Project acronym aCROBAT
Project Circadian Regulation Of Brown Adipose Thermogenesis
Researcher (PI) Zachary Philip Gerhart-Hines
Host Institution (HI) KOBENHAVNS UNIVERSITET
Call Details Starting Grant (StG), LS4, ERC-2014-STG
Summary Obesity and diabetes have reached pandemic proportions and new therapeutic strategies are critically needed. Brown adipose tissue (BAT), a major source of heat production, possesses significant energy-dissipating capacity and therefore represents a promising target to use in combating these diseases. Recently, I discovered a novel link between circadian rhythm and thermogenic stress in the control of the conserved, calorie-burning functions of BAT. Circadian and thermogenic signaling to BAT incorporates blood-borne hormonal and nutrient cues with direct neuronal input. Yet how these responses coordinately shape BAT energy-expending potential through the regulation of cell surface receptors, metabolic enzymes, and transcriptional effectors is still not understood. My primary goal is to investigate this previously unappreciated network of crosstalk that allows mammals to effectively orchestrate daily rhythms in BAT metabolism, while maintaining their ability to adapt to abrupt changes in energy demand. My group will address this question using gain and loss-of-function in vitro and in vivo studies, newly-generated mouse models, customized physiological phenotyping, and cutting-edge advances in next generation RNA sequencing and mass spectrometry. Preliminary, small-scale validations of our methodologies have already yielded a number of novel candidates that may drive key facets of BAT metabolism. Additionally, we will extend our circadian and thermogenic studies into humans to evaluate the translational potential. Our results will advance the fundamental understanding of how daily oscillations in bioenergetic networks establish a framework for the anticipation of and adaptation to environmental challenges. Importantly, we expect that these mechanistic insights will reveal pharmacological targets through which we can unlock evolutionary constraints and harness the energy-expending potential of BAT for the prevention and treatment of obesity and diabetes.
Summary
Obesity and diabetes have reached pandemic proportions and new therapeutic strategies are critically needed. Brown adipose tissue (BAT), a major source of heat production, possesses significant energy-dissipating capacity and therefore represents a promising target to use in combating these diseases. Recently, I discovered a novel link between circadian rhythm and thermogenic stress in the control of the conserved, calorie-burning functions of BAT. Circadian and thermogenic signaling to BAT incorporates blood-borne hormonal and nutrient cues with direct neuronal input. Yet how these responses coordinately shape BAT energy-expending potential through the regulation of cell surface receptors, metabolic enzymes, and transcriptional effectors is still not understood. My primary goal is to investigate this previously unappreciated network of crosstalk that allows mammals to effectively orchestrate daily rhythms in BAT metabolism, while maintaining their ability to adapt to abrupt changes in energy demand. My group will address this question using gain and loss-of-function in vitro and in vivo studies, newly-generated mouse models, customized physiological phenotyping, and cutting-edge advances in next generation RNA sequencing and mass spectrometry. Preliminary, small-scale validations of our methodologies have already yielded a number of novel candidates that may drive key facets of BAT metabolism. Additionally, we will extend our circadian and thermogenic studies into humans to evaluate the translational potential. Our results will advance the fundamental understanding of how daily oscillations in bioenergetic networks establish a framework for the anticipation of and adaptation to environmental challenges. Importantly, we expect that these mechanistic insights will reveal pharmacological targets through which we can unlock evolutionary constraints and harness the energy-expending potential of BAT for the prevention and treatment of obesity and diabetes.
