(-) Remove <label class='research-domain' title='Physiology, Pathophysiology and Endocrinology'>LS4 (17)</label> filter LS4 (17)
Project acronym AMBH
Project Ancient Music Beyond Hellenisation
Researcher (PI) Stefan HAGEL
Host Institution (HI) OESTERREICHISCHE AKADEMIE DER WISSENSCHAFTEN
Summary From medieval times, Arabic as well as European music was analysed in terms that were inherited from Classical Antiquity and had thus developed in a very different music culture. In spite of recent breakthroughs in the understanding of the latter, whose technicalities we access not only through texts and iconography, but also through instrument finds and surviving notated melodies, its relation to music traditions known from later periods and different places is almost uncharted territory. The present project explores relations between Hellenic/Hellenistic music as pervaded the theatres and concert halls throughout and beyond the Roman empire, Near Eastern traditions – from the diatonic system emerging from cuneiform sources to the flourishing musical world of the caliphates – and, as far as possible, African musical life south of Egypt as well – a region that maintained close ties both with the Hellenised culture of its northern neighbours and with the Arabian Peninsula. On the one hand, this demands collaboration between Classical Philology and Arabic Studies, extending methods recently developed within music archaeological research related to the Classical Mediterranean. Arabic writings need to be examined in close reading, using recent insights into the interplay between ancient music theory and practice, in order to segregate the influence of Greek thinking from ideas and facts that must relate to contemporaneous 'Arabic' music-making. In this way we hope better to define the relation of this tradition to the 'Classical world', potentially breaking free of Orientalising bias informing modern views. On the other hand, the study and reconstruction, virtual and material, of wind instruments of Hellenistic pedigree but found outside the confinements of the Hellenistic 'heartlands' may provide evidence of 'foreign' tonality employed in those regions – specifically the royal city of Meroë in modern Sudan and the Oxus Temple in modern Tajikistan.
From medieval times, Arabic as well as European music was analysed in terms that were inherited from Classical Antiquity and had thus developed in a very different music culture. In spite of recent breakthroughs in the understanding of the latter, whose technicalities we access not only through texts and iconography, but also through instrument finds and surviving notated melodies, its relation to music traditions known from later periods and different places is almost uncharted territory. The present project explores relations between Hellenic/Hellenistic music as pervaded the theatres and concert halls throughout and beyond the Roman empire, Near Eastern traditions – from the diatonic system emerging from cuneiform sources to the flourishing musical world of the caliphates – and, as far as possible, African musical life south of Egypt as well – a region that maintained close ties both with the Hellenised culture of its northern neighbours and with the Arabian Peninsula. On the one hand, this demands collaboration between Classical Philology and Arabic Studies, extending methods recently developed within music archaeological research related to the Classical Mediterranean. Arabic writings need to be examined in close reading, using recent insights into the interplay between ancient music theory and practice, in order to segregate the influence of Greek thinking from ideas and facts that must relate to contemporaneous 'Arabic' music-making. In this way we hope better to define the relation of this tradition to the 'Classical world', potentially breaking free of Orientalising bias informing modern views. On the other hand, the study and reconstruction, virtual and material, of wind instruments of Hellenistic pedigree but found outside the confinements of the Hellenistic 'heartlands' may provide evidence of 'foreign' tonality employed in those regions – specifically the royal city of Meroë in modern Sudan and the Oxus Temple in modern Tajikistan.
Project acronym Angiolnc
Project Endothelial long non-coding RNAs
Researcher (PI) Stefanie Dimmeler
Host Institution (HI) JOHANN WOLFGANG GOETHE-UNIVERSITATFRANKFURT AM MAIN
Summary Endothelial cells comprise the inner cellular cover of the vasculature, which delivers metabolites and oxygen to the tissue. Dysfunction of endothelial cells as it occurs during aging or metabolic syndromes can result in atherosclerosis, which can lead to myocardial infarction or stroke, whereas pathological angiogenesis contributes to tumor growth and diabetic retinopathy. Thus, endothelial cells play central roles in pathophysiological processes of many diseases including cardiovascular diseases and cancer. Many studies explored the regulation of endothelial cell functions by growth factors, but the impact of epigenetic mechanisms and particularly the role of novel non-coding RNAs is largely unknown. More than 70 % of the human genome encodes for non-coding RNAs (ncRNAs) and increasing evidence suggests that a significant portion of these ncRNAs are functionally active as RNA molecules. Angiolnc aims to explore the function of long ncRNAs (lncRNAs) and particular circular RNAs (circRNAs) in the endothelium. LncRNAs comprise a heterogenic class of RNAs with a length of > 200 nucleotides and circRNAs are generated by back splicing. Angiolnc is based on the discovery of novel endothelial hypoxia-regulated lncRNAs and circRNAs by next generation sequencing. To begin to understand the potential functions of lncRNAs in the endothelium, we will study two lncRNAs, named Angiolnc1 und Angiolnc2, as prototypical examples of endothelial cell-enriched lncRNAs that are regulated by oxygen levels. We will further dissect the epigenetic mechanisms, by which these lncRNAs regulate endothelial cell function. In the second part of the application, we will determine the regulation and function of circRNAs, which may act as molecular sponges in the cytoplasm. Finally, we will study the function of identified lncRNAs and circRNAs in mouse models and measure their expression in human specimens in order to determine their role as therapeutic targets or diagnostic tools.
Endothelial cells comprise the inner cellular cover of the vasculature, which delivers metabolites and oxygen to the tissue. Dysfunction of endothelial cells as it occurs during aging or metabolic syndromes can result in atherosclerosis, which can lead to myocardial infarction or stroke, whereas pathological angiogenesis contributes to tumor growth and diabetic retinopathy. Thus, endothelial cells play central roles in pathophysiological processes of many diseases including cardiovascular diseases and cancer. Many studies explored the regulation of endothelial cell functions by growth factors, but the impact of epigenetic mechanisms and particularly the role of novel non-coding RNAs is largely unknown. More than 70 % of the human genome encodes for non-coding RNAs (ncRNAs) and increasing evidence suggests that a significant portion of these ncRNAs are functionally active as RNA molecules. Angiolnc aims to explore the function of long ncRNAs (lncRNAs) and particular circular RNAs (circRNAs) in the endothelium. LncRNAs comprise a heterogenic class of RNAs with a length of > 200 nucleotides and circRNAs are generated by back splicing. Angiolnc is based on the discovery of novel endothelial hypoxia-regulated lncRNAs and circRNAs by next generation sequencing. To begin to understand the potential functions of lncRNAs in the endothelium, we will study two lncRNAs, named Angiolnc1 und Angiolnc2, as prototypical examples of endothelial cell-enriched lncRNAs that are regulated by oxygen levels. We will further dissect the epigenetic mechanisms, by which these lncRNAs regulate endothelial cell function. In the second part of the application, we will determine the regulation and function of circRNAs, which may act as molecular sponges in the cytoplasm. Finally, we will study the function of identified lncRNAs and circRNAs in mouse models and measure their expression in human specimens in order to determine their role as therapeutic targets or diagnostic tools.
Project acronym AngioMature
Project Mechanisms of vascular maturation and quiescence during development, homeostasis and aging
Researcher (PI) Hellmut AUGUSTIN
Host Institution (HI) RUPRECHT-KARLS-UNIVERSITAET HEIDELBERG
Summary Angiogenesis research has focused on the sprouting of new capillaries. The mechanisms of vessel maturation are much less well understood. Yet, the maintenance of a mature, quiescent, and organotypically-differentiated layer of endothelial cells (ECs) lining the inside of all blood vessels is vital for human health. The goal of ANGIOMATURE is to identify, validate, and implement novel mechanisms of vascular maturation and organotypic EC differentiation that are active during development, maintenance of vascular stability in adults, and undergo changes in aging. We recently identified previously unrecognized gene expression signatures of vascular maturation in a genome-wide screen of ECs isolated from newborn and adult mice. Epigenetic mechanisms were identified that control the EC transcriptome through gain and loss of DNA methylation as well as EC differentiation and signaling specification. These findings pave the way for groundbreaking novel opportunities to study vascular maturation. By characterizing functionally diverse types of blood vessels, including continuous ECs in lung and brain and sinusoidal ECs in liver and bone marrow, the ANGIOMATURE project will (1) determine up to single cell resolution the transcriptional and epigenetic program(s) of vascular maturation and organotypic differentiation during adolescence, (2) analyze the functional consequences of such program(s) in differentiated ECs and their adaptation to challenge, and (3) study changes of maturation and differentiation program(s) and vascular responses during aging. We will towards this end employ an interdisciplinary matrix of approaches involving omics, systems biology, conditional gene targeting, organoid cell culture, and experimental pathology to create a high-resolution structural and functional organotypic angioarchitectural map. The project will thereby yield transformative mechanistic insights into vital biological processes that are most important for human health and healthy aging.
Angiogenesis research has focused on the sprouting of new capillaries. The mechanisms of vessel maturation are much less well understood. Yet, the maintenance of a mature, quiescent, and organotypically-differentiated layer of endothelial cells (ECs) lining the inside of all blood vessels is vital for human health. The goal of ANGIOMATURE is to identify, validate, and implement novel mechanisms of vascular maturation and organotypic EC differentiation that are active during development, maintenance of vascular stability in adults, and undergo changes in aging. We recently identified previously unrecognized gene expression signatures of vascular maturation in a genome-wide screen of ECs isolated from newborn and adult mice. Epigenetic mechanisms were identified that control the EC transcriptome through gain and loss of DNA methylation as well as EC differentiation and signaling specification. These findings pave the way for groundbreaking novel opportunities to study vascular maturation. By characterizing functionally diverse types of blood vessels, including continuous ECs in lung and brain and sinusoidal ECs in liver and bone marrow, the ANGIOMATURE project will (1) determine up to single cell resolution the transcriptional and epigenetic program(s) of vascular maturation and organotypic differentiation during adolescence, (2) analyze the functional consequences of such program(s) in differentiated ECs and their adaptation to challenge, and (3) study changes of maturation and differentiation program(s) and vascular responses during aging. We will towards this end employ an interdisciplinary matrix of approaches involving omics, systems biology, conditional gene targeting, organoid cell culture, and experimental pathology to create a high-resolution structural and functional organotypic angioarchitectural map. The project will thereby yield transformative mechanistic insights into vital biological processes that are most important for human health and healthy aging.
Project acronym ArsNova
Project European Ars Nova: Multilingual Poetry and Polyphonic Song in the Late Middle Ages
Researcher (PI) Maria Sofia LANNUTTI
Host Institution (HI) UNIVERSITA DEGLI STUDI DI FIRENZE
Summary Dante Alighieri at the dawn of the 1300s, as well as Eustache Deschamps almost a century later, conceived poetry as music in itself. But what happens with poetry when it is involved in the complex architecture of polyphony? The aim of this project is to study for the first time the corpus of 14th- and early 15th-century poetry set to music by Ars Nova polyphonists (more than 1200 texts). This repertoire gathers different poetic and musical traditions, as shown by the multilingual anthologies copied during the last years of the Schism. The choice of this corpus is motivated by two primary goals: a) to offer a new interpretation of its meaning and function in the cultural and historical context, one that may be then applied to the rest of coeval European lyric poetry; b) to overcome current disciplinary divisions in order to generate a new methodological balance between the project's two main fields of interest (Comparative Literature / Musicology). Most Ars Nova polyphonists were directly associated with religious institutions. In many texts, the language of courtly love expresses the values of caritas, the theological virtue that guides wise rulers and leads them to desire the common good. Thus, the poetic figure of the lover becomes a metaphor for the political man, and love poetry can be used as a device for diplomacy, as well as for personal and institutional propaganda. From this unprecedented point of view, the project will develop three research lines in response to the following questions: 1) How is the relationship between poetry and music, and how is the dialogue between the different poetic and musical traditions viewed in relation to each context of production? 2) To what extent does Ars Nova poetry take part in the 'soft power' strategies exercised by the entire European political class of the time? 3) Is there a connection between the multilingualism of the manuscript tradition and the perception of the Ars Nova as a European, intercultural repertoire?
