Project acronym AGNES
Project ACTIVE AGEING – RESILIENCE AND EXTERNAL SUPPORT AS MODIFIERS OF THE DISABLEMENT OUTCOME
Researcher (PI) Taina Tuulikki RANTANEN
Host Institution (HI) JYVASKYLAN YLIOPISTO
Country Finland
Call Details Advanced Grant (AdG), SH3, ERC-2015-AdG
Summary The goals are 1. To develop a scale assessing the diversity of active ageing with four dimensions that are ability (what people can do), activity (what people do do), ambition (what are the valued activities that people want to do), and autonomy (how satisfied people are with the opportunity to do valued activities); 2. To examine health and physical and psychological functioning as the determinants and social and build environment, resilience and personal skills as modifiers of active ageing; 3. To develop a multicomponent sustainable intervention aiming to promote active ageing (methods: counselling, information technology, help from volunteers); 4. To test the feasibility and effectiveness on the intervention; and 5. To study cohort effects on the phenotypes on the pathway to active ageing.
“If You Can Measure It, You Can Change It.” Active ageing assessment needs conceptual progress, which I propose to do. A quantifiable scale will be developed that captures the diversity of active ageing stemming from the WHO definition of active ageing as the process of optimizing opportunities for health and participation in the society for all people in line with their needs, goals and capacities as they age. I will collect cross-sectional data (N=1000, ages 75, 80 and 85 years) and model the pathway to active ageing with state-of-the art statistical methods. By doing this I will create novel knowledge on preconditions for active ageing. The collected cohort data will be compared to a pre-existing cohort data that was collected 25 years ago to obtain knowledge about changes over time in functioning of older people. A randomized controlled trial (N=200) will be conducted to assess the effectiveness of the envisioned intervention promoting active ageing through participation. The project will regenerate ageing research by launching a novel scale, by training young scientists, by creating new concepts and theory development and by producing evidence for active ageing promotion
Summary
The goals are 1. To develop a scale assessing the diversity of active ageing with four dimensions that are ability (what people can do), activity (what people do do), ambition (what are the valued activities that people want to do), and autonomy (how satisfied people are with the opportunity to do valued activities); 2. To examine health and physical and psychological functioning as the determinants and social and build environment, resilience and personal skills as modifiers of active ageing; 3. To develop a multicomponent sustainable intervention aiming to promote active ageing (methods: counselling, information technology, help from volunteers); 4. To test the feasibility and effectiveness on the intervention; and 5. To study cohort effects on the phenotypes on the pathway to active ageing.
“If You Can Measure It, You Can Change It.” Active ageing assessment needs conceptual progress, which I propose to do. A quantifiable scale will be developed that captures the diversity of active ageing stemming from the WHO definition of active ageing as the process of optimizing opportunities for health and participation in the society for all people in line with their needs, goals and capacities as they age. I will collect cross-sectional data (N=1000, ages 75, 80 and 85 years) and model the pathway to active ageing with state-of-the art statistical methods. By doing this I will create novel knowledge on preconditions for active ageing. The collected cohort data will be compared to a pre-existing cohort data that was collected 25 years ago to obtain knowledge about changes over time in functioning of older people. A randomized controlled trial (N=200) will be conducted to assess the effectiveness of the envisioned intervention promoting active ageing through participation. The project will regenerate ageing research by launching a novel scale, by training young scientists, by creating new concepts and theory development and by producing evidence for active ageing promotion
Max ERC Funding
2 044 364 €
Duration
Start date: 2016-09-01, End date: 2021-08-31
Project acronym ANTILEAK
Project Development of antagonists of vascular leakage
Researcher (PI) Pipsa SAHARINEN
Host Institution (HI) HELSINGIN YLIOPISTO
Country Finland
Call Details Consolidator Grant (CoG), LS4, ERC-2017-COG
Summary Dysregulation of capillary permeability is a severe problem in critically ill patients, but the mechanisms involved are poorly understood. Further, there are no targeted therapies to stabilize leaky vessels in various common, potentially fatal diseases, such as systemic inflammation and sepsis, which affect millions of people annually. Although a multitude of signals that stimulate opening of endothelial cell-cell junctions leading to permeability have been characterized using cellular and in vivo models, approaches to reverse the harmful process of capillary leakage in disease conditions are yet to be identified. I propose to explore a novel autocrine endothelial permeability regulatory system as a potentially universal mechanism that antagonizes vascular stabilizing ques and sustains vascular leakage in inflammation. My group has identified inflammation-induced mechanisms that switch vascular stabilizing factors into molecules that destabilize vascular barriers, and identified tools to prevent the barrier disruption. Building on these discoveries, my group will use mouse genetics, structural biology and innovative, systematic antibody development coupled with gene editing and gene silencing technology, in order to elucidate mechanisms of vascular barrier breakdown and repair in systemic inflammation. The expected outcomes include insights into endothelial cell signaling and permeability regulation, and preclinical proof-of-concept antibodies to control endothelial activation and vascular leakage in systemic inflammation and sepsis models. Ultimately, the new knowledge and preclinical tools developed in this project may facilitate future development of targeted approaches against vascular leakage.
