Project acronym DENOVOSTEM
Project DE NOVO GENERATION OF SOMATIC STEM CELLS: REGULATION AND MECHANISMS OF CELL PLASTICITY
Researcher (PI) Stefano Piccolo
Host Institution (HI) UNIVERSITA DEGLI STUDI DI PADOVA
Call Details Advanced Grant (AdG), LS4, ERC-2014-ADG
Summary The possibility to artificially induce and expand in vitro tissue-specific stem cells (SCs) is an important goal for regenerative medicine, to understand organ physiology, for in vitro modeling of human diseases and many other applications. Here we found that this goal can be achieved in the culture dish by transiently inducing expression of YAP or TAZ - nuclear effectors of the Hippo and biomechanical pathways - into primary/terminally differentiated cells of distinct tissue origins. Moreover, YAP/TAZ are essential endogenous factors that preserve ex-vivo naturally arising SCs of distinct tissues.
In this grant, we aim to gain insights into YAP/TAZ molecular networks (upstream regulators and downstream targets) involved in somatic SC reprogramming and SC identity. Our studies will entail the identification of the genetic networks and epigenetic changes controlled by YAP/TAZ during cell de-differentiation and the re-acquisition of SC-traits in distinct cell types. We will also investigate upstream inputs establishing YAP/TAZ activity, with particular emphasis on biomechanical and cytoskeletal cues that represent overarching regulators of YAP/TAZ in tissues.
For many tumors, it appears that acquisition of an immature, stem-like state is a prerequisite for tumor progression and an early step in oncogene-mediated transformation. YAP/TAZ activation is widespread in human tumors. However, a connection between YAP/TAZ and oncogene-induced cell plasticity has never been investigated. We will also pursue some intriguing preliminary results and investigate how oncogenes and chromatin remodelers may link to cell mechanics, and the plasticity of the differentiated and SC states by controlling YAP/TAZ.
In sum, this research should advance our understanding of the cellular and molecular basis underpinning organ growth, tissue regeneration and tumor initiation.
Summary
The possibility to artificially induce and expand in vitro tissue-specific stem cells (SCs) is an important goal for regenerative medicine, to understand organ physiology, for in vitro modeling of human diseases and many other applications. Here we found that this goal can be achieved in the culture dish by transiently inducing expression of YAP or TAZ - nuclear effectors of the Hippo and biomechanical pathways - into primary/terminally differentiated cells of distinct tissue origins. Moreover, YAP/TAZ are essential endogenous factors that preserve ex-vivo naturally arising SCs of distinct tissues.
In this grant, we aim to gain insights into YAP/TAZ molecular networks (upstream regulators and downstream targets) involved in somatic SC reprogramming and SC identity. Our studies will entail the identification of the genetic networks and epigenetic changes controlled by YAP/TAZ during cell de-differentiation and the re-acquisition of SC-traits in distinct cell types. We will also investigate upstream inputs establishing YAP/TAZ activity, with particular emphasis on biomechanical and cytoskeletal cues that represent overarching regulators of YAP/TAZ in tissues.
For many tumors, it appears that acquisition of an immature, stem-like state is a prerequisite for tumor progression and an early step in oncogene-mediated transformation. YAP/TAZ activation is widespread in human tumors. However, a connection between YAP/TAZ and oncogene-induced cell plasticity has never been investigated. We will also pursue some intriguing preliminary results and investigate how oncogenes and chromatin remodelers may link to cell mechanics, and the plasticity of the differentiated and SC states by controlling YAP/TAZ.
In sum, this research should advance our understanding of the cellular and molecular basis underpinning organ growth, tissue regeneration and tumor initiation.
