Project acronym AsthmaVir
Project The roles of innate lymphoid cells and rhinovirus in asthma exacerbations
Researcher (PI) Hergen Spits
Host Institution (HI) ACADEMISCH MEDISCH CENTRUM BIJ DE UNIVERSITEIT VAN AMSTERDAM
Call Details Advanced Grant (AdG), LS6, ERC-2013-ADG
Summary Asthma exacerbations represent a high unmet medical need in particular in young children. Human Rhinoviruses (HRV) are the main triggers of these exacerbations. Till now Th2 cells were considered the main initiating effector cell type in asthma in general and asthma exacerbations in particular. However, exaggerated Th2 cell activities alone do not explain all aspects of asthma and exacerbations. Building on our recent discovery of type 2 human innate lymphoid cells (ILC2) capable of promptly producing high amounts of IL-5, IL-9 and IL-13 upon activation and on mouse data pointing to an essential role of these cells in asthma and asthma exacerbations, ILC2 may be the main initiating cells in asthma exacerbations in humans. Thus we hypothesize that HRV directly or indirectly stimulate ILC2s to produce cytokines driving the effector functions leading to the end organ effects that characterize this debilitating disease. Targeting ILC2 and HRV in parallel will provide a highly attractive therapeutic option for the treatment of asthma exacerbations. In depth study of the mechanisms of ILC2 differentiation and function will lead to the design effective drugs targeting these cells; thus the first two objectives of this project are: 1) To unravel the lineage relationship of ILC populations and to decipher the signal transduction pathways that regulate the function of ILCs, 2) to test the functions of lung-residing human ILCs and the effects of compounds that affect these functions in mice which harbour a human immune system and human lung epithelium under homeostatic conditions and after infections with respiratory viruses. The third objective of this project is developing reagents that target HRV; to this end we will develop broadly reacting highly neutralizing human monoclonal antibodies that can be used for prophylaxis and therapy of patients at high risk for developing severe asthma exacerbations.
Summary
Asthma exacerbations represent a high unmet medical need in particular in young children. Human Rhinoviruses (HRV) are the main triggers of these exacerbations. Till now Th2 cells were considered the main initiating effector cell type in asthma in general and asthma exacerbations in particular. However, exaggerated Th2 cell activities alone do not explain all aspects of asthma and exacerbations. Building on our recent discovery of type 2 human innate lymphoid cells (ILC2) capable of promptly producing high amounts of IL-5, IL-9 and IL-13 upon activation and on mouse data pointing to an essential role of these cells in asthma and asthma exacerbations, ILC2 may be the main initiating cells in asthma exacerbations in humans. Thus we hypothesize that HRV directly or indirectly stimulate ILC2s to produce cytokines driving the effector functions leading to the end organ effects that characterize this debilitating disease. Targeting ILC2 and HRV in parallel will provide a highly attractive therapeutic option for the treatment of asthma exacerbations. In depth study of the mechanisms of ILC2 differentiation and function will lead to the design effective drugs targeting these cells; thus the first two objectives of this project are: 1) To unravel the lineage relationship of ILC populations and to decipher the signal transduction pathways that regulate the function of ILCs, 2) to test the functions of lung-residing human ILCs and the effects of compounds that affect these functions in mice which harbour a human immune system and human lung epithelium under homeostatic conditions and after infections with respiratory viruses. The third objective of this project is developing reagents that target HRV; to this end we will develop broadly reacting highly neutralizing human monoclonal antibodies that can be used for prophylaxis and therapy of patients at high risk for developing severe asthma exacerbations.
Max ERC Funding
2 499 593 €
Duration
Start date: 2014-03-01, End date: 2019-02-28
Project acronym BABYLON
Project By the Rivers of Babylon: New Perspectives on Second Temple Judaism from Cuneiform Texts
Researcher (PI) Caroline Waerzeggers
Host Institution (HI) UNIVERSITEIT LEIDEN
Call Details Starting Grant (StG), SH6, ERC-2009-StG
Summary This project has the potential to radically change current understanding of cultic and social transformation in the post-exilic temple community of Jerusalem (c. 6th-4th centuries BCE), an important formative phase of ancient Judaism. “BABYLON” draws on recent, ground-breaking advances in the study of cuneiform texts to illuminate the Babylonian environment of the Judean exile, the socio-historical context which gave rise to the transformative era in Second Temple Judaism. In particular, these new data show that the parallels between Babylonian and post-exilic forms of cultic and social organization were substantially more far-reaching than presently recognized in Biblical scholarship. “BABYLON” will study the extent of these similarities and explore the question how Babylonian models could have influenced the restoration effort in Jerusalem.