Dante Alighieri at the dawn of the 1300s, as well as Eustache Deschamps almost a century later, conceived poetry as music in itself. But what happens with poetry when it is involved in the complex architecture of polyphony? The aim of this project is to study for the first time the corpus of 14th- and early 15th-century poetry set to music by Ars Nova polyphonists (more than 1200 texts). This repertoire gathers different poetic and musical traditions, as shown by the multilingual anthologies copied during the last years of the Schism. The choice of this corpus is motivated by two primary goals: a) to offer a new interpretation of its meaning and function in the cultural and historical context, one that may be then applied to the rest of coeval European lyric poetry; b) to overcome current disciplinary divisions in order to generate a new methodological balance between the project's two main fields of interest (Comparative Literature / Musicology). Most Ars Nova polyphonists were directly associated with religious institutions. In many texts, the language of courtly love expresses the values of caritas, the theological virtue that guides wise rulers and leads them to desire the common good. Thus, the poetic figure of the lover becomes a metaphor for the political man, and love poetry can be used as a device for diplomacy, as well as for personal and institutional propaganda. From this unprecedented point of view, the project will develop three research lines in response to the following questions: 1) How is the relationship between poetry and music, and how is the dialogue between the different poetic and musical traditions viewed in relation to each context of production? 2) To what extent does Ars Nova poetry take part in the 'soft power' strategies exercised by the entire European political class of the time? 3) Is there a connection between the multilingualism of the manuscript tradition and the perception of the Ars Nova as a European, intercultural repertoire?
Project acronym AUROMYC
Project N-Myc and Aurora A: From Protein Stability to Chromosome TopologyN-Myc and Aurora A: From Protein Stability to Chromosome TopologyMyc and Aurora A: From Protein Stability to Chromosome Topology
Researcher (PI) Martin Eilers
Host Institution (HI) JULIUS-MAXIMILIANS-UNIVERSITAT WURZBURG
Summary There is an intense interest in the function of human Myc proteins that stems from their pervasive role in the genesis of human tumors. A large body of evidence has established that expression levels of one of three closely related Myc proteins are enhanced in the majority of all human tumors and that multiple tumor entities depend on elevated Myc function, arguing that targeting Myc will have significant therapeutic efficacy. This hope awaits clinical confirmation, since the strategies that are currently under investigation to target Myc function or expression have yet to enter the clinic. Myc proteins are global regulators of transcription, but their mechanism of action is poorly understood. Myc proteins are highly unstable in normal cells and rapidly turned over by the ubiquitin/proteasome system. In contrast, they are stabilized in tumor cells. Work by us and by others has shown that stabilization of Myc is required for tumorigenesis and has identified strategies to destabilize Myc for tumor therapy. This work has also led to the surprising observation that the N-Myc protein, which drives neuroendocrine tumorigenesis, is stabilized by association with the Aurora-A kinase and that clinically available Aurora-A inhibitors can dissociate the complex and destabilize N-Myc. Aurora-A has not previously been implicated in transcription, prompting us to use protein crystallography, proteomics and shRNA screening to understand its interaction with N-Myc. We have now identified a novel protein complex of N-Myc and Aurora-A that provides an unexpected and potentially groundbreaking insight into Myc function. We have also solved the crystal structure of the N-Myc/Aurora-A complex. Collectively, both findings open new strategies to target Myc function for tumor therapy.
There is an intense interest in the function of human Myc proteins that stems from their pervasive role in the genesis of human tumors. A large body of evidence has established that expression levels of one of three closely related Myc proteins are enhanced in the majority of all human tumors and that multiple tumor entities depend on elevated Myc function, arguing that targeting Myc will have significant therapeutic efficacy. This hope awaits clinical confirmation, since the strategies that are currently under investigation to target Myc function or expression have yet to enter the clinic. Myc proteins are global regulators of transcription, but their mechanism of action is poorly understood. Myc proteins are highly unstable in normal cells and rapidly turned over by the ubiquitin/proteasome system. In contrast, they are stabilized in tumor cells. Work by us and by others has shown that stabilization of Myc is required for tumorigenesis and has identified strategies to destabilize Myc for tumor therapy. This work has also led to the surprising observation that the N-Myc protein, which drives neuroendocrine tumorigenesis, is stabilized by association with the Aurora-A kinase and that clinically available Aurora-A inhibitors can dissociate the complex and destabilize N-Myc. Aurora-A has not previously been implicated in transcription, prompting us to use protein crystallography, proteomics and shRNA screening to understand its interaction with N-Myc. We have now identified a novel protein complex of N-Myc and Aurora-A that provides an unexpected and potentially groundbreaking insight into Myc function. We have also solved the crystal structure of the N-Myc/Aurora-A complex. Collectively, both findings open new strategies to target Myc function for tumor therapy.
Project acronym BIOCARD
Project Deep BIOmodeling of human CARDiogenesis
Researcher (PI) Alessandra MORETTI
Host Institution (HI) KLINIKUM RECHTS DER ISAR DER TECHNISCHEN UNIVERSITAT MUNCHEN
Summary The heart is one of the first and most complex organs formed during human embryogenesis. While its anatomy and physiology have been extensively studied over centuries, the normal development of human heart and dysregulation in disease still remain poorly understood at the molecular/cellular level. Stem cell technologies hold promise for modelling development, analysing disease mechanisms, and developing potential therapies. By combining multidisciplinary approaches centred on human induced pluripotent stem cells (hiPSCs), BIOCARD aims at decoding the cellular and molecular principles of human cardiogenesis and developing advanced inter-chimeric human-pig models of cardiac development and disease. State-of-the-art genetic modification techniques and functional genomics will be used to establish a molecular atlas of cell type intermediates of human cardiogenesis in vitro and unravel how their proliferation, differentiation and lineage choice are regulated in health and disease. This in vitro approach will be complemented by detailed analyses of how distinct hiPSC-derived cardiac progenitor populations commit and contribute to specific cardiac compartments in interspecies chimeric hearts in vivo. Finally, we will capitalize on the novel concept that combinations of different well-defined hiPSC-derived cardiac progenitor pools with timely-matched, native extracellular matrix from embryonic hearts will accomplish for the first time the realization of human heart organoids as 3D culture systems of developing heart structures. Clearly, BIOCARD will open game-changing opportunities for devising novel biomedical applications, such as human heart chamber-specific disease modelling, large-scale drug testing in appropriate human 3D cardiac bio-mimics, and regenerative cell therapies based on functional ventricular-muscle patches and direct cell conversion in vivo.
The heart is one of the first and most complex organs formed during human embryogenesis. While its anatomy and physiology have been extensively studied over centuries, the normal development of human heart and dysregulation in disease still remain poorly understood at the molecular/cellular level. Stem cell technologies hold promise for modelling development, analysing disease mechanisms, and developing potential therapies. By combining multidisciplinary approaches centred on human induced pluripotent stem cells (hiPSCs), BIOCARD aims at decoding the cellular and molecular principles of human cardiogenesis and developing advanced inter-chimeric human-pig models of cardiac development and disease. State-of-the-art genetic modification techniques and functional genomics will be used to establish a molecular atlas of cell type intermediates of human cardiogenesis in vitro and unravel how their proliferation, differentiation and lineage choice are regulated in health and disease. This in vitro approach will be complemented by detailed analyses of how distinct hiPSC-derived cardiac progenitor populations commit and contribute to specific cardiac compartments in interspecies chimeric hearts in vivo. Finally, we will capitalize on the novel concept that combinations of different well-defined hiPSC-derived cardiac progenitor pools with timely-matched, native extracellular matrix from embryonic hearts will accomplish for the first time the realization of human heart organoids as 3D culture systems of developing heart structures. Clearly, BIOCARD will open game-changing opportunities for devising novel biomedical applications, such as human heart chamber-specific disease modelling, large-scale drug testing in appropriate human 3D cardiac bio-mimics, and regenerative cell therapies based on functional ventricular-muscle patches and direct cell conversion in vivo.
Project acronym CardHeal
Project Novel strategies for mammalian cardiac repair
Researcher (PI) Eldad TZAHOR
Summary Recent ground-breaking studies by my team and others demonstrated that latent heart regeneration machinery can be awakened even in adult mammals. My lab's main contribution is the identification of two, apparently different, molecular mechanisms for augmenting cardiac regeneration in adult mice. The first requires transient activation of ErbB2 signalling in cardiomyocytes and the second involves extra cellular matrix-driven signalling by the proteoglycan agrin. Impressively, both mechanisms promote a major regenerative response that, in turn, enhances cardiac repair. In CardHeal we will use the two powerful regenerative models to obtain a holistic view of cardiac regeneration and repair mechanisms in mammals (mice and pigs). In Aim 1, we will explore the molecular mechanisms underlying our discovery that transient activation of ErbB2 in adult cardiomyocytes results in massive cardiomyocyte dedifferentiation and proliferation followed by new vessels formation, scar resolution and functional cardiac repair. Specific objectives focus on ErbB2-Yap/Hippo signalling during cardiac regeneration; ErbB2 activation in a chronic heart failure model; ErbB2-induced regenerative EMT-like process; and cardiomyocyte re-differentiation. In Aim 2, we will investigate the therapeutic effects of agrin, whose administration into injured hearts of mice and pigs elicits a significant regenerative response. Specific objectives are matrix-related cardiac regenerative cues, modulation of the immune response, angiogenesis, matrix remodeling, and developing a preclinical, large animal model to study agrin efficacy for cardiac repair. Interrogating the differences and similarities between our two regenerative models should give us a detailed roadmap for cardiac regenerative medicine by providing deeper knowledge of the regenerative process in the heart and pointing to novel targets for cardiac repair in human patients.
Recent ground-breaking studies by my team and others demonstrated that latent heart regeneration machinery can be awakened even in adult mammals. My lab's main contribution is the identification of two, apparently different, molecular mechanisms for augmenting cardiac regeneration in adult mice. The first requires transient activation of ErbB2 signalling in cardiomyocytes and the second involves extra cellular matrix-driven signalling by the proteoglycan agrin. Impressively, both mechanisms promote a major regenerative response that, in turn, enhances cardiac repair. In CardHeal we will use the two powerful regenerative models to obtain a holistic view of cardiac regeneration and repair mechanisms in mammals (mice and pigs). In Aim 1, we will explore the molecular mechanisms underlying our discovery that transient activation of ErbB2 in adult cardiomyocytes results in massive cardiomyocyte dedifferentiation and proliferation followed by new vessels formation, scar resolution and functional cardiac repair. Specific objectives focus on ErbB2-Yap/Hippo signalling during cardiac regeneration; ErbB2 activation in a chronic heart failure model; ErbB2-induced regenerative EMT-like process; and cardiomyocyte re-differentiation. In Aim 2, we will investigate the therapeutic effects of agrin, whose administration into injured hearts of mice and pigs elicits a significant regenerative response. Specific objectives are matrix-related cardiac regenerative cues, modulation of the immune response, angiogenesis, matrix remodeling, and developing a preclinical, large animal model to study agrin efficacy for cardiac repair. Interrogating the differences and similarities between our two regenerative models should give us a detailed roadmap for cardiac regenerative medicine by providing deeper knowledge of the regenerative process in the heart and pointing to novel targets for cardiac repair in human patients.
Project acronym CELLPLASTICITY
Project New Frontiers in Cellular Reprogramming: Exploiting Cellular Plasticity
Researcher (PI) Manuel SERRANO MARUGAN
Host Institution (HI) FUNDACIO INSTITUT DE RECERCA BIOMEDICA (IRB BARCELONA)
Summary "Our research group has worked over the years at the interface between cancer and ageing, with a strong emphasis on mouse models. More recently, we became interested in cellular reprogramming because we hypothesized that understanding cellular plasticity could yield new insights into cancer and ageing. Indeed, during the previous ERC Advanced Grant, we made relevant contributions to the fields of cellular reprogramming (Nature 2013), cellular senescence (Cell 2013), cancer (Cancer Cell 2012), and ageing (Cell Metabolism 2012). Now, we take advantage of our diverse background and integrate the above processes. Our unifying hypothesis is that cellular plasticity lies at the basis of tissue regeneration ("adaptive cellular plasticity"), as well as at the origin of cancer ("maladaptive gain of cellular plasticity") and ageing ("maladaptive loss of cellular plasticity"). A key experimental system will be our "reprogrammable mice" (with inducible expression of the four Yamanaka factors), which we regard as a tool to induce cellular plasticity in vivo. The project is divided as follows: Objective #1 – Cellular plasticity and cancer: role of tumour suppressors in in vivo de-differentiation and reprogramming / impact of transient de-differentiation on tumour initiation / lineage tracing of Oct4 to determine whether a transient pluripotent-state occurs during cancer. Objective #2 – Cellular plasticity in tissue regeneration and ageing: impact of transient de-differentiation on tissue regeneration / contribution of the damage-induced microenvironment to tissue regeneration / impact of transient de-differentiation on ageing. Objective #3: New frontiers in cellular plasticity: chemical manipulation of cellular plasticity in vivo / new states of pluripotency / characterization of in vivo induced pluripotency and its unique properties. We anticipate that the completion of this project will yield new fundamental insights into cancer, regeneration and ageing."