Max ERC Funding
2 498 934 €
Duration
Start date: 2015-09-01, End date: 2020-08-31
Project acronym EUROCORR
Project The European correspondence to Jacob Burckhardt
Researcher (PI) Maurizio Ghelardi
Host Institution (HI) SCUOLA NORMALE SUPERIORE
Call Details Advanced Grant (AdG), SH5, ERC-2009-AdG
Summary The aim of this project is to map and publish in a critical edition the extensive correspondence of European intellectuals with the Swiss cultural historian Jacob Burckhardt over a period of more than half a century, from 1842 to 1897. This correspondence documents a crucial period in European history and culture, one which witnessed the emergence of art history as a separate discipline; serious political conflict in France, Germany, Italy and Switzerland; the birth of the nation-states of Italy and Germany; debate on the meaning and consequences of democracy as a system of government; and the rise of Caesarism in France. The effects of modernism are also discussed in this correspondence, from the culture of museums, art exhibitions and the first universal expositions (e.g., the Expositions Universelles in Paris) to the clash between industrial culture and neo-humanist ideals of education. The large body of correspondence received by Jacob Burckhardt (about two thousand letters conserved in various libraries and private archives) provides a cultural map of this crucial phase in the development of a new European identity.
Summary
The aim of this project is to map and publish in a critical edition the extensive correspondence of European intellectuals with the Swiss cultural historian Jacob Burckhardt over a period of more than half a century, from 1842 to 1897. This correspondence documents a crucial period in European history and culture, one which witnessed the emergence of art history as a separate discipline; serious political conflict in France, Germany, Italy and Switzerland; the birth of the nation-states of Italy and Germany; debate on the meaning and consequences of democracy as a system of government; and the rise of Caesarism in France. The effects of modernism are also discussed in this correspondence, from the culture of museums, art exhibitions and the first universal expositions (e.g., the Expositions Universelles in Paris) to the clash between industrial culture and neo-humanist ideals of education. The large body of correspondence received by Jacob Burckhardt (about two thousand letters conserved in various libraries and private archives) provides a cultural map of this crucial phase in the development of a new European identity.
Max ERC Funding
1 215 600 €
Duration
Start date: 2010-06-01, End date: 2015-05-31
Project acronym GREEK INTO ARABIC
Project Greek into Arabic: Philosophical Concepts and Linguistic Bridges
Researcher (PI) Cristina D'ancona
Host Institution (HI) UNIVERSITA DI PISA
Call Details Advanced Grant (AdG), SH5, ERC-2009-AdG
Summary One of the prominent features of Medieval Aristotelianism, both Arabic and Latin, is the fact that Aristotle has been credited with writings that, albeit Neoplatonic in origin, circulated under his name. Crucial as it might be for the genesis of Arabic-Islamic philosophy, the main text of the Neoplatonic tradition into Arabic, i.e., the so-called Theology of Aristotle, is still poorly edited and no running commentary exists on it. The Theology of Aristotle, derived in reality from Plotinus' Enneads, will be critically edited, translated and commented upon. This project will also study the Graeco-Arabic translations from a linguistic viewpoint. It will develop the extant Greek and Arabic Lexicon; of the Medieval translations of philosophical works into a computational resource. For the first time, the project allows Ancient and Arabic philosophy to interact with computational linguistics.
Summary
One of the prominent features of Medieval Aristotelianism, both Arabic and Latin, is the fact that Aristotle has been credited with writings that, albeit Neoplatonic in origin, circulated under his name. Crucial as it might be for the genesis of Arabic-Islamic philosophy, the main text of the Neoplatonic tradition into Arabic, i.e., the so-called Theology of Aristotle, is still poorly edited and no running commentary exists on it. The Theology of Aristotle, derived in reality from Plotinus' Enneads, will be critically edited, translated and commented upon. This project will also study the Graeco-Arabic translations from a linguistic viewpoint. It will develop the extant Greek and Arabic Lexicon; of the Medieval translations of philosophical works into a computational resource. For the first time, the project allows Ancient and Arabic philosophy to interact with computational linguistics.
