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
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 CANCER&AGEING
Project COMMOM MECHANISMS UNDERLYING CANCER AND AGEING
Researcher (PI) Manuel Serrano
Host Institution (HI) FUNDACION CENTRO NACIONAL DE INVESTIGACIONES ONCOLOGICAS CARLOS III
Call Details Advanced Grant (AdG), LS1, ERC-2008-AdG
Summary "In recent years, we have made significant contributions to the understanding of the tumour suppressors p53, p16INK4a, and ARF, particularly in relation with cellular senescence and aging. The current project is motivated by two hypothesis: 1) that the INK4/ARF locus is a sensor of epigenetic damage and this is at the basis of its activation by oncogenes and aging; and, 2) that the accumulation of cellular damage and stress is at the basis of both cancer and aging, and consequently ""anti-damage genes"", such as tumour suppressors, simultaneously counteract both cancer and aging. With regard to the INK4/ARF locus, the project includes: 1.1) the generation of null mice for the Regulatory Domain (RD) thought to be essential for the proper regulation of the locus; 1.2) the study of the INK4/ARF anti-sense transcription and its importance for the assembly of Polycomb repressive complexes; 1.3) the generation of mice carrying the human INK4/ARF locus to analyze, among other aspects, whether the known differences between the human and murine loci are ""locus autonomous""; and, 1.4) to analyze the INK4/ARF locus in the process of epigenetic reprogramming both from ES cells to differentiated cells and, conversely, from differentiated cells to induced-pluripotent stem (iPS) cells. With regard to the impact of ""anti-damage genes"" on cancer and aging, the project includes: 2.1) the analysis of the aging of super-INK4/ARF mice and super-p53 mice; 2.2) we have generated super-PTEN mice and we will examine whether PTEN not only confers cancer resistance but also anti-aging activity; and, finally, 2.3) we have generated super-SIRT1 mice, which is among the best-characterized anti-aging genes in non-mammalian model systems (where it is named Sir2) involved in protection from metabolic damage, and we will study the cancer and aging of these mice. Together, this project will significantly advance our understanding of the molecular mechanisms underlying cancer and aging."
Summary
"In recent years, we have made significant contributions to the understanding of the tumour suppressors p53, p16INK4a, and ARF, particularly in relation with cellular senescence and aging. The current project is motivated by two hypothesis: 1) that the INK4/ARF locus is a sensor of epigenetic damage and this is at the basis of its activation by oncogenes and aging; and, 2) that the accumulation of cellular damage and stress is at the basis of both cancer and aging, and consequently ""anti-damage genes"", such as tumour suppressors, simultaneously counteract both cancer and aging. With regard to the INK4/ARF locus, the project includes: 1.1) the generation of null mice for the Regulatory Domain (RD) thought to be essential for the proper regulation of the locus; 1.2) the study of the INK4/ARF anti-sense transcription and its importance for the assembly of Polycomb repressive complexes; 1.3) the generation of mice carrying the human INK4/ARF locus to analyze, among other aspects, whether the known differences between the human and murine loci are ""locus autonomous""; and, 1.4) to analyze the INK4/ARF locus in the process of epigenetic reprogramming both from ES cells to differentiated cells and, conversely, from differentiated cells to induced-pluripotent stem (iPS) cells. With regard to the impact of ""anti-damage genes"" on cancer and aging, the project includes: 2.1) the analysis of the aging of super-INK4/ARF mice and super-p53 mice; 2.2) we have generated super-PTEN mice and we will examine whether PTEN not only confers cancer resistance but also anti-aging activity; and, finally, 2.3) we have generated super-SIRT1 mice, which is among the best-characterized anti-aging genes in non-mammalian model systems (where it is named Sir2) involved in protection from metabolic damage, and we will study the cancer and aging of these mice. Together, this project will significantly advance our understanding of the molecular mechanisms underlying cancer and aging."