This goal will be achieved through four sub-projects. P1 will study the social dynamics and intellectual universe of the Babylonian priesthood. P2 will finalize the publication of cuneiform archives of Babylonian priests living in the time of the exile. P3 will identify the exact areas of change in the post-exilic temple community of Jerusalem. P4, the synthesis, will draw from each of these sub-projects to present a comparative study of the Second Temple and contemporary Babylonian models of cultic and social organization, and to propose a strategy of research into the possible routes of transmission between Babylonia and Jerusalem.
The research will be carried out by three team members: the PI (P1 and P4), a PhD in Assyriology (P2) and a post-doctoral researcher in Biblical Studies specialized in the Second Temple period (P3 and P4). The participation of the wider academic community will be invited at two moments in the course of the project, in the form of a workshop and an international conference.
“BABYLON” will adopt an interdisciplinary approach by bringing together Assyriologists and Biblical scholars for a much-needed dialogue, thereby exploding the artificial boundaries that currently exist in the academic landscape between these two fields.
Summary
This project has the potential to radically change current understanding of cultic and social transformation in the post-exilic temple community of Jerusalem (c. 6th-4th centuries BCE), an important formative phase of ancient Judaism. “BABYLON” draws on recent, ground-breaking advances in the study of cuneiform texts to illuminate the Babylonian environment of the Judean exile, the socio-historical context which gave rise to the transformative era in Second Temple Judaism. In particular, these new data show that the parallels between Babylonian and post-exilic forms of cultic and social organization were substantially more far-reaching than presently recognized in Biblical scholarship. “BABYLON” will study the extent of these similarities and explore the question how Babylonian models could have influenced the restoration effort in Jerusalem.
This goal will be achieved through four sub-projects. P1 will study the social dynamics and intellectual universe of the Babylonian priesthood. P2 will finalize the publication of cuneiform archives of Babylonian priests living in the time of the exile. P3 will identify the exact areas of change in the post-exilic temple community of Jerusalem. P4, the synthesis, will draw from each of these sub-projects to present a comparative study of the Second Temple and contemporary Babylonian models of cultic and social organization, and to propose a strategy of research into the possible routes of transmission between Babylonia and Jerusalem.
The research will be carried out by three team members: the PI (P1 and P4), a PhD in Assyriology (P2) and a post-doctoral researcher in Biblical Studies specialized in the Second Temple period (P3 and P4). The participation of the wider academic community will be invited at two moments in the course of the project, in the form of a workshop and an international conference.
“BABYLON” will adopt an interdisciplinary approach by bringing together Assyriologists and Biblical scholars for a much-needed dialogue, thereby exploding the artificial boundaries that currently exist in the academic landscape between these two fields.
Max ERC Funding
1 200 000 €
Duration
Start date: 2009-09-01, End date: 2015-08-31
Project acronym ChinaCreative
Project From Made in China to Created in China - A Comparative Study of Creative Practice and Production in Contemporary China
Researcher (PI) Bastiaan Jeroen De Kloet
Host Institution (HI) UNIVERSITEIT VAN AMSTERDAM
Call Details Consolidator Grant (CoG), SH5, ERC-2013-CoG
Summary With its emergence as a global power, China aspires to move from a “made in China” towards a “created in China” country. Creativity and culture have become a crucial source for innovation and financial growth, but are also mobilised to promote a new and open China to both the citizenry as well as the outside world. They are part of what is termed China’s “soft power.”
What does creativity mean in the context of China, and what does it do? When both the state and profoundly globalised creative industries are so deeply implicated in the promotion of creativity, what are the possibilities of criticality, if any? Whereas creativity has been extensively researched in the fields of psychology, law and neurosciences, scholarship in the humanities has by and large side-tracked the thorny issue of creativity. Yet, the worldwide resurgence of the term under the banner of creative industries makes it all the more urgent to develop a theory of creativity. This project understands creativity as a textual, a social as well as a heritage practice. It aims to analyse claims of creativity in different cultural practices, and to analyse how emerging creativities in China are part of tactics of governmentality and disable or enable possibilities of criticality.
Using a comparative, multi-disciplinary, multi-method and multi-sited research design, five subprojects analyse (1) contemporary art, (2) calligraphy, (3) independent documentary cinema, (4) television from Hunan Satellite TV and (5) “fake” (shanzhai) art. By including both popular and high arts, by including both more Westernized as well as more specifically Chinese art forms, by including both the “real” as well as the “fake,” by studying different localities, and by mobilising methods from both the social sciences and the humanities, this project is pushing the notion of comparative research to a new level.