"Our research group has worked over the years at the interface between cancer and ageing, with a strong emphasis on mouse models. More recently, we became interested in cellular reprogramming because we hypothesized that understanding cellular plasticity could yield new insights into cancer and ageing. Indeed, during the previous ERC Advanced Grant, we made relevant contributions to the fields of cellular reprogramming (Nature 2013), cellular senescence (Cell 2013), cancer (Cancer Cell 2012), and ageing (Cell Metabolism 2012). Now, we take advantage of our diverse background and integrate the above processes. Our unifying hypothesis is that cellular plasticity lies at the basis of tissue regeneration ("adaptive cellular plasticity"), as well as at the origin of cancer ("maladaptive gain of cellular plasticity") and ageing ("maladaptive loss of cellular plasticity"). A key experimental system will be our "reprogrammable mice" (with inducible expression of the four Yamanaka factors), which we regard as a tool to induce cellular plasticity in vivo. The project is divided as follows: Objective #1 – Cellular plasticity and cancer: role of tumour suppressors in in vivo de-differentiation and reprogramming / impact of transient de-differentiation on tumour initiation / lineage tracing of Oct4 to determine whether a transient pluripotent-state occurs during cancer. Objective #2 – Cellular plasticity in tissue regeneration and ageing: impact of transient de-differentiation on tissue regeneration / contribution of the damage-induced microenvironment to tissue regeneration / impact of transient de-differentiation on ageing. Objective #3: New frontiers in cellular plasticity: chemical manipulation of cellular plasticity in vivo / new states of pluripotency / characterization of in vivo induced pluripotency and its unique properties. We anticipate that the completion of this project will yield new fundamental insights into cancer, regeneration and ageing."
Project acronym CodingHeart
Project Novel Coding Factors in Heart Disease
Researcher (PI) Norbert HUBNER
Host Institution (HI) MAX DELBRUECK CENTRUM FUER MOLEKULARE MEDIZIN IN DER HELMHOLTZ-GEMEINSCHAFT (MDC)
Summary Heart failure has become a worldwide epidemic with more than 23 million people affected resulting in devastating consequences for patients and an enormous burden on health care systems. One in five heart failure patients dies within a year of diagnosis and survival estimates after diagnosis are 50% and 10% at 5 and 10 years, respectively. Despite intensive investigation, the molecular mechanisms leading to heart failure remain poorly understood. We will narrow this critical gap in knowledge by proposing a previously unattainable, comprehensive approach to define the genomic architecture and functional consequences of newly identified micropeptides from multiple classes of RNAs that previously were classified to be non-coding in cardiac biology and heart failure. Our approach is unique and novel in several ways. Thematically, our studies focus on novel classes of orphan peptides and their role in heart failure that have not been discovered previously. Our approach relies on innovative interdisciplinary efforts of scientists working in molecular genetics, genomics, computational biology, and cardiovascular research to identify and characterize pathophysiological pathways that converge on these novel peptides. We will identify these short peptides by using genome-wide measures of active translation and will harness unique clinical resources to ensure human relevance. Analysis of animal and cell models coupled with state-of-the-art biochemical and genetic tools will elucidate the function of newly identified micropeptides within the molecular and cellular pathways of cardiac biology and failure. Through these efforts we will discern fundamental causes of maladaptive responses in the heart and strategies to monitor and limit these.
Heart failure has become a worldwide epidemic with more than 23 million people affected resulting in devastating consequences for patients and an enormous burden on health care systems. One in five heart failure patients dies within a year of diagnosis and survival estimates after diagnosis are 50% and 10% at 5 and 10 years, respectively. Despite intensive investigation, the molecular mechanisms leading to heart failure remain poorly understood. We will narrow this critical gap in knowledge by proposing a previously unattainable, comprehensive approach to define the genomic architecture and functional consequences of newly identified micropeptides from multiple classes of RNAs that previously were classified to be non-coding in cardiac biology and heart failure. Our approach is unique and novel in several ways. Thematically, our studies focus on novel classes of orphan peptides and their role in heart failure that have not been discovered previously. Our approach relies on innovative interdisciplinary efforts of scientists working in molecular genetics, genomics, computational biology, and cardiovascular research to identify and characterize pathophysiological pathways that converge on these novel peptides. We will identify these short peptides by using genome-wide measures of active translation and will harness unique clinical resources to ensure human relevance. Analysis of animal and cell models coupled with state-of-the-art biochemical and genetic tools will elucidate the function of newly identified micropeptides within the molecular and cellular pathways of cardiac biology and failure. Through these efforts we will discern fundamental causes of maladaptive responses in the heart and strategies to monitor and limit these.
Project acronym COSMOS
Project COSMOS: Computational Shaping and Modeling of Musical Structures
Researcher (PI) Elaine Chew
Summary Music performance is considered by many to be one of the most breath taking feats of human intelligence. That music performance is a creative act is no longer a disputed fact, but the very nature of this creative work remains illusive. Taking the view that the creative work of performance is the making and shaping of music structures, and that this creative thinking is a form of problem solving, COSMOS proposes an integrated programme of research to transform our understanding of the human experience of performed music, which is almost all music that we hear, and of the creativity of music performance, which addresses how music is made. The research themes are as follows: i) to find new ways to represent, explore, and talk about performance; ii) to harness volunteer thinking (citizen science) for music performance research by focussing on structures experienced and problem solving; iii) to create sandbox environments to experiment with making performed structures; iv) to create theoretical frameworks to discover the reasoning behind the structures perceived and made; and, v) to foster community engagement by training experts to provide feedback on structure solutions so as to increase public understanding of the creative work in music performance. Analysis of the perceived and designed structures will be based on a novel duality paradigm that turns conventional computational music structure analysis on its head to reverse engineer why a perceiver or a performer chooses a particular structure. Embedded in the approach is the use of computational thinking to optimise representations and theories to ensure accuracy, robustness, efficiency, and scalability. The PI is an established performer and a leading authority in music representation, music information research, and music perception and cognition. The project will have far reaching impact, reconfiguring expert and public views of music performance and time-varying music-like sequences such as cardiac arrhythmia.
Music performance is considered by many to be one of the most breath taking feats of human intelligence. That music performance is a creative act is no longer a disputed fact, but the very nature of this creative work remains illusive. Taking the view that the creative work of performance is the making and shaping of music structures, and that this creative thinking is a form of problem solving, COSMOS proposes an integrated programme of research to transform our understanding of the human experience of performed music, which is almost all music that we hear, and of the creativity of music performance, which addresses how music is made. The research themes are as follows: i) to find new ways to represent, explore, and talk about performance; ii) to harness volunteer thinking (citizen science) for music performance research by focussing on structures experienced and problem solving; iii) to create sandbox environments to experiment with making performed structures; iv) to create theoretical frameworks to discover the reasoning behind the structures perceived and made; and, v) to foster community engagement by training experts to provide feedback on structure solutions so as to increase public understanding of the creative work in music performance. Analysis of the perceived and designed structures will be based on a novel duality paradigm that turns conventional computational music structure analysis on its head to reverse engineer why a perceiver or a performer chooses a particular structure. Embedded in the approach is the use of computational thinking to optimise representations and theories to ensure accuracy, robustness, efficiency, and scalability. The PI is an established performer and a leading authority in music representation, music information research, and music perception and cognition. The project will have far reaching impact, reconfiguring expert and public views of music performance and time-varying music-like sequences such as cardiac arrhythmia.
Project acronym CRAACE
Project Continuity and Rupture in Central European Art and Architecture, 1918-1939
Researcher (PI) Matthew RAMPLEY
Host Institution (HI) Masarykova univerzita
Summary When new political elites and social structures emerge out of a historical rupture, how are art and architecture affected? In 1918 the political map of central Europe was redrawn as a result of the collapse of Austria-Hungary, marking a new era for the region. Through comparative analysis of the visual arts in 3 states built on the ruins of the Habsburg Empire (Austria, Hungary and [former] Czechoslovakia), this project examines how such political discontinuity affected art and architecture between 1918 and 1939. The project is organised into 4 themes, each resulting in a monograph: 1. Vernacular modernisms, nostalgia and the avant-garde 2. Presenting the state: world fairs and exhibitionary cultures 3. Piety, reaction and renewal 4. Contested histories: monuments, memory and representations of the historical past It is the first systematic and comprehensive trans-national study of this type, based on the claim that the successor states to Austria-Hungary belonged to a common cultural space informed by the shared memory of the long years of Habsburg society and culture. The project focuses on the contradictory ways that visual arts of artists and architects in central Europe adapted to and tried to shape new socio-political circumstances in the light of the past. The project thus examines the long shadow of the Habsburg Empire over the art and culture of the twentieth century. The project also considers the impact of the political and ideological imperatives of the three successor states on the visual arts; how did governments treat the past? Did they encourage a sense of historical caesura or look to the past for legitimation? How did artists and architects respond to such new impulses? In answering these questions the project analyses the conflicts between avant-gardes and more conservative artistic movements; the role of the visual arts in interwar memory politics; the place of art in the nexus of religion, national and state identity.
When new political elites and social structures emerge out of a historical rupture, how are art and architecture affected? In 1918 the political map of central Europe was redrawn as a result of the collapse of Austria-Hungary, marking a new era for the region. Through comparative analysis of the visual arts in 3 states built on the ruins of the Habsburg Empire (Austria, Hungary and [former] Czechoslovakia), this project examines how such political discontinuity affected art and architecture between 1918 and 1939. The project is organised into 4 themes, each resulting in a monograph: 1. Vernacular modernisms, nostalgia and the avant-garde 2. Presenting the state: world fairs and exhibitionary cultures 3. Piety, reaction and renewal 4. Contested histories: monuments, memory and representations of the historical past It is the first systematic and comprehensive trans-national study of this type, based on the claim that the successor states to Austria-Hungary belonged to a common cultural space informed by the shared memory of the long years of Habsburg society and culture. The project focuses on the contradictory ways that visual arts of artists and architects in central Europe adapted to and tried to shape new socio-political circumstances in the light of the past. The project thus examines the long shadow of the Habsburg Empire over the art and culture of the twentieth century. The project also considers the impact of the political and ideological imperatives of the three successor states on the visual arts; how did governments treat the past? Did they encourage a sense of historical caesura or look to the past for legitimation? How did artists and architects respond to such new impulses? In answering these questions the project analyses the conflicts between avant-gardes and more conservative artistic movements; the role of the visual arts in interwar memory politics; the place of art in the nexus of religion, national and state identity.
Project acronym CuRE
Project Cardiac REgeneration from within
Researcher (PI) Mauro GIACCA
Summary Biotechnological therapies for patients with myocardial infarction and heart failure are urgently needed, in light of the breadth of these diseases and a lack of curative treatments. CuRE is an ambitious project aimed at identifying novel factors (cytokines, growth factors, microRNAs) that promote cardiomyocyte proliferation and can thus be transformed into innovative therapeutics to stimulate cardiac regeneration. The Project leads from two concepts: first, that cardiac regeneration can be obtained by stimulating the endogenous capacity of cardiomyocytes to proliferate, second that effective biotherapeutics might be identified through systematic screenings both in vivo and ex vivo. In the mouse, CuRE will take advantage of two unique arrayed libraries cloned in adeno-associated virus (AAV) vectors, one corresponding to the secretome (1200 factors) and the other to the miRNAome (800 pri-miRNA genes). Both libraries will be functionally screened in mice to search for factors that enhance cardiac regeneration. This in vivo selection approach will be complemented by a series of high throughput screenings on primary cardiomyocytes ex vivo, aimed at systematically assessing the involvement of all components of the ubiquitin/proteasome pathway, the cytoskeleton and the sarcomere on cell proliferation. Cytokines and miRNAs can both be developed to become therapeutic molecules, in the form of recombinant proteins and synthetic nucleic acids, respectively. Therefore, a key aim of CuRE will be to establish procedures for their production and administration in vivo, and to assess their efficacy in both small and large animal models of myocardial damage. In addition to this translational goal, the project will entail the successful achievement of several intermediate objectives, each of which possesses intrinsic validity in terms of basic discovery and is thus expected to extend technology and knowledge in the cardiovascular field beyond state-of-the art.