Max ERC Funding
2 000 000 €
Duration
Start date: 2009-04-01, End date: 2015-03-31
Project acronym ECHO
Project Early conditions, delayed adult effects and morbidity, disability and mortality in modern human populations
Researcher (PI) Alberto Palloni
Host Institution (HI) AGENCIA ESTATAL CONSEJO SUPERIOR DEINVESTIGACIONES CIENTIFICAS
Call Details Advanced Grant (AdG), SH3, ERC-2017-ADG
Summary This project aims to reformulate and generalize standard theories of human health and mortality. It proposes new formal models and a systematic agenda to empirically test hypotheses that link developmental biology, epigenetics and adult human illness, disability and mortality. We seek to break new ground developing innovative formal models for illnesses and mortality, testing new hypotheses about the evolution of human health and, to the extent permitted by findings, reformulating standard theories to make them applicable to a less restrictive segment of populations than they are now. Over the past two decades there has been massive growth of research on the nature of delayed adult effects of conditions experienced in early life. This field of research is known as the Developmental Origins of Adult Health and Disease (DOHaD). Increasing evidence suggests that the mechanisms that are implicated are epigenetic and constitute an evolved adaptation selected over thousands of years to improve fitness in changing landscapes. The emergence of DOHaD is as close as we will ever come to a paradigmatic shift in the study of human health, disability and mortality. The most tantalizing possibility is that advances in our understanding of epigenetic mechanisms will shed light on pathways linking early exposures and delayed adult health thus fundamentally transforming our understanding of human illnesses and, in one fell swoop, bridge population health, epigenetics, and developmental and evolutionary biology. The overarching goal of this project is to contribute to this nascent area of study by (a) proposing new formal demographic models of health, disability and mortality; (b) empirically testing DOHaD predictions with population data; (c) testing a microsimulation model to verify DOHaD predictions about two conditions, obesity and Type 2 Diabetes, and (d) assessing the adult health, disability and mortality toll implicated by relations between early conditions, obesity and T2D.
Summary
This project aims to reformulate and generalize standard theories of human health and mortality. It proposes new formal models and a systematic agenda to empirically test hypotheses that link developmental biology, epigenetics and adult human illness, disability and mortality. We seek to break new ground developing innovative formal models for illnesses and mortality, testing new hypotheses about the evolution of human health and, to the extent permitted by findings, reformulating standard theories to make them applicable to a less restrictive segment of populations than they are now. Over the past two decades there has been massive growth of research on the nature of delayed adult effects of conditions experienced in early life. This field of research is known as the Developmental Origins of Adult Health and Disease (DOHaD). Increasing evidence suggests that the mechanisms that are implicated are epigenetic and constitute an evolved adaptation selected over thousands of years to improve fitness in changing landscapes. The emergence of DOHaD is as close as we will ever come to a paradigmatic shift in the study of human health, disability and mortality. The most tantalizing possibility is that advances in our understanding of epigenetic mechanisms will shed light on pathways linking early exposures and delayed adult health thus fundamentally transforming our understanding of human illnesses and, in one fell swoop, bridge population health, epigenetics, and developmental and evolutionary biology. The overarching goal of this project is to contribute to this nascent area of study by (a) proposing new formal demographic models of health, disability and mortality; (b) empirically testing DOHaD predictions with population data; (c) testing a microsimulation model to verify DOHaD predictions about two conditions, obesity and Type 2 Diabetes, and (d) assessing the adult health, disability and mortality toll implicated by relations between early conditions, obesity and T2D.
Max ERC Funding
2 852 655 €
Duration
Start date: 2019-03-01, End date: 2024-02-29
Project acronym EnvJustice
Project A GLOBAL MOVEMENT FOR ENVIRONMENTAL JUSTICE: The EJAtlas
Researcher (PI) Joan MARTÍNEZ ALIER
Host Institution (HI) UNIVERSITAT AUTONOMA DE BARCELONA
Call Details Advanced Grant (AdG), SH3, ERC-2015-AdG
Summary "The Environmental Justice Atlas (www.ejatlas.org) is a global database built by us, drawing on activist and academic knowledge. It maps 1500 conflicts. To improve geographical and thematic coverage it will grow to 3000 by 2019. It systematizes conflicts across 100+ fields documenting the commodities at stake, the actors involved, impacts, forms of mobilizations and outcomes allowing analyses that will lead to a general theory of ecological distribution conflicts.