Summary
Dysregulation of capillary permeability is a severe problem in critically ill patients, but the mechanisms involved are poorly understood. Further, there are no targeted therapies to stabilize leaky vessels in various common, potentially fatal diseases, such as systemic inflammation and sepsis, which affect millions of people annually. Although a multitude of signals that stimulate opening of endothelial cell-cell junctions leading to permeability have been characterized using cellular and in vivo models, approaches to reverse the harmful process of capillary leakage in disease conditions are yet to be identified. I propose to explore a novel autocrine endothelial permeability regulatory system as a potentially universal mechanism that antagonizes vascular stabilizing ques and sustains vascular leakage in inflammation. My group has identified inflammation-induced mechanisms that switch vascular stabilizing factors into molecules that destabilize vascular barriers, and identified tools to prevent the barrier disruption. Building on these discoveries, my group will use mouse genetics, structural biology and innovative, systematic antibody development coupled with gene editing and gene silencing technology, in order to elucidate mechanisms of vascular barrier breakdown and repair in systemic inflammation. The expected outcomes include insights into endothelial cell signaling and permeability regulation, and preclinical proof-of-concept antibodies to control endothelial activation and vascular leakage in systemic inflammation and sepsis models. Ultimately, the new knowledge and preclinical tools developed in this project may facilitate future development of targeted approaches against vascular leakage.
Max ERC Funding
1 999 770 €
Duration
Start date: 2018-05-01, End date: 2023-04-30
Project acronym AXIAL.EC
Project PRINCIPLES OF AXIAL POLARITY-DRIVEN VASCULAR PATTERNING
Researcher (PI) Claudio Franco
Host Institution (HI) INSTITUTO DE MEDICINA MOLECULAR JOAO LOBO ANTUNES
Country Portugal
Call Details Starting Grant (StG), LS4, ERC-2015-STG
Summary The formation of a functional patterned vascular network is essential for development, tissue growth and organ physiology. Several human vascular disorders arise from the mis-patterning of blood vessels, such as arteriovenous malformations, aneurysms and diabetic retinopathy. Although blood flow is recognised as a stimulus for vascular patterning, very little is known about the molecular mechanisms that regulate endothelial cell behaviour in response to flow and promote vascular patterning.
Recently, we uncovered that endothelial cells migrate extensively in the immature vascular network, and that endothelial cells polarise against the blood flow direction. Here, we put forward the hypothesis that vascular patterning is dependent on the polarisation and migration of endothelial cells against the flow direction, in a continuous flux of cells going from low-shear stress to high-shear stress regions. We will establish new reporter mouse lines to observe and manipulate endothelial polarity in vivo in order to investigate how polarisation and coordination of endothelial cells movements are orchestrated to generate vascular patterning. We will manipulate cell polarity using mouse models to understand the importance of cell polarisation in vascular patterning. Also, using a unique zebrafish line allowing analysis of endothelial cell polarity, we will perform a screen to identify novel regulators of vascular patterning. Finally, we will explore the hypothesis that defective flow-dependent endothelial polarisation underlies arteriovenous malformations using two genetic models.
This integrative approach, based on high-resolution imaging and unique experimental models, will provide a unifying model defining the cellular and molecular principles involved in vascular patterning. Given the physiological relevance of vascular patterning in health and disease, this research plan will set the basis for the development of novel clinical therapies targeting vascular disorders.
Summary
The formation of a functional patterned vascular network is essential for development, tissue growth and organ physiology. Several human vascular disorders arise from the mis-patterning of blood vessels, such as arteriovenous malformations, aneurysms and diabetic retinopathy. Although blood flow is recognised as a stimulus for vascular patterning, very little is known about the molecular mechanisms that regulate endothelial cell behaviour in response to flow and promote vascular patterning.