Biotechnological therapies for patients with myocardial infarction and heart failure are urgently needed, in light of the breadth of these diseases and a lack of curative treatments. CuRE is an ambitious project aimed at identifying novel factors (cytokines, growth factors, microRNAs) that promote cardiomyocyte proliferation and can thus be transformed into innovative therapeutics to stimulate cardiac regeneration. The Project leads from two concepts: first, that cardiac regeneration can be obtained by stimulating the endogenous capacity of cardiomyocytes to proliferate, second that effective biotherapeutics might be identified through systematic screenings both in vivo and ex vivo. In the mouse, CuRE will take advantage of two unique arrayed libraries cloned in adeno-associated virus (AAV) vectors, one corresponding to the secretome (1200 factors) and the other to the miRNAome (800 pri-miRNA genes). Both libraries will be functionally screened in mice to search for factors that enhance cardiac regeneration. This in vivo selection approach will be complemented by a series of high throughput screenings on primary cardiomyocytes ex vivo, aimed at systematically assessing the involvement of all components of the ubiquitin/proteasome pathway, the cytoskeleton and the sarcomere on cell proliferation. Cytokines and miRNAs can both be developed to become therapeutic molecules, in the form of recombinant proteins and synthetic nucleic acids, respectively. Therefore, a key aim of CuRE will be to establish procedures for their production and administration in vivo, and to assess their efficacy in both small and large animal models of myocardial damage. In addition to this translational goal, the project will entail the successful achievement of several intermediate objectives, each of which possesses intrinsic validity in terms of basic discovery and is thus expected to extend technology and knowledge in the cardiovascular field beyond state-of-the art.
Project acronym DecodeDiabetes
Project Expanding the genetic etiological and diagnostic spectrum of monogenic diabetes mellitus
Researcher (PI) Jorge FERRER
Host Institution (HI) FUNDACIO CENTRE DE REGULACIO GENOMICA
Summary Whole genome sequencing is quickly becoming a routine clinical instrument. However, our ability to decipher DNA variants is still largely limited to protein-coding exons, which comprise 1% of the genome. Most known Mendelian mutations are in exons, yet genetic testing still fails to show causal coding mutations in more than 50% of well-characterized Mendelian disorders. This defines a pressing need to interpret noncoding genome sequences, and to establish the role of noncoding mutations in Mendelian disease. A recent case study harnessed whole genome sequencing, epigenomics, and functional genomics to show that mutations in an enhancer cause most cases of neonatal diabetes due to pancreas agenesis. This example raises major questions: (i) what is the overall impact of penetrant regulatory mutations in human diabetes? (ii) do regulatory mutations cause distinct forms of diabetes? (iii) more generally, can we develop a strategy to systematically tackle regulatory variation in Mendelian disease? The current project will address these questions with unique resources. First, we have created epigenomic and functional perturbation resources to interpret the regulatory genome in embryonic pancreas and adult pancreatic islets. Second, we have collected an unprecedented international cohort of patients with a phenotype consistent with monogenic diabetes, yet lacking mutations in known gene culprits after genetic testing, and therefore with increased likelihood of harboring noncoding mutations. Third, we have developed a prototype platform to sequence regulatory mutations in a large number of patients. These resources will be combined with innovative strategies to uncover causal enhancer mutations underlying Mendelian diabetes. If successful, this project will expand the diagnostic spectrum of diabetes, it will discover new genetic regulators of diabetes-relevant networks, and will provide a framework to understand regulatory variation in Mendelian disease.
Whole genome sequencing is quickly becoming a routine clinical instrument. However, our ability to decipher DNA variants is still largely limited to protein-coding exons, which comprise 1% of the genome. Most known Mendelian mutations are in exons, yet genetic testing still fails to show causal coding mutations in more than 50% of well-characterized Mendelian disorders. This defines a pressing need to interpret noncoding genome sequences, and to establish the role of noncoding mutations in Mendelian disease. A recent case study harnessed whole genome sequencing, epigenomics, and functional genomics to show that mutations in an enhancer cause most cases of neonatal diabetes due to pancreas agenesis. This example raises major questions: (i) what is the overall impact of penetrant regulatory mutations in human diabetes? (ii) do regulatory mutations cause distinct forms of diabetes? (iii) more generally, can we develop a strategy to systematically tackle regulatory variation in Mendelian disease? The current project will address these questions with unique resources. First, we have created epigenomic and functional perturbation resources to interpret the regulatory genome in embryonic pancreas and adult pancreatic islets. Second, we have collected an unprecedented international cohort of patients with a phenotype consistent with monogenic diabetes, yet lacking mutations in known gene culprits after genetic testing, and therefore with increased likelihood of harboring noncoding mutations. Third, we have developed a prototype platform to sequence regulatory mutations in a large number of patients. These resources will be combined with innovative strategies to uncover causal enhancer mutations underlying Mendelian diabetes. If successful, this project will expand the diagnostic spectrum of diabetes, it will discover new genetic regulators of diabetes-relevant networks, and will provide a framework to understand regulatory variation in Mendelian disease.
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
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.
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.
Project acronym DIDONE
Project The Sources of Absolute Music: Mapping Emotions in Eighteenth-Century Italian Opera
Researcher (PI) Álvaro TORRENTE SANCHEZ GUISANDE
Host Institution (HI) UNIVERSIDAD COMPLUTENSE DE MADRID
Summary The belief that 'the end of music is to move human affections' (Descartes, Compendium musicae) has been a central issue in European musical thought since Plato. Opera was invented to recover the power of Ancient music to move the human heart, and its history is a permanent exploration of the capacity of action, words and music to convey emotions. In the eighteenth century a new type of opera consolidated with the chief concern of expressing the character's emotions as they changed throughout the drama, inspired by Descartes' theory of human passions. The key expressive medium was the aria col da capo, where a single, distinct passion was represented, like a concentrated pill of emotional meaning. The ideal corpus to study this issue are the 900 operas set to music by 300 composers on the 27 dramas by Pietro Metastasio (1698-1782). It contains a comprehensive catalogue of emotions in music, a unique window of opportunity to scrutinize conventions that defined music expression and meaning for over a century, paving the way for the emergence of 'absolute' instrumental music, autonomous from any other art form. DIDONE presents an innovative approach to unveil these conventions: the creation of a corpus of 4,000 digitized arias from 200 opera scores based on Metastasio's eight most popular dramas, to be analysed using traditional methods and big data computer technology. The comparative scrutiny of dozens of different musical settings of the same librettos will reveal how composers correlate specific dramatic circumstances and emotions with distinct poetic and musical features. The results will be applicable to three main fields: (i) opera performance; (ii) analysis and interpretation of other types of music; and (iii) composition in several scenarios, from film soundtracks to creation by Artificial Intelligence. An opera festival will be designed to recover and disseminate this hitherto ignored repertoire, which was essential to define the European musical identity.
The belief that 'the end of music is to move human affections' (Descartes, Compendium musicae) has been a central issue in European musical thought since Plato. Opera was invented to recover the power of Ancient music to move the human heart, and its history is a permanent exploration of the capacity of action, words and music to convey emotions. In the eighteenth century a new type of opera consolidated with the chief concern of expressing the character's emotions as they changed throughout the drama, inspired by Descartes' theory of human passions. The key expressive medium was the aria col da capo, where a single, distinct passion was represented, like a concentrated pill of emotional meaning. The ideal corpus to study this issue are the 900 operas set to music by 300 composers on the 27 dramas by Pietro Metastasio (1698-1782). It contains a comprehensive catalogue of emotions in music, a unique window of opportunity to scrutinize conventions that defined music expression and meaning for over a century, paving the way for the emergence of 'absolute' instrumental music, autonomous from any other art form. DIDONE presents an innovative approach to unveil these conventions: the creation of a corpus of 4,000 digitized arias from 200 opera scores based on Metastasio's eight most popular dramas, to be analysed using traditional methods and big data computer technology. The comparative scrutiny of dozens of different musical settings of the same librettos will reveal how composers correlate specific dramatic circumstances and emotions with distinct poetic and musical features. The results will be applicable to three main fields: (i) opera performance; (ii) analysis and interpretation of other types of music; and (iii) composition in several scenarios, from film soundtracks to creation by Artificial Intelligence. An opera festival will be designed to recover and disseminate this hitherto ignored repertoire, which was essential to define the European musical identity.
Project acronym EDJ
Project An Etymological Dictionary of the Japonic Languages
Researcher (PI) Alexander VOVIN
Host Institution (HI) ECOLE DES HAUTES ETUDES EN SCIENCES SOCIALES
Summary It is a paradoxical situation that with Japan being the third modern economy and Japanese, the main Japonic language, being the 10th in the world in terms of native speakers and the most widely studied Asian language, the Japonic language family still lacks an etymological dictionary. The present research project will rectify this situation. The benefits of an etymological dictionary of Japonic are obvious: not only it will be of a great use to the specialists working on pre-modern Japan and Ryukyuan islands in various disciplines; it will have its impact on modern studies, especially on linguistic identities in East Asia. And offer a new reading of regional linguistic identities The Etymological Dictionary of the Japonic languages has never been compiled, and the time for the realization of such a project is ripe, as it would have been impossible to carry on 30 or 40 years ago, since many important resources available now did not yet exist then such as numerous dictionaries and descriptions of dialects and historical stages of the language development. The same is true regarding the editions of many textual sources and compilation of their indexes. One very important difference with the previous era is also the fact that nowadays many sources are available electronically, which greatly facilitates the search and management of information. This project is highly innovative because it provides a presentation in context based on the extensive use of the IT technology, as compared to the previous research on Japonic etymology which was essentially word-list-oriented. In contrast with the current practice, where only word entries with their translations were provided (and often without any reference to the source), thanks to internet link to database, and cross-referenced entries, the electronic etymological dictionary will present the words in their textual historical and cultural context.
It is a paradoxical situation that with Japan being the third modern economy and Japanese, the main Japonic language, being the 10th in the world in terms of native speakers and the most widely studied Asian language, the Japonic language family still lacks an etymological dictionary. The present research project will rectify this situation. The benefits of an etymological dictionary of Japonic are obvious: not only it will be of a great use to the specialists working on pre-modern Japan and Ryukyuan islands in various disciplines; it will have its impact on modern studies, especially on linguistic identities in East Asia. And offer a new reading of regional linguistic identities The Etymological Dictionary of the Japonic languages has never been compiled, and the time for the realization of such a project is ripe, as it would have been impossible to carry on 30 or 40 years ago, since many important resources available now did not yet exist then such as numerous dictionaries and descriptions of dialects and historical stages of the language development. The same is true regarding the editions of many textual sources and compilation of their indexes. One very important difference with the previous era is also the fact that nowadays many sources are available electronically, which greatly facilitates the search and management of information. This project is highly innovative because it provides a presentation in context based on the extensive use of the IT technology, as compared to the previous research on Japonic etymology which was essentially word-list-oriented. In contrast with the current practice, where only word entries with their translations were provided (and often without any reference to the source), thanks to internet link to database, and cross-referenced entries, the electronic etymological dictionary will present the words in their textual historical and cultural context.
Project acronym Filmcolors
Project Film Colors. An Interdisciplinary Approach.
Researcher (PI) Barbara Flueckiger
Host Institution (HI) UNIVERSITAT ZURICH
Summary Film is in essence colored light projected onto a screen. Its aesthetics are thus highly determined by the material properties of film and the optical configuration of the cinematic apparatus. To this day, however, there is no systematic study of the relationship between the technology and aesthetics of film colors, despite the fact that, following the digital turn in film production and distribution, the understanding of this relationship is more essential than ever before. Over 200 film color processes were developed since the invention of film. They are presented on the Timeline of Historical Film Colors, which will be an integral part of the project. The groundbreaking nature of this project lies in a truly interdisciplinary research design with a novel methodology to explore the interaction of technological advances and limitations with film color aesthetics, identifying diachronic patterns of stylistic means. To this end it develops a tool through recent advancements in digital humanities for crowd-sourcing of color analyses of large groups of films. In-depth studies of technical papers and scientific measurements of film colors will investigate the technical basis of films' aesthetic appearance. These insights will be applied to the digitization and restoration of historical films to explore and disseminate the results. While every serious art restoration connects scientific analyses with art-historical and aesthetic investigations, a similar approach is rarely applied to film. In summary, the present research proposal capitalizes on the principal investigator's preceding studies to bridge the gap between technology and aesthetics. With the methods described here, the results will trace previously hidden roots of aesthetic developments of film colors. While the project is ambitious, it builds on a sizable methodological foundation to optimize risk management and guarantee significant advances in the understanding of film colors.