We shall research the links between changes in social metabolism and resource extraction conflicts at the “commodity frontiers”. Also other questions in political ecology and social movement theory such as the effectiveness of direct action by grassroots protesters compared to institutional forms of contention. Does the involvement of different actors, e.g. indigenous groups, relate to different conflict outcomes? How often does the IUCN ally itself to ""the environmentalism of the poor""? Do mobilizations and outcomes vary across sectors (mining, hydroelectric dams, waste incinerators) according to project differences in economic and biophysical dimensions, environmental and health risks? Are conflicts on point resources (mining, oil extraction) regularly different from conflicts in agriculture? Can we track networked resistances against Western companies, compared to those from China or other countries?
Resistance to environmental damage has brought into being many local and some international EJOs pushing for alternative social transformations. We shall study the Vocabulary of Environmental Justice they deploy: climate justice, water justice, food sovereignty, biopiracy, sacrifice zones, and other terms specific to countries: Chinese “cancer villages”, Indian “sand mafias”, Brazilian “green deserts” (eucalyptus plantations). Finally, are there signs of an alliance between the Global Environmental Justice Movement and the small European movement for “prosperity without growth”, décroissance, Post-Wachstum?"
Summary
"The Environmental Justice Atlas (www.ejatlas.org) is a global database built by us, drawing on activist and academic knowledge. It maps 1500 conflicts. To improve geographical and thematic coverage it will grow to 3000 by 2019. It systematizes conflicts across 100+ fields documenting the commodities at stake, the actors involved, impacts, forms of mobilizations and outcomes allowing analyses that will lead to a general theory of ecological distribution conflicts.
We shall research the links between changes in social metabolism and resource extraction conflicts at the “commodity frontiers”. Also other questions in political ecology and social movement theory such as the effectiveness of direct action by grassroots protesters compared to institutional forms of contention. Does the involvement of different actors, e.g. indigenous groups, relate to different conflict outcomes? How often does the IUCN ally itself to ""the environmentalism of the poor""? Do mobilizations and outcomes vary across sectors (mining, hydroelectric dams, waste incinerators) according to project differences in economic and biophysical dimensions, environmental and health risks? Are conflicts on point resources (mining, oil extraction) regularly different from conflicts in agriculture? Can we track networked resistances against Western companies, compared to those from China or other countries?
Resistance to environmental damage has brought into being many local and some international EJOs pushing for alternative social transformations. We shall study the Vocabulary of Environmental Justice they deploy: climate justice, water justice, food sovereignty, biopiracy, sacrifice zones, and other terms specific to countries: Chinese “cancer villages”, Indian “sand mafias”, Brazilian “green deserts” (eucalyptus plantations). Finally, are there signs of an alliance between the Global Environmental Justice Movement and the small European movement for “prosperity without growth”, décroissance, Post-Wachstum?"
