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 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 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 METABOMIT
Project Metabolic consequences of mitochondrial dysfunction
Researcher (PI) Anu Elina Wartiovaara
Host Institution (HI) HELSINGIN YLIOPISTO
Country Finland
Call Details Advanced Grant (AdG), LS4, ERC-2010-AdG_20100317
Summary This proposal aims to clarify mitochondrial contribution to obesity and thinness, using carefully characterized mitochondrial disease and obese patient materials, and genetically modified disease models. Manifestations of mitochondrial respiratory chain (RC) defects range from infantile multisystem disorders to adult-onset myopathies or neurodegeneration, and even aging-related wasting. Why defects in oxidative ATP production can lead to such variety of manifestations and tissue specificity is unknown. We have previously identified a number of gene defects that lead to RC disorders. In addition to neurological symptoms, these patients often show various metabolic manifestations: specific gene defects associate with short stature and thinness, whereas others with metabolic syndrome or obesity. This implies that specific mitochondrial defects can have opposing effects for fat storage or utilization. The involved pathways may contribute to mitochondrial disease progression, but are unknown.
We propose to a) undertake a major clinical study on genetically defined, obese or thin, mitochondrial patients, and examine their metabolic phenotype in finest detail. These data will be compared to those from normal obesity, to search for common mechanisms between mitochondrial and general obesity. b) generate a set of disease models for mitochondrial disorders associated with obesity, and knock-out models for specific signallers for crossing with the disease models. c) identify in detail the involved regulatory pathways, and utilize these for searching chemical compounds that could modulate the response, and have therapeutic potential. The project has potential for major breakthroughs in the fields of mitochondrial disease pathogenesis and treatment, neurodegeneration and obesity.
Summary
This proposal aims to clarify mitochondrial contribution to obesity and thinness, using carefully characterized mitochondrial disease and obese patient materials, and genetically modified disease models. Manifestations of mitochondrial respiratory chain (RC) defects range from infantile multisystem disorders to adult-onset myopathies or neurodegeneration, and even aging-related wasting. Why defects in oxidative ATP production can lead to such variety of manifestations and tissue specificity is unknown. We have previously identified a number of gene defects that lead to RC disorders. In addition to neurological symptoms, these patients often show various metabolic manifestations: specific gene defects associate with short stature and thinness, whereas others with metabolic syndrome or obesity. This implies that specific mitochondrial defects can have opposing effects for fat storage or utilization. The involved pathways may contribute to mitochondrial disease progression, but are unknown.
We propose to a) undertake a major clinical study on genetically defined, obese or thin, mitochondrial patients, and examine their metabolic phenotype in finest detail. These data will be compared to those from normal obesity, to search for common mechanisms between mitochondrial and general obesity. b) generate a set of disease models for mitochondrial disorders associated with obesity, and knock-out models for specific signallers for crossing with the disease models. c) identify in detail the involved regulatory pathways, and utilize these for searching chemical compounds that could modulate the response, and have therapeutic potential. The project has potential for major breakthroughs in the fields of mitochondrial disease pathogenesis and treatment, neurodegeneration and obesity.
Max ERC Funding
2 500 000 €
Duration
Start date: 2011-06-01, End date: 2016-05-31
Project acronym MITO BY-PASS
Project Molecular by-pass therapy for mitochondrial dysfunction
Researcher (PI) Howard Trevor Jacobs
Host Institution (HI) TAMPEREEN YLIOPISTO
Country Finland
Call Details Advanced Grant (AdG), LS4, ERC-2008-AdG
Summary Many eukaryotes, but not the higher metazoans such as vertebrates or arthropods, possess intrinsic by-pass systems that provide alternative routes for electron flow from NADH to oxygen. Whereas the standard mitochondrial OXPHOS system couples electron transport to proton pumping across the inner mitochondrial membrane, creating the proton gradient which is used to drive ATP synthesis and other energy-requiring processes, the by-pass enzymes are non-proton-pumping, and their activity is redox-regulated rather than subject to ATP requirements. My laboratory has engineered two of these by-pass enzymes, the single-subunit NADH dehydrogenase Ndi1p from yeast, and the alternative oxidase AOX from Ciona intestinalis, for expression in Drosophila and mammalian cells. Their expression is benign, and the enzymes appear to be almost inert, except under conditions of redox stress induced by OXPHOS toxins or mutations. The research set out in this proposal will explore the utility of these by-passes for alleviating metabolic stress in the whole organism and in specific tissues, arising from mitochondrial OXPHOS dysfunction. Specifically, I will test the ability of Ndi1p and AOX in Drosophila and in mammalian models to compensate for the toxicity of OXPHOS poisons, to complement disease-equivalent mutations impairing the assembly or function of the OXPHOS system, and to diminish the pathological excess production of reactive oxygen species seen in many neurodegenerative disorders associated with OXPHOS impairment, and under conditions of ischemia-reperfusion. The attenuation of endogenous mitochondrial ROS production by deployment of these by-pass enzymes also offers a novel route to testing the mitochondrial (oxyradical) theory of ageing.