Film is in essence colored light projected onto a screen. Its aesthetics are thus highly determined by the material properties of film and the optical configuration of the cinematic apparatus. To this day, however, there is no systematic study of the relationship between the technology and aesthetics of film colors, despite the fact that, following the digital turn in film production and distribution, the understanding of this relationship is more essential than ever before. Over 200 film color processes were developed since the invention of film. They are presented on the Timeline of Historical Film Colors, which will be an integral part of the project. The groundbreaking nature of this project lies in a truly interdisciplinary research design with a novel methodology to explore the interaction of technological advances and limitations with film color aesthetics, identifying diachronic patterns of stylistic means. To this end it develops a tool through recent advancements in digital humanities for crowd-sourcing of color analyses of large groups of films. In-depth studies of technical papers and scientific measurements of film colors will investigate the technical basis of films' aesthetic appearance. These insights will be applied to the digitization and restoration of historical films to explore and disseminate the results. While every serious art restoration connects scientific analyses with art-historical and aesthetic investigations, a similar approach is rarely applied to film. In summary, the present research proposal capitalizes on the principal investigator's preceding studies to bridge the gap between technology and aesthetics. With the methods described here, the results will trace previously hidden roots of aesthetic developments of film colors. While the project is ambitious, it builds on a sizable methodological foundation to optimize risk management and guarantee significant advances in the understanding of film colors.
Project acronym GTCMR
Project Global Terrorism and Collective Moral Responsibility: Redesigning Military, Police and Intelligence Institutions in Liberal Democracies
Researcher (PI) Seumas Miller
Summary International terrorism, e.g. Al Qaeda, IS, is a major global security threat. Counter-terrorism is a morally complex enterprise involving police, military, intelligence agencies and non-security agencies. Counter-terrorism should be framed as a collective moral responsibility of governments, security institutions and citizens. (1) How is international terrorism to be defined? (2) What is the required theoretical notion of collective moral responsibility? (3) What counter-terrorist strategies and tactics are effective, morally permissible and consistent with liberal democracy? Tactics: targeted killing, drone warfare, preventative detention, and bulk metadata collection (e.g. by NSA); (4) How is this inchoate collective moral responsibility to be institutionally embedded in security agencies? (i) How are security institutions to be redesigned to enable them to realise and coordinate their counter-terrorism strategies without over-reaching their various core institutional purposes which have hitherto been disparate, (e.g. law enforcement versus military combat), and without compromising human rights, (e.g. right to life of innocent civilians, right to freedom, right to privacy), including by means of morally unacceptable counter-terrorism tactics? (ii) How are these tactics to be integrated with a broad-based counter-terrorism strategy which has such measures as anti-radicalisation and state-to-state engagement to address key sources of terrorism, such as the dissemination of extremist religious ideology (e.g. militant Wahhabi ideology emanating from Saudi Arabia) and the legitimate grievances of some terrorist groups (e.g. Palestinian state)? What ought a morally permissible and efficacious (i) structure of counter-terrorist institutional arrangements, and (ii) set of counter-terrorist tactics, for a contemporary liberal democracy collaborating with other liberal democracies facing the common problem of international terrorism consist of?
International terrorism, e.g. Al Qaeda, IS, is a major global security threat. Counter-terrorism is a morally complex enterprise involving police, military, intelligence agencies and non-security agencies. Counter-terrorism should be framed as a collective moral responsibility of governments, security institutions and citizens. (1) How is international terrorism to be defined? (2) What is the required theoretical notion of collective moral responsibility? (3) What counter-terrorist strategies and tactics are effective, morally permissible and consistent with liberal democracy? Tactics: targeted killing, drone warfare, preventative detention, and bulk metadata collection (e.g. by NSA); (4) How is this inchoate collective moral responsibility to be institutionally embedded in security agencies? (i) How are security institutions to be redesigned to enable them to realise and coordinate their counter-terrorism strategies without over-reaching their various core institutional purposes which have hitherto been disparate, (e.g. law enforcement versus military combat), and without compromising human rights, (e.g. right to life of innocent civilians, right to freedom, right to privacy), including by means of morally unacceptable counter-terrorism tactics? (ii) How are these tactics to be integrated with a broad-based counter-terrorism strategy which has such measures as anti-radicalisation and state-to-state engagement to address key sources of terrorism, such as the dissemination of extremist religious ideology (e.g. militant Wahhabi ideology emanating from Saudi Arabia) and the legitimate grievances of some terrorist groups (e.g. Palestinian state)? What ought a morally permissible and efficacious (i) structure of counter-terrorist institutional arrangements, and (ii) set of counter-terrorist tactics, for a contemporary liberal democracy collaborating with other liberal democracies facing the common problem of international terrorism consist of?
Project acronym HisTochText
Project History of the Tocharian Texts of the Pelliot Collection
Researcher (PI) Georges-jean PINAULT
Host Institution (HI) ECOLE PRATIQUE DES HAUTES ETUDES
Summary HisTochText addresses written Buddhist culture of the northern Silk Road in an innovative and path-breaking way, by going beyond the frontier of disciplines which have been cultivated separately: philology, digital humanities and in-depth analysis of materials, edition of Tocharian texts and comparative Buddhist literature, Sanskrit poetics and narratology, texts and social contexts. The flourishing Buddhist culture of the northern Silk Road during the 1st millennium CE in the Tarim Basin in present-day Xinjiang (NW China) is known by archaeological findings, artifacts and manuscripts in various languages. Since Buddhism was introduced from India, Sanskrit was the dominant religious language. By contrast, Tocharian belongs to the few local languages that are known to us thanks to Buddhist written culture. The two closely related Tocharian languages (Tocharian A and Tocharian B) were deciphered in 1908 on the basis of manuscripts discovered at the beginning of the past century in Buddhist sites of this region, together with Sanskrit manuscripts. The collection of the Bibliothèque nationale de France issued from the Pelliot expedition is a major collection of Tocharian manuscripts, counting around 2,000 fragments, second only to the Berlin collection, but in comparison hardly investigated, despite its containing numerous unique masterpieces and the broadest cross-section of manuscript and document styles and types. Only one fourth has been edited, mostly in a provisional manner, without translation nor commentary. Many texts of the Pelliot collection, literary and non-literary, are of the utmost importance because they have no match in any other collection of Tocharian manuscripts, nor in Buddhist corpora in other languages. As most Pelliot manuscripts in Sanskrit and in Tocharian were found in Buddhist sites of the Kucha region, the comprehensive edition and analysis of the texts will provide precious information about an important centre of Central Asian Buddhism.
HisTochText addresses written Buddhist culture of the northern Silk Road in an innovative and path-breaking way, by going beyond the frontier of disciplines which have been cultivated separately: philology, digital humanities and in-depth analysis of materials, edition of Tocharian texts and comparative Buddhist literature, Sanskrit poetics and narratology, texts and social contexts. The flourishing Buddhist culture of the northern Silk Road during the 1st millennium CE in the Tarim Basin in present-day Xinjiang (NW China) is known by archaeological findings, artifacts and manuscripts in various languages. Since Buddhism was introduced from India, Sanskrit was the dominant religious language. By contrast, Tocharian belongs to the few local languages that are known to us thanks to Buddhist written culture. The two closely related Tocharian languages (Tocharian A and Tocharian B) were deciphered in 1908 on the basis of manuscripts discovered at the beginning of the past century in Buddhist sites of this region, together with Sanskrit manuscripts. The collection of the Bibliothèque nationale de France issued from the Pelliot expedition is a major collection of Tocharian manuscripts, counting around 2,000 fragments, second only to the Berlin collection, but in comparison hardly investigated, despite its containing numerous unique masterpieces and the broadest cross-section of manuscript and document styles and types. Only one fourth has been edited, mostly in a provisional manner, without translation nor commentary. Many texts of the Pelliot collection, literary and non-literary, are of the utmost importance because they have no match in any other collection of Tocharian manuscripts, nor in Buddhist corpora in other languages. As most Pelliot manuscripts in Sanskrit and in Tocharian were found in Buddhist sites of the Kucha region, the comprehensive edition and analysis of the texts will provide precious information about an important centre of Central Asian Buddhism.
Project acronym IslamAnimals
Project Animals in the Philosophy of the Islamic World
Researcher (PI) Peter Scott ADAMSON
Host Institution (HI) LUDWIG-MAXIMILIANS-UNIVERSITAET MUENCHEN
Summary Are animals conscious? Can they think or feel emotions? What makes them different from humans on the one hand and plants on the other? And how should we treat them? This project will bring to light a rich body of texts written in the Islamic world, which address just such questions about the value and nature of animals. Contrary to common assumptions, such questions were taken seriously in pre-modern thought. Scholars have explored ancient Greek and Indian discussions of animals, but little attention has been paid to the contribution of Islamic culture, which produced e.g. philosophical and scientific works on animals, moralizing fables featuring animal characters, and treatises on veterinary medicine and on the types and uses of animals. We will uncover the changing conceptions of animals revealed in such works, taking an innovative approach which explores the interaction between descriptive and normative accounts of animals. We seek to understand, for instance, how developments in ideas about animal souls impacted ideas about the ethical treatment of animals. We will also investigate the historical genesis of this corpus of texts on animals, by exploring the influence of three literary traditions: Aristotelian zoology, medicine, and the founding religious texts of Islam. An ideal host environment, along with the PI's expertise in Greek-Arabic cultural transmission and prior work on the interaction between philosophy, medicine, and theology, provide an ideal opportunity to explore the shift in attitudes towards animals that grew out of these three traditions. The impact of the project will be three-fold. It will (1) open up the philosophy of animals as a hitherto neglected field within Islamic studies; (2) provide a generalizable model of research on the interplay between normative and descriptive drivers of conceptual change; and (3) demonstrate that classical Islamic culture can speak to a moral issue that is hotly debated in contemporary European society.
Are animals conscious? Can they think or feel emotions? What makes them different from humans on the one hand and plants on the other? And how should we treat them? This project will bring to light a rich body of texts written in the Islamic world, which address just such questions about the value and nature of animals. Contrary to common assumptions, such questions were taken seriously in pre-modern thought. Scholars have explored ancient Greek and Indian discussions of animals, but little attention has been paid to the contribution of Islamic culture, which produced e.g. philosophical and scientific works on animals, moralizing fables featuring animal characters, and treatises on veterinary medicine and on the types and uses of animals. We will uncover the changing conceptions of animals revealed in such works, taking an innovative approach which explores the interaction between descriptive and normative accounts of animals. We seek to understand, for instance, how developments in ideas about animal souls impacted ideas about the ethical treatment of animals. We will also investigate the historical genesis of this corpus of texts on animals, by exploring the influence of three literary traditions: Aristotelian zoology, medicine, and the founding religious texts of Islam. An ideal host environment, along with the PI's expertise in Greek-Arabic cultural transmission and prior work on the interaction between philosophy, medicine, and theology, provide an ideal opportunity to explore the shift in attitudes towards animals that grew out of these three traditions. The impact of the project will be three-fold. It will (1) open up the philosophy of animals as a hitherto neglected field within Islamic studies; (2) provide a generalizable model of research on the interplay between normative and descriptive drivers of conceptual change; and (3) demonstrate that classical Islamic culture can speak to a moral issue that is hotly debated in contemporary European society.
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
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.
'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.