Recently, we uncovered that endothelial cells migrate extensively in the immature vascular network, and that endothelial cells polarise against the blood flow direction. Here, we put forward the hypothesis that vascular patterning is dependent on the polarisation and migration of endothelial cells against the flow direction, in a continuous flux of cells going from low-shear stress to high-shear stress regions. We will establish new reporter mouse lines to observe and manipulate endothelial polarity in vivo in order to investigate how polarisation and coordination of endothelial cells movements are orchestrated to generate vascular patterning. We will manipulate cell polarity using mouse models to understand the importance of cell polarisation in vascular patterning. Also, using a unique zebrafish line allowing analysis of endothelial cell polarity, we will perform a screen to identify novel regulators of vascular patterning. Finally, we will explore the hypothesis that defective flow-dependent endothelial polarisation underlies arteriovenous malformations using two genetic models.
This integrative approach, based on high-resolution imaging and unique experimental models, will provide a unifying model defining the cellular and molecular principles involved in vascular patterning. Given the physiological relevance of vascular patterning in health and disease, this research plan will set the basis for the development of novel clinical therapies targeting vascular disorders.
Max ERC Funding
1 618 750 €
Duration
Start date: 2016-09-01, End date: 2022-02-28
Project acronym CHALLENGE
Project Persistent bullying cases: towards tailored intervention approaches to maximize efficiency
Researcher (PI) Christina SALMIVALLI
Host Institution (HI) TURUN YLIOPISTO
Country Finland
Call Details Advanced Grant (AdG), SH3, ERC-2019-ADG
Summary Bullying in schools is widespread, with adverse effects on youth and high costs for societies. Research on bullying prevention has so far focused on average effects of anti-bullying programs and mainly concerned universal, preventive measures. While important, this has overshadowed attempts to uncover how exactly school personnel intervene in particular bullying cases and when and why that fails. CHALLENGE will open up new research horizons by shifting the focus from average program effects to the characteristics and conditions of youth who remain victimized or continue bullying despite targeted interventions. The next big questions in the field are tackled in four work packages:
WP1 uncovers the key features of persistent bullying, such as the extent to which it is due to school-level factors or rather varies across bullying cases (within schools).
WP2 elucidates the plight of persistent victims by testing why victimized youth are most maladjusted in contexts where the overall level of victimization is decreasing (healthy context paradox, Garandeau & Salmivalli, 2019).
WP3 tests the efficacy of different targeted interventions in real-life conditions, uncovering challenge factors that increase the risk of a bullying case remaining unresolved. Moreover, it tests how youth characteristics affect their cognitive, emotional and motivational responses to different interventions.
WP4 utilizes molecular genetics to test genetic susceptibility to intervention effects at the individual level.
CHALLENGE uses quantitative, qualitative, and DNA analyses, combines longitudinal and experimental designs, and harnesses novel tools to collect real-time intervention data and to register children’s responses to interventions. It bridges the perspectives of developmental and social psychology, child psychiatry, and genetics, builds theory on persistent bullying and enables the development of tailored measures for specific target groups where available interventions have failed
Summary
Bullying in schools is widespread, with adverse effects on youth and high costs for societies. Research on bullying prevention has so far focused on average effects of anti-bullying programs and mainly concerned universal, preventive measures. While important, this has overshadowed attempts to uncover how exactly school personnel intervene in particular bullying cases and when and why that fails. CHALLENGE will open up new research horizons by shifting the focus from average program effects to the characteristics and conditions of youth who remain victimized or continue bullying despite targeted interventions. The next big questions in the field are tackled in four work packages:
WP1 uncovers the key features of persistent bullying, such as the extent to which it is due to school-level factors or rather varies across bullying cases (within schools).
WP2 elucidates the plight of persistent victims by testing why victimized youth are most maladjusted in contexts where the overall level of victimization is decreasing (healthy context paradox, Garandeau & Salmivalli, 2019).
WP3 tests the efficacy of different targeted interventions in real-life conditions, uncovering challenge factors that increase the risk of a bullying case remaining unresolved. Moreover, it tests how youth characteristics affect their cognitive, emotional and motivational responses to different interventions.
WP4 utilizes molecular genetics to test genetic susceptibility to intervention effects at the individual level.