Summary
Many eukaryotes, but not the higher metazoans such as vertebrates or arthropods, possess intrinsic by-pass systems that provide alternative routes for electron flow from NADH to oxygen. Whereas the standard mitochondrial OXPHOS system couples electron transport to proton pumping across the inner mitochondrial membrane, creating the proton gradient which is used to drive ATP synthesis and other energy-requiring processes, the by-pass enzymes are non-proton-pumping, and their activity is redox-regulated rather than subject to ATP requirements. My laboratory has engineered two of these by-pass enzymes, the single-subunit NADH dehydrogenase Ndi1p from yeast, and the alternative oxidase AOX from Ciona intestinalis, for expression in Drosophila and mammalian cells. Their expression is benign, and the enzymes appear to be almost inert, except under conditions of redox stress induced by OXPHOS toxins or mutations. The research set out in this proposal will explore the utility of these by-passes for alleviating metabolic stress in the whole organism and in specific tissues, arising from mitochondrial OXPHOS dysfunction. Specifically, I will test the ability of Ndi1p and AOX in Drosophila and in mammalian models to compensate for the toxicity of OXPHOS poisons, to complement disease-equivalent mutations impairing the assembly or function of the OXPHOS system, and to diminish the pathological excess production of reactive oxygen species seen in many neurodegenerative disorders associated with OXPHOS impairment, and under conditions of ischemia-reperfusion. The attenuation of endogenous mitochondrial ROS production by deployment of these by-pass enzymes also offers a novel route to testing the mitochondrial (oxyradical) theory of ageing.
Max ERC Funding
2 436 000 €
Duration
Start date: 2009-04-01, End date: 2015-03-31
Project acronym Near-infrared probes
Project Near-infrared fluorescent probes based on bacterial phytochromes for in vivo imaging
Researcher (PI) Vladislav Verkhusha
Host Institution (HI) HELSINGIN YLIOPISTO
Country Finland
Call Details Advanced Grant (AdG), LS9, ERC-2013-ADG
Summary Non-invasive monitoring of deep-tissue developmental, metabolic and pathogenic processes will advance modern biology. Imaging of live mammals using fluorescent probes is more feasible within the near-infrared (NIR) transparency window (NIRW: 650-900 nm) where hemoglobin and melanin absorbance significantly decreases, and water absorbance is still low. The most red-shifted fluorescent proteins (FPs) of the GFP-like family exhibit fluorescence outside of the NIRW and suffer from low brightness and modest photostability. Natural bacterial phytochrome photoreceptors (BphPs) utilize low molecular weight biliverdin as a chromophore and provide many advantages over other chromophore binding proteins. First, unlike the chromophores of non-bacterial phytochromes, biliverdin is ubiquitous in mammals. This makes BphP applications in mammalian cells, tissues and mammals as easy as conventional GFP-like FPs, without supplying chromophore through an external solution. Second, BphPs exhibit NIR absorbance and fluorescence, which are red-shifted relative to that of any other phytochromes, and lie within the NIRW. This makes BphPs spectrally complementary to GFP-like FPs and available optogenetic tools. Third, independent domain architecture and conformational changes upon biliverdin photoisomerization make BphPs attractive templates to design various photoactivatable probes. Based on the analysis of the photochemistry and structural changes of BphPs we plan to develop three new types of the BphP-based probes. These include bright and spectrally resolvable permanently fluorescent NIRFPs, NIRFPs photoswitchable either irreversibly or repeatedly with non-phototoxic NIR light, and NIR reporters and biosensors. The resulting NIR probes will extend fluorescence imaging methods to deep-tissue in vivo macroscopy including multicolor cell and tissue labeling, cell photoactivation and tracking, detection of enzymatic activities and protein interactions in mammalian tissues and whole animals.
Summary
Non-invasive monitoring of deep-tissue developmental, metabolic and pathogenic processes will advance modern biology. Imaging of live mammals using fluorescent probes is more feasible within the near-infrared (NIR) transparency window (NIRW: 650-900 nm) where hemoglobin and melanin absorbance significantly decreases, and water absorbance is still low. The most red-shifted fluorescent proteins (FPs) of the GFP-like family exhibit fluorescence outside of the NIRW and suffer from low brightness and modest photostability. Natural bacterial phytochrome photoreceptors (BphPs) utilize low molecular weight biliverdin as a chromophore and provide many advantages over other chromophore binding proteins. First, unlike the chromophores of non-bacterial phytochromes, biliverdin is ubiquitous in mammals. This makes BphP applications in mammalian cells, tissues and mammals as easy as conventional GFP-like FPs, without supplying chromophore through an external solution. Second, BphPs exhibit NIR absorbance and fluorescence, which are red-shifted relative to that of any other phytochromes, and lie within the NIRW. This makes BphPs spectrally complementary to GFP-like FPs and available optogenetic tools. Third, independent domain architecture and conformational changes upon biliverdin photoisomerization make BphPs attractive templates to design various photoactivatable probes. Based on the analysis of the photochemistry and structural changes of BphPs we plan to develop three new types of the BphP-based probes. These include bright and spectrally resolvable permanently fluorescent NIRFPs, NIRFPs photoswitchable either irreversibly or repeatedly with non-phototoxic NIR light, and NIR reporters and biosensors. The resulting NIR probes will extend fluorescence imaging methods to deep-tissue in vivo macroscopy including multicolor cell and tissue labeling, cell photoactivation and tracking, detection of enzymatic activities and protein interactions in mammalian tissues and whole animals.