Summary
With its emergence as a global power, China aspires to move from a “made in China” towards a “created in China” country. Creativity and culture have become a crucial source for innovation and financial growth, but are also mobilised to promote a new and open China to both the citizenry as well as the outside world. They are part of what is termed China’s “soft power.”
What does creativity mean in the context of China, and what does it do? When both the state and profoundly globalised creative industries are so deeply implicated in the promotion of creativity, what are the possibilities of criticality, if any? Whereas creativity has been extensively researched in the fields of psychology, law and neurosciences, scholarship in the humanities has by and large side-tracked the thorny issue of creativity. Yet, the worldwide resurgence of the term under the banner of creative industries makes it all the more urgent to develop a theory of creativity. This project understands creativity as a textual, a social as well as a heritage practice. It aims to analyse claims of creativity in different cultural practices, and to analyse how emerging creativities in China are part of tactics of governmentality and disable or enable possibilities of criticality.
Using a comparative, multi-disciplinary, multi-method and multi-sited research design, five subprojects analyse (1) contemporary art, (2) calligraphy, (3) independent documentary cinema, (4) television from Hunan Satellite TV and (5) “fake” (shanzhai) art. By including both popular and high arts, by including both more Westernized as well as more specifically Chinese art forms, by including both the “real” as well as the “fake,” by studying different localities, and by mobilising methods from both the social sciences and the humanities, this project is pushing the notion of comparative research to a new level.
Max ERC Funding
1 947 448 €
Duration
Start date: 2014-09-01, End date: 2019-08-31
Project acronym COORDINATINGforLIFE
Project Coordinating for life. Success and failure of Western European societies in coping with rural hazards and disasters, 1300-1800
Researcher (PI) Balthassar Jozef Paul (Bas) Van Bavel
Host Institution (HI) UNIVERSITEIT UTRECHT
Call Details Advanced Grant (AdG), SH6, ERC-2013-ADG
Summary Societies in past and present are regularly confronted with major hazards, which sometimes have disastrous effects. Some societies are successful in preventing these effects and buffering threats, or they recover quickly, while others prove highly vulnerable. Why is this?
Increasingly it is clear that disasters are not merely natural events, and also that wealth and technology alone are not adequate to prevent them. Rather, hazards and disasters are social occurrences as well, and they form a tough test for the organizational capacities of a society, both in mitigation and recovery. This project targets a main element of this capacity, namely: the way societies have organized the exchange, allocation and use of resources. It aims to explain why some societies do well in preventing or remedying disasters through these institutional arrangements and others not.
In order to do so, this project analyses four key variables: the mix of coordination systems available within that society, its degree of autarky, economic equity and political equality. The recent literature on historical and present-day disasters suggests these factors as possible causes of success or failure of institutional arrangements in their confrontation with hazards, but their discussion remains largely descriptive and they have never been systematically analyzed.
This research project offers such a systematic investigation, using rural societies in Western Europe in the period 1300-1800 - with their variety of socio-economic characteristics - as a testing ground. The historical perspective enables us to compare widely differing cases, also over the long run, and to test for the variables chosen, in order to isolate the determining factors in the resilience of different societies. By using the opportunities offered by history in this way, we will increase our insight into the relative performance of societies and gain a better understanding of a critical determinant of human wellbeing.
Summary
Societies in past and present are regularly confronted with major hazards, which sometimes have disastrous effects. Some societies are successful in preventing these effects and buffering threats, or they recover quickly, while others prove highly vulnerable. Why is this?
Increasingly it is clear that disasters are not merely natural events, and also that wealth and technology alone are not adequate to prevent them. Rather, hazards and disasters are social occurrences as well, and they form a tough test for the organizational capacities of a society, both in mitigation and recovery. This project targets a main element of this capacity, namely: the way societies have organized the exchange, allocation and use of resources. It aims to explain why some societies do well in preventing or remedying disasters through these institutional arrangements and others not.
In order to do so, this project analyses four key variables: the mix of coordination systems available within that society, its degree of autarky, economic equity and political equality. The recent literature on historical and present-day disasters suggests these factors as possible causes of success or failure of institutional arrangements in their confrontation with hazards, but their discussion remains largely descriptive and they have never been systematically analyzed.