CHALLENGE uses quantitative, qualitative, and DNA analyses, combines longitudinal and experimental designs, and harnesses novel tools to collect real-time intervention data and to register children’s responses to interventions. It bridges the perspectives of developmental and social psychology, child psychiatry, and genetics, builds theory on persistent bullying and enables the development of tailored measures for specific target groups where available interventions have failed
Max ERC Funding
2 424 001 €
Duration
Start date: 2020-10-01, End date: 2025-09-30
Project acronym DIRECT-fMRI
Project Sensing activity-induced cell swellings and ensuing neurotransmitter releases for in-vivo functional imaging sans hemodynamics
Researcher (PI) Noam Shemesh
Host Institution (HI) FUNDACAO D. ANNA SOMMER CHAMPALIMAUD E DR. CARLOS MONTEZ CHAMPALIMAUD
Country Portugal
Call Details Starting Grant (StG), PE4, ERC-2015-STG
Summary Functional-Magnetic Resonance Imaging (fMRI) has transformed our understanding of brain function due to its ability to noninvasively tag ‘active’ brain regions. Nevertheless, fMRI only detects neural activity indirectly, by relying on slow hemodynamic couplings whose relationships with underlying neural activity are not fully known.
We have recently pioneered two unique MR approaches: Non-Uniform Oscillating-Gradient Spin-Echo (NOGSE) MRI and Relaxation Enhanced MR Spectroscopy (RE MRS). NOGSE-MRI is an exquisite microstructural probe, sensing cell sizes (l) with an unprecedented l^6 sensitivity (compared to l^2 in conventional approaches); RE MRS is a new spectral technique capable of recording metabolic signals with extraordinary fidelity at ultrahigh fields.
This proposal aims to harness these novel concepts for mapping neural activity directly, without relying on hemodynamics. The specific objectives of this proposal are:
(1) Mapping neural activity via sensing cell swellings upon activity (μfMRI): we hypothesize that NOGSE can robustly sense subtle changes in cellular microstructure upon neural firings and hence convey neural activity directly.
(2) Probing the nature of elicited activity via detection of neurotransmitter release: we posit that RE MRS is sufficiently sensitive to robustly detect changes in Glutamate and GABA signals upon activation.
(3) Network mapping in optogenetically-stimulated, behaving mice: we propose to couple our novel approaches with optogenetics to resolve neural correlates of behavior in awake, behaving mice.
Simulations for μfMRI predict >4% signal changes upon subtle cell swellings; further, our in vivo RE MRS experiments have detected metabolites with SNR>50 in only 6 seconds. Hence, these two complementary –and importantly, hemodynamics-independent– approaches will represent a true paradigm shift: from indirect detection of neurovasculature couplings towards direct and noninvasive mapping of neural activity in vivo.
Summary
Functional-Magnetic Resonance Imaging (fMRI) has transformed our understanding of brain function due to its ability to noninvasively tag ‘active’ brain regions. Nevertheless, fMRI only detects neural activity indirectly, by relying on slow hemodynamic couplings whose relationships with underlying neural activity are not fully known.
We have recently pioneered two unique MR approaches: Non-Uniform Oscillating-Gradient Spin-Echo (NOGSE) MRI and Relaxation Enhanced MR Spectroscopy (RE MRS). NOGSE-MRI is an exquisite microstructural probe, sensing cell sizes (l) with an unprecedented l^6 sensitivity (compared to l^2 in conventional approaches); RE MRS is a new spectral technique capable of recording metabolic signals with extraordinary fidelity at ultrahigh fields.
This proposal aims to harness these novel concepts for mapping neural activity directly, without relying on hemodynamics. The specific objectives of this proposal are:
(1) Mapping neural activity via sensing cell swellings upon activity (μfMRI): we hypothesize that NOGSE can robustly sense subtle changes in cellular microstructure upon neural firings and hence convey neural activity directly.
(2) Probing the nature of elicited activity via detection of neurotransmitter release: we posit that RE MRS is sufficiently sensitive to robustly detect changes in Glutamate and GABA signals upon activation.
(3) Network mapping in optogenetically-stimulated, behaving mice: we propose to couple our novel approaches with optogenetics to resolve neural correlates of behavior in awake, behaving mice.
Simulations for μfMRI predict >4% signal changes upon subtle cell swellings; further, our in vivo RE MRS experiments have detected metabolites with SNR>50 in only 6 seconds. Hence, these two complementary –and importantly, hemodynamics-independent– approaches will represent a true paradigm shift: from indirect detection of neurovasculature couplings towards direct and noninvasive mapping of neural activity in vivo.