Project acronym LIPOMET
Project Dietary Influences on Metastasis: How, When, and Why
Researcher (PI) Salvador Aznar Benitah
Summary We have recently identified metastasis-initiating cells (MICs) in several types of tumors (Nature, 2017)1. Intriguingly, MICs: (i) are exclusive in their ability to generate metastases when transplanted; (ii) express the fatty acid channel CD36 and have a unique lipid metabolic signature; (iii) are exquisitely sensitive to the levels of fat in circulation, thus providing a link between the predisposition of metastasis and dietary fat; (iv) are highly sensitive to CD36 inhibition, which almost completely abolishes their metastatic potential. We still do not know how MICs promote metastasis or how MICs are influenced by dietary fat. In particular: (A) where are MICs located within the tumor, and does this location influence their behavior? How and where do they attach and expand at metastatic sites? (B) Why are MICs so sensitive to specific dietary lipids, and how do these lipids promote metastasis at the molecular and cellular levels? (C) Is the prolonged consumption of a high-fat diet a risk factor for developing metastatic tumors? If so, what are the underlying genetic and epigenetic causes for this effect? Can we revert these causes? To answer these questions, we will combine state-of-the-art in vivo functional models of metastasis, with quantitative metabolomics and proteomics, epigenetic and geographical position (3D) single-cell transcriptomic studies, as well as integrative computational analyses, using preclinical models and patientderived carcinomas of melanoma, oral cancer and breast cancer. We expect our project to provide fundamental insights into the mechanisms of metastasis, and how they are influenced by diet. This is highly relevant as 1) large quantities of fatty acids are typically consumed in Western diets; and 2) metastasis is the leading cause of cancer-related deaths. We also tackle a timely medical unmet need by exploring the therapeutic anti-metastatic potential of targeting fatty acid metabolism in cancer patients.
We have recently identified metastasis-initiating cells (MICs) in several types of tumors (Nature, 2017)1. Intriguingly, MICs: (i) are exclusive in their ability to generate metastases when transplanted; (ii) express the fatty acid channel CD36 and have a unique lipid metabolic signature; (iii) are exquisitely sensitive to the levels of fat in circulation, thus providing a link between the predisposition of metastasis and dietary fat; (iv) are highly sensitive to CD36 inhibition, which almost completely abolishes their metastatic potential. We still do not know how MICs promote metastasis or how MICs are influenced by dietary fat. In particular: (A) where are MICs located within the tumor, and does this location influence their behavior? How and where do they attach and expand at metastatic sites? (B) Why are MICs so sensitive to specific dietary lipids, and how do these lipids promote metastasis at the molecular and cellular levels? (C) Is the prolonged consumption of a high-fat diet a risk factor for developing metastatic tumors? If so, what are the underlying genetic and epigenetic causes for this effect? Can we revert these causes? To answer these questions, we will combine state-of-the-art in vivo functional models of metastasis, with quantitative metabolomics and proteomics, epigenetic and geographical position (3D) single-cell transcriptomic studies, as well as integrative computational analyses, using preclinical models and patientderived carcinomas of melanoma, oral cancer and breast cancer. We expect our project to provide fundamental insights into the mechanisms of metastasis, and how they are influenced by diet. This is highly relevant as 1) large quantities of fatty acids are typically consumed in Western diets; and 2) metastasis is the leading cause of cancer-related deaths. We also tackle a timely medical unmet need by exploring the therapeutic anti-metastatic potential of targeting fatty acid metabolism in cancer patients.
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
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.
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.
Project acronym MMUVR
Project Elucidating the role of ultraviolet radiation in melanoma
Researcher (PI) Richard Marais
Host Institution (HI) THE UNIVERSITY OF MANCHESTER
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.
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.
Project acronym Mulosige
Project Multilingual locals, significant geographies: a new approach to world literature
Researcher (PI) Francesca Orsini
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.
"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.
Project acronym NEEM
Project The New Ecology of Expressive Modes in Early Modern South India
Researcher (PI) David Dean Shulman
Summary Southern India in the fifteenth, sixteenth, and seventeenth centuries comprised a single, strongly interwoven, multilingual cultural world that generated innovative literary, musical, theatrical and visual masterpieces as well as a theoretical erudite literature that explored the aesthetic and philosophical bases of these new works. New literary genres such as the compact, self-contained prabandha narratives crossed linguistic boundaries, emerging in and rapidly coming to dominate Tamil, Telugu, Kannada, Malayalam, and the trans-local languages of Sanskrit, Persian, Marathi and Dakhni. Such texts, seen together with major genres evolving in the other expressive domains (the early varnams and kirttanas in music, the great mural paintings of the Tamil and Karnataka regions, Kudiyattam drama), were building blocks of an eco-system whose rules, themes, forms, and intertextual relations have never been studied as a whole. We propose to explore this large corpus in relation to the new grammars of language, poetics, music, drama, and painting that evolved at the same time. Among major themes common to all these traditions are the interiority and states of mind of the individual human person, the question of how such a person is created and fashioned, the problem of the fate or destiny that a person faces or generates out of himself or herself, and the autonomy of the natural world within which he or she lives and acts. All the major expressive domains, with their thematic and theoretical continuities, give voice to a historic shift in the dynamics and underlying axioms of south Indian civilization at the start of the modern age; this shift becomes fully articulate and apparent only when we see the expressive eco-system as a whole.
Southern India in the fifteenth, sixteenth, and seventeenth centuries comprised a single, strongly interwoven, multilingual cultural world that generated innovative literary, musical, theatrical and visual masterpieces as well as a theoretical erudite literature that explored the aesthetic and philosophical bases of these new works. New literary genres such as the compact, self-contained prabandha narratives crossed linguistic boundaries, emerging in and rapidly coming to dominate Tamil, Telugu, Kannada, Malayalam, and the trans-local languages of Sanskrit, Persian, Marathi and Dakhni. Such texts, seen together with major genres evolving in the other expressive domains (the early varnams and kirttanas in music, the great mural paintings of the Tamil and Karnataka regions, Kudiyattam drama), were building blocks of an eco-system whose rules, themes, forms, and intertextual relations have never been studied as a whole. We propose to explore this large corpus in relation to the new grammars of language, poetics, music, drama, and painting that evolved at the same time. Among major themes common to all these traditions are the interiority and states of mind of the individual human person, the question of how such a person is created and fashioned, the problem of the fate or destiny that a person faces or generates out of himself or herself, and the autonomy of the natural world within which he or she lives and acts. All the major expressive domains, with their thematic and theoretical continuities, give voice to a historic shift in the dynamics and underlying axioms of south Indian civilization at the start of the modern age; this shift becomes fully articulate and apparent only when we see the expressive eco-system as a whole.
Project acronym NOTAE
Project NOT A writtEn word but graphic symbols. NOTAE: An evidence-based reconstruction of another written world in pragmatic literacy from Late Antiquity to early medieval Europe.
Researcher (PI) Antonella GHIGNOLI
Host Institution (HI) UNIVERSITA DEGLI STUDI DI ROMA LA SAPIENZA
Summary The use of graphic symbols in documentary records from the 4th to the 10th c. has so far received scant attention. 'Graphic symbols' are graphic signs (including alphabetical ones) drawn as a visual unit in a written text and representing something other than a word. They therefore broadly cover the semantic spectrum of the Latin 'notae' (signs) as opposed to 'litterae' (letters of the alphabet). With the gradual introduction of signature and the increasing use of papyrus from the 4th. c., the presence of graphic symbols became widespread in legal documents as it already was in other written records, and continued in post-Roman kingdoms as part of the same historical process of reception of the late antique documentary practice. Drawing symbols had a major social impact, because, provided it was done in one's own hand, it placed on the same footing professional scribes, basic literates and illiterates. For illiterates, it certainly meant, both in the late Roman state (a Greek-Latin graphic and linguistic community) and in the post-Roman kindgdoms (as long as Latin functioned as language of vertical communication) a way of taking an active part in the writing process. A thorough investigation of this 'other side' of the written world can therefore provide precious insights about the spread of literacy as a whole. The available instances of graphic symbols, which number in their thousands, will be investigated in their contemporary context as well as diachronically, bringing together methods developed in the fields of palaeography, diplomatics and history. Archaeology, sociolinguistics, social anthropology and history of christianity will also provide important methodological angles. The census, description and images of these graphic symbols will be made available on the web through the relational and dynamic NOTAE-Database, which will be the main result of the project and, at the same time, the research tool for both the team members and all the interested scholars.
The use of graphic symbols in documentary records from the 4th to the 10th c. has so far received scant attention. 'Graphic symbols' are graphic signs (including alphabetical ones) drawn as a visual unit in a written text and representing something other than a word. They therefore broadly cover the semantic spectrum of the Latin 'notae' (signs) as opposed to 'litterae' (letters of the alphabet). With the gradual introduction of signature and the increasing use of papyrus from the 4th. c., the presence of graphic symbols became widespread in legal documents as it already was in other written records, and continued in post-Roman kingdoms as part of the same historical process of reception of the late antique documentary practice. Drawing symbols had a major social impact, because, provided it was done in one's own hand, it placed on the same footing professional scribes, basic literates and illiterates. For illiterates, it certainly meant, both in the late Roman state (a Greek-Latin graphic and linguistic community) and in the post-Roman kindgdoms (as long as Latin functioned as language of vertical communication) a way of taking an active part in the writing process. A thorough investigation of this 'other side' of the written world can therefore provide precious insights about the spread of literacy as a whole. The available instances of graphic symbols, which number in their thousands, will be investigated in their contemporary context as well as diachronically, bringing together methods developed in the fields of palaeography, diplomatics and history. Archaeology, sociolinguistics, social anthropology and history of christianity will also provide important methodological angles. The census, description and images of these graphic symbols will be made available on the web through the relational and dynamic NOTAE-Database, which will be the main result of the project and, at the same time, the research tool for both the team members and all the interested scholars.
Project acronym OxygenSensing
Project Molecular mechanisms of acute oxygen sensing.
Researcher (PI) Jose Lopez Barneo
Host Institution (HI) UNIVERSIDAD DE SEVILLA
Summary Oxygen (O2) is essential for life on Earth. This proposal deals with the study of the molecular mechanisms underlying acute O2 sensing by cells, a long-standing issue that is yet to be elucidated. In recent years, the discovery of hypoxia inducible transcription factors and their regulation by the O2-dependent hydroxylases has provided a solid framework for understanding genetic responses to sustained (chronic) hypoxia. However the mechanisms of acute O2 sensing, necessary for the activation of rapid, life-saving, compensatory respiratory and cardiovascular reflexes (e.g. hyperventilation and sympathetic activation), are unknown. While the primary goal of the project is to characterize the molecular mechanisms underlying acute O2 sensing by arterial chemoreceptors (carotid body –CB- and adrenal medulla –AM-), we will also extend our study to other organs (e.g. pulmonary and systemic arteries) of the homeostatic acute O2-sensing system. We will investigate the role of mitochondria, in particular complex I (MCI), in acute O2 sensing. Previous data from our group demonstrated that rotenone, a MCI blocker, selectively occludes responsiveness to hypoxia in CB cells. In addition, our unpublished data indicate that sensitivity to hypoxia (but not to other stimuli) is lost in mice with genetic disruption of MCI genes in CB and AM cells. We have shown that the adult CB is a plastic organ that contains a population of multipotent neural stem cells. Hence, another objective of the project is to study the role of these stem cells in CB modulation (over- or infra-activation), which may participate in the pathogenesis of diseases. In the past, our group has made seminal contributions to unveiling the cellular bases of arterial chemoreception. The discovery of stem cells in the CB and the generation of new genetically modified mouse models, put us in a leading position to elucidate the molecular bases of acute O2 sensing and their biomedical implications.
Oxygen (O2) is essential for life on Earth. This proposal deals with the study of the molecular mechanisms underlying acute O2 sensing by cells, a long-standing issue that is yet to be elucidated. In recent years, the discovery of hypoxia inducible transcription factors and their regulation by the O2-dependent hydroxylases has provided a solid framework for understanding genetic responses to sustained (chronic) hypoxia. However the mechanisms of acute O2 sensing, necessary for the activation of rapid, life-saving, compensatory respiratory and cardiovascular reflexes (e.g. hyperventilation and sympathetic activation), are unknown. While the primary goal of the project is to characterize the molecular mechanisms underlying acute O2 sensing by arterial chemoreceptors (carotid body –CB- and adrenal medulla –AM-), we will also extend our study to other organs (e.g. pulmonary and systemic arteries) of the homeostatic acute O2-sensing system. We will investigate the role of mitochondria, in particular complex I (MCI), in acute O2 sensing. Previous data from our group demonstrated that rotenone, a MCI blocker, selectively occludes responsiveness to hypoxia in CB cells. In addition, our unpublished data indicate that sensitivity to hypoxia (but not to other stimuli) is lost in mice with genetic disruption of MCI genes in CB and AM cells. We have shown that the adult CB is a plastic organ that contains a population of multipotent neural stem cells. Hence, another objective of the project is to study the role of these stem cells in CB modulation (over- or infra-activation), which may participate in the pathogenesis of diseases. In the past, our group has made seminal contributions to unveiling the cellular bases of arterial chemoreception. The discovery of stem cells in the CB and the generation of new genetically modified mouse models, put us in a leading position to elucidate the molecular bases of acute O2 sensing and their biomedical implications.