Max ERC Funding
1 497 008 €
Duration
Start date: 2015-05-01, End date: 2020-04-30
Project acronym AlchemEast
Project Alchemy in the Making: From ancient Babylonia via Graeco-Roman Egypt into the Byzantine, Syriac and Arabic traditions (1500 BCE - 1000 AD)
Researcher (PI) Matteo MARTELLI
Host Institution (HI) ALMA MATER STUDIORUM - UNIVERSITA DI BOLOGNA
Call Details Consolidator Grant (CoG), SH5, ERC-2016-COG
Summary The AlchemEast project is devoted to the study of alchemical theory and practice as it appeared and developed in distinct, albeit contiguous (both chronologically and geographically) areas: Graeco-Roman Egypt, Byzantium, and the Near East, from Ancient Babylonian times to the early Islamic Period. This project combines innovative textual investigations with experimental replications of ancient alchemical procedures. It uses sets of historically and philologically informed laboratory replications in order to reconstruct the actual practice of ancient alchemists, and it studies the texts and literary forms in which this practice was conceptualized and transmitted. It proposes new models for textual criticism in order to capture the fluidity of the transmission of ancient alchemical writings. AlchemEast is designed to carry out a comparative investigation of cuneiform tablets as well as a vast corpus of Greek, Syriac and Arabic writings. It will overcome the old, pejorative paradigm that dismissed ancient alchemy as a "pseudo-science", by proposing a new theoretical framework for comprehending the entirety of ancient alchemical practices and theories. Alongside established forms of scholarly output, such as critical editions of key texts, AlchemEast will provide an integrative, longue durée perspective on the many different phases of ancient alchemy. It will thus offer a radically new vision of this discipline as a dynamic and diversified art that developed across different technical and scholastic traditions. This new representation will allow us to connect ancient alchemy with medieval and early modern alchemy and thus fully reintegrate ancient alchemy in the history of pre-modern alchemy as well as in the history of ancient science more broadly.
Summary
The AlchemEast project is devoted to the study of alchemical theory and practice as it appeared and developed in distinct, albeit contiguous (both chronologically and geographically) areas: Graeco-Roman Egypt, Byzantium, and the Near East, from Ancient Babylonian times to the early Islamic Period. This project combines innovative textual investigations with experimental replications of ancient alchemical procedures. It uses sets of historically and philologically informed laboratory replications in order to reconstruct the actual practice of ancient alchemists, and it studies the texts and literary forms in which this practice was conceptualized and transmitted. It proposes new models for textual criticism in order to capture the fluidity of the transmission of ancient alchemical writings. AlchemEast is designed to carry out a comparative investigation of cuneiform tablets as well as a vast corpus of Greek, Syriac and Arabic writings. It will overcome the old, pejorative paradigm that dismissed ancient alchemy as a "pseudo-science", by proposing a new theoretical framework for comprehending the entirety of ancient alchemical practices and theories. Alongside established forms of scholarly output, such as critical editions of key texts, AlchemEast will provide an integrative, longue durée perspective on the many different phases of ancient alchemy. It will thus offer a radically new vision of this discipline as a dynamic and diversified art that developed across different technical and scholastic traditions. This new representation will allow us to connect ancient alchemy with medieval and early modern alchemy and thus fully reintegrate ancient alchemy in the history of pre-modern alchemy as well as in the history of ancient science more broadly.
Max ERC Funding
1 997 000 €
Duration
Start date: 2017-12-01, End date: 2022-11-30
Project acronym AlgoFinance
Project Algorithmic Finance: Inquiring into the Reshaping of Financial Markets
Researcher (PI) Christian BORCH
Host Institution (HI) COPENHAGEN BUSINESS SCHOOL
Call Details Consolidator Grant (CoG), SH3, ERC-2016-COG
Summary Present-day financial markets are turning algorithmic, as market orders are increasingly being executed by fully automated computer algorithms, without any direct human intervention. Although algorithmic finance seems to fundamentally reshape the central dynamics in financial markets, and even though it prompts core sociological questions, it has not yet received any systematic attention. In a pioneering contribution to economic sociology and social studies of finance, ALGOFINANCE aims to understand how and with what consequences the turn to algorithms is changing financial markets. The overall concept and central contributions of ALGOFINANCE are the following: (1) on an intra-firm level, the project examines how the shift to algorithmic finance reshapes the ways in which trading firms operate, and does so by systematically and empirically investigating the reconfiguration of organizational structures and employee subjectivity; (2) on an inter-algorithmic level, it offers a ground-breaking methodology (agent-based modelling informed by qualitative data) to grasp how trading algorithms interact with one another in a fully digital space; and (3) on the level of market sociality, it proposes a novel theorization of how intra-firm and inter-algorithmic dynamics can be conceived of as introducing a particular form of sociality that is characteristic to algorithmic finance: a form of sociality-as-association heuristically analyzed as imitation. None of these three levels have received systematic attention in the state-of-the-art literature. Addressing them will significantly advance the understanding of present-day algorithmic finance in economic sociology. By contributing novel empirical, methodological, and theoretical understandings of the functioning and consequences of algorithms, ALGOFINANCE will pave the way for other research into digital sociology and the broader algorithmization of society.