Max ERC Funding
1 787 500 €
Duration
Start date: 2016-03-01, End date: 2021-02-28
Project acronym EnDeCAD
Project Enhancers Decoding the Mechanisms Underlying CAD Risk
Researcher (PI) Minna Unelma KAIKKONEN-MaeaeTTae
Host Institution (HI) ITA-SUOMEN YLIOPISTO
Country Finland
Call Details Starting Grant (StG), LS4, ERC-2018-STG
Summary In recent years, genome-wide association studies (GWAS) have discovered hundreds of single nucleotide polymorphisms (SNPs) which are significantly associated with coronary artery disease (CAD). However, the SNPs identified by GWAS explain typically only small portion of the trait heritability and vast majority of variants do not have known biological roles. This is explained by variants lying within noncoding regions such as in cell type specific enhancers and additionally ‘the lead SNP’ identified in GWAS may not be the ‘the causal SNP’ but only linked with a trait associated SNP. Therefore, a major priority for understanding disease mechanisms is to understand at the molecular level the function of each CAD loci. In this study we aim to bring the functional characterization of SNPs associated with CAD risk to date by focusing our search for causal SNPs to enhancers of disease relevant cell types, namely endothelial cells, macrophages and smooth muscle cells of the vessel wall, hepatocytes and adipocytes. By combination of massively parallel enhancer activity measurements, collection of novel eQTL data throughout cell types under disease relevant stimuli, identification of the target genes in physical interaction with the candidate enhancers and establishment of correlative relationships between enhancer activity and gene expression we hope to identify causal enhancer variants and link them with target genes to obtain a more complete picture of the gene regulatory events driving disease progression and the genetic basis of CAD. Linking these findings with our deep phenotypic data for cardiovascular risk factors, gene expression and metabolomics has the potential to improve risk prediction, biomarker identification and treatment selection in clinical practice. Ultimately, this research strives for fundamental discoveries and breakthrough that advance our knowledge of CAD and provides pioneering steps towards taking the growing array of GWAS for translatable results.
Summary
In recent years, genome-wide association studies (GWAS) have discovered hundreds of single nucleotide polymorphisms (SNPs) which are significantly associated with coronary artery disease (CAD). However, the SNPs identified by GWAS explain typically only small portion of the trait heritability and vast majority of variants do not have known biological roles. This is explained by variants lying within noncoding regions such as in cell type specific enhancers and additionally ‘the lead SNP’ identified in GWAS may not be the ‘the causal SNP’ but only linked with a trait associated SNP. Therefore, a major priority for understanding disease mechanisms is to understand at the molecular level the function of each CAD loci. In this study we aim to bring the functional characterization of SNPs associated with CAD risk to date by focusing our search for causal SNPs to enhancers of disease relevant cell types, namely endothelial cells, macrophages and smooth muscle cells of the vessel wall, hepatocytes and adipocytes. By combination of massively parallel enhancer activity measurements, collection of novel eQTL data throughout cell types under disease relevant stimuli, identification of the target genes in physical interaction with the candidate enhancers and establishment of correlative relationships between enhancer activity and gene expression we hope to identify causal enhancer variants and link them with target genes to obtain a more complete picture of the gene regulatory events driving disease progression and the genetic basis of CAD. Linking these findings with our deep phenotypic data for cardiovascular risk factors, gene expression and metabolomics has the potential to improve risk prediction, biomarker identification and treatment selection in clinical practice. Ultimately, this research strives for fundamental discoveries and breakthrough that advance our knowledge of CAD and provides pioneering steps towards taking the growing array of GWAS for translatable results.
Max ERC Funding
1 498 647 €
Duration
Start date: 2019-01-01, End date: 2023-12-31
Project acronym FARE
Project FAKE NEWS AND REAL PEOPLE – USING BIG DATA TO UNDERSTAND HUMAN BEHAVIOUR
Researcher (PI) Maria Joana GONcALVES-Sa
Host Institution (HI) LABORATORIO DE INSTRUMENTACAO E FISICA EXPERIMENTAL DE PARTICULAS LIP
Country Portugal
Call Details Starting Grant (StG), SH3, ERC-2019-STG
Summary Recent events, from the anti-vaccination movement, to Brexit and even to mob killings, have raised serious concerns about the influence of the so-called fake news (FN). False information is not new in human history, but the recent surge in online activity, coupled with poor digital literacy, consumer profiling, and large profits from ad revenues, created a perfect storm for the FN epidemic, with still unimaginable consequences.
