ceased, as the organization and the dynamics of the spore macromolecules remain obscure. The unusual biochemical and biophysical characteristics of the dormant spore make it a challenging biological system to investigate using conventional methods, and thus set the need to develop innovative approaches to study spore biology. We propose to explore the nature of spores by using B. subtilis as a primary experimental system. We intend to: (1) define the architecture of the spore chromosome, (2) track the complexity and fate of mRNA and protein molecules during sporulation, dormancy and germination, (3) revisit the basic notion of the spore dormancy (is it metabolically inert?), (4) compare the characteristics of bacilli spores from diverse ecophysiological groups, (5) investigate the features of spores belonging to distant bacterial genera, (6) generate an integrative database that categorizes the molecular features of spores. Our study will provide original insights and introduce novel concepts to the field of spore biology and may help devise innovative ways to combat spore forming pathogens.
Max ERC Funding
1 630 000 €
Duration
Start date: 2008-10-01, End date: 2013-09-30