Summary
Present-day financial markets are turning algorithmic, as market orders are increasingly being executed by fully automated computer algorithms, without any direct human intervention. Although algorithmic finance seems to fundamentally reshape the central dynamics in financial markets, and even though it prompts core sociological questions, it has not yet received any systematic attention. In a pioneering contribution to economic sociology and social studies of finance, ALGOFINANCE aims to understand how and with what consequences the turn to algorithms is changing financial markets. The overall concept and central contributions of ALGOFINANCE are the following: (1) on an intra-firm level, the project examines how the shift to algorithmic finance reshapes the ways in which trading firms operate, and does so by systematically and empirically investigating the reconfiguration of organizational structures and employee subjectivity; (2) on an inter-algorithmic level, it offers a ground-breaking methodology (agent-based modelling informed by qualitative data) to grasp how trading algorithms interact with one another in a fully digital space; and (3) on the level of market sociality, it proposes a novel theorization of how intra-firm and inter-algorithmic dynamics can be conceived of as introducing a particular form of sociality that is characteristic to algorithmic finance: a form of sociality-as-association heuristically analyzed as imitation. None of these three levels have received systematic attention in the state-of-the-art literature. Addressing them will significantly advance the understanding of present-day algorithmic finance in economic sociology. By contributing novel empirical, methodological, and theoretical understandings of the functioning and consequences of algorithms, ALGOFINANCE will pave the way for other research into digital sociology and the broader algorithmization of society.
Max ERC Funding
1 590 036 €
Duration
Start date: 2017-05-01, End date: 2021-04-30
Project acronym BEAT
Project The functional interaction of EGFR and beta-catenin signalling in colorectal cancer: Genetics, mechanisms, and therapeutic potential.
Researcher (PI) Andrea BERTOTTI
Host Institution (HI) UNIVERSITA DEGLI STUDI DI TORINO
Call Details Consolidator Grant (CoG), LS7, ERC-2016-COG
Summary Monoclonal antibodies against the EGF receptor (EGFR) provide substantive benefit to colorectal cancer (CRC) patients. However, no genetic lesions that robustly predict ‘addiction’ to the EGFR pathway have been yet identified. Further, even in tumours that regress after EGFR blockade, subsets of drug-tolerant cells often linger and foster ‘minimal residual disease’ (MRD), which portends tumour relapse.
Our preliminary evidence suggests that reliance on EGFR activity, as opposed to MRD persistence, could be assisted by genetically-based variations in transcription factor partnerships and activities, gene expression outputs, and biological fates controlled by the WNT/beta-catenin pathway. On such premises, BEAT (Beta-catenin and EGFR Abrogation Therapy) will elucidate the mechanisms of EGFR dependency, and escape from it, with the goal to identify biomarkers for more efficient clinical management of CRC and develop new therapies for MRD eradication.
A multidisciplinary approach will be pursued spanning from integrative gene regulation analyses to functional genomics in vitro, pharmacological experiments in vivo, and clinical investigation, to address whether: (i) specific genetic alterations of the WNT pathway affect anti-EGFR sensitivity; (ii) combined neutralisation of EGFR and WNT signals fuels MRD deterioration; (iii) data from analysis of this synergy can lead to the discovery of clinically meaningful biomarkers with predictive and prognostic significance.
This proposal capitalises on a unique proprietary platform for high-content studies based on a large biobank of viable CRC samples, which ensures strong analytical power and unprecedented biological flexibility. By providing fresh insight into the mechanisms whereby WNT/beta-catenin signalling differentially sustains EGFR dependency or drug tolerance, the project is expected to put forward an innovative reinterpretation of CRC molecular bases and advance the rational application of more effective therapies.
Summary
Monoclonal antibodies against the EGF receptor (EGFR) provide substantive benefit to colorectal cancer (CRC) patients. However, no genetic lesions that robustly predict ‘addiction’ to the EGFR pathway have been yet identified. Further, even in tumours that regress after EGFR blockade, subsets of drug-tolerant cells often linger and foster ‘minimal residual disease’ (MRD), which portends tumour relapse.
Our preliminary evidence suggests that reliance on EGFR activity, as opposed to MRD persistence, could be assisted by genetically-based variations in transcription factor partnerships and activities, gene expression outputs, and biological fates controlled by the WNT/beta-catenin pathway. On such premises, BEAT (Beta-catenin and EGFR Abrogation Therapy) will elucidate the mechanisms of EGFR dependency, and escape from it, with the goal to identify biomarkers for more efficient clinical management of CRC and develop new therapies for MRD eradication.