This challenge is interdisciplinary and requires academic research to guide current calls for action issued by academics, governmental and non-governmental agencies, and the social network platforms themselves. FARE will enrich current efforts, which mostly confront FN spreading from an applied perspective, by offering a theoretical framework that allows to make testable predictions. FARE argues that sharing of FN is a deviation from pure rationality and brings together 1) state of the art knowledge in behavioural psychology, to assess the role that cognitive biases play in susceptibility to FN, and 2) current models in network science and epidemiology, to test whether FN spread more like simple or complex contagions. Finally, fully recognizing that these novel big-data approaches carry great risks, FARE will develop a new strategy, mostly based on distributed computing, and guidelines to the ethical handling of human-related big-data.
Together, FARE will offer a comprehensive model to ask questions such as: 1) What role(s) cognitive biases play in FN spreading? 2) How does network architecture affect FNs spread? 3) How do biases and position on networks build on each other to impact propagation? 4) What monitoring and mitigation interventions are likely to be more efficient?
Moreover, the study of FN from such a conceptual perspective has the potential to profoundly increase our knowledge on human behaviour and information spread, beyond specific problems, with implications for communication (science, political), economics, and psychology.
Summary
Recent events, from the anti-vaccination movement, to Brexit and even to mob killings, have raised serious concerns about the influence of the so-called fake news (FN). False information is not new in human history, but the recent surge in online activity, coupled with poor digital literacy, consumer profiling, and large profits from ad revenues, created a perfect storm for the FN epidemic, with still unimaginable consequences.
This challenge is interdisciplinary and requires academic research to guide current calls for action issued by academics, governmental and non-governmental agencies, and the social network platforms themselves. FARE will enrich current efforts, which mostly confront FN spreading from an applied perspective, by offering a theoretical framework that allows to make testable predictions. FARE argues that sharing of FN is a deviation from pure rationality and brings together 1) state of the art knowledge in behavioural psychology, to assess the role that cognitive biases play in susceptibility to FN, and 2) current models in network science and epidemiology, to test whether FN spread more like simple or complex contagions. Finally, fully recognizing that these novel big-data approaches carry great risks, FARE will develop a new strategy, mostly based on distributed computing, and guidelines to the ethical handling of human-related big-data.
Together, FARE will offer a comprehensive model to ask questions such as: 1) What role(s) cognitive biases play in FN spreading? 2) How does network architecture affect FNs spread? 3) How do biases and position on networks build on each other to impact propagation? 4) What monitoring and mitigation interventions are likely to be more efficient?
Moreover, the study of FN from such a conceptual perspective has the potential to profoundly increase our knowledge on human behaviour and information spread, beyond specific problems, with implications for communication (science, political), economics, and psychology.
Max ERC Funding
1 499 844 €
Duration
Start date: 2020-10-01, End date: 2025-09-30
Project acronym GLUCOSE SENSING
Project Transcriptional networks in glucose sensing
Researcher (PI) Ville Ilmari Hietakangas
Host Institution (HI) HELSINGIN YLIOPISTO
Country Finland
Call Details Starting Grant (StG), LS4, ERC-2011-StG_20101109
Summary Glucose is key source of nutritional energy and raw material for biosynthetic processes. Maintaining glucose homeostasis requires a regulatory network that functions both in the systemic level through hormonal signaling and locally at the intracellular level. Insulin signalling is the main hormonal mechanism involved in maintaining the levels of circulating glucose through regulation of cellular glucose intake and metabolism. While the signalling pathways mediating the effects of insulin have been thoroughly studied, the transcriptional networks downstream of insulin signalling are not comprehensively understood. In addition to insulin signalling, intracellular glucose sensing mechanisms, including transcription factor complex MondoA/B-Mlx, have recently emerged as important regulators of glucose metabolism. In the proposed project we aim to take a systematic approach to characterize the transcriptional regulators involved in glucose sensing and metabolism in physiological context, using Drosophila as the main model system. We will use several complementary screening strategies, both in vivo and in cell culture, to identify transcription factors regulated by insulin and intracellular glucose. Identified transcription factors will be exposed to a panel of in vivo tests measuring parameters related to glucose and energy metabolism, aiming to identify those transcriptional regulators most essential in maintaining glucose homeostasis. With these factors, we will proceed to in-depth analysis, generating mutant alleles, analysing their metabolic profile and physiologically important target genes as well as functional conservation in mammals. Our aim is to identify and characterize several novel transcriptional regulators involved in glucose metabolism and to achieve a comprehensive overview on how these transcriptional regulators act together to achieve metabolic homeostasis in response to fluctuating dietary glucose intake.