This research project offers such a systematic investigation, using rural societies in Western Europe in the period 1300-1800 - with their variety of socio-economic characteristics - as a testing ground. The historical perspective enables us to compare widely differing cases, also over the long run, and to test for the variables chosen, in order to isolate the determining factors in the resilience of different societies. By using the opportunities offered by history in this way, we will increase our insight into the relative performance of societies and gain a better understanding of a critical determinant of human wellbeing.
Max ERC Funding
2 227 326 €
Duration
Start date: 2014-03-01, End date: 2019-02-28
Project acronym InflaMet
Project Mechanistic insights into the impact of tumor-associated neutrophils on metastatic breast cancer
Researcher (PI) Karina Elizabeth De Visser
Host Institution (HI) STICHTING HET NEDERLANDS KANKER INSTITUUT-ANTONI VAN LEEUWENHOEK ZIEKENHUIS
Call Details Consolidator Grant (CoG), LS6, ERC-2013-CoG
Summary Metastatic disease is still largely unexplored, poorly understood and incurable. Accumulating evidence indicates that cells and mediators of the immune system can facilitate metastasis. Neutrophil accumulation in cancer patients has been associated with metastasis formation. In mouse tumor models, neutrophils have been reported to be pro- or anti- metastatic, but the underlying mechanisms involved in either function remain largely elusive. This proposal outlines a research program aimed at resolving the pro-metastatic role of neutrophils in breast cancer, as our preliminary data indicate that neutrophils proactively mediate breast cancer metastasis. Using a state-of-the art spontaneous breast cancer metastasis mouse model, we will mechanistically study how neutrophils facilitate metastasis formation and how mammary tumors provoke the metastasis-facilitating function of neutrophils. Building upon my previous studies and our current data, we will focus on the unexplored crosstalk between the adaptive immune system and neutrophils in facilitating spontaneous metastatic disease. These crucial questions will be addressed by undertaking a multidisciplinary approach, involving sophisticated mouse models for metastatic breast cancer, RNA sequencing on tumor-associated neutrophil populations, state-of-the-art mouse engineering, intravital imaging and in vivo neutrophil manipulations. Moreover, we will validate our findings from the mouse metastasis model in human breast cancer samples. We will determine the metastasis predicting power of the identified murine pro-metastatic neutrophil-specific pathways by immunohistochemistry and multi-parameter immunofluorescence on breast cancer samples and blood of untreated patients of which clinical follow-up is available. Thus, we will identify novel molecular pathways that can be targeted to selectively inhibit the pro-metastatic activity of the immune system.
Summary
Metastatic disease is still largely unexplored, poorly understood and incurable. Accumulating evidence indicates that cells and mediators of the immune system can facilitate metastasis. Neutrophil accumulation in cancer patients has been associated with metastasis formation. In mouse tumor models, neutrophils have been reported to be pro- or anti- metastatic, but the underlying mechanisms involved in either function remain largely elusive. This proposal outlines a research program aimed at resolving the pro-metastatic role of neutrophils in breast cancer, as our preliminary data indicate that neutrophils proactively mediate breast cancer metastasis. Using a state-of-the art spontaneous breast cancer metastasis mouse model, we will mechanistically study how neutrophils facilitate metastasis formation and how mammary tumors provoke the metastasis-facilitating function of neutrophils. Building upon my previous studies and our current data, we will focus on the unexplored crosstalk between the adaptive immune system and neutrophils in facilitating spontaneous metastatic disease. These crucial questions will be addressed by undertaking a multidisciplinary approach, involving sophisticated mouse models for metastatic breast cancer, RNA sequencing on tumor-associated neutrophil populations, state-of-the-art mouse engineering, intravital imaging and in vivo neutrophil manipulations. Moreover, we will validate our findings from the mouse metastasis model in human breast cancer samples. We will determine the metastasis predicting power of the identified murine pro-metastatic neutrophil-specific pathways by immunohistochemistry and multi-parameter immunofluorescence on breast cancer samples and blood of untreated patients of which clinical follow-up is available. Thus, we will identify novel molecular pathways that can be targeted to selectively inhibit the pro-metastatic activity of the immune system.