Max ERC Funding
2 106 381 €
Duration
Start date: 2010-04-01, End date: 2015-03-31
Project acronym K4U
Project Knowledge For Use [K4U]: Making the Most of Social Science to Build Better Policies
Researcher (PI) Nancy Cartwright
Host Institution (HI) UNIVERSITY OF DURHAM
Call Details Advanced Grant (AdG), SH5, ERC-2014-ADG
Summary ‘Research is an investment in our future’ says Horizon 2020. That’s only true if you know what to do with it. When it comes to social policy, we don’t really know how to put our research results to use. K4U aims to remedy this. K4U will construct a radically new picture of how to use social science to build better social policies. This picture will be founded on an ambitious philosophical study of the technology of social science including a thorough reconceptualisation of objectivity, deliberation and the role of values in the science/society interface. Current work, primarily by the evidence-based policy and practice movement, focusses on knowledge production: encouraging high quality studies and vetting them. Little attention goes to knowledge use: How is social science knowledge to be used in policy design and deliberation – how should it be used so that policy outcomes are more effective and more reliably predictable and competing values and points of view are respected in policy choice and implementation?
K4U will provide not just a theoretical but a practical understanding— for users: intelligible and practically helpful to those who need to estimate and balance the effectiveness, the evidence, the chances of success, the costs, the benefits, the winners and losers, and the social, moral, political and cultural acceptability of proposed policies.
The philosophical approach of K4U is broadly Popperian. It views ‘science and technology as a means of understanding social problems and responding to them’ and it emphasises the concrete and detailed, where the real content of general philosophical concepts and claims is embodied and interrogated. K4U is a showcase for the kind of philosophy that makes a difference to real life -- philosophy for practice. And it will launch an entire new field in philosophy: the philosophy of social technology.
Summary
‘Research is an investment in our future’ says Horizon 2020. That’s only true if you know what to do with it. When it comes to social policy, we don’t really know how to put our research results to use. K4U aims to remedy this. K4U will construct a radically new picture of how to use social science to build better social policies. This picture will be founded on an ambitious philosophical study of the technology of social science including a thorough reconceptualisation of objectivity, deliberation and the role of values in the science/society interface. Current work, primarily by the evidence-based policy and practice movement, focusses on knowledge production: encouraging high quality studies and vetting them. Little attention goes to knowledge use: How is social science knowledge to be used in policy design and deliberation – how should it be used so that policy outcomes are more effective and more reliably predictable and competing values and points of view are respected in policy choice and implementation?
K4U will provide not just a theoretical but a practical understanding— for users: intelligible and practically helpful to those who need to estimate and balance the effectiveness, the evidence, the chances of success, the costs, the benefits, the winners and losers, and the social, moral, political and cultural acceptability of proposed policies.
The philosophical approach of K4U is broadly Popperian. It views ‘science and technology as a means of understanding social problems and responding to them’ and it emphasises the concrete and detailed, where the real content of general philosophical concepts and claims is embodied and interrogated. K4U is a showcase for the kind of philosophy that makes a difference to real life -- philosophy for practice. And it will launch an entire new field in philosophy: the philosophy of social technology.
Max ERC Funding
2 092 125 €
Duration
Start date: 2015-11-01, End date: 2020-10-31
Project acronym MALMECC
Project Music and Late Medieval European Court Cultures: Towards a Trans-Disciplinary and Post-National Cultural Poetics of the Performative Arts
Researcher (PI) Karl Kuegle
Host Institution (HI) THE CHANCELLOR, MASTERS AND SCHOLARS OF THE UNIVERSITY OF OXFORD
Call Details Advanced Grant (AdG), SH5, ERC-2014-ADG
Summary Late medieval European court cultures have traditionally been studied from a mono-disciplinary and national(ist) perspective. This focus has obscured much of the interplay of cultural performances that informed “courtly life”. Recent research has begun to reverse this, focusing on issues such as the tensions between orality, writing, and performance; the sociocultural dimensions of making and owning manuscripts (musical and otherwise); the interstices between musical, literary and visual texts and political, social and religious rituals; and the impact of gender, kinship, and social status on the genesis and transmission of culture and music. These “new medievalist” studies have significantly enhanced our understanding of the cultural meanings of singing, listening, and sound in late medieval times.