Summary
Glucose is key source of nutritional energy and raw material for biosynthetic processes. Maintaining glucose homeostasis requires a regulatory network that functions both in the systemic level through hormonal signaling and locally at the intracellular level. Insulin signalling is the main hormonal mechanism involved in maintaining the levels of circulating glucose through regulation of cellular glucose intake and metabolism. While the signalling pathways mediating the effects of insulin have been thoroughly studied, the transcriptional networks downstream of insulin signalling are not comprehensively understood. In addition to insulin signalling, intracellular glucose sensing mechanisms, including transcription factor complex MondoA/B-Mlx, have recently emerged as important regulators of glucose metabolism. In the proposed project we aim to take a systematic approach to characterize the transcriptional regulators involved in glucose sensing and metabolism in physiological context, using Drosophila as the main model system. We will use several complementary screening strategies, both in vivo and in cell culture, to identify transcription factors regulated by insulin and intracellular glucose. Identified transcription factors will be exposed to a panel of in vivo tests measuring parameters related to glucose and energy metabolism, aiming to identify those transcriptional regulators most essential in maintaining glucose homeostasis. With these factors, we will proceed to in-depth analysis, generating mutant alleles, analysing their metabolic profile and physiologically important target genes as well as functional conservation in mammals. Our aim is to identify and characterize several novel transcriptional regulators involved in glucose metabolism and to achieve a comprehensive overview on how these transcriptional regulators act together to achieve metabolic homeostasis in response to fluctuating dietary glucose intake.
Max ERC Funding
1 496 930 €
Duration
Start date: 2012-01-01, End date: 2017-02-28
Project acronym GULAGECHOES
Project Gulag Echoes in the “multicultural prison”: historical and geographical influences on the identity and politics of ethnic minority prisoners in the communist successor states of Russia Europe.
Researcher (PI) Judith PALLOT
Host Institution (HI) HELSINGIN YLIOPISTO
Country Finland
Call Details Advanced Grant (AdG), SH3, ERC-2017-ADG
Summary "The project will examine the impact of the system of penality developed in the Soviet gulag on the ethnic identification and political radicalisation of prisoners in the Soviet Union and the communist successor states of Europe today. It is informed by the proposition that prisons are sites of ethnic identity construction but that the processes involved vary within and between states. In the project, the focus is on the extent to which particular ""prison-styles"" affect the social relationships, self-identification and political association of ethnic minority prisoners. After the collapse of the Soviet Union, the communist successor states all set about reforming their prison systems to bring them into line with international and European norms. However, all to a lesser or greater extent still have legacies of the system gestated in the Soviet Gulag and exported to East-Central-Europe after WWII. These may include the internal organisation of penal space, a collectivist approach to prisoner management, penal labour and, as in Russian case, a geographical distribution of the penal estate that results in prisoners being sent excessively long distances to serve their sentences. It is the how these legacies, interacting with other forces (including official and popular discourses, formal policy and individual life-histories) transform, confirm, and suppress the ethnic identification of prisoners that the project seeks to excavate. It will use a mixed method approach to answer research questions, including interviews with ex-prisoners and prisoners' families, the use of archival and documentary sources and social media. The research will use case studies to analyze the experiences of ethnic minority prisoners over time and through space. These provisionally will be Chechens, Tartars, Ukrainians, Estonians, migrant Uzbek and Tadjik workers and Roma and the country case studies are the Russian Federation, Georgia and Romania."
Summary
"The project will examine the impact of the system of penality developed in the Soviet gulag on the ethnic identification and political radicalisation of prisoners in the Soviet Union and the communist successor states of Europe today. It is informed by the proposition that prisons are sites of ethnic identity construction but that the processes involved vary within and between states. In the project, the focus is on the extent to which particular ""prison-styles"" affect the social relationships, self-identification and political association of ethnic minority prisoners. After the collapse of the Soviet Union, the communist successor states all set about reforming their prison systems to bring them into line with international and European norms. However, all to a lesser or greater extent still have legacies of the system gestated in the Soviet Gulag and exported to East-Central-Europe after WWII. These may include the internal organisation of penal space, a collectivist approach to prisoner management, penal labour and, as in Russian case, a geographical distribution of the penal estate that results in prisoners being sent excessively long distances to serve their sentences. It is the how these legacies, interacting with other forces (including official and popular discourses, formal policy and individual life-histories) transform, confirm, and suppress the ethnic identification of prisoners that the project seeks to excavate. It will use a mixed method approach to answer research questions, including interviews with ex-prisoners and prisoners' families, the use of archival and documentary sources and social media. The research will use case studies to analyze the experiences of ethnic minority prisoners over time and through space. These provisionally will be Chechens, Tartars, Ukrainians, Estonians, migrant Uzbek and Tadjik workers and Roma and the country case studies are the Russian Federation, Georgia and Romania."