Max ERC Funding
1 999 360 €
Duration
Start date: 2014-03-01, End date: 2019-02-28
Project acronym INTERCOM
Project Communication between immune cells via release of RNA-carrying vesicles: Lessons from viruses
Researcher (PI) Esther Neline Marielle Nolte
Host Institution (HI) UNIVERSITEIT UTRECHT
Call Details Starting Grant (StG), LS6, ERC-2013-StG
Summary "Communication between immune cells is crucial for regulating the magnitude and quality of immune responses. A newly uncovered means of intercellular communication involves transfer of small cell-derived vesicles. I recently discovered that vesicles released by immune cells are enriched for small noncoding RNAs, which may act as regulatory RNAs that can influence gene expression in vesicle-targeted cells. Furthermore, remarkable parallels emerged between RNAs abundantly present in cell-derived vesicles and a group of host RNAs specifically incorporated into retroviruses. These shared RNAs may underlie the formation or function of both cell-derived vesicles and retroviruses. Until now, mechanisms behind selective incorporation of small RNAs into cell-derived vesicles and their function in vesicle-targeted cells are poorly understood.
Aim of INTERCOM: To resolve how the exchange of small RNAs via cell-derived vesicles contributes to intercellular communication between immune cells. Key objectives: 1. To determine the diversity and plasticity of the RNA content of vesicle subpopulations released by immune cells. 2. To explain functional differences between immune cell vesicle populations based on their RNA contents. 3. To determine the function of structural RNAs shared by immune cell-derived vesicles and retroviruses.
Tools in virology research will be used in combination with several high-end technologies, which were uniquely adapted in my lab for vesicle-related research. These include a high-resolution flow cytometric method suited to analyze individual nano-sized vesicles, RNA deep sequencing with previously developed data analysis methods, and super-resolution microscopic imaging.
The proposed work advances our understanding of communication processes in the immune system. This knowledge can be applied in defining vesicle RNA-based biomarkers for immune-related diseases and in designing genetically engineered cell-derived vesicles for therapeutic application."
Summary
"Communication between immune cells is crucial for regulating the magnitude and quality of immune responses. A newly uncovered means of intercellular communication involves transfer of small cell-derived vesicles. I recently discovered that vesicles released by immune cells are enriched for small noncoding RNAs, which may act as regulatory RNAs that can influence gene expression in vesicle-targeted cells. Furthermore, remarkable parallels emerged between RNAs abundantly present in cell-derived vesicles and a group of host RNAs specifically incorporated into retroviruses. These shared RNAs may underlie the formation or function of both cell-derived vesicles and retroviruses. Until now, mechanisms behind selective incorporation of small RNAs into cell-derived vesicles and their function in vesicle-targeted cells are poorly understood.
Aim of INTERCOM: To resolve how the exchange of small RNAs via cell-derived vesicles contributes to intercellular communication between immune cells. Key objectives: 1. To determine the diversity and plasticity of the RNA content of vesicle subpopulations released by immune cells. 2. To explain functional differences between immune cell vesicle populations based on their RNA contents. 3. To determine the function of structural RNAs shared by immune cell-derived vesicles and retroviruses.
Tools in virology research will be used in combination with several high-end technologies, which were uniquely adapted in my lab for vesicle-related research. These include a high-resolution flow cytometric method suited to analyze individual nano-sized vesicles, RNA deep sequencing with previously developed data analysis methods, and super-resolution microscopic imaging.
The proposed work advances our understanding of communication processes in the immune system. This knowledge can be applied in defining vesicle RNA-based biomarkers for immune-related diseases and in designing genetically engineered cell-derived vesicles for therapeutic application."
Max ERC Funding
1 499 806 €
Duration
Start date: 2013-11-01, End date: 2018-10-31
Project acronym MHC CLASS II-OMICS
Project Towards understanding and manipulation of MHC class II antigen presentation
Researcher (PI) Jacobus Jozef Cornelis Neefjes
Host Institution (HI) STICHTING HET NEDERLANDS KANKER INSTITUUT-ANTONI VAN LEEUWENHOEK ZIEKENHUIS
Call Details Advanced Grant (AdG), LS6, ERC-2009-AdG
Summary MHC class II molecules are crucial for specific immune responses. In a complicated series of cell biological events, they catch a peptide in the endosomal route for presentation at the plasma membrane to the immune system. At present some 20 factors have been identified as involved in the process of MHC class II antigen presentation that are potential targets for manipulating these responses as MHC class II molecules are involved in most auto-immune diseases. Defining further targets for manipulating MHC class II responses would have implications for various disease states when these can be inhibited by chemical compounds or biologicals. We have performed a genome-wide FACS-based siRNA screen for molecules affecting MHC class II expression and peptide loading. After 100.000 individual 2-color FACS analyses, we identified 276 proteins that can be functionally sub-clustered for expression and for cell biological effects. We now propose to study the cell biology of these 276 hits to elucidate the molecular and cell biological mechanisms of MHC class II antigen presentation (the MHC class II-ome). As a first step, the 276 hits are sub-clustered for effects on MHC class II transcription or cell biology. These sub-clusters may correspond to networks. We propose to validate and extend these networks by experiments by a team of scientists concentrating on the various aspects of the cell biology of MHC class II antigen presentation. A parallel chemical compound screen will be performed to identify compounds affecting MHC class II antigen presentation. By cross-correlating the biological phenotypes of compounds with those of siRNA silencing, novel target-lead combinations will be defined by reciprocal chemical genetics. Our experiments should result in a global understanding of MHC class II antigen presentation. In addition, it should reveal target-lead combinations for manipulation of MHC class II antigen presentation in infection, auto-immune disease and transplantation.
