Project acronym ALLELECHOKER
Project DNA binding proteins for treatment of gain of function mutations
Researcher (PI) Enrico Maria Surace
Host Institution (HI) FONDAZIONE TELETHON
Call Details Starting Grant (StG), LS7, ERC-2012-StG_20111109
Summary Zinc finger (ZF) and transcription activator-like effector (TALE) based technologies are been allowing the tailored design of “artificial” DNA-binding proteins targeted to specific and unique DNA genomic sequences. Coupling DNA binding proteins to effectors domains enables the constitution of DNA binding factors for genomic directed transcriptional modulation or targeted genomic editing. We have demonstrated that pairing a ZF DNA binding protein to the transcriptional repressor Kruppel-associated box enables in vivo, the transcriptional repression of one of the most abundantly expressed gene in mammals, the human rhodopsin gene (RHO). We propose to generate RHO DNA binding silencers (“AlleleChoker”), which inactivate RHO either by transcriptional repression or targeted genome modification, irrespectively to wild-type or mutated alleles (mutational-independent approach), and combine RHO endogenous silencing to RHO replacement (silencing-replacement strategy). With this strategy in principle a single bimodal bio-therapeutic will enable the correction of any photoreceptor disease associated with RHO mutation. Adeno-associated viral (AAV) vector-based delivery will be used for photoreceptors gene transfer. Specifically our objectives are: 1) Construction of transcriptional repressors and nucleases for RHO silencing. Characterization and comparison of RHO silencing mediated by transcriptional repressors (ZFR/ TALER) or nucleases (ZFN/ TALEN) to generate genomic directed inactivation by non-homologous end-joining (NHEJ), and refer these results to RNA interference (RNAi) targeted to RHO; 2) RHO silencing in photoreceptors. to determine genome-wide DNA binding specificity of silencers, chromatin modifications and expression profile on human retinal explants; 3) Tuning silencing and replacement. To determine the impact of gene silencing-replacement strategy on disease progression in animal models of autosomal dominant retinitis pigmentosa (adRP) associated to RHO mutations
Summary
Zinc finger (ZF) and transcription activator-like effector (TALE) based technologies are been allowing the tailored design of “artificial” DNA-binding proteins targeted to specific and unique DNA genomic sequences. Coupling DNA binding proteins to effectors domains enables the constitution of DNA binding factors for genomic directed transcriptional modulation or targeted genomic editing. We have demonstrated that pairing a ZF DNA binding protein to the transcriptional repressor Kruppel-associated box enables in vivo, the transcriptional repression of one of the most abundantly expressed gene in mammals, the human rhodopsin gene (RHO). We propose to generate RHO DNA binding silencers (“AlleleChoker”), which inactivate RHO either by transcriptional repression or targeted genome modification, irrespectively to wild-type or mutated alleles (mutational-independent approach), and combine RHO endogenous silencing to RHO replacement (silencing-replacement strategy). With this strategy in principle a single bimodal bio-therapeutic will enable the correction of any photoreceptor disease associated with RHO mutation. Adeno-associated viral (AAV) vector-based delivery will be used for photoreceptors gene transfer. Specifically our objectives are: 1) Construction of transcriptional repressors and nucleases for RHO silencing. Characterization and comparison of RHO silencing mediated by transcriptional repressors (ZFR/ TALER) or nucleases (ZFN/ TALEN) to generate genomic directed inactivation by non-homologous end-joining (NHEJ), and refer these results to RNA interference (RNAi) targeted to RHO; 2) RHO silencing in photoreceptors. to determine genome-wide DNA binding specificity of silencers, chromatin modifications and expression profile on human retinal explants; 3) Tuning silencing and replacement. To determine the impact of gene silencing-replacement strategy on disease progression in animal models of autosomal dominant retinitis pigmentosa (adRP) associated to RHO mutations
