Project acronym DISINTEGRATION
Project The Mass Politics of Disintegration
Researcher (PI) Stefanie Walter
Host Institution (HI) UNIVERSITAT ZURICH
Country Switzerland
Call Details Consolidator Grant (CoG), SH2, ERC-2018-COG
Summary In the past few years, there has been a growing popular backlash against international institutions. Examples include the 2015 Greek bailout referendum, the 2016 Brexit referendum, or the 2016 election of a US President seemingly determined to withdraw US support from various international treaties. The implications of these mass-based disintegration efforts reach far beyond the countries in which they originate. First, the disintegration process is shaped by how remaining member states respond to one member’s bid to unilaterally change or terminate the terms of an existing international agreement. Second, mass-based disintegration bids pose considerable political contagion risks by encouraging disintegrative tendencies in other countries. Unfortunately, our theoretical tools to understand such international disintegration processes are underdeveloped. DISINTEGRATION therefore conducts a broad, systematic, and comparative inquiry into the mass politics of disintegration that pays particular attention to reactions in the remaining member states. It explores when and how one country’s mass-based disintegration experience encourages or deters demands for disintegration in other countries, how these contagion effects are transmitted through domestic elites and domestic discourse, and how the remaining member states ultimately respond during disintegration negotiations. It undertakes large-scale multi-method data collection that exploits the research opportunities offered by two ongoing mass-based disintegration processes: the Brexit negotiations and an upcoming Swiss referendum aimed at terminating a Swiss-EU bilateral treaty. DISINTEGRATION’s main objective is to develop a much-needed theory of mass-based disintegration that helps us understand the transnational dynamics that unfold between governments, political elites and the mass public when one member state attempts to unilaterally withdraw from an international agreement on the basis of widespread popular support.
Summary
In the past few years, there has been a growing popular backlash against international institutions. Examples include the 2015 Greek bailout referendum, the 2016 Brexit referendum, or the 2016 election of a US President seemingly determined to withdraw US support from various international treaties. The implications of these mass-based disintegration efforts reach far beyond the countries in which they originate. First, the disintegration process is shaped by how remaining member states respond to one member’s bid to unilaterally change or terminate the terms of an existing international agreement. Second, mass-based disintegration bids pose considerable political contagion risks by encouraging disintegrative tendencies in other countries. Unfortunately, our theoretical tools to understand such international disintegration processes are underdeveloped. DISINTEGRATION therefore conducts a broad, systematic, and comparative inquiry into the mass politics of disintegration that pays particular attention to reactions in the remaining member states. It explores when and how one country’s mass-based disintegration experience encourages or deters demands for disintegration in other countries, how these contagion effects are transmitted through domestic elites and domestic discourse, and how the remaining member states ultimately respond during disintegration negotiations. It undertakes large-scale multi-method data collection that exploits the research opportunities offered by two ongoing mass-based disintegration processes: the Brexit negotiations and an upcoming Swiss referendum aimed at terminating a Swiss-EU bilateral treaty. DISINTEGRATION’s main objective is to develop a much-needed theory of mass-based disintegration that helps us understand the transnational dynamics that unfold between governments, political elites and the mass public when one member state attempts to unilaterally withdraw from an international agreement on the basis of widespread popular support.
Max ERC Funding
1 998 626 €
Duration
Start date: 2019-05-01, End date: 2024-04-30
Project acronym Healthybiota
Project Microbiota-host interactions for integrative metabolic health reprogramming
Researcher (PI) Mirko TRAJKOVSKI
Host Institution (HI) UNIVERSITE DE GENEVE
Country Switzerland
Call Details Consolidator Grant (CoG), LS4, ERC-2018-COG
Summary Obesity is a metabolic disorder leading to various health risks and reduced life expectancy. Insulin resistance is a major obesity related disorder, and a main cause for the onset of type 2 diabetes. During cold exposure or caloric restriction (CR), brown adipocytes emerge within the white fat (known as “beige” cells). This process, referred to as fat browning, increases the metabolic capacity of the adipose tissues to combust energy and is seen as promising anti-obesity and anti-diabetic strategy. The intestinal microbiota co-develops with the host; microbiota depletion, or cold-induced shift of its composition are sufficient to improve insulin sensitivity and glucose metabolism, in part mediated by the innate immune system-mediated fat browning. The microbial signals and composition, critical for our understanding of the microbiota-host mutualism and metabolic improvements during cold and CR, remain unclear.