Summary
MHC class II molecules are crucial for specific immune responses. In a complicated series of cell biological events, they catch a peptide in the endosomal route for presentation at the plasma membrane to the immune system. At present some 20 factors have been identified as involved in the process of MHC class II antigen presentation that are potential targets for manipulating these responses as MHC class II molecules are involved in most auto-immune diseases. Defining further targets for manipulating MHC class II responses would have implications for various disease states when these can be inhibited by chemical compounds or biologicals. We have performed a genome-wide FACS-based siRNA screen for molecules affecting MHC class II expression and peptide loading. After 100.000 individual 2-color FACS analyses, we identified 276 proteins that can be functionally sub-clustered for expression and for cell biological effects. We now propose to study the cell biology of these 276 hits to elucidate the molecular and cell biological mechanisms of MHC class II antigen presentation (the MHC class II-ome). As a first step, the 276 hits are sub-clustered for effects on MHC class II transcription or cell biology. These sub-clusters may correspond to networks. We propose to validate and extend these networks by experiments by a team of scientists concentrating on the various aspects of the cell biology of MHC class II antigen presentation. A parallel chemical compound screen will be performed to identify compounds affecting MHC class II antigen presentation. By cross-correlating the biological phenotypes of compounds with those of siRNA silencing, novel target-lead combinations will be defined by reciprocal chemical genetics. Our experiments should result in a global understanding of MHC class II antigen presentation. In addition, it should reveal target-lead combinations for manipulation of MHC class II antigen presentation in infection, auto-immune disease and transplantation.
Max ERC Funding
2 112 300 €
Duration
Start date: 2010-09-01, End date: 2015-08-31
Project acronym PneumoCell
Project Noise in gene expression as a determinant of virulence of the human pathogen Streptococcus pneumoniae
Researcher (PI) Jan-Willem Veening
Host Institution (HI) RIJKSUNIVERSITEIT GRONINGEN
Call Details Starting Grant (StG), LS6, ERC-2013-StG
Summary Not all cells in bacterial populations exhibit exactly the same phenotype, even though they grow in the same environment and are genetically identical. One of the main driving forces of phenotypic variation is stochasticity, or noise, in gene expression. Possible molecular origins contributing to noise in protein synthesis are stochastic fluctuations in the biochemical reactions of gene expression itself, namely transcription and translation.
The driving hypothesis of this application is that the human pathogen Streptococcus pneumoniae utilizes noisy gene expression to successfully colonize and invade its host. To test this supposition, the total amount of noise in key regulatory networks for virulence factor production will be quantified. Using natural and synthetic bistable switches as highly sensitive probes for noise, in combination with state-of-the-art single-cell imaging, microfluidics and direct transcriptome sequencing, the molecular mechanisms underlying noise generation in S. pneumoniae will be determined. By constructing strains with altered levels of phenotypic variation, the importance of noisy gene expression in S. pneumoniae pathogenesis will be tested.
S. pneumoniae is a leading cause of bacterial pneumoniae, meningitis, and sepsis worldwide. The molecular mechanisms that cause switching of S. pneumoniae to its virulent states are barely understood, although it becomes increasingly clear that noise-driven phenotypic variation plays an important role in pneumococcal pathogenesis. Therefore, understanding the molecular origins of phenotypic variation in S. pneumoniae might not only provide novel fundamental insights in gene expression, but also result in the identification of new anti-pneumococcal targets.
Summary
Not all cells in bacterial populations exhibit exactly the same phenotype, even though they grow in the same environment and are genetically identical. One of the main driving forces of phenotypic variation is stochasticity, or noise, in gene expression. Possible molecular origins contributing to noise in protein synthesis are stochastic fluctuations in the biochemical reactions of gene expression itself, namely transcription and translation.