Max ERC Funding
2 496 946 €
Duration
Start date: 2014-05-01, End date: 2019-04-30
Project acronym PRESSBIRTH
Project Arginine vasopressin and ion transporters in the modulation of brain excitability during birth and birth asphyxia seizures
Researcher (PI) Kai Kalervo Kaila
Host Institution (HI) HELSINGIN YLIOPISTO
Country Finland
Call Details Advanced Grant (AdG), LS4, ERC-2013-ADG
Summary A transient period of asphyxia in the newborn is an obligatory part of normal parturition. A more prolonged disturbance in cerebral blood supply is a major cause of neonatal seizures. Current therapies of birth asphyxia seizures are ineffective and the underlying mechanisms are unknown.
Our recent landmark work on a rat model of birth asphyxia showed that asphyxia is followed by brain alkalosis, which triggers seizures. The brain-confined alkalosis is generated by activation of Na/H exchange in the blood-brain barrier (BBB). Both alkalosis and the consequent seizures can be suppressed by graded restoration of the high CO2 level after asphyxia and with blockers of Na/H exchange.
Our pilot data indicate that arginine vasopressin (AVP) triggers the post-asphyxia seizures by activating the BBB-located luminal V1a receptor-coupled Na/H exchanger. Akin to human infants, a very high level of plasma copeptin (a part of pro-AVP) is seen following asphyxia but, notably, the copeptin levels remain low with graded restoration of normocapnia. Moreover, intravenous AVP V1a receptor antagonists, acting on the BBB, block the generation of seizures. In striking contrast, AVP suppresses network excitability when acting on V1aRs in the neonate hippocampus.
Thus, I hypothesize that AVP acts on the BBB to promote neonatal seizures, and that this effect is paralleled by a central anticonvulsant action. Next to nothing is known about AVP actions on ionic regulation in the brain. Our pilot data indicate that AVP inhibits the Na-K-2Cl cotransporter NKCC1 and activates the K-Cl cotransporter KCC2 in a manner consistent with reduction of excitability.
My laboratory has an internationally leading role in work on neuronal pH and Cl- regulation and on functions of the immature brain. Understanding the mechanisms of AVP actions during normal birth and birth asphyxia will provide novel insights on the control of the excitability of the newborn brain. This work has a high translational impact.
Summary
A transient period of asphyxia in the newborn is an obligatory part of normal parturition. A more prolonged disturbance in cerebral blood supply is a major cause of neonatal seizures. Current therapies of birth asphyxia seizures are ineffective and the underlying mechanisms are unknown.
Our recent landmark work on a rat model of birth asphyxia showed that asphyxia is followed by brain alkalosis, which triggers seizures. The brain-confined alkalosis is generated by activation of Na/H exchange in the blood-brain barrier (BBB). Both alkalosis and the consequent seizures can be suppressed by graded restoration of the high CO2 level after asphyxia and with blockers of Na/H exchange.
Our pilot data indicate that arginine vasopressin (AVP) triggers the post-asphyxia seizures by activating the BBB-located luminal V1a receptor-coupled Na/H exchanger. Akin to human infants, a very high level of plasma copeptin (a part of pro-AVP) is seen following asphyxia but, notably, the copeptin levels remain low with graded restoration of normocapnia. Moreover, intravenous AVP V1a receptor antagonists, acting on the BBB, block the generation of seizures. In striking contrast, AVP suppresses network excitability when acting on V1aRs in the neonate hippocampus.
Thus, I hypothesize that AVP acts on the BBB to promote neonatal seizures, and that this effect is paralleled by a central anticonvulsant action. Next to nothing is known about AVP actions on ionic regulation in the brain. Our pilot data indicate that AVP inhibits the Na-K-2Cl cotransporter NKCC1 and activates the K-Cl cotransporter KCC2 in a manner consistent with reduction of excitability.
My laboratory has an internationally leading role in work on neuronal pH and Cl- regulation and on functions of the immature brain. Understanding the mechanisms of AVP actions during normal birth and birth asphyxia will provide novel insights on the control of the excitability of the newborn brain. This work has a high translational impact.
Max ERC Funding
2 497 419 €
Duration
Start date: 2014-02-01, End date: 2019-01-31