Max ERC Funding
1 910 811 €
Duration
Start date: 2016-06-01, End date: 2021-05-31
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
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 MASCP
Project Mechanisms of alternative pre-mRNA splicing regulation in cancer and pluripotent cells
Researcher (PI) Juan Alberto Valcárcel Juárez
Host Institution (HI) FUNDACIO CENTRE DE REGULACIO GENOMICA
Call Details Advanced Grant (AdG), LS1, ERC-2014-ADG
Summary Alternative splicing of messenger RNA precursors is a prevalent form of gene regulation that greatly expands the coding capacity and regulatory opportunities of higher eukaryotic genomes. It contributes to cell differentiation and pluripotency and its deregulation promotes cancer progression, as evidenced by the frequent occurrence of cancer-associated mutations in splicing factors, which are also targets of anti-tumor drugs. Despite its prevalence and relevance, the underlying mechanisms of regulation remain poorly understood. This proposal aims to develop and apply systematic approaches that can allow us to carry out the equivalent of genetic analysis of splicing regulation in cancer and pluripotent cells. These technologies can help to unweave the complex network of functional interactions within the spliceosome and of the spliceosome with regulatory factors, exhaustively map the contribution of regulatory sequences and be used to investigate, with unprecedented detail, mechanisms of regulation for essentially any regulator or alternative splicing event operating in a particular cell line. Such approaches can offer a unique opportunity to address key unresolved mechanistic questions, including the molecular basis for positional effects of splicing regulatory factors (RNA Maps), the regulatory potential of the core spliceosome and the integration of alternative splicing with other cell regulatory programs. We will combine these approaches with biochemical and cellular assays to investigate detailed mechanisms of regulation relevant for the control of cell proliferation and/or pluripotency in cancer and induced pluripotent stem (iPS) cells. Progress in this area can contribute to reveal the molecular logic governing a key layer of gene regulation and has the potential to discover novel factors and regulatory circuits that trigger or modulate cell growth, differentiation and cancer progression.
Summary
Alternative splicing of messenger RNA precursors is a prevalent form of gene regulation that greatly expands the coding capacity and regulatory opportunities of higher eukaryotic genomes. It contributes to cell differentiation and pluripotency and its deregulation promotes cancer progression, as evidenced by the frequent occurrence of cancer-associated mutations in splicing factors, which are also targets of anti-tumor drugs. Despite its prevalence and relevance, the underlying mechanisms of regulation remain poorly understood. This proposal aims to develop and apply systematic approaches that can allow us to carry out the equivalent of genetic analysis of splicing regulation in cancer and pluripotent cells. These technologies can help to unweave the complex network of functional interactions within the spliceosome and of the spliceosome with regulatory factors, exhaustively map the contribution of regulatory sequences and be used to investigate, with unprecedented detail, mechanisms of regulation for essentially any regulator or alternative splicing event operating in a particular cell line. Such approaches can offer a unique opportunity to address key unresolved mechanistic questions, including the molecular basis for positional effects of splicing regulatory factors (RNA Maps), the regulatory potential of the core spliceosome and the integration of alternative splicing with other cell regulatory programs. We will combine these approaches with biochemical and cellular assays to investigate detailed mechanisms of regulation relevant for the control of cell proliferation and/or pluripotency in cancer and induced pluripotent stem (iPS) cells. Progress in this area can contribute to reveal the molecular logic governing a key layer of gene regulation and has the potential to discover novel factors and regulatory circuits that trigger or modulate cell growth, differentiation and cancer progression.
Max ERC Funding
2 159 574 €
Duration
Start date: 2015-10-01, End date: 2020-09-30
Project acronym MOLRHEOSTAT
Project Downhill Folding Protein Modules as Conformational Rheostats: Roles in Molecular Biology and Applications as Biosensors
Researcher (PI) Victor Muñoz
Host Institution (HI) FUNDACION IMDEA NANOCIENCIA
Call Details Advanced Grant (AdG), LS1, ERC-2012-ADG_20120314
Summary Protein folding and function is a perfect arena towards growing the grassroots of quantitative and synthetic biology. This is so because all cellular processes controlled by proteins can ultimately be traced back to physico-chemical properties encoded in their aminoacid sequences. MOLRHEOSTAT is framed within these goals, focusing on the investigation of novel connections between protein folding and function via a multidisciplinary approach that combines experiment (single molecule spectroscopy, high-resolution NMR, protein engineering and design), theory and computer simulations.