A multidisciplinary approach will be pursued spanning from integrative gene regulation analyses to functional genomics in vitro, pharmacological experiments in vivo, and clinical investigation, to address whether: (i) specific genetic alterations of the WNT pathway affect anti-EGFR sensitivity; (ii) combined neutralisation of EGFR and WNT signals fuels MRD deterioration; (iii) data from analysis of this synergy can lead to the discovery of clinically meaningful biomarkers with predictive and prognostic significance.
This proposal capitalises on a unique proprietary platform for high-content studies based on a large biobank of viable CRC samples, which ensures strong analytical power and unprecedented biological flexibility. By providing fresh insight into the mechanisms whereby WNT/beta-catenin signalling differentially sustains EGFR dependency or drug tolerance, the project is expected to put forward an innovative reinterpretation of CRC molecular bases and advance the rational application of more effective therapies.
Max ERC Funding
1 793 421 €
Duration
Start date: 2017-10-01, End date: 2022-09-30
Project acronym BIFLOW
Project Bilingualism in Florentine and Tuscan Works (ca. 1260 - ca. 1416)
Researcher (PI) Antonio Montefusco
Host Institution (HI) UNIVERSITA CA' FOSCARI VENEZIA
Call Details Starting Grant (StG), SH5, ERC-2014-STG
Summary This project will undertake the first systematic investigation of the various literary documents that circulated simultaneously in more than one language in Tuscany, and especially Florence, between the mid-13th Century and the beginning of 15th Century.
During that period, Florence was both a prominent literary centre in the vernacular, and home to a renewal of classical Latin eloquence. While both fields are well studied, their interaction remains largely unexplored. This research, at the convergence of several disciplines (literature, philology, linguistics and medieval history), has a strong pioneering character. It aims at changing the perception of medieval Italian culture and interpretation of the break between medieval Culture and Humanism.
For this reason, the project will develop research in varying degrees of depth. First, it will provide the first catalogue of bilingual texts and manuscripts of medieval Tuscany. Organized as a database, this tool of analysis will stir innovative research in this field, some of which will be immediately promoted during the project.
Secondly, two case studies, considered as important and methodologically exemplary, will be researched in detail, through the publication of two important set of texts, of secular and religious nature : 1. The vernacular translation of the Latin Epistles of Dante Alighieri; 2. A collection of polemical, historiographical, devotional and prophetical documents produced by the Tuscan dissident Franciscans in last decades of the 14th Century.
Finally, the entire team, led by the PI, will be involved in the preparation of a synthesis volume on Tuscan culture in the fourteenth century viewed through bilingualism, entitled Cartography of bilingual culture in Fourteenth-Century Tuscany. From this general map of the Italian culture of the time, no literary genre nor field (be it religious or lay) shall be excluded.
Summary
This project will undertake the first systematic investigation of the various literary documents that circulated simultaneously in more than one language in Tuscany, and especially Florence, between the mid-13th Century and the beginning of 15th Century.
During that period, Florence was both a prominent literary centre in the vernacular, and home to a renewal of classical Latin eloquence. While both fields are well studied, their interaction remains largely unexplored. This research, at the convergence of several disciplines (literature, philology, linguistics and medieval history), has a strong pioneering character. It aims at changing the perception of medieval Italian culture and interpretation of the break between medieval Culture and Humanism.
For this reason, the project will develop research in varying degrees of depth. First, it will provide the first catalogue of bilingual texts and manuscripts of medieval Tuscany. Organized as a database, this tool of analysis will stir innovative research in this field, some of which will be immediately promoted during the project.
Secondly, two case studies, considered as important and methodologically exemplary, will be researched in detail, through the publication of two important set of texts, of secular and religious nature : 1. The vernacular translation of the Latin Epistles of Dante Alighieri; 2. A collection of polemical, historiographical, devotional and prophetical documents produced by the Tuscan dissident Franciscans in last decades of the 14th Century.
Finally, the entire team, led by the PI, will be involved in the preparation of a synthesis volume on Tuscan culture in the fourteenth century viewed through bilingualism, entitled Cartography of bilingual culture in Fourteenth-Century Tuscany. From this general map of the Italian culture of the time, no literary genre nor field (be it religious or lay) shall be excluded.