By integrating expertise from several areas including physiology, bioinformatics, immunology, microbiology and developmental biology; and by developing computational approaches for comparing the metagenomics, metabolomics and transcriptomics data from the CR- and the cold-exposed mice with cohorts of human subjects, we will establish the microbiota role in orchestrating the CR-induced metabolic improvements and innate immune response, and provide mechanistic explanations on the microbiota-host mutualism during CR and cold. Finally, by using lineage-tracing studies and developing transgenic mouse models, we will determine the importance of the beige fat in the CR-induced beneficial effects on the host, and the importance of the microbiota in mediating this process. Manipulating the gut microbiota and exploiting the mechanistic links revealed by this study would be of conceptual importance for our understanding of microbiota-host mutualism in the metabolic homeostasis, and could lead to development of novel therapeutics for improving metabolic health.
Summary
Obesity is a metabolic disorder leading to various health risks and reduced life expectancy. Insulin resistance is a major obesity related disorder, and a main cause for the onset of type 2 diabetes. During cold exposure or caloric restriction (CR), brown adipocytes emerge within the white fat (known as “beige” cells). This process, referred to as fat browning, increases the metabolic capacity of the adipose tissues to combust energy and is seen as promising anti-obesity and anti-diabetic strategy. The intestinal microbiota co-develops with the host; microbiota depletion, or cold-induced shift of its composition are sufficient to improve insulin sensitivity and glucose metabolism, in part mediated by the innate immune system-mediated fat browning. The microbial signals and composition, critical for our understanding of the microbiota-host mutualism and metabolic improvements during cold and CR, remain unclear.
By integrating expertise from several areas including physiology, bioinformatics, immunology, microbiology and developmental biology; and by developing computational approaches for comparing the metagenomics, metabolomics and transcriptomics data from the CR- and the cold-exposed mice with cohorts of human subjects, we will establish the microbiota role in orchestrating the CR-induced metabolic improvements and innate immune response, and provide mechanistic explanations on the microbiota-host mutualism during CR and cold. Finally, by using lineage-tracing studies and developing transgenic mouse models, we will determine the importance of the beige fat in the CR-induced beneficial effects on the host, and the importance of the microbiota in mediating this process. Manipulating the gut microbiota and exploiting the mechanistic links revealed by this study would be of conceptual importance for our understanding of microbiota-host mutualism in the metabolic homeostasis, and could lead to development of novel therapeutics for improving metabolic health.
Max ERC Funding
1 999 999 €
Duration
Start date: 2019-06-01, End date: 2024-05-31
Project acronym INSPIRE
Project System-wide discovery and analysis of inositol pyrophosphate signaling networks in plants
Researcher (PI) Michael HOTHORN
Host Institution (HI) UNIVERSITE DE GENEVE
Country Switzerland
Call Details Consolidator Grant (CoG), LS1, ERC-2018-COG
Summary Inositol pyrophosphates (PP-InsPs) are soluble signaling molecules known to play diverse roles in fungal and animal cell signaling. The metabolism of PP-InsPs in plants however is poorly understood and many signaling pathways controlled by PP-InsPs remain to be discovered. Funded by an ERC starting grant, we have previously identified protein sensor domains for PP-InsPs, which allow PP-InsPs to act as central regulators of phosphate homeostasis in all eukaryotes. Genetic disruption of PP-InsP synthesis results in dramatic phenotypes in the model plant Arabidopsis, which however cannot be rationalized by defects in phosphate signaling only. Based on these physiological observations, we generated a system-wide Arabidopsis PP-InsP interactome, using an affinity-matrix absorbed non-hydrolyzable PP-InsP analog. Surprisingly, hundreds of novel candidates from different protein families were identified in this screen, now enabling us to study PP-InsP catabolism and a multitude of PP-InsP-mediated signaling processes. Here, I propose to combine quantitative biochemistry and structural biology with cell biology and genome editing to dissect plant PP-InsP signaling networks at the physiological level and in mechanistic detail. Specifically, we will define the roles for PP-InsPs in plant light sensing and signaling, in flowering time regulation and in plant immune responses. Our ultimate goal will be to investigate the cross-talk between different PP-InsP-controlled signaling pathways and to define central signaling hubs. I envision that the work outlined in this proposal will yield a mechanistically validated system’s-level view of PP-InsP signal transduction in plants, which may allow us to better understand how plants develop and interact with their environment, and that may enable us to improve crop performance in the future.