Taking a decisive step further, MALMECC will, for the first time, systematically explore late medieval (c. 1280-1450) court cultures and their music synoptically across Europe. England, the Low Countries, Avignon, Bohemia, south-eastern Germany/Salzburg, Savoy, and Cyprus have been selected for study as each was a vibrant site of cultural production but has been relatively neglected due to prevailing discursive formations favouring “centres” like Paris and Florence. Linking these courts in a large-scale comparative study focused on the role of music in courtly life but embedded within a multidisciplinary framework encompassing all the arts as well as politics and religion will reveal the complex ecology of late medieval performances of noblesse in unheard-of depth while at the same time throwing the unique qualities of each court into distinct relief. The project will apply an innovative research paradigm that develops a trans-disciplinary and post-national(ist), “relational” approach to the study of music in late-medieval court cultures. In doing so it will integrate all late medieval arts and re-constitute the fullness of their potential meanings.
Summary
Late medieval European court cultures have traditionally been studied from a mono-disciplinary and national(ist) perspective. This focus has obscured much of the interplay of cultural performances that informed “courtly life”. Recent research has begun to reverse this, focusing on issues such as the tensions between orality, writing, and performance; the sociocultural dimensions of making and owning manuscripts (musical and otherwise); the interstices between musical, literary and visual texts and political, social and religious rituals; and the impact of gender, kinship, and social status on the genesis and transmission of culture and music. These “new medievalist” studies have significantly enhanced our understanding of the cultural meanings of singing, listening, and sound in late medieval times.
Taking a decisive step further, MALMECC will, for the first time, systematically explore late medieval (c. 1280-1450) court cultures and their music synoptically across Europe. England, the Low Countries, Avignon, Bohemia, south-eastern Germany/Salzburg, Savoy, and Cyprus have been selected for study as each was a vibrant site of cultural production but has been relatively neglected due to prevailing discursive formations favouring “centres” like Paris and Florence. Linking these courts in a large-scale comparative study focused on the role of music in courtly life but embedded within a multidisciplinary framework encompassing all the arts as well as politics and religion will reveal the complex ecology of late medieval performances of noblesse in unheard-of depth while at the same time throwing the unique qualities of each court into distinct relief. The project will apply an innovative research paradigm that develops a trans-disciplinary and post-national(ist), “relational” approach to the study of music in late-medieval court cultures. In doing so it will integrate all late medieval arts and re-constitute the fullness of their potential meanings.
Max ERC Funding
2 186 400 €
Duration
Start date: 2016-01-01, End date: 2020-12-31
Project acronym MMUVR
Project Elucidating the role of ultraviolet radiation in melanoma
Researcher (PI) Richard Marais
Host Institution (HI) THE UNIVERSITY OF MANCHESTER
Call Details Advanced Grant (AdG), LS4, ERC-2014-ADG
Summary Melanoma incidence continues to increase across Europe and compared to other cancers, it disproportionately affects young people, causing a significant loss in life-years in those affected. Ultraviolet radiation (UVR) is the only environmental risk factor in melanoma, but the underlying genetic constitution of the individual also plays an important role. However, our knowledge of the gene-gene and gene-environment interactions in melanomagenesis is still very limited and here we will use various cutting-edge technologies to investigate the role of UVR in melanoma initiation and progression. We have developed mouse models of UVR-driven melanoma that closely mimic UVR-driven melanoma in humans and these provide an unprecedented opportunity to dissect how different wavelengths and patterns of UVR exposure affect melanomagenesis. We propose a multidisciplinary programme of work to examine how host genetic susceptibility factors and responses such as DNA damage repair and inflammation affect melanoma development and progression following UVR exposure. We will integrate knowledge from our animal experiments with epidemiological, histopathological, clinical, and genetic features of human tumours to improve stratification of human melanoma and thereby assist clinical management of this deadly disease. Our overarching aim is to develop a validated stratification approach to melanoma patients that will assist in the development of effective public health campaigns for individuals at risk across Europe.