Max ERC Funding
1 354 840 €
Duration
Start date: 2013-02-01, End date: 2018-01-31
Project acronym ANGIOPLACE
Project Expression and Methylation Status of Genes Regulating Placental Angiogenesis in Normal, Cloned, IVF and Monoparental Sheep Foetuses
Researcher (PI) Grazyna Ewa Ptak
Host Institution (HI) UNIVERSITA DEGLI STUDI DI TERAMO
Call Details Starting Grant (StG), LS7, ERC-2007-StG
Summary Normal placental angiogenesis is critical for embryonic survival and development. Epigenetic modifications, such as methylation of CpG islands, regulate the expression and imprinting of genes. Epigenetic abnormalities have been observed in embryos from assisted reproductive technologies (ART), which could explain the poor placental vascularisation, embryonic/fetal death, and altered fetal growth in these pregnancies. Both cloned (somatic cell nuclear transfer, or SNCT) and monoparental (parthogenotes, only maternal genes; androgenotes, only paternal genes) embryos provide important models for studying defects in expression and methylation status/imprinting of genes regulating placental function. Our hypothesis is that placental vascular development is compromised during early pregnancy in embryos from ART, in part due to altered expression or imprinting/methylation status of specific genes regulating placental angiogenesis. We will evaluate fetal growth, placental vascular growth, and expression and epigenetic status of genes regulating placental angiogenesis during early pregnancy in 3 Specific Aims: (1) after natural mating; (2) after transfer of biparental embryos from in vitro fertilization, and SCNT; and (3) after transfer of parthenogenetic or androgenetic embryos. These studies will therefore contribute substantially to our understanding of the regulation of placental development and vascularisation during early pregnancy, and could pinpoint the mechanism contributing to embryonic loss and developmental abnormalities in foetuses from ART. Any or all of these observations will contribute to our understanding of and also our ability to successfully employ ART, which are becoming very wide spread and important in human medicine as well as in animal production.
Summary
Normal placental angiogenesis is critical for embryonic survival and development. Epigenetic modifications, such as methylation of CpG islands, regulate the expression and imprinting of genes. Epigenetic abnormalities have been observed in embryos from assisted reproductive technologies (ART), which could explain the poor placental vascularisation, embryonic/fetal death, and altered fetal growth in these pregnancies. Both cloned (somatic cell nuclear transfer, or SNCT) and monoparental (parthogenotes, only maternal genes; androgenotes, only paternal genes) embryos provide important models for studying defects in expression and methylation status/imprinting of genes regulating placental function. Our hypothesis is that placental vascular development is compromised during early pregnancy in embryos from ART, in part due to altered expression or imprinting/methylation status of specific genes regulating placental angiogenesis. We will evaluate fetal growth, placental vascular growth, and expression and epigenetic status of genes regulating placental angiogenesis during early pregnancy in 3 Specific Aims: (1) after natural mating; (2) after transfer of biparental embryos from in vitro fertilization, and SCNT; and (3) after transfer of parthenogenetic or androgenetic embryos. These studies will therefore contribute substantially to our understanding of the regulation of placental development and vascularisation during early pregnancy, and could pinpoint the mechanism contributing to embryonic loss and developmental abnormalities in foetuses from ART. Any or all of these observations will contribute to our understanding of and also our ability to successfully employ ART, which are becoming very wide spread and important in human medicine as well as in animal production.