The driving hypothesis of this application is that the human pathogen Streptococcus pneumoniae utilizes noisy gene expression to successfully colonize and invade its host. To test this supposition, the total amount of noise in key regulatory networks for virulence factor production will be quantified. Using natural and synthetic bistable switches as highly sensitive probes for noise, in combination with state-of-the-art single-cell imaging, microfluidics and direct transcriptome sequencing, the molecular mechanisms underlying noise generation in S. pneumoniae will be determined. By constructing strains with altered levels of phenotypic variation, the importance of noisy gene expression in S. pneumoniae pathogenesis will be tested.
S. pneumoniae is a leading cause of bacterial pneumoniae, meningitis, and sepsis worldwide. The molecular mechanisms that cause switching of S. pneumoniae to its virulent states are barely understood, although it becomes increasingly clear that noise-driven phenotypic variation plays an important role in pneumococcal pathogenesis. Therefore, understanding the molecular origins of phenotypic variation in S. pneumoniae might not only provide novel fundamental insights in gene expression, but also result in the identification of new anti-pneumococcal targets.
Max ERC Funding
1 498 846 €
Duration
Start date: 2013-11-01, End date: 2018-10-31
Project acronym SECURE
Project "Securing Europe, Fighting its Enemies: The making of a security culture in Europe and beyond, 1815-1914"
Researcher (PI) Beatrice Albertha De Graaf
Host Institution (HI) UNIVERSITEIT UTRECHT
Call Details Consolidator Grant (CoG), SH6, ERC-2013-CoG
Summary "This project examines the development of a European security culture as the sum of mutually shared perceptions on “enemies of the states,” “vital interests,” and corresponding practices, between 1815 and 1914. By studying seven distinct instances of supranational security cooperation and their professional agents we will analyze how this European security culture emerged as early as 1815 as an open process of convergence and divergence, and of inclusion and exclusion. The team consists of the PI, 3 PhDs, 1 Post-Doc, and a research assistant.
The postulated existence of a shared European security culture in the 19th century may seem counterintuitive. Historians and scholars of international relations generally view the first half of this age through the lenses of “balance of power” and hegemony, and the second half as shaped by bellicose nationalism rather than collective security. European security cooperation and culture is generally situated after 1918, or 1945, as a reaction to the horrors of war and motivated by economic considerations. Nevertheless, after 1815 several concrete transnational security regimes were forged, (partly) designed to deal with “enemies of the states,” such as the Commissions on the Rhine and the Danube (to fight smugglers), the European Commissions on Syria and China (to fight colonial rebels), the Anti-Piracy and Anti-Anarchism Campaigns, and others. These security regimes, dictated by the threats and interests, were highly dynamic, encompassing a growing corpus of professional agents from different branches (police, judicial, military), and evolving from military interventions into police and judicial regimes. They were midwife to a veritable European security culture. This important development has not received the attention it deserves within the framework of the history of international relations and international studies.
Our hypothesis is that the development of this culture (threat/interest perceptions and practices) was dependent on four determinants: 1) the quality of the epistemic community (agents), 2) their threat/interest demarcations (subject/object), 3) the level of juridification and the use of military/police force (norms), and 4) innovations in the information, communication, and transportation technologies (technology). These determinants explain variance and change, ranging from inclusion to exclusion of groups and interests, and from juridical convergence between the European states/societies regarding the security practices in some cases to a total dissolution in other cases.
This project pioneers a new multidisciplinary approach to the combined history of international relations and internal policy, aiming to “historicize security.” Using new material, we are comparing seven different security regimes where Europe engaged globally, that stretched across the political and commercial domain, affected urban and maritime environments, and reached around the world to the Ottoman Empire and China."
Summary
"This project examines the development of a European security culture as the sum of mutually shared perceptions on “enemies of the states,” “vital interests,” and corresponding practices, between 1815 and 1914. By studying seven distinct instances of supranational security cooperation and their professional agents we will analyze how this European security culture emerged as early as 1815 as an open process of convergence and divergence, and of inclusion and exclusion. The team consists of the PI, 3 PhDs, 1 Post-Doc, and a research assistant.