Summary
Melanoma incidence continues to increase across Europe and compared to other cancers, it disproportionately affects young people, causing a significant loss in life-years in those affected. Ultraviolet radiation (UVR) is the only environmental risk factor in melanoma, but the underlying genetic constitution of the individual also plays an important role. However, our knowledge of the gene-gene and gene-environment interactions in melanomagenesis is still very limited and here we will use various cutting-edge technologies to investigate the role of UVR in melanoma initiation and progression. We have developed mouse models of UVR-driven melanoma that closely mimic UVR-driven melanoma in humans and these provide an unprecedented opportunity to dissect how different wavelengths and patterns of UVR exposure affect melanomagenesis. We propose a multidisciplinary programme of work to examine how host genetic susceptibility factors and responses such as DNA damage repair and inflammation affect melanoma development and progression following UVR exposure. We will integrate knowledge from our animal experiments with epidemiological, histopathological, clinical, and genetic features of human tumours to improve stratification of human melanoma and thereby assist clinical management of this deadly disease. Our overarching aim is to develop a validated stratification approach to melanoma patients that will assist in the development of effective public health campaigns for individuals at risk across Europe.
Max ERC Funding
2 171 623 €
Duration
Start date: 2016-03-01, End date: 2021-02-28
Project acronym Mulosige
Project Multilingual locals, significant geographies: a new approach to world literature
Researcher (PI) Francesca Orsini
Host Institution (HI) SCHOOL OF ORIENTAL AND AFRICAN STUDIES ROYAL CHARTER
Call Details Advanced Grant (AdG), SH5, ERC-2014-ADG
Summary “World literature is literature that circulates globally. It is mostly in English. Its main genre is the novel.” These are caricatures of how World literature as a set of discourses is shaping the field of literary studies, but in fact Non-Western literatures are positioned with reference to a single global timeline and a single map, and translations supposedly ensure that worthy texts enter the global canon. What does not circulate globally is provincial, not good enough, not “world literature”.
This picture bears little resemblance to the multilingual world of literature, which consists not of a single map but of many “significant geographies” specific to language, group, and genre. By exploring the often fractured “multilingual locals” and “significant geographies” of literature in north India, Morocco, and Ethiopia—each with different experiences of literary multilingualism, colonial diglossia, and continuing oral traditions—we seek to establish a multilingual and located approach to world literature in place of meta-categories like “global” and “world”. Mindful of older histories and networks of literary multilingualism and critical of the monolingual straitjacket of modern literary histories that partition Anglophone and Francophone literature from Arabic, Amharic, and Hindi/Urdu, we focus on three periods: imperial consolidation, decolonization, and the current globalizing moment. We will study local transculturations, local debates on world literature, old and new forms of multilingualism, actors and technologies of print and orality, to highlight dynamics of appropriation rather than imitation, co-constitution rather than diffusion, and the multiplicity of choices and trajectories that together form local and transnational literary fields (“world literature”). The project will propose a theoretical approach, methods for multilingual training and research, and strategic dialogues with scholars and writers in Morocco, Ethiopia, India, UK and France.
Summary
“World literature is literature that circulates globally. It is mostly in English. Its main genre is the novel.” These are caricatures of how World literature as a set of discourses is shaping the field of literary studies, but in fact Non-Western literatures are positioned with reference to a single global timeline and a single map, and translations supposedly ensure that worthy texts enter the global canon. What does not circulate globally is provincial, not good enough, not “world literature”.
This picture bears little resemblance to the multilingual world of literature, which consists not of a single map but of many “significant geographies” specific to language, group, and genre. By exploring the often fractured “multilingual locals” and “significant geographies” of literature in north India, Morocco, and Ethiopia—each with different experiences of literary multilingualism, colonial diglossia, and continuing oral traditions—we seek to establish a multilingual and located approach to world literature in place of meta-categories like “global” and “world”. Mindful of older histories and networks of literary multilingualism and critical of the monolingual straitjacket of modern literary histories that partition Anglophone and Francophone literature from Arabic, Amharic, and Hindi/Urdu, we focus on three periods: imperial consolidation, decolonization, and the current globalizing moment. We will study local transculturations, local debates on world literature, old and new forms of multilingualism, actors and technologies of print and orality, to highlight dynamics of appropriation rather than imitation, co-constitution rather than diffusion, and the multiplicity of choices and trajectories that together form local and transnational literary fields (“world literature”). The project will propose a theoretical approach, methods for multilingual training and research, and strategic dialogues with scholars and writers in Morocco, Ethiopia, India, UK and France.