Max ERC Funding
363 600 €
Duration
Start date: 2008-10-01, End date: 2012-06-30
Project acronym ARISTOTLE
Project Aristotle in the Italian Vernacular: Rethinking Renaissance and Early-Modern Intellectual History (c. 1400–c. 1650)
Researcher (PI) Marco Sgarbi
Host Institution (HI) UNIVERSITA CA' FOSCARI VENEZIA
Call Details Starting Grant (StG), SH5, ERC-2013-StG
Summary From the twelfth to the seventeenth century, Aristotle’s writings lay at the foundation of Western culture, providing a body of knowledge and a set of analytical tools applicable to all areas of human investigation. Scholars of the Renaissance have emphasized the remarkable longevity and versatility of Aristotelianism, but their attention has remained firmly, and almost exclusively, fixed on the transmission of Aristotle’s works in Latin. Scarce attention has gone to works in the vernacular. Nonetheless, several important Renaissance figures wished to make Aristotle’s works accessible and available outside the narrow circle of professional philosophers and university professors. They believed that his works could provide essential knowledge to a broad set of readers, and embarked on an intense programme of translation and commentary to see this happen. It is the argument of this project that vernacular Aristotelianism made fundamental contributions to the thought of the period, anticipating many of the features of early modern philosophy and contributing to a new encyclopaedia of knowledge. Our project aims to offer the first detailed and comprehensive study of the vernacular diffusion of Aristotle through a series of analyses of its main texts. We will thus study works that fall within the two main Renaissance divisions of speculative philosophy (metaphysics, natural philosophy, mathematics, and logic) and civil philosophy (ethics, politics, rhetoric, and poetics). We will give strong attention to the contextualization of the texts they examine, as is standard practice in the best kind of intellectual history, focusing on institutional contexts, reading publics, the value of the vernacular, new visions of knowledge and eclecticism. With the work of the PI, two professors, 5 post-docs and two PhD students we aim to make considerable advances in the understanding of both speculative and civil philosophy within vernacular Aristotelianism.
Summary
From the twelfth to the seventeenth century, Aristotle’s writings lay at the foundation of Western culture, providing a body of knowledge and a set of analytical tools applicable to all areas of human investigation. Scholars of the Renaissance have emphasized the remarkable longevity and versatility of Aristotelianism, but their attention has remained firmly, and almost exclusively, fixed on the transmission of Aristotle’s works in Latin. Scarce attention has gone to works in the vernacular. Nonetheless, several important Renaissance figures wished to make Aristotle’s works accessible and available outside the narrow circle of professional philosophers and university professors. They believed that his works could provide essential knowledge to a broad set of readers, and embarked on an intense programme of translation and commentary to see this happen. It is the argument of this project that vernacular Aristotelianism made fundamental contributions to the thought of the period, anticipating many of the features of early modern philosophy and contributing to a new encyclopaedia of knowledge. Our project aims to offer the first detailed and comprehensive study of the vernacular diffusion of Aristotle through a series of analyses of its main texts. We will thus study works that fall within the two main Renaissance divisions of speculative philosophy (metaphysics, natural philosophy, mathematics, and logic) and civil philosophy (ethics, politics, rhetoric, and poetics). We will give strong attention to the contextualization of the texts they examine, as is standard practice in the best kind of intellectual history, focusing on institutional contexts, reading publics, the value of the vernacular, new visions of knowledge and eclecticism. With the work of the PI, two professors, 5 post-docs and two PhD students we aim to make considerable advances in the understanding of both speculative and civil philosophy within vernacular Aristotelianism.
Max ERC Funding
1 483 180 €
Duration
Start date: 2014-05-01, End date: 2019-04-30
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 CBCD
Project Understanding the basis of cerebellar and brainstem congenital defects: from clinical and molecular characterisation to the development of a novel neuroembryonic in vitro model
Researcher (PI) Enza Maria Valente
Host Institution (HI) FONDAZIONE SANTA LUCIA
Call Details Starting Grant (StG), LS7, ERC-2010-StG_20091118
Summary Cerebellar and brainstem congenital defects (CBCDs) are heterogeneous disorders with high pre-and post-natal mortality and morbidity. Their genetic basis and pathogenetic mechanisms are largely unknown, hampering patients’ diagnosis and management and family counselling. This project aims at improve current understanding of primary CBCDs through a multidisciplinary approach combining innovative clinical, neuroimaging, molecular and functional studies, that will be articulated in four workpackages:
WP1- Clinical and neuroimaging studies: collection of detailed data and biological samples from a large cohort of patients covering a broad spectrum of CBCDs, neuroimaging classification based on magnetic resonance imaging and tractography, genotype-phenotype correlates and follow-up studies.
WP2 - Molecular studies on mendelian CBCDs: high-throughput resequencing of ciliary genes to identify pathogenic mutations and genetic modifiers in patients with ciliopathies, identification of novel disease genes, mutation analysis of genes causative of other mendelian CBCDs.