Conventionally, proteins are portrayed as conformational switches that fold and function by flipping between an on-state (native, active) and an off-state (inactive, unfolded) in response to stimuli. However, last years have witnessed the discovery of protein modules that undergo continuous conformational changes upon unfolding (downhill folding). MOLRHEOSTAT aims at investigating the functional and technological implications of downhill folding. The goal is to determine whether downhill folding modules can be exploited to build conformational rheostats; that is, proteins that continuously modulate a signal or response at the single molecule level by tuning their folding conformational ensemble. Conformational rheostats could open a new realm of applications as synthetic biomolecular devices as well as regulatory mechanisms for controlling complex biochemical processes carried out by macromolecular assemblies. These ideas will be explored on two specific objectives:
1) Implementation of a general approach for building high-performance, ultrafast, single-molecule sensors based on downhill protein folding modules.
2) Analysis of the roles of conformational rheostats in the regulation of three fundamental processes in molecular biology (coordination in protein networks, DNA sliding and homing-to-target of transcription factors, and molecular springs in macromolecular assemblies).
Summary
Protein folding and function is a perfect arena towards growing the grassroots of quantitative and synthetic biology. This is so because all cellular processes controlled by proteins can ultimately be traced back to physico-chemical properties encoded in their aminoacid sequences. MOLRHEOSTAT is framed within these goals, focusing on the investigation of novel connections between protein folding and function via a multidisciplinary approach that combines experiment (single molecule spectroscopy, high-resolution NMR, protein engineering and design), theory and computer simulations.
Conventionally, proteins are portrayed as conformational switches that fold and function by flipping between an on-state (native, active) and an off-state (inactive, unfolded) in response to stimuli. However, last years have witnessed the discovery of protein modules that undergo continuous conformational changes upon unfolding (downhill folding). MOLRHEOSTAT aims at investigating the functional and technological implications of downhill folding. The goal is to determine whether downhill folding modules can be exploited to build conformational rheostats; that is, proteins that continuously modulate a signal or response at the single molecule level by tuning their folding conformational ensemble. Conformational rheostats could open a new realm of applications as synthetic biomolecular devices as well as regulatory mechanisms for controlling complex biochemical processes carried out by macromolecular assemblies. These ideas will be explored on two specific objectives:
1) Implementation of a general approach for building high-performance, ultrafast, single-molecule sensors based on downhill protein folding modules.
2) Analysis of the roles of conformational rheostats in the regulation of three fundamental processes in molecular biology (coordination in protein networks, DNA sliding and homing-to-target of transcription factors, and molecular springs in macromolecular assemblies).
Max ERC Funding
2 290 319 €
Duration
Start date: 2013-05-01, End date: 2018-04-30
Project acronym NANO-MEMEC
Project Membrane-based nano-mechanobiology: Role of mechanical forces in remodelling the spatiotemporal nanoarchitecture of the plasma membrane
Researcher (PI) María Filomena García Parajo
Host Institution (HI) FUNDACIO INSTITUT DE CIENCIES FOTONIQUES
Call Details Advanced Grant (AdG), LS1, ERC-2017-ADG
Summary Through evolution, cells have developed the exquisite ability to sense, transduce and integrate mechanical and biochemical signals (i.e. mechanobiology) to generate appropriate responses. These key events are rooted at the molecular and nanoscale levels, a size regime difficult to access, hindering our progress towards mechanistic understanding of mechanobiology. Recent evidence from my Lab (and others) shows that the lateral nanoscale organisation of mechanosensitive membrane receptors and signalling molecules is crucial for cell function. Yet, current models of mechanosensing are based on force-induced molecular conformations, completely overlooking the chief role of mechanical forces on the nanoscale spatiotemporal organisation of the plasma membrane.
The GOAL of NANO-MEMEC is to provide mechanistic understanding on the role of mechanical stimuli in the spatiotemporal nanoarchitecture of adhesion signalling platforms at the cell membrane. To overcome the technical challenges of probing these processes at the relevant spatiotemporal scales, I will exploit cuttingedge biophysical tools exclusively developed in my Lab that combine super-resolution optical nanoscopy and single molecule dynamics in conjunction with simultaneous mechanical stimulation of living cells. Using this integrated approach, I will: First: dissect mechanical and biochemical coupling of membrane mechanosensing at the nanoscale. Second: visualise the coordinated recruitment of integrin-associated signalling proteins in response to force, i.e., mechanotransduction. Third: test how force-induced spatiotemporal membrane remodelling influences the migratory capacity of immune cells, i.e., mechanoresponse. NANO-MEMEC conveys a new fundamental concept to the field of mechanobiology: the roles of mechanical stimuli in the
dynamic remodelling of membrane nanocompartments, modulating signal transduction and ultimately affecting cell response, opening new-fangled research avenues in the years to come.