Summary
Inositol pyrophosphates (PP-InsPs) are soluble signaling molecules known to play diverse roles in fungal and animal cell signaling. The metabolism of PP-InsPs in plants however is poorly understood and many signaling pathways controlled by PP-InsPs remain to be discovered. Funded by an ERC starting grant, we have previously identified protein sensor domains for PP-InsPs, which allow PP-InsPs to act as central regulators of phosphate homeostasis in all eukaryotes. Genetic disruption of PP-InsP synthesis results in dramatic phenotypes in the model plant Arabidopsis, which however cannot be rationalized by defects in phosphate signaling only. Based on these physiological observations, we generated a system-wide Arabidopsis PP-InsP interactome, using an affinity-matrix absorbed non-hydrolyzable PP-InsP analog. Surprisingly, hundreds of novel candidates from different protein families were identified in this screen, now enabling us to study PP-InsP catabolism and a multitude of PP-InsP-mediated signaling processes. Here, I propose to combine quantitative biochemistry and structural biology with cell biology and genome editing to dissect plant PP-InsP signaling networks at the physiological level and in mechanistic detail. Specifically, we will define the roles for PP-InsPs in plant light sensing and signaling, in flowering time regulation and in plant immune responses. Our ultimate goal will be to investigate the cross-talk between different PP-InsP-controlled signaling pathways and to define central signaling hubs. I envision that the work outlined in this proposal will yield a mechanistically validated system’s-level view of PP-InsP signal transduction in plants, which may allow us to better understand how plants develop and interact with their environment, and that may enable us to improve crop performance in the future.
Max ERC Funding
1 781 251 €
Duration
Start date: 2019-06-01, End date: 2024-05-31
Project acronym TransReg
Project Transgenerational epigenetic inheritance of cardiac regenerative capacity in the zebrafish
Researcher (PI) Nadia MERCADER HUBER
Host Institution (HI) UNIVERSITAET BERN
Country Switzerland
Call Details Consolidator Grant (CoG), LS4, ERC-2018-COG
Summary While myocardial infarction leads to adverse ventricular remodeling ultimately causing heart failure in humans, some animals, including zebrafish can regenerate the injured heart. We recently revealed a high degree of plasticity in cardiomyocyte subpopulations involved in the reconstruction of the injured heart. The gene regulatory network involved in heart regeneration is starting to be elucidated and epigenetic remodeling has been suggested to play a pivotal role during this process. Similarly it is known that the environment can influence the regenerative capacity but whether such an effect can be transmitted from one generation to the next has not been addressed. This mechanism is called transgenerational epigenetic inheritance (TEI) and describes the transfer of experiences from parents to their offspring through the gametes, independent on changes in DNA sequence. TEI has also been described in humans: starvation suffered by grandparents affects the metabolism of grandchildren. TEI is also relevant to organ injury: in rats, offspring from parents exposed to liver toxicants revealed reduced hepatic fibrosis in response to the same injury. Changes in DNA methylation, histone modifications and non-coding RNAs have been associated to TEI. We aim to describe for the first time epigenetic inheritance of organ regeneration and unravel its underlying mechanism using the zebrafish model. We will assess whether cardiac injury elicits epigenetic modifications in sperm and determine if offspring from injured parental fish reveal altered heart regeneration. Genetic models will be developed for functional assessment of identified modifications. We will also further analyze cell plasticity during heart regeneration and address whether hearts regenerated from different progenitors respond equally well to further injuries. Our expected findings will constitute a paradigm shift on the origins of cardiovascular disease and define epigenetic priming as a basis for regeneration.
Summary
While myocardial infarction leads to adverse ventricular remodeling ultimately causing heart failure in humans, some animals, including zebrafish can regenerate the injured heart. We recently revealed a high degree of plasticity in cardiomyocyte subpopulations involved in the reconstruction of the injured heart. The gene regulatory network involved in heart regeneration is starting to be elucidated and epigenetic remodeling has been suggested to play a pivotal role during this process. Similarly it is known that the environment can influence the regenerative capacity but whether such an effect can be transmitted from one generation to the next has not been addressed. This mechanism is called transgenerational epigenetic inheritance (TEI) and describes the transfer of experiences from parents to their offspring through the gametes, independent on changes in DNA sequence. TEI has also been described in humans: starvation suffered by grandparents affects the metabolism of grandchildren. TEI is also relevant to organ injury: in rats, offspring from parents exposed to liver toxicants revealed reduced hepatic fibrosis in response to the same injury. Changes in DNA methylation, histone modifications and non-coding RNAs have been associated to TEI. We aim to describe for the first time epigenetic inheritance of organ regeneration and unravel its underlying mechanism using the zebrafish model. We will assess whether cardiac injury elicits epigenetic modifications in sperm and determine if offspring from injured parental fish reveal altered heart regeneration. Genetic models will be developed for functional assessment of identified modifications. We will also further analyze cell plasticity during heart regeneration and address whether hearts regenerated from different progenitors respond equally well to further injuries. Our expected findings will constitute a paradigm shift on the origins of cardiovascular disease and define epigenetic priming as a basis for regeneration.
Max ERC Funding
1 999 125 €
Duration
Start date: 2019-08-01, End date: 2024-07-31