WP3 - Molecular studies on sporadic CBCDs: identification of cryptic chromosomal rearrangements by high resolution SNP-array analysis, selection and mutation analysis of candidate genes mapping to the rearranged regions.
WP4 - Functional studies: optimisation of a novel neuroembryonic in vitro model derived from mouse embryonic stem cells, to test the role of known and candidate disease genes (from WP2 and 3) on cerebellar and brainstem development, define the pathways in which they are involved and the effect of disease-causative mutations.
This project is expected to improve the current CBCD nosology, identify novel genes and mechanisms involved in cerebellar and brainstem development that are responsible for mendelian or sporadic defects, expand the available tools for pre- and post-natal diagnosis and identify clinical-genetic correlates and prognostic indexes.
Summary
Cerebellar and brainstem congenital defects (CBCDs) are heterogeneous disorders with high pre-and post-natal mortality and morbidity. Their genetic basis and pathogenetic mechanisms are largely unknown, hampering patients’ diagnosis and management and family counselling. This project aims at improve current understanding of primary CBCDs through a multidisciplinary approach combining innovative clinical, neuroimaging, molecular and functional studies, that will be articulated in four workpackages:
WP1- Clinical and neuroimaging studies: collection of detailed data and biological samples from a large cohort of patients covering a broad spectrum of CBCDs, neuroimaging classification based on magnetic resonance imaging and tractography, genotype-phenotype correlates and follow-up studies.
WP2 - Molecular studies on mendelian CBCDs: high-throughput resequencing of ciliary genes to identify pathogenic mutations and genetic modifiers in patients with ciliopathies, identification of novel disease genes, mutation analysis of genes causative of other mendelian CBCDs.
WP3 - Molecular studies on sporadic CBCDs: identification of cryptic chromosomal rearrangements by high resolution SNP-array analysis, selection and mutation analysis of candidate genes mapping to the rearranged regions.
WP4 - Functional studies: optimisation of a novel neuroembryonic in vitro model derived from mouse embryonic stem cells, to test the role of known and candidate disease genes (from WP2 and 3) on cerebellar and brainstem development, define the pathways in which they are involved and the effect of disease-causative mutations.
This project is expected to improve the current CBCD nosology, identify novel genes and mechanisms involved in cerebellar and brainstem development that are responsible for mendelian or sporadic defects, expand the available tools for pre- and post-natal diagnosis and identify clinical-genetic correlates and prognostic indexes.
Max ERC Funding
1 367 960 €
Duration
Start date: 2011-08-01, End date: 2018-03-31
Project acronym CGT HEMOPHILIA A
Project Cell and gene therapy based strategies to correct the bleeding phenotype in Hemophilia A
Researcher (PI) Antonia Follenzi
Host Institution (HI) UNIVERSITA DEGLI STUDI DEL PIEMONTE ORIENTALE AMEDEO AVOGADRO
Call Details Starting Grant (StG), LS7, ERC-2010-StG_20091118
Summary Currently, haemophilia A cannot be cured. To prevent major bleeding episodes in haemophilia, human Factor VIII (FVIII) protein must be frequently administered as prophylaxis or on demand. This treatment is complicated by its high cost and development of antibodies that neutralize FVIII activity in 20 to 30% of the patients. Therefore, permanent solutions in the form of cell and gene therapy are very attractive for haemophilia A. Recently, we demonstrated in a murine model that liver sinusoidal endothelial cells (LSEC) produce and secrete FVIII, although not exclusively. We have also found that these mice can be treated by reconstitution with wild-type bone marrow, indicating that bone marrow-derived cells, of hematopoietic, mesenchymal or even endothelial origin, can produce and secrete FVIII. Based on these findings in mice, I propose that human LSEC, umbilical cord blood cells, and bone marrow cells might be suitable sources of FVIII to be used for cell replacement therapy for haemophilia A. To advance opportunities for cell and gene therapies in haemophilia A and for identifying additional cell sources of FVIII, I intend to explore whether replacement of liver endothelium and bone marrow in immnocompromised Haemophilia A mice with healthy human cells will provide therapeutic correction. Recently, the possibility of reprogramming mature somatic cells to generate induced pluripotent stem (iPS) cells has enabled the derivation of disease-specific pluripotent cells, thus providing unprecedented experimental platforms to treat human diseases. Therefore, I intend to study whether the generation of patient-specific iPS cells may be applied to cell and gene therapy of coagulation disorders and in particular for the treatment of Haemophilia A. Studies with these novel target cells may impact significantly the future course of Haemophilia A by providing proof-of feasibility of a novel therapy strategies.