Project acronym POLICE
Project The PIDDosome in Centrosome and Ploidy-Surveillance
Researcher (PI) Andreas VILLUNGER
Host Institution (HI) MEDIZINISCHE UNIVERSITAT INNSBRUCK
Summary Tight control of the number of chromosome sets in a cell (ploidy) is fundamental for normal development and organismal health. Most cells in our body are diploid, yet, some cells, including cardiomyocytes or hepatocytes require a balanced increase in ploidy for proper function. Polyploidization is accompanied by an accumulation of centrosomes, structures needed for nucleating the mitotic spindle and ciliogenesis. Extra centrosomes, however, promote aneuploidy in proliferating cells by causing errors in chromosome segregation, underlying a series of human pathologies, most notably cancer and premature ageing. How polyploidization is controlled in organogenesis and how errors in ploidy control contribute to disease is poorly understood. We recently demonstrated that the "PIDDosome" complex polices centrosome numbers in mammalian cells, alerting the tumor suppressor p53 in response to extra centrosomes. This is achieved by inactivating MDM2, the key-inhibitor of p53, by targeted proteolysis. MDM2-processing is mediated by caspase-2, a neglected member in a protease family that controls cell death and inflammation, activated in the PIDDosome. This exciting finding allows examining the consequences of deregulated ploidy and centrosome number in development and disease without interfering with p53, nor the cell fusion or cytokinesis machineries. This puts us in pole position to carry out an integrative study that aims to develop the PIDDosome as a new therapeutic target in cancer, related inflammation and in regenerative medicine. To meet this aim, we will define (i) the relevance of the PIDDosome in aneuploidy tolerance of cancer (ii) the role of the PIDDosome in controlling sterile inflammation and immunity (iii) the PIDDosome as a key-regulator of organ development and regeneration POLICE will open new lines of research at the interface of cell cycle, cell death & inflammation control and promote the PIDDosome as new target in our efforts to improve human health.
Tight control of the number of chromosome sets in a cell (ploidy) is fundamental for normal development and organismal health. Most cells in our body are diploid, yet, some cells, including cardiomyocytes or hepatocytes require a balanced increase in ploidy for proper function. Polyploidization is accompanied by an accumulation of centrosomes, structures needed for nucleating the mitotic spindle and ciliogenesis. Extra centrosomes, however, promote aneuploidy in proliferating cells by causing errors in chromosome segregation, underlying a series of human pathologies, most notably cancer and premature ageing. How polyploidization is controlled in organogenesis and how errors in ploidy control contribute to disease is poorly understood. We recently demonstrated that the "PIDDosome" complex polices centrosome numbers in mammalian cells, alerting the tumor suppressor p53 in response to extra centrosomes. This is achieved by inactivating MDM2, the key-inhibitor of p53, by targeted proteolysis. MDM2-processing is mediated by caspase-2, a neglected member in a protease family that controls cell death and inflammation, activated in the PIDDosome. This exciting finding allows examining the consequences of deregulated ploidy and centrosome number in development and disease without interfering with p53, nor the cell fusion or cytokinesis machineries. This puts us in pole position to carry out an integrative study that aims to develop the PIDDosome as a new therapeutic target in cancer, related inflammation and in regenerative medicine. To meet this aim, we will define (i) the relevance of the PIDDosome in aneuploidy tolerance of cancer (ii) the role of the PIDDosome in controlling sterile inflammation and immunity (iii) the PIDDosome as a key-regulator of organ development and regeneration POLICE will open new lines of research at the interface of cell cycle, cell death & inflammation control and promote the PIDDosome as new target in our efforts to improve human health.
Project acronym PROVEC
Project Promoting Osteogenesis through Vascular Endothelial Cells
Researcher (PI) Ralf Heinrich ADAMS
Summary The skeletal system and its vasculature form a functional unit with great relevance in health, regeneration, and disease. Our recent work has provided fundamental insights into the organization of the bone vasculature in mouse, its changes during aging, the heterogeneity and functional specialization of bone capillaries and endothelial cells, the regulation of these properties by Notch and hypoxia-inducible factor signaling, and the crosstalk with osteoblast lineage cells. Most importantly, we found that the manipulation of ECs in the aging animal can trigger the expansion of osteoprogenitors and thereby induce bone formation. PROVEC will now systemically identify and characterize endothelial cell subpopulations, their gene expression and functional properties in the healthy, aging, diseased and regenerating skeletal system. Preclinical models will establish whether endothelial cells are involved in the response to therapeutic treatments aiming at osteoblasts or osteoclasts, or if the modulation of ECs alone is sufficient to generate beneficial effects. Finally, PROVEC will investigate whether cultured mouse and human ECs can be endowed with beneficial properties to enhance bone formation in 3D organoid cultures and after transplantation into mice, which will be monitored by imaging in living animals. To achieve its ambitions aims, PROVEC will use a powerful combination of mouse genetics, disease models, genetic fate mapping, RNA-seq and single cell sequencing, computational biology, confocal and 2-photon microscopy, micro-CT imaging, pharmacological treatments, and cell biology methods to establish if and how vascular endothelial cells can be used to increase bone mineral density in preclinical models. The successful completion of PROVEC would be highly relevant for diseases such as osteoporosis, which affects around 27.5 million patients in the EU, generates annual costs of about 37 billion Euros, and for which we currently lack appropriate treatments.
The skeletal system and its vasculature form a functional unit with great relevance in health, regeneration, and disease. Our recent work has provided fundamental insights into the organization of the bone vasculature in mouse, its changes during aging, the heterogeneity and functional specialization of bone capillaries and endothelial cells, the regulation of these properties by Notch and hypoxia-inducible factor signaling, and the crosstalk with osteoblast lineage cells. Most importantly, we found that the manipulation of ECs in the aging animal can trigger the expansion of osteoprogenitors and thereby induce bone formation. PROVEC will now systemically identify and characterize endothelial cell subpopulations, their gene expression and functional properties in the healthy, aging, diseased and regenerating skeletal system. Preclinical models will establish whether endothelial cells are involved in the response to therapeutic treatments aiming at osteoblasts or osteoclasts, or if the modulation of ECs alone is sufficient to generate beneficial effects. Finally, PROVEC will investigate whether cultured mouse and human ECs can be endowed with beneficial properties to enhance bone formation in 3D organoid cultures and after transplantation into mice, which will be monitored by imaging in living animals. To achieve its ambitions aims, PROVEC will use a powerful combination of mouse genetics, disease models, genetic fate mapping, RNA-seq and single cell sequencing, computational biology, confocal and 2-photon microscopy, micro-CT imaging, pharmacological treatments, and cell biology methods to establish if and how vascular endothelial cells can be used to increase bone mineral density in preclinical models. The successful completion of PROVEC would be highly relevant for diseases such as osteoporosis, which affects around 27.5 million patients in the EU, generates annual costs of about 37 billion Euros, and for which we currently lack appropriate treatments.
Project acronym ReAct
Project Remembering Activism: The Cultural Memory of Protest in Europe
Researcher (PI) Ann Rigney
Summary Mass demonstrations are newsworthy. But how are they remembered when they are no longer news? Social movements are usually studied in terms of their emergence and subsidence. Despite recognition that activists are 'inspired' by precedents, the afterlife of activism in story and image has never been systematically explored. ReAct contends that knowledge about this cultural memory is needed for a full understanding civil resistance. ReAct will provide the first in-depth account of the remembering and forgetting of activism in Europe since the late 19th century. It will reveal continuities and changes in how protest has been depicted in different media regimes; demonstrate the role of texts, images, and commemorative practices in conveying the memory of protest to later generations; and show how this memory feeds back into later movements at home and abroad. The project is designed around case studies from periods of heightened activism in Europe: 1871-1914; 1960-1970; 2011-2012. Work packages follow 3 intersecting lines of inquiry: mediation (what cultural frames have been used to turn activism into transferable knowledge?); afterlives (how has the memory of particular movements been culturally transmitted?); memoryscapes (how have later movements referenced earlier ones?). A key innovation is network visualization to map the reproduction of narratives and references to predecessors. ReAct will effect a major reorientation in cultural memory research: by developing analytic tools with which to capture the cultural transmission of hope, it provides an alternative to the trauma-based models that currently dominate the field. It will also open up a new area of social movement research by revealing traditions of civic memory and how it is culturally produced. Outside of the academy, ReAct will provide critical literacies with which to rethink collective memory and identity in terms of active citizenship rather than ethnic-national grievances.
Mass demonstrations are newsworthy. But how are they remembered when they are no longer news? Social movements are usually studied in terms of their emergence and subsidence. Despite recognition that activists are 'inspired' by precedents, the afterlife of activism in story and image has never been systematically explored. ReAct contends that knowledge about this cultural memory is needed for a full understanding civil resistance. ReAct will provide the first in-depth account of the remembering and forgetting of activism in Europe since the late 19th century. It will reveal continuities and changes in how protest has been depicted in different media regimes; demonstrate the role of texts, images, and commemorative practices in conveying the memory of protest to later generations; and show how this memory feeds back into later movements at home and abroad. The project is designed around case studies from periods of heightened activism in Europe: 1871-1914; 1960-1970; 2011-2012. Work packages follow 3 intersecting lines of inquiry: mediation (what cultural frames have been used to turn activism into transferable knowledge?); afterlives (how has the memory of particular movements been culturally transmitted?); memoryscapes (how have later movements referenced earlier ones?). A key innovation is network visualization to map the reproduction of narratives and references to predecessors. ReAct will effect a major reorientation in cultural memory research: by developing analytic tools with which to capture the cultural transmission of hope, it provides an alternative to the trauma-based models that currently dominate the field. It will also open up a new area of social movement research by revealing traditions of civic memory and how it is culturally produced. Outside of the academy, ReAct will provide critical literacies with which to rethink collective memory and identity in terms of active citizenship rather than ethnic-national grievances.
Project acronym RESPONSIBILITY
Project The Roots of Responsibility: Metaphysics, Humanity, and Society
Researcher (PI) John HYMAN
Host Institution (HI) UNIVERSITY COLLEGE LONDON
Summary Philosophical research on responsibility today stems from early modern debates about causal necessity and freedom of the will, and ultimately from the Stoic problem of reconciling ethics with physics. It is therefore mainly focused on scepticism about the existence of free will and on the question whether moral responsibility is compatible with physical determinism. The main premises of this project are that this focus is too narrow, and that the traditional problems can only be solved with a deeper understanding of the network of human capacities responsibility involves and the social and interpersonal context in which questions about responsibility arise. This in turn depends on a wide range of philosophical and scientific research that has been neglected in debates about determinism, responsibility and free will, in particular, legal theory, where the literature on the relationships between responsibility, liability and culpability is more sophisticated and more nuanced than it is in philosophy; biological systems theory, which has shown how the activity of more complex systems can harness stochasticity in the activity of the less complex systems of which they are composed; and the philosophy of action, in which the physical, psychological, ethical and intellectual dimensions of human agency are now more clearly articulated and better understood. The Roots of Responsibility will draw on all of these resources, in order to develop a comprehensive theory of responsibility, which cuts across traditional boundaries between metaphysics, epistemology, ethics, and philosophy of law. It will foster collaborative research in these branches of philosophy, and include expertise in psychology and theoretical biology at the relevant stages.
Philosophical research on responsibility today stems from early modern debates about causal necessity and freedom of the will, and ultimately from the Stoic problem of reconciling ethics with physics. It is therefore mainly focused on scepticism about the existence of free will and on the question whether moral responsibility is compatible with physical determinism. The main premises of this project are that this focus is too narrow, and that the traditional problems can only be solved with a deeper understanding of the network of human capacities responsibility involves and the social and interpersonal context in which questions about responsibility arise. This in turn depends on a wide range of philosophical and scientific research that has been neglected in debates about determinism, responsibility and free will, in particular, legal theory, where the literature on the relationships between responsibility, liability and culpability is more sophisticated and more nuanced than it is in philosophy; biological systems theory, which has shown how the activity of more complex systems can harness stochasticity in the activity of the less complex systems of which they are composed; and the philosophy of action, in which the physical, psychological, ethical and intellectual dimensions of human agency are now more clearly articulated and better understood. The Roots of Responsibility will draw on all of these resources, in order to develop a comprehensive theory of responsibility, which cuts across traditional boundaries between metaphysics, epistemology, ethics, and philosophy of law. It will foster collaborative research in these branches of philosophy, and include expertise in psychology and theoretical biology at the relevant stages.