Summary
Through evolution, cells have developed the exquisite ability to sense, transduce and integrate mechanical and biochemical signals (i.e. mechanobiology) to generate appropriate responses. These key events are rooted at the molecular and nanoscale levels, a size regime difficult to access, hindering our progress towards mechanistic understanding of mechanobiology. Recent evidence from my Lab (and others) shows that the lateral nanoscale organisation of mechanosensitive membrane receptors and signalling molecules is crucial for cell function. Yet, current models of mechanosensing are based on force-induced molecular conformations, completely overlooking the chief role of mechanical forces on the nanoscale spatiotemporal organisation of the plasma membrane.
The GOAL of NANO-MEMEC is to provide mechanistic understanding on the role of mechanical stimuli in the spatiotemporal nanoarchitecture of adhesion signalling platforms at the cell membrane. To overcome the technical challenges of probing these processes at the relevant spatiotemporal scales, I will exploit cuttingedge biophysical tools exclusively developed in my Lab that combine super-resolution optical nanoscopy and single molecule dynamics in conjunction with simultaneous mechanical stimulation of living cells. Using this integrated approach, I will: First: dissect mechanical and biochemical coupling of membrane mechanosensing at the nanoscale. Second: visualise the coordinated recruitment of integrin-associated signalling proteins in response to force, i.e., mechanotransduction. Third: test how force-induced spatiotemporal membrane remodelling influences the migratory capacity of immune cells, i.e., mechanoresponse. NANO-MEMEC conveys a new fundamental concept to the field of mechanobiology: the roles of mechanical stimuli in the
dynamic remodelling of membrane nanocompartments, modulating signal transduction and ultimately affecting cell response, opening new-fangled research avenues in the years to come.
Max ERC Funding
2 212 063 €
Duration
Start date: 2018-12-01, End date: 2023-11-30
Project acronym TARLOOP
Project R-loops as a major modulator of transcription-associated recombination and chromatin dynamics
Researcher (PI) Andres Aguilera Lopez
Host Institution (HI) UNIVERSIDAD DE SEVILLA
Call Details Advanced Grant (AdG), LS1, ERC-2014-ADG
Summary Understanding the causes of genome instability, a condition linked to cancer and cancer-prone genetic diseases, is a major question in Molecular Biology and Biomedicine. Probably the most important natural cause of genome instability is transcription, which is known to induce both mutation and recombination from bacteria to human cells. Different studies suggest that transcription-associated recombination (TAR) is in large part due to collisions between transcription and replication, but increasing evidence indicate that R-loops, formed by a DNA-RNA hybrid and a displaced single-stranded DNA, may be a major determinant of genome instability. This is of particular relevance, provided our recent observation that tumor suppressor BRCA2 gene is involved in R-loop prevention/resolution and that, therefore, R-loops may represent a major potential source of tumorigenesis. The goal of this project is to understand the mechanisms of R-loop dynamics by identifying the functions and elements acting in cis and trans, that is, the DNA sequences and genes controlling R-loop formation and removal. The project will be based on a multidisciplinary approach using Saccharomyces cerevisiae and human cell lines. We plan: a) to identify the proteins and mechanism that actively works in the formation and prevention of intermediates responsible for R-loop-mediated TAR; b) to define the histone residues linked to R-loop formation and its role in chromatin dynamics, and c) to establish how the different trans and cis elements control genome-wide R-loop–mediated genome instability whether or not in association with replication fork impairment, double-strand break accumulation, chromatin structure and mRNP biogenesis and export. The functional relevance of selected conserved genes will be validated in Caenorhabditis elegans as a model organism. The long-term objective of the proposal is to decipher the mechanisms by which R-loops modulate chromatin dynamics and genome instability.