Summary
Currently, haemophilia A cannot be cured. To prevent major bleeding episodes in haemophilia, human Factor VIII (FVIII) protein must be frequently administered as prophylaxis or on demand. This treatment is complicated by its high cost and development of antibodies that neutralize FVIII activity in 20 to 30% of the patients. Therefore, permanent solutions in the form of cell and gene therapy are very attractive for haemophilia A. Recently, we demonstrated in a murine model that liver sinusoidal endothelial cells (LSEC) produce and secrete FVIII, although not exclusively. We have also found that these mice can be treated by reconstitution with wild-type bone marrow, indicating that bone marrow-derived cells, of hematopoietic, mesenchymal or even endothelial origin, can produce and secrete FVIII. Based on these findings in mice, I propose that human LSEC, umbilical cord blood cells, and bone marrow cells might be suitable sources of FVIII to be used for cell replacement therapy for haemophilia A. To advance opportunities for cell and gene therapies in haemophilia A and for identifying additional cell sources of FVIII, I intend to explore whether replacement of liver endothelium and bone marrow in immnocompromised Haemophilia A mice with healthy human cells will provide therapeutic correction. Recently, the possibility of reprogramming mature somatic cells to generate induced pluripotent stem (iPS) cells has enabled the derivation of disease-specific pluripotent cells, thus providing unprecedented experimental platforms to treat human diseases. Therefore, I intend to study whether the generation of patient-specific iPS cells may be applied to cell and gene therapy of coagulation disorders and in particular for the treatment of Haemophilia A. Studies with these novel target cells may impact significantly the future course of Haemophilia A by providing proof-of feasibility of a novel therapy strategies.
Max ERC Funding
1 123 000 €
Duration
Start date: 2011-05-01, End date: 2017-04-30
Project acronym DiGe
Project Ethnobotany of divided generations in the context of centralization
Researcher (PI) Renata SÕUKAND
Host Institution (HI) UNIVERSITA CA' FOSCARI VENEZIA
Call Details Starting Grant (StG), SH5, ERC-2016-STG
Summary Understanding the logics of obtaining, managing and perceiving of local natural resources, particularly plants, is crucial for ensuring sustainability of human life, as the use of plants is a key for survival of humans. The proposed research will create an advanced understanding of the mechanisms of changes in ethnobotanical knowledge experienced by traditional societies/minor ethnic groups when dominating group try to unify and/or erode this practical knowledge. It will also evaluate the effects of the sudden cease to existence of such centralization and following impact of the trial of revival of discontinued traditional etnobotanical knowledge. Research will evaluate the effect of several social and cultural factors on the evolution of ethnobotanical knowledge of four compact, but divided ethnic minorities that had experienced for shorter (25 years) or longer (70 years) period different influences affecting their plant use and very different social conditions (including welfare and economy). As a long-term outcome, based on the result of present and consequent studies scientists will be able to predict the extent and depth of the changes occurring in the ethnobotanical knowledge and as a applied outcome learn to direct and educate people in the way that the knowledge necessary for sustainable maintenance and utilization of local plant resources will be constantly evolving in the way supporting health and well-being of different populations.