The postulated existence of a shared European security culture in the 19th century may seem counterintuitive. Historians and scholars of international relations generally view the first half of this age through the lenses of “balance of power” and hegemony, and the second half as shaped by bellicose nationalism rather than collective security. European security cooperation and culture is generally situated after 1918, or 1945, as a reaction to the horrors of war and motivated by economic considerations. Nevertheless, after 1815 several concrete transnational security regimes were forged, (partly) designed to deal with “enemies of the states,” such as the Commissions on the Rhine and the Danube (to fight smugglers), the European Commissions on Syria and China (to fight colonial rebels), the Anti-Piracy and Anti-Anarchism Campaigns, and others. These security regimes, dictated by the threats and interests, were highly dynamic, encompassing a growing corpus of professional agents from different branches (police, judicial, military), and evolving from military interventions into police and judicial regimes. They were midwife to a veritable European security culture. This important development has not received the attention it deserves within the framework of the history of international relations and international studies.
Our hypothesis is that the development of this culture (threat/interest perceptions and practices) was dependent on four determinants: 1) the quality of the epistemic community (agents), 2) their threat/interest demarcations (subject/object), 3) the level of juridification and the use of military/police force (norms), and 4) innovations in the information, communication, and transportation technologies (technology). These determinants explain variance and change, ranging from inclusion to exclusion of groups and interests, and from juridical convergence between the European states/societies regarding the security practices in some cases to a total dissolution in other cases.
This project pioneers a new multidisciplinary approach to the combined history of international relations and internal policy, aiming to “historicize security.” Using new material, we are comparing seven different security regimes where Europe engaged globally, that stretched across the political and commercial domain, affected urban and maritime environments, and reached around the world to the Ottoman Empire and China."
Max ERC Funding
1 973 419 €
Duration
Start date: 2014-06-01, End date: 2019-05-31
Project acronym UNITEDWESTAND
Project The dynamics and consequences of institutions for collective action in pre-industrial Europe
Researcher (PI) Martina De Moor
Host Institution (HI) UNIVERSITEIT UTRECHT
Call Details Starting Grant (StG), SH6, ERC-2009-StG
Summary Europe s economic development in the centuries leading up to the Industrial Revolution, continues to fascinate scholars. In recent debates, institutionalised forms of collective action have been put forward as a key feature of Europe s precocious development. This project examines that connection between institutions and economic development in detail. It also harks back to the origins of such institutions, teasing out the impact of changing family patterns that emerged in Western Europe in the Late Middle Ages, which are often described as the European Marriage Pattern . Together with such factors as the absence of a strong state, and a helpful legal framework, the weakening of family relations may have created opportunities for other, non-kin social organisations to emerge, explaining the strength of institutions for collective action in this part of the world. Interactions between economic growth, marriage patterns and collective action institutions will be examined on several levels. A European wide-analysis, using specific indicators for institutional development and demographic patterns, should help clarify our understanding of their temporal and geographical co-evolution. Regulations for several types of collective action institutions will be analysed for Western Europe and Southern Europe to study the impact of household constitution and marriage patterns on institutional arrangements. A third level of the project, to be subdivided in an urban and a rural study, will look into the application of such regulations in everyday practices, through the analysis of several case-studies of guilds, commons and beguinages in the Low Countries. Finally, a sub-project is will promote dissemination and exchange of the project s data among the wider academic community. Several events will be organised to stimulate debates about the topics raised by the project.
Summary
Europe s economic development in the centuries leading up to the Industrial Revolution, continues to fascinate scholars. In recent debates, institutionalised forms of collective action have been put forward as a key feature of Europe s precocious development. This project examines that connection between institutions and economic development in detail. It also harks back to the origins of such institutions, teasing out the impact of changing family patterns that emerged in Western Europe in the Late Middle Ages, which are often described as the European Marriage Pattern . Together with such factors as the absence of a strong state, and a helpful legal framework, the weakening of family relations may have created opportunities for other, non-kin social organisations to emerge, explaining the strength of institutions for collective action in this part of the world. Interactions between economic growth, marriage patterns and collective action institutions will be examined on several levels. A European wide-analysis, using specific indicators for institutional development and demographic patterns, should help clarify our understanding of their temporal and geographical co-evolution. Regulations for several types of collective action institutions will be analysed for Western Europe and Southern Europe to study the impact of household constitution and marriage patterns on institutional arrangements. A third level of the project, to be subdivided in an urban and a rural study, will look into the application of such regulations in everyday practices, through the analysis of several case-studies of guilds, commons and beguinages in the Low Countries. Finally, a sub-project is will promote dissemination and exchange of the project s data among the wider academic community. Several events will be organised to stimulate debates about the topics raised by the project.
Max ERC Funding
1 199 721 €
Duration
Start date: 2010-01-01, End date: 2014-12-31