Max ERC Funding
1 480 625 €
Duration
Start date: 2015-10-01, End date: 2020-09-30
Project acronym BONEPHAGY
Project Defining the role of the FGF – autophagy axis in bone physiology
Researcher (PI) Carmine SETTEMBRE
Host Institution (HI) FONDAZIONE TELETHON
Call Details Starting Grant (StG), LS4, ERC-2016-STG
Summary Autophagy is a fundamental cellular catabolic process deputed to the degradation and recycling of a variety of intracellular materials. Autophagy plays a significant role in multiple human physio-pathological processes and is now emerging as a critical regulator of skeletal development and homeostasis. We have discovered that during postnatal development in mice, the growth factor FGF18 induces autophagy in the chondrocyte cells of the growth plate to regulate the secretion of type II collagen, a major component of cartilaginous extracellular matrix. The FGF signaling pathways play crucial roles during skeletal development and maintenance and are deregulated in many skeletal disorders. Hence our findings may offer the unique opportunity to uncover new molecular mechanisms through which FGF pathways regulate skeletal development and maintenance and to identify new targets for the treatment of FGF-related skeletal disorders. In this grant application we propose to study the role played by the different FGF ligands and receptors on autophagy regulation and to investigate the physiological relevance of these findings in the context of skeletal growth, homeostasis and maintenance. We will also investigate the intracellular machinery that links FGF signalling pathways to the regulation of autophagy. In addition, we generated preliminary data showing an impairment of autophagy in chondrocyte models of Achondroplasia (ACH) and Thanathoporic dysplasia, two skeletal disorders caused by mutations in FGFR3. We propose to study the role of autophagy in the pathogenesis of FGFR3-related dwarfisms and explore the pharmacological modulation of autophagy as new therapeutic approach for achondroplasia. This application, which combines cell biology, mouse genetics and pharmacological approaches, has the potential to shed light on new mechanisms involved in organismal development and homeostasis, which could be targeted to treat bone and cartilage diseases.
Summary
Autophagy is a fundamental cellular catabolic process deputed to the degradation and recycling of a variety of intracellular materials. Autophagy plays a significant role in multiple human physio-pathological processes and is now emerging as a critical regulator of skeletal development and homeostasis. We have discovered that during postnatal development in mice, the growth factor FGF18 induces autophagy in the chondrocyte cells of the growth plate to regulate the secretion of type II collagen, a major component of cartilaginous extracellular matrix. The FGF signaling pathways play crucial roles during skeletal development and maintenance and are deregulated in many skeletal disorders. Hence our findings may offer the unique opportunity to uncover new molecular mechanisms through which FGF pathways regulate skeletal development and maintenance and to identify new targets for the treatment of FGF-related skeletal disorders. In this grant application we propose to study the role played by the different FGF ligands and receptors on autophagy regulation and to investigate the physiological relevance of these findings in the context of skeletal growth, homeostasis and maintenance. We will also investigate the intracellular machinery that links FGF signalling pathways to the regulation of autophagy. In addition, we generated preliminary data showing an impairment of autophagy in chondrocyte models of Achondroplasia (ACH) and Thanathoporic dysplasia, two skeletal disorders caused by mutations in FGFR3. We propose to study the role of autophagy in the pathogenesis of FGFR3-related dwarfisms and explore the pharmacological modulation of autophagy as new therapeutic approach for achondroplasia. This application, which combines cell biology, mouse genetics and pharmacological approaches, has the potential to shed light on new mechanisms involved in organismal development and homeostasis, which could be targeted to treat bone and cartilage diseases.