Summary
Understanding the logics of obtaining, managing and perceiving of local natural resources, particularly plants, is crucial for ensuring sustainability of human life, as the use of plants is a key for survival of humans. The proposed research will create an advanced understanding of the mechanisms of changes in ethnobotanical knowledge experienced by traditional societies/minor ethnic groups when dominating group try to unify and/or erode this practical knowledge. It will also evaluate the effects of the sudden cease to existence of such centralization and following impact of the trial of revival of discontinued traditional etnobotanical knowledge. Research will evaluate the effect of several social and cultural factors on the evolution of ethnobotanical knowledge of four compact, but divided ethnic minorities that had experienced for shorter (25 years) or longer (70 years) period different influences affecting their plant use and very different social conditions (including welfare and economy). As a long-term outcome, based on the result of present and consequent studies scientists will be able to predict the extent and depth of the changes occurring in the ethnobotanical knowledge and as a applied outcome learn to direct and educate people in the way that the knowledge necessary for sustainable maintenance and utilization of local plant resources will be constantly evolving in the way supporting health and well-being of different populations.
Max ERC Funding
1 496 675 €
Duration
Start date: 2017-06-01, End date: 2022-07-31
Project acronym DisConn
Project Neural drivers of functional disconnectivity in brain disorders
Researcher (PI) Alessandro GOZZI
Host Institution (HI) FONDAZIONE ISTITUTO ITALIANO DI TECNOLOGIA
Call Details Starting Grant (StG), LS5, ERC-2018-STG
Summary A rapidly expanding approach to understanding neural organization is to map patterns of spontaneous neural activity as an index of functional communication and connectivity across brain regions. Fostered by the advent of neuroimaging methods like resting-state fMRI (rsfMRI), this approach has revealed that functional connectivity is almost invariably disrupted in severe psychiatric disorders, such as autism or schizophrenia. However, the neural basis of such functional disconnectivity remains mysterious. What drives brain-wide functional synchronization? And are there shared pathophysiological mechanisms leading to impaired large-scale neural coupling?
This project aims to elucidate the neural drivers of macroscale functional connectivity, as well as its breakdown in brain connectopathies. To achieve this goal, I propose a multi-scale perturbational approach to establish causal relationships between specific neural events and brain-wide functional connectivity via a novel combination of rsfMRI and advanced neural manipulations and recordings in the awake mouse.
By directionally silencing functional hubs as well as more peripheral cortical regions, I will provide a hierarchical description of spontaneous network organization that will uncover regional substrates vulnerable to network disruption. I will also manipulate physiologically-distinct excitatory or inhibitory populations to probe a unifying mechanistic link between excitatory/inhibitory imbalances and aberrant functional connectivity. Finally, to account for the hallmark co-occurrence of synaptic deficits and functional disconnectivity in developmental disorders, I will link cellular mechanisms of synaptic plasticity and learning to the generation of canonical and aberrant spontaneous activity patterns. These studies will pave the way to a back-translation of aberrant functional connectivity into interpretable neurophysiological events and models that can help understand, diagnose or treat brain disorders.
Summary
A rapidly expanding approach to understanding neural organization is to map patterns of spontaneous neural activity as an index of functional communication and connectivity across brain regions. Fostered by the advent of neuroimaging methods like resting-state fMRI (rsfMRI), this approach has revealed that functional connectivity is almost invariably disrupted in severe psychiatric disorders, such as autism or schizophrenia. However, the neural basis of such functional disconnectivity remains mysterious. What drives brain-wide functional synchronization? And are there shared pathophysiological mechanisms leading to impaired large-scale neural coupling?
This project aims to elucidate the neural drivers of macroscale functional connectivity, as well as its breakdown in brain connectopathies. To achieve this goal, I propose a multi-scale perturbational approach to establish causal relationships between specific neural events and brain-wide functional connectivity via a novel combination of rsfMRI and advanced neural manipulations and recordings in the awake mouse.
By directionally silencing functional hubs as well as more peripheral cortical regions, I will provide a hierarchical description of spontaneous network organization that will uncover regional substrates vulnerable to network disruption. I will also manipulate physiologically-distinct excitatory or inhibitory populations to probe a unifying mechanistic link between excitatory/inhibitory imbalances and aberrant functional connectivity. Finally, to account for the hallmark co-occurrence of synaptic deficits and functional disconnectivity in developmental disorders, I will link cellular mechanisms of synaptic plasticity and learning to the generation of canonical and aberrant spontaneous activity patterns. These studies will pave the way to a back-translation of aberrant functional connectivity into interpretable neurophysiological events and models that can help understand, diagnose or treat brain disorders.