Project acronym SENCAN
Project Senescence therapy for cancer
Researcher (PI) Rene BERNARDS
Summary Systemic treatment of advanced cancers is hampered by the development of drug resistance. To prevent resistance, my laboratory has in the past used functional genetic screens to discover several "synthetic lethal" drug combination therapies, which has resulted in 8 clinical trials to date, including one global phase 3 study. In this program, I propose a new approach to the treatment of cancer, which is not based on combinations of drugs, but rather on the sequential treatment with drugs. In a first treatment step, cells will not only be induced to stop dividing, but they will at the same time acquire a major new vulnerability that is subsequently targeted with a second drug that selectively kills cells having the newly acquired vulnerability. To accomplish this, we will take advantage of recent observations that the cellular senescence response is not only a property of primary cells, but can also be triggered in advanced cancers. Such senescent cells have dramatic changes in gene expression, chromatin structure and metabolism that we will exploit for their selective eradication. Using chemical compound libraries and loss-of-function genetic screens in cancer cells harboring a reporter gene that is activated selectively in senescent cells, we will search for genes and compounds that induce senescence in cancer cells. This will lead to the identification of compounds and/or signaling pathways whose inhibition induces senescence in cancer cells. We will also use chemical compound screens to find tools to selectively kill senescent cancer cells. We will use the targets and compounds identified in this program to test the in vivo efficacy of this "one-two punch" consecutive therapy approach: the first to induce senescence in cancer cells, the subsequent therapy to eradicate the senescent cells. We present here preliminary data that the concept of sequential drug treatment can be effective, which serves as an important proof of concept for the strategy proposed here.
Systemic treatment of advanced cancers is hampered by the development of drug resistance. To prevent resistance, my laboratory has in the past used functional genetic screens to discover several "synthetic lethal" drug combination therapies, which has resulted in 8 clinical trials to date, including one global phase 3 study. In this program, I propose a new approach to the treatment of cancer, which is not based on combinations of drugs, but rather on the sequential treatment with drugs. In a first treatment step, cells will not only be induced to stop dividing, but they will at the same time acquire a major new vulnerability that is subsequently targeted with a second drug that selectively kills cells having the newly acquired vulnerability. To accomplish this, we will take advantage of recent observations that the cellular senescence response is not only a property of primary cells, but can also be triggered in advanced cancers. Such senescent cells have dramatic changes in gene expression, chromatin structure and metabolism that we will exploit for their selective eradication. Using chemical compound libraries and loss-of-function genetic screens in cancer cells harboring a reporter gene that is activated selectively in senescent cells, we will search for genes and compounds that induce senescence in cancer cells. This will lead to the identification of compounds and/or signaling pathways whose inhibition induces senescence in cancer cells. We will also use chemical compound screens to find tools to selectively kill senescent cancer cells. We will use the targets and compounds identified in this program to test the in vivo efficacy of this "one-two punch" consecutive therapy approach: the first to induce senescence in cancer cells, the subsequent therapy to eradicate the senescent cells. We present here preliminary data that the concept of sequential drug treatment can be effective, which serves as an important proof of concept for the strategy proposed here.
Project acronym SICLE
Project Saadian Intellectual and Cultural Life
Researcher (PI) François Déroche
Host Institution (HI) COLLEGE DE FRANCE
Summary The aim of the interdisciplinary investigation project SICLE is to investigate in a completely new way the intellectual and cultural history of the Saadian period in Morocco (1554-1660), using primarily the Saadian sultans' library, exceptionally preserved as a 'time capsule' in the El Escorial monastery following king Felipe III's decision to include it in his own library. The period is a time of direct involvement of Morocco in international politics and exchanges, both in their East-West (with the Ottoman empire) and North-South (with Europe) dimensions, without forgetting Timbuktu and the Songhay empire conquered by Ahmad al-Mansur, the most brilliant ruler of the dynasty. The manuscripts kept in El Escorial mirror the interests and the tastes of the Saadian rulers and of the elite at large. The paratextual information they contain (but ignored by the catalogues) like the various notes, the colophons, the illuminations or the bindings will be systematically collected and analyzed in a trans-disciplinary approach which can be defined as an 'archaeology of the book', combining codicology, philology, archaeometry, anthropology and art history. The same approach will be applied to the books of the 'ordinary people' from Saadian times preserved in Moroccan collections. SICLE goals are to offer: a) a history of the Saadian sultans' library and an analysis of their interests; b) a cultural and intellectual history of Morocco during the 16th century, with groundbreaking studies on the history of the book, on its economy and on education; c) an evaluation of the relationship with the 'outside' (Christian Europe, the Ottoman empire and sub-Saharan Africa) and the possible influence it had on Saadian intellectual production. Special attention will be paid to the Jewish and Morisco communities in their role of culture brokers.
The aim of the interdisciplinary investigation project SICLE is to investigate in a completely new way the intellectual and cultural history of the Saadian period in Morocco (1554-1660), using primarily the Saadian sultans' library, exceptionally preserved as a 'time capsule' in the El Escorial monastery following king Felipe III's decision to include it in his own library. The period is a time of direct involvement of Morocco in international politics and exchanges, both in their East-West (with the Ottoman empire) and North-South (with Europe) dimensions, without forgetting Timbuktu and the Songhay empire conquered by Ahmad al-Mansur, the most brilliant ruler of the dynasty. The manuscripts kept in El Escorial mirror the interests and the tastes of the Saadian rulers and of the elite at large. The paratextual information they contain (but ignored by the catalogues) like the various notes, the colophons, the illuminations or the bindings will be systematically collected and analyzed in a trans-disciplinary approach which can be defined as an 'archaeology of the book', combining codicology, philology, archaeometry, anthropology and art history. The same approach will be applied to the books of the 'ordinary people' from Saadian times preserved in Moroccan collections. SICLE goals are to offer: a) a history of the Saadian sultans' library and an analysis of their interests; b) a cultural and intellectual history of Morocco during the 16th century, with groundbreaking studies on the history of the book, on its economy and on education; c) an evaluation of the relationship with the 'outside' (Christian Europe, the Ottoman empire and sub-Saharan Africa) and the possible influence it had on Saadian intellectual production. Special attention will be paid to the Jewish and Morisco communities in their role of culture brokers.
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
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
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
Project acronym TVOF
Project The values of French language and literature in the European Middle Ages
Researcher (PI) Simon Benjamin Gaunt
Summary Two questions about linguistic identity lie at the heart of this project. What is the relation historically between language and identity in Europe? How are cognate languages demarcated from each other? Normative models of national languages helped shape Europe. Yet they did not become hegemonic until the 19th century. Indeed, they were imposed (not always successfully) on a linguistic map of Europe more fluid and complex than most histories of national languages allow. In the Middle Ages multilingualism was common, as was the use of non-local languages, notably Latin, but also French. This project undertakes a revaluation of the nature and value of the use of French in Europe during a crucial period, 1100-1450, less in terms of its cultural prestige (the traditional focus of scholarship) than of its role as a supralocal, transnational language, particularly in Western Europe and the Eastern Mediterranean. The project fosters collaboration between, and cuts across, different intellectual and national scholarly traditions, drawing on expertise in codicology, critical theory, linguistics, literature, and philology; it involves scholars from a range of European countries and North America, entailing empirical research around a complex and widely disseminated textual tradition vital to medieval understandings of European history and identity, L'Histoire ancienne jusqu'à César. This case study will ground and stimulate broader speculative reflection on the two core questions concerning linguistic identity. While the project builds on prior critiques of the construction of, and investment in, national languages and literary traditions, it has a broad historical scope, and will offer an innovative, genuinely international perspective, in terms of both its object of study and method. Indeed, its final aim, through and beyond its consideration of French as a lingua franca, is to interrogate that language's role in the emergence of a European identity in the Middle Ages.
Two questions about linguistic identity lie at the heart of this project. What is the relation historically between language and identity in Europe? How are cognate languages demarcated from each other? Normative models of national languages helped shape Europe. Yet they did not become hegemonic until the 19th century. Indeed, they were imposed (not always successfully) on a linguistic map of Europe more fluid and complex than most histories of national languages allow. In the Middle Ages multilingualism was common, as was the use of non-local languages, notably Latin, but also French. This project undertakes a revaluation of the nature and value of the use of French in Europe during a crucial period, 1100-1450, less in terms of its cultural prestige (the traditional focus of scholarship) than of its role as a supralocal, transnational language, particularly in Western Europe and the Eastern Mediterranean. The project fosters collaboration between, and cuts across, different intellectual and national scholarly traditions, drawing on expertise in codicology, critical theory, linguistics, literature, and philology; it involves scholars from a range of European countries and North America, entailing empirical research around a complex and widely disseminated textual tradition vital to medieval understandings of European history and identity, L'Histoire ancienne jusqu'à César. This case study will ground and stimulate broader speculative reflection on the two core questions concerning linguistic identity. While the project builds on prior critiques of the construction of, and investment in, national languages and literary traditions, it has a broad historical scope, and will offer an innovative, genuinely international perspective, in terms of both its object of study and method. Indeed, its final aim, through and beyond its consideration of French as a lingua franca, is to interrogate that language's role in the emergence of a European identity in the Middle Ages.
Project acronym ValueChange
Project Design for changing values: a theory of value change in sociotechnical systems
Researcher (PI) Ibo VAN DE POEL
Summary One of the key insights from the philosophy of technology is that technological artifacts and sociotechnical systems are not value neutral but supports or inhibits certain values. Several philosophical accounts for understanding the embedding of values in technological artifacts have been proposed and approaches like Value Sensitive Design, Design for Values and Responsible Research and Innovation have been established for integrating values into technical design. A blind spot is, however, the possibility of value change after a sociotechnical system has been designed. For example, when many of our current energy and transportation systems were designed sustainability was not yet a central value, and we are now struggling to incorporate this value into these systems. Progress in the field is currently inhibited by the lack of a philosophical theory of value change in sociotechnical systems. This proposal fills this gap by developing such a theory. It moves beyond the start of the art by proposing a dynamic rather than a static account of values, by developing insights in the dynamics of value change, by extending analysis about the embedding of values in technical artifacts to sociotechnical systems and by developing design strategies that aim at designing sociotechnical systems that can better deal with value change. The proposal has the following more specific objectives: 1) to propose a notion of value that is applicable to sociotechnical systems and that can account for value change, 2) to develop a taxonomy and mechanisms of value change in sociotechnical systems, 3) to extend philosophical analyses of the embedding of values in technological artifacts to sociotechnical systems 4) to carry out empirical studies about value change in energy systems and robot systems to support the development of a theory of value change, and 5) to develop strategies that can better deal with value change in sociotechnical systems than current value sensitive design approaches.
One of the key insights from the philosophy of technology is that technological artifacts and sociotechnical systems are not value neutral but supports or inhibits certain values. Several philosophical accounts for understanding the embedding of values in technological artifacts have been proposed and approaches like Value Sensitive Design, Design for Values and Responsible Research and Innovation have been established for integrating values into technical design. A blind spot is, however, the possibility of value change after a sociotechnical system has been designed. For example, when many of our current energy and transportation systems were designed sustainability was not yet a central value, and we are now struggling to incorporate this value into these systems. Progress in the field is currently inhibited by the lack of a philosophical theory of value change in sociotechnical systems. This proposal fills this gap by developing such a theory. It moves beyond the start of the art by proposing a dynamic rather than a static account of values, by developing insights in the dynamics of value change, by extending analysis about the embedding of values in technical artifacts to sociotechnical systems and by developing design strategies that aim at designing sociotechnical systems that can better deal with value change. The proposal has the following more specific objectives: 1) to propose a notion of value that is applicable to sociotechnical systems and that can account for value change, 2) to develop a taxonomy and mechanisms of value change in sociotechnical systems, 3) to extend philosophical analyses of the embedding of values in technological artifacts to sociotechnical systems 4) to carry out empirical studies about value change in energy systems and robot systems to support the development of a theory of value change, and 5) to develop strategies that can better deal with value change in sociotechnical systems than current value sensitive design approaches.