Max ERC Funding
1 586 430 €
Duration
Start date: 2017-01-01, End date: 2021-12-31
Project acronym CIRCUITASSEMBLY
Project Development of functional organization of the visual circuits in mice
Researcher (PI) Keisuke Yonehara
Host Institution (HI) AARHUS UNIVERSITET
Call Details Starting Grant (StG), LS5, ERC-2014-STG
Summary The key organizing principles that characterize neuronal systems include asymmetric, parallel, and topographic connectivity of the neural circuits. The main aim of my research is to elucidate the key principles underlying functional development of neural circuits by focusing on those organizing principles. I choose mouse visual system as my model since it contains all of these principles and provides sophisticated genetic tools to label and manipulate individual circuit components. My research is based on the central hypothesis that the mechanisms of brain development cannot be fully understood without first identifying individual functional cell types in adults, and then understanding how the functions of these cell types become established, using cell-type-specific molecular and synaptic mechanisms in developing animals. Recently, I have identified several transgenic mouse lines in which specific cell types in a visual center, the superior colliculus, are labeled with Cre recombinase in both developing and adult animals. Here I will take advantage of these mouse lines to ask fundamental questions about the functional development of neural circuits. First, how are distinct sensory features processed by the parallel topographic neuronal pathways, and how do they contribute to behavior? Second, what are the molecular and synaptic mechanisms that underlie developmental circuit plasticity for forming parallel topographic neuronal maps in the brain? Third, what are the molecular mechanisms that set up spatially asymmetric circuit connectivity without the need for sensory experience? I predict that my insights into the developmental mechanism of asymmetric, parallel, and topographic connectivity and circuit plasticity will be instructive when studying other brain circuits which contain similar organizing principles.
Summary
The key organizing principles that characterize neuronal systems include asymmetric, parallel, and topographic connectivity of the neural circuits. The main aim of my research is to elucidate the key principles underlying functional development of neural circuits by focusing on those organizing principles. I choose mouse visual system as my model since it contains all of these principles and provides sophisticated genetic tools to label and manipulate individual circuit components. My research is based on the central hypothesis that the mechanisms of brain development cannot be fully understood without first identifying individual functional cell types in adults, and then understanding how the functions of these cell types become established, using cell-type-specific molecular and synaptic mechanisms in developing animals. Recently, I have identified several transgenic mouse lines in which specific cell types in a visual center, the superior colliculus, are labeled with Cre recombinase in both developing and adult animals. Here I will take advantage of these mouse lines to ask fundamental questions about the functional development of neural circuits. First, how are distinct sensory features processed by the parallel topographic neuronal pathways, and how do they contribute to behavior? Second, what are the molecular and synaptic mechanisms that underlie developmental circuit plasticity for forming parallel topographic neuronal maps in the brain? Third, what are the molecular mechanisms that set up spatially asymmetric circuit connectivity without the need for sensory experience? I predict that my insights into the developmental mechanism of asymmetric, parallel, and topographic connectivity and circuit plasticity will be instructive when studying other brain circuits which contain similar organizing principles.
Max ERC Funding
1 500 000 €
Duration
Start date: 2015-04-01, End date: 2020-03-31
Project acronym ContraNPM1AML
Project Dissecting to hit the therapeutic targets in nucleophosmin (NPM1)-mutated acute myeloid leukemia
Researcher (PI) Maria Paola MARTELLI
Host Institution (HI) UNIVERSITA DEGLI STUDI DI PERUGIA
Call Details Consolidator Grant (CoG), LS7, ERC-2016-COG
Summary Acute myeloid leukemia (AML) is a group of hematologic malignancies which, due to their molecular and clinical heterogeneity, have been traditionally difficult to classify and treat. Recently, next-generation, whole-genome sequencing has uncovered several recurrent somatic mutations that better define the landscape of AML genomics. Despite these advances in deciphering AML molecular subsets, there have been no concurrent improvements in AML therapy which still relies on the ‘antracycline+cytarabine’ scheme. Hereto, only about 40-50% of adult young patients are cured whilst most of the elderly succumb to their disease. Therefore, new therapeutic approaches which would take advantage of the new discoveries are clearly needed. In the past years, we discovered and characterized nucleophosmin (NPM1) mutations as the most frequent genetic alteration (about 30%) in AML, and today NPM1-mutated AML is a new entity in the WHO classification of myeloid neoplasms. However, mechanisms of leukemogenesis and a specific therapy for this leukemia are missing. Here, I aim to unravel the complex network of molecular interactions that take place in this distinct genetic subtype, and find their vulnerabilities to identify new targets for therapy. To address this issue, I will avail of relevant pre-clinical models developed in our laboratories and propose two complementary strategies: 1) a screening-based approach, focused either on the target, by analyzing synthetic lethal interactions through CRISPR-based genome-wide interference, or on the drug, by high-throughput chemical libraries screenings; 2) a hypothesis-driven approach, based on our recent gained novel insights on the role of specific intracellular pathways/genes in NPM1-mutated AML and on pharmacological studies with ‘old’ drugs, which we have revisited in the specific AML genetic context. I expect our discoveries will lead to find novel therapeutic approaches and make clinical trials available to patients as soon as possible.