Max ERC Funding
2 482 416 €
Duration
Start date: 2016-01-01, End date: 2020-12-31
Project acronym MUSDIG
Project Music, Digitization, Mediation: Towards Interdisciplinary Music Studies
Researcher (PI) Georgina Born
Host Institution (HI) THE CHANCELLOR, MASTERS AND SCHOLARS OF THE UNIVERSITY OF OXFORD
Call Details Advanced Grant (AdG), SH5, ERC-2009-AdG
Summary Music is rapidly being transformed by digital technologies; it is in the vanguard of the changes to contemporary cultures and cultural economies afforded by digitization, and is widely seen as a test case of digitization’s effects. Yet the academic music disciplines have not responded with research on these fundamental developments. This project, by combining two innovative interdisciplinary components, aims systematically to advance the state of contemporary music research, while contributing to social and media theory. It will be the first research programme to analyse comprehensively the range of interrelated transformations in music and musical experience wrought by digital technologies. The first element of the project is a comparative programme of ethnographic studies examining transformations in creative, performance and improvisation practices, the nature of music as a cultural object, new aesthetic forms, altered modes of musical consumption and circulation, and changing industry and institutional structures. Given the ease of transnational distribution of digitized musics, research will also follow certain genres as they circulate among diasporic groups. These and related issues will be studied in five countries, each intrinsically significant as well as yielding instructive comparisons between them: the UK, Cuba, Kenya, India and Turkey. The emphasis in each ethnography will be on analyzing the embedded nature of digital musical practices in local cultural, social, economic and political conditions. Second, on the basis of this programme, the project aims to advance contemporary music research by developing an interdisciplinary theory and methodology which progresses beyond the current state of the field. Music research has been divided between disciplines such as musicology and music analysis which address the musical object and centre on art musics, and sociological and anthropological approaches which privilege music’s social, institutional and discursive forms and focus primarily on popular and vernacular musics. The present project bridges these divisions by expounding an innovative theory and methodology focused on music’s mediation, one that integrates recent elements of social, anthropological and media theory. Moreover it addresses music’s digital transformations across the spectrum of contemporary musics: art, popular and vernacular, commercial and non-commercial. Given that music’s core properties – mediation, performance, improvisation, affect, complex materialities – are also core concerns of contemporary social theory, the research will in turn contribute to ‘musicalising’ social theory. The project aims to have far-reaching impacts, creating a field of comparative studies of digital music cultures while reconfiguring the interdisciplinary foundations of music research.
Summary
Music is rapidly being transformed by digital technologies; it is in the vanguard of the changes to contemporary cultures and cultural economies afforded by digitization, and is widely seen as a test case of digitization’s effects. Yet the academic music disciplines have not responded with research on these fundamental developments. This project, by combining two innovative interdisciplinary components, aims systematically to advance the state of contemporary music research, while contributing to social and media theory. It will be the first research programme to analyse comprehensively the range of interrelated transformations in music and musical experience wrought by digital technologies. The first element of the project is a comparative programme of ethnographic studies examining transformations in creative, performance and improvisation practices, the nature of music as a cultural object, new aesthetic forms, altered modes of musical consumption and circulation, and changing industry and institutional structures. Given the ease of transnational distribution of digitized musics, research will also follow certain genres as they circulate among diasporic groups. These and related issues will be studied in five countries, each intrinsically significant as well as yielding instructive comparisons between them: the UK, Cuba, Kenya, India and Turkey. The emphasis in each ethnography will be on analyzing the embedded nature of digital musical practices in local cultural, social, economic and political conditions. Second, on the basis of this programme, the project aims to advance contemporary music research by developing an interdisciplinary theory and methodology which progresses beyond the current state of the field. Music research has been divided between disciplines such as musicology and music analysis which address the musical object and centre on art musics, and sociological and anthropological approaches which privilege music’s social, institutional and discursive forms and focus primarily on popular and vernacular musics. The present project bridges these divisions by expounding an innovative theory and methodology focused on music’s mediation, one that integrates recent elements of social, anthropological and media theory. Moreover it addresses music’s digital transformations across the spectrum of contemporary musics: art, popular and vernacular, commercial and non-commercial. Given that music’s core properties – mediation, performance, improvisation, affect, complex materialities – are also core concerns of contemporary social theory, the research will in turn contribute to ‘musicalising’ social theory. The project aims to have far-reaching impacts, creating a field of comparative studies of digital music cultures while reconfiguring the interdisciplinary foundations of music research.