Summary
Understanding the causes of genome instability, a condition linked to cancer and cancer-prone genetic diseases, is a major question in Molecular Biology and Biomedicine. Probably the most important natural cause of genome instability is transcription, which is known to induce both mutation and recombination from bacteria to human cells. Different studies suggest that transcription-associated recombination (TAR) is in large part due to collisions between transcription and replication, but increasing evidence indicate that R-loops, formed by a DNA-RNA hybrid and a displaced single-stranded DNA, may be a major determinant of genome instability. This is of particular relevance, provided our recent observation that tumor suppressor BRCA2 gene is involved in R-loop prevention/resolution and that, therefore, R-loops may represent a major potential source of tumorigenesis. The goal of this project is to understand the mechanisms of R-loop dynamics by identifying the functions and elements acting in cis and trans, that is, the DNA sequences and genes controlling R-loop formation and removal. The project will be based on a multidisciplinary approach using Saccharomyces cerevisiae and human cell lines. We plan: a) to identify the proteins and mechanism that actively works in the formation and prevention of intermediates responsible for R-loop-mediated TAR; b) to define the histone residues linked to R-loop formation and its role in chromatin dynamics, and c) to establish how the different trans and cis elements control genome-wide R-loop–mediated genome instability whether or not in association with replication fork impairment, double-strand break accumulation, chromatin structure and mRNP biogenesis and export. The functional relevance of selected conserved genes will be validated in Caenorhabditis elegans as a model organism. The long-term objective of the proposal is to decipher the mechanisms by which R-loops modulate chromatin dynamics and genome instability.
Max ERC Funding
2 312 500 €
Duration
Start date: 2015-12-01, End date: 2020-11-30
Project acronym TEL STEM CELL
Project FROM TELOMERE CHROMATIN TO STEM CELL BIOLOGY
Researcher (PI) Maria A. Blasco
Host Institution (HI) FUNDACION CENTRO NACIONAL DE INVESTIGACIONES ONCOLOGICAS CARLOS III
Call Details Advanced Grant (AdG), LS1, ERC-2008-AdG
Summary Telomeres are ribonucleoprotein complexes at the ends of chromosomes that are essential for chromosome protection and genomic stability. Telomeres consist of tandem TTAGGG repeats bound to a 6-protein complex known as shelterin. More recently, telomeres have been also shown to contain long non-coding telomeric RNAs (TelRNAs or TERRAs), which are associated to the telomeric chromatin and have been proposed to be potential regulators of telomerase activity and telomere length. In addition, telomeric chromatin is enriched in epigenetic marks characteristic of constitutive heterochromatin, such as histone trimethylation (H3K9 and H4K20 tri-methylation) and DNA hypermethylation, which act as negative regulators of telomere length. Telomere length defects are associated to both cancer and aging processes, and have been recently shown to have a profound effect on stem cell behaviour. Here, we propose to determine the role of both genetic and epigenetic telomere regulators in cancer and aging by generating new mouse models. Finally, we will study the role of these factors in stem cell biology.
Summary
Telomeres are ribonucleoprotein complexes at the ends of chromosomes that are essential for chromosome protection and genomic stability. Telomeres consist of tandem TTAGGG repeats bound to a 6-protein complex known as shelterin. More recently, telomeres have been also shown to contain long non-coding telomeric RNAs (TelRNAs or TERRAs), which are associated to the telomeric chromatin and have been proposed to be potential regulators of telomerase activity and telomere length. In addition, telomeric chromatin is enriched in epigenetic marks characteristic of constitutive heterochromatin, such as histone trimethylation (H3K9 and H4K20 tri-methylation) and DNA hypermethylation, which act as negative regulators of telomere length. Telomere length defects are associated to both cancer and aging processes, and have been recently shown to have a profound effect on stem cell behaviour. Here, we propose to determine the role of both genetic and epigenetic telomere regulators in cancer and aging by generating new mouse models. Finally, we will study the role of these factors in stem cell biology.