Summary
Acute myeloid leukemia (AML) is a group of hematologic malignancies which, due to their molecular and clinical heterogeneity, have been traditionally difficult to classify and treat. Recently, next-generation, whole-genome sequencing has uncovered several recurrent somatic mutations that better define the landscape of AML genomics. Despite these advances in deciphering AML molecular subsets, there have been no concurrent improvements in AML therapy which still relies on the ‘antracycline+cytarabine’ scheme. Hereto, only about 40-50% of adult young patients are cured whilst most of the elderly succumb to their disease. Therefore, new therapeutic approaches which would take advantage of the new discoveries are clearly needed. In the past years, we discovered and characterized nucleophosmin (NPM1) mutations as the most frequent genetic alteration (about 30%) in AML, and today NPM1-mutated AML is a new entity in the WHO classification of myeloid neoplasms. However, mechanisms of leukemogenesis and a specific therapy for this leukemia are missing. Here, I aim to unravel the complex network of molecular interactions that take place in this distinct genetic subtype, and find their vulnerabilities to identify new targets for therapy. To address this issue, I will avail of relevant pre-clinical models developed in our laboratories and propose two complementary strategies: 1) a screening-based approach, focused either on the target, by analyzing synthetic lethal interactions through CRISPR-based genome-wide interference, or on the drug, by high-throughput chemical libraries screenings; 2) a hypothesis-driven approach, based on our recent gained novel insights on the role of specific intracellular pathways/genes in NPM1-mutated AML and on pharmacological studies with ‘old’ drugs, which we have revisited in the specific AML genetic context. I expect our discoveries will lead to find novel therapeutic approaches and make clinical trials available to patients as soon as possible.
Max ERC Funding
1 883 750 €
Duration
Start date: 2017-04-01, End date: 2022-03-31
Project acronym CRASK
Project Cortical Representation of Abstract Semantic Knowledge
Researcher (PI) Scott Laurence Fairhall
Host Institution (HI) UNIVERSITA DEGLI STUDI DI TRENTO
Call Details Starting Grant (StG), SH4, ERC-2014-STG
Summary The study of semantic memory considers a broad range of knowledge extending from basic elemental concepts that allow us to recognise and understand objects like ‘an apple’, to elaborated semantic information such as knowing when it is appropriate to use a Wilcoxon Rank-Sum test. Such elaborated semantic knowledge is fundamental to our daily lives yet our understanding of the neural substrates is minimal. The objective of CRASK is to advance rapidly beyond the state-of-the-art to address this issue. CRASK will begin by building a fundamental understanding of regional contributions, hierarchical organisation and regional coordination to form a predictive systems model of semantic representation in the brain. This will be accomplished through convergent evidence from an innovative combination of fine cognitive manipulations, multimodal imaging techniques (fMRI, MEG), and advanced analytical approaches (multivariate analysis of response patterns, representational similarity analysis, functional connectivity). Progress will proceed in stages. First the systems-level network underlying our knowledge of other people will be determined. Once this is accomplished CRASK will investigate general semantic knowledge in terms of the relative contribution of canonical, feature-selective and category-selective semantic representations and their respective roles in automatic and effortful semantic access. The systems-level model of semantic representation will be used to predict and test how the brain manifests elaborated semantic knowledge. The resulting understanding of the neural substrates of elaborated semantic knowledge will open up new areas of research. In the final stage of CRASK we chart this territory in terms of human factors: understanding the role of the representational semantic system in transient failures in access, neural factors that lead to optimal encoding and retrieval and the effects of ageing on the system.