Max ERC Funding
1 708 075 €
Duration
Start date: 2010-10-01, End date: 2015-12-31
Project acronym PRECORT
Project Pre-receptor cortisol metabolism and human ageing
Researcher (PI) Paul Michael Stewart
Host Institution (HI) UNIVERSITY OF LEEDS
Call Details Advanced Grant (AdG), LS4, ERC-2009-AdG
Summary The number of people over the age of 80 years in the 25 EU member states is currently 18.2 million or 4% of the total population; by 2020, 20% of the EU population will be >65 years old which will place considerable burden upon limited health care resources. 70% of older adults report at least one chronic disease that contributes to a reduction in healthspan or the number of extra years spent in good health. The European Commission is committed to identify rational and evidence based approaches to improve health in old age and as such has identified Ageing research as a priority. The most prevalent conditions that contribute to the ageing phenotype are sarcopaenia, hypertension and cardiovascular disease, central adiposity and type 2 diabetes mellitus and osteoporosis. Here there are remarkable similarities to patients with Cushing s syndrome caused by excessive secretion of glucocortiocoids such as cortisol. PRECORT Prereceptor Cortisol metabolism and human Ageing will test the hypothesis that age-related changes in body composition (central adiposity, reduced bone and muscle mass, skin thinning) and resulting chronic disease (diabetes, osteoporosis, sarcopaenia, hypertension, cardiovascular disease) are caused by excessive glucocorticoids as a result of age-related activation of the pituitary-adrenal axis and/or increased 11b-hydroxysteroid dehydrogenase type 1 (11b-HSD1), an enzyme that can generate cortisol locally within fat, bone, muscle and skin. The proposal will complete the full cycle of translational research and will potentially offer a new therapeutic approach through selective 11b-HSD1 inhibitors to modulate the ageing phenotype thereby improving the healthspan of the Ageing EU community.
Summary
The number of people over the age of 80 years in the 25 EU member states is currently 18.2 million or 4% of the total population; by 2020, 20% of the EU population will be >65 years old which will place considerable burden upon limited health care resources. 70% of older adults report at least one chronic disease that contributes to a reduction in healthspan or the number of extra years spent in good health. The European Commission is committed to identify rational and evidence based approaches to improve health in old age and as such has identified Ageing research as a priority. The most prevalent conditions that contribute to the ageing phenotype are sarcopaenia, hypertension and cardiovascular disease, central adiposity and type 2 diabetes mellitus and osteoporosis. Here there are remarkable similarities to patients with Cushing s syndrome caused by excessive secretion of glucocortiocoids such as cortisol. PRECORT Prereceptor Cortisol metabolism and human Ageing will test the hypothesis that age-related changes in body composition (central adiposity, reduced bone and muscle mass, skin thinning) and resulting chronic disease (diabetes, osteoporosis, sarcopaenia, hypertension, cardiovascular disease) are caused by excessive glucocorticoids as a result of age-related activation of the pituitary-adrenal axis and/or increased 11b-hydroxysteroid dehydrogenase type 1 (11b-HSD1), an enzyme that can generate cortisol locally within fat, bone, muscle and skin. The proposal will complete the full cycle of translational research and will potentially offer a new therapeutic approach through selective 11b-HSD1 inhibitors to modulate the ageing phenotype thereby improving the healthspan of the Ageing EU community.