Max ERC Funding
2 000 000 €
Duration
Start date: 2009-05-01, End date: 2014-12-31
Project acronym TRANSGANG
Project Transnational Gangs as Agents of Mediation: Experiences of Conflict Resolution in Street Youth Organizations in Southern Europe, North Africa and the Americas
Researcher (PI) Carles FEIXA PAMPOLS
Host Institution (HI) UNIVERSIDAD POMPEU FABRA
Call Details Advanced Grant (AdG), SH3, ERC-2016-ADG
Summary TRANSGANG aims to develop a renewed model for the analysis of transnational youth gangs in the global age, in dialogue with two classics of urban ethnography, published nearly a century ago: The Gang, by F.M. Thrasher (1926) and The Polish Peasant in Europe and America, by W. I. Thomas and F. Znaniecki (1918-1920). To do this, the project will start by a systematic review of the historical literature on youth gangs, which will try to overcome the north-american-centrism, dominant in contemporary criminology. The central phase of the research will focus on a multisited and multilevel ethnography that will explore experiences in which gangs have acted as agents of mediation, as well as the barriers that have blocked these attempts. The project will compare street youth organizations from two transnational communities -Latinos and Arabs-, both in their homelands and in their new European neigbourhoods. Starting with three case studies of “good practices” in Barcelona, Medellin and Casablanca, which will be studied in depth, contrasts with other cases in which other policies have been implemented will be established: Madrid, Marseille and Milan in southern Europe; Oran Tunis and Cairo in north Africa; Chicago, Santiago de Cuba and San Salvador in the Americas. Using an experimental approach based on the “extended case method”, it will have as its theme the making of a film that collects the experience of members or former members of gangs who have participated in mediation experiences. The ultimate goal is to develop a renewed transnational, inter-generational, intergeneric and transmedia approach to Twenty-First-century gangs, very different from the local, coeval, male and face-to-face model used for understanding gangs in the Twentieth century. Although the focus of the project is theoretical, its purpose is applied: to deduce more effective ways of intervention to prevent the hegemony of the criminal gang model that appears as dominant in the neoliberal era.
Summary
TRANSGANG aims to develop a renewed model for the analysis of transnational youth gangs in the global age, in dialogue with two classics of urban ethnography, published nearly a century ago: The Gang, by F.M. Thrasher (1926) and The Polish Peasant in Europe and America, by W. I. Thomas and F. Znaniecki (1918-1920). To do this, the project will start by a systematic review of the historical literature on youth gangs, which will try to overcome the north-american-centrism, dominant in contemporary criminology. The central phase of the research will focus on a multisited and multilevel ethnography that will explore experiences in which gangs have acted as agents of mediation, as well as the barriers that have blocked these attempts. The project will compare street youth organizations from two transnational communities -Latinos and Arabs-, both in their homelands and in their new European neigbourhoods. Starting with three case studies of “good practices” in Barcelona, Medellin and Casablanca, which will be studied in depth, contrasts with other cases in which other policies have been implemented will be established: Madrid, Marseille and Milan in southern Europe; Oran Tunis and Cairo in north Africa; Chicago, Santiago de Cuba and San Salvador in the Americas. Using an experimental approach based on the “extended case method”, it will have as its theme the making of a film that collects the experience of members or former members of gangs who have participated in mediation experiences. The ultimate goal is to develop a renewed transnational, inter-generational, intergeneric and transmedia approach to Twenty-First-century gangs, very different from the local, coeval, male and face-to-face model used for understanding gangs in the Twentieth century. Although the focus of the project is theoretical, its purpose is applied: to deduce more effective ways of intervention to prevent the hegemony of the criminal gang model that appears as dominant in the neoliberal era.
Max ERC Funding
2 343 249 €
Duration
Start date: 2018-01-01, End date: 2022-12-31