Max ERC Funding
2 494 685 €
Duration
Start date: 2018-11-01, End date: 2023-10-31
Project acronym IL7sigNETure
Project IL-7/IL-7R signaling networks in health and malignancy
Researcher (PI) Joao Pedro Taborda Barata
Host Institution (HI) INSTITUTO DE MEDICINA MOLECULAR JOAO LOBO ANTUNES
Country Portugal
Call Details Consolidator Grant (CoG), LS4, ERC-2014-CoG
Summary Deregulation of signal transduction is a feature of tumor cells and signaling therapies are gaining importance in the growing arsenal against cancer. However, their full potential can only be achieved once we overcome the limited knowledge on how signaling networks are wired in cancer cells. Interleukin 7 (IL7) and its receptor (IL7R) are essential for normal T-cell development and function. However, they can also promote autoimmunity, chronic inflammation and cancer. We showed that patients with T-cell acute lymphoblastic leukemia (T-ALL), an aggressive hematological cancer, can display IL7R gain-of-function mutations leading to downstream signaling activation and cell transformation. Despite the biological relevance of IL7 and IL7R, the characterization of their signaling effectors remains limited. Here, we propose to move from the single molecule/pathway-centered analysis that has characterized the research on IL7/IL7R signaling, into a ‘holistic’ view of the IL7/IL7R signaling landscape. To do so, we will employ a multidisciplinary strategy, in which data from complementary high throughput analyses, informing on different levels of regulation of the IL7/IL7R signaling network, will be integrated via a systems biology approach, and complemented by cell and molecular biology experimentation and state-of-the-art in vivo models. The knowledge we will generate should have a profound impact on the understanding of the fundamental mechanisms by which IL7/IL7R signaling promotes leukemia and reveal novel targets for fine-tuned therapeutic intervention in T-ALL. Moreover, the scope of insights gained should extend beyond leukemia. Our in-depth, systems-level characterization of IL7/IL7R signaling will constitute a platform with extraordinary potential to illuminate the molecular role of the IL7/IL7R axis in other cancers (e.g. breast and lung) and pathological settings where IL7 has been implicated, such as HIV infection, multiple sclerosis and rheumatoid arthritis.
Summary
Deregulation of signal transduction is a feature of tumor cells and signaling therapies are gaining importance in the growing arsenal against cancer. However, their full potential can only be achieved once we overcome the limited knowledge on how signaling networks are wired in cancer cells. Interleukin 7 (IL7) and its receptor (IL7R) are essential for normal T-cell development and function. However, they can also promote autoimmunity, chronic inflammation and cancer. We showed that patients with T-cell acute lymphoblastic leukemia (T-ALL), an aggressive hematological cancer, can display IL7R gain-of-function mutations leading to downstream signaling activation and cell transformation. Despite the biological relevance of IL7 and IL7R, the characterization of their signaling effectors remains limited. Here, we propose to move from the single molecule/pathway-centered analysis that has characterized the research on IL7/IL7R signaling, into a ‘holistic’ view of the IL7/IL7R signaling landscape. To do so, we will employ a multidisciplinary strategy, in which data from complementary high throughput analyses, informing on different levels of regulation of the IL7/IL7R signaling network, will be integrated via a systems biology approach, and complemented by cell and molecular biology experimentation and state-of-the-art in vivo models. The knowledge we will generate should have a profound impact on the understanding of the fundamental mechanisms by which IL7/IL7R signaling promotes leukemia and reveal novel targets for fine-tuned therapeutic intervention in T-ALL. Moreover, the scope of insights gained should extend beyond leukemia. Our in-depth, systems-level characterization of IL7/IL7R signaling will constitute a platform with extraordinary potential to illuminate the molecular role of the IL7/IL7R axis in other cancers (e.g. breast and lung) and pathological settings where IL7 has been implicated, such as HIV infection, multiple sclerosis and rheumatoid arthritis.
Max ERC Funding
1 988 125 €
Duration
Start date: 2015-09-01, End date: 2021-08-31