Max ERC Funding
2 499 760 €
Duration
Start date: 2010-05-01, End date: 2016-04-30
Project acronym StemBAT
Project New players in human BAT differentiation and activation: a human PSC-derived BAT approach combined with state of the art genome engineering and –omics based methodologies
Researcher (PI) Antonio Vidal-Puig
Host Institution (HI) GENOME RESEARCH LIMITED
Call Details Advanced Grant (AdG), LS4, ERC-2014-ADG
Summary Here we propose a strategy to control body weight and prevent/reverse obesity based on targeting brown adipose tissue (BAT) to facilitate negative energy balance and prevent adaptive responses to dietary restriction. However, BAT in humans is limited and poorly characterised. Thus, we propose to use stem cells as a tool to gain unique insights into the biology of human brown adipocytes.
The General Objective is to identify pathways and factors of potential therapeutic relevance that promote BAT development and/or activation/recruitment using a stem cell based BAT differentiation approach, and then to functionally validate the role of these factors in vitro by genome engineering human stem cell derived adipocytes and in vivo by transplanting these cells into mice.
Specific Aims are: 1.To identify molecular mechanisms involved in human brown adipose tissue development and activation. 2. To investigate the molecular mechanisms involved in human white adipose tissue browning/beige cells recruitment 3. To identify new agents/compounds of therapeutic value, able to activate or recruit human brown adipose tissue/brite cells.
Experimental strategy: We will use a UCP1-reporter human pluripotent stem cell (PSC) line differentiated into brown and white adipocytes to identify genetic factors that may contribute to brown adipocyte differentiation/activation and white adipocyte browning. Following the identification of candidate genes, we will knock out, constitutively and/or inducibly, both alleles of these genes in human PSC cells, producing a total loss of function. Following the in vitro phenotyping of the cells we will proceed to the in vivo validation of the functional properties/phenotype of human PSC derived brown/brite adipocytes (wild-type and loss of function) by transplanting these cells into mice. Using these reporter tools we will also perform in vitro pharmacological screening and in vivo validation of new compounds that stimulate BAT activation and WAT browning
Summary
Here we propose a strategy to control body weight and prevent/reverse obesity based on targeting brown adipose tissue (BAT) to facilitate negative energy balance and prevent adaptive responses to dietary restriction. However, BAT in humans is limited and poorly characterised. Thus, we propose to use stem cells as a tool to gain unique insights into the biology of human brown adipocytes.
The General Objective is to identify pathways and factors of potential therapeutic relevance that promote BAT development and/or activation/recruitment using a stem cell based BAT differentiation approach, and then to functionally validate the role of these factors in vitro by genome engineering human stem cell derived adipocytes and in vivo by transplanting these cells into mice.
Specific Aims are: 1.To identify molecular mechanisms involved in human brown adipose tissue development and activation. 2. To investigate the molecular mechanisms involved in human white adipose tissue browning/beige cells recruitment 3. To identify new agents/compounds of therapeutic value, able to activate or recruit human brown adipose tissue/brite cells.
Experimental strategy: We will use a UCP1-reporter human pluripotent stem cell (PSC) line differentiated into brown and white adipocytes to identify genetic factors that may contribute to brown adipocyte differentiation/activation and white adipocyte browning. Following the identification of candidate genes, we will knock out, constitutively and/or inducibly, both alleles of these genes in human PSC cells, producing a total loss of function. Following the in vitro phenotyping of the cells we will proceed to the in vivo validation of the functional properties/phenotype of human PSC derived brown/brite adipocytes (wild-type and loss of function) by transplanting these cells into mice. Using these reporter tools we will also perform in vitro pharmacological screening and in vivo validation of new compounds that stimulate BAT activation and WAT browning
Max ERC Funding
2 500 000 €
Duration
Start date: 2016-01-01, End date: 2020-12-31