Summary
The study of semantic memory considers a broad range of knowledge extending from basic elemental concepts that allow us to recognise and understand objects like ‘an apple’, to elaborated semantic information such as knowing when it is appropriate to use a Wilcoxon Rank-Sum test. Such elaborated semantic knowledge is fundamental to our daily lives yet our understanding of the neural substrates is minimal. The objective of CRASK is to advance rapidly beyond the state-of-the-art to address this issue. CRASK will begin by building a fundamental understanding of regional contributions, hierarchical organisation and regional coordination to form a predictive systems model of semantic representation in the brain. This will be accomplished through convergent evidence from an innovative combination of fine cognitive manipulations, multimodal imaging techniques (fMRI, MEG), and advanced analytical approaches (multivariate analysis of response patterns, representational similarity analysis, functional connectivity). Progress will proceed in stages. First the systems-level network underlying our knowledge of other people will be determined. Once this is accomplished CRASK will investigate general semantic knowledge in terms of the relative contribution of canonical, feature-selective and category-selective semantic representations and their respective roles in automatic and effortful semantic access. The systems-level model of semantic representation will be used to predict and test how the brain manifests elaborated semantic knowledge. The resulting understanding of the neural substrates of elaborated semantic knowledge will open up new areas of research. In the final stage of CRASK we chart this territory in terms of human factors: understanding the role of the representational semantic system in transient failures in access, neural factors that lead to optimal encoding and retrieval and the effects of ageing on the system.
Max ERC Funding
1 472 502 €
Duration
Start date: 2015-05-01, End date: 2020-04-30
Project acronym CRIMTANG
Project Criminal Entanglements.A new ethnographic approach to transnational organised crime.
Researcher (PI) Henrik VIGH
Host Institution (HI) KOBENHAVNS UNIVERSITET
Call Details Consolidator Grant (CoG), SH3, ERC-2016-COG
Summary Linked to terrorism, moral breakdown, and societal decay, Transnational Organised Crime (TOC) has come to embody current global anxieties as a figure of fear and cause of disquiet. Yet despite its central position on the social and political radar, our knowledge of it remains limited and fragmentary. Quantitative analyses may have identified the scale of the problem, but its underlying socio-cultural logic and practices remain under-researched and largely obscure. TOC is on the rise, and we need better insights into how it develops and expands, who engages in it and why, and how it is linked to and embedded in social networks that straddle countries and contexts.
CRIMTANG proposes a unique approach to the study of the social infrastructure of contemporary TOC. It develops a research strategy that is ethnographic and transnational in design and so attuned to the human flows and formations of TOC. The project comprises a trans-disciplinary research team of anthropologists, criminologists and political scientists, and builds on their prior experience of the people, regions and languages under study. It explores the illegal and overlapping flows of migrants and drugs from North-West Africa into Europe, following a key trafficking trajectory stretching from Tangiers to Barcelona, Paris and beyond.
In so doing, CRIMTANG sheds new light on the actual empirical processes in operation at different points along this trafficking route, whilst simultaneously developing new theoretical and methodological apparatuses for apprehending TOC that can be exported and applied in other regions and contexts. It reimagines the idea of social entanglement and proposes new transnational and collective fieldwork strategies. Finally, it will advance and consolidate the European research environment on TOC by creating a research hub for transnational ethnographic criminology at the University of Copenhagen.
Summary
Linked to terrorism, moral breakdown, and societal decay, Transnational Organised Crime (TOC) has come to embody current global anxieties as a figure of fear and cause of disquiet. Yet despite its central position on the social and political radar, our knowledge of it remains limited and fragmentary. Quantitative analyses may have identified the scale of the problem, but its underlying socio-cultural logic and practices remain under-researched and largely obscure. TOC is on the rise, and we need better insights into how it develops and expands, who engages in it and why, and how it is linked to and embedded in social networks that straddle countries and contexts.
CRIMTANG proposes a unique approach to the study of the social infrastructure of contemporary TOC. It develops a research strategy that is ethnographic and transnational in design and so attuned to the human flows and formations of TOC. The project comprises a trans-disciplinary research team of anthropologists, criminologists and political scientists, and builds on their prior experience of the people, regions and languages under study. It explores the illegal and overlapping flows of migrants and drugs from North-West Africa into Europe, following a key trafficking trajectory stretching from Tangiers to Barcelona, Paris and beyond.
In so doing, CRIMTANG sheds new light on the actual empirical processes in operation at different points along this trafficking route, whilst simultaneously developing new theoretical and methodological apparatuses for apprehending TOC that can be exported and applied in other regions and contexts. It reimagines the idea of social entanglement and proposes new transnational and collective fieldwork strategies. Finally, it will advance and consolidate the European research environment on TOC by creating a research hub for transnational ethnographic criminology at the University of Copenhagen.
Max ERC Funding
1 999 909 €
Duration
Start date: 2018-02-01, End date: 2023-01-31