Max ERC Funding
1 498 125 €
Duration
Start date: 2019-02-01, End date: 2024-01-31
Project acronym DMAP
Project Data Mining Algorithms in Practice
Researcher (PI) Flavio Chierichetti
Host Institution (HI) UNIVERSITA DEGLI STUDI DI ROMA LA SAPIENZA
Call Details Starting Grant (StG), PE6, ERC-2015-STG
Summary Data Mining algorithms are a cornerstone of today's Internet-related services and products. We aim to tackle some of the most important problems in Data Mining --- our goal is to develop a systematic theoretical understanding of certain simple algorithms that, in spite of being at the core of today's web industry, are not yet well understood in terms of their properties and performances, and to develop new simple algorithms for fundamental problems in this domain that have so far escaped a satisfactory solution.
Summary
Data Mining algorithms are a cornerstone of today's Internet-related services and products. We aim to tackle some of the most important problems in Data Mining --- our goal is to develop a systematic theoretical understanding of certain simple algorithms that, in spite of being at the core of today's web industry, are not yet well understood in terms of their properties and performances, and to develop new simple algorithms for fundamental problems in this domain that have so far escaped a satisfactory solution.
Max ERC Funding
1 137 500 €
Duration
Start date: 2016-02-01, End date: 2021-01-31
Project acronym FLOS
Project Florilegia Syriaca. The Intercultural Dissemination of Greek Christian Thought in Syriac and Arabic in the First Millennium CE
Researcher (PI) Emiliano FIORI
Host Institution (HI) UNIVERSITA CA' FOSCARI VENEZIA
Call Details Starting Grant (StG), SH5, ERC-2017-STG
Summary FLOS will focus on the metamorphoses of Greek Christian thought in Syriac (Aramaic) and Arabic in Late Antiquity, within the timeframe of the first millennium CE. Syriac Christianity was a pivotal mediator of culture in the Late Antique epistemic space, but is little-known today. FLOS aims to bring to light for the first time a body of highly relevant Syriac and Christian Arabic sources that have hardly ever been studied before. At the end of the millennium, in Islamic-ruled Syria, Mesopotamia, and Iran, Syriac Christians strived to define their religious identity. One of their strategies was the production of florilegia, i.e. anthologies that they used to excerpt and reinvent the patristic canon, a corpus of Greek Christian works of the 2nd–6th centuries shared by European and Middle Eastern Christian cultures. A Greco-centric bias has prevented scholars from viewing these florilegia as laboratories of cultural creativity. FLOS will reverse the state of the art through two groundbreaking endeavours: 1) open-access digital editions of a set of Syriac florilegia of the 8th–10th centuries; 2) a study of many neglected writings of Syriac and Christian Arabic authors of the 8th–11th centuries. These tremendously important writings drew from Syriac patristic florilegia to pinpoint topics like incarnation and the Trinity against other Christians or Islam, showing how patristic sources were used to create new knowledge for the entangled environment of the Abbasid era. FLOS will thus dramatically improve our understanding of the cultural dynamics of Late Antiquity; patristic Christianity will emerge as a bridge between the intellectual history of Europe and of the Middle East. By studying how this shared patrimony was transformed in situations of interreligious interaction, especially with Islam, FLOS will facilitate the comprehension of Europe’s current religious discourses, and the preservation of the endangered cultural heritage of the Syriac Christians.
Summary
FLOS will focus on the metamorphoses of Greek Christian thought in Syriac (Aramaic) and Arabic in Late Antiquity, within the timeframe of the first millennium CE. Syriac Christianity was a pivotal mediator of culture in the Late Antique epistemic space, but is little-known today. FLOS aims to bring to light for the first time a body of highly relevant Syriac and Christian Arabic sources that have hardly ever been studied before. At the end of the millennium, in Islamic-ruled Syria, Mesopotamia, and Iran, Syriac Christians strived to define their religious identity. One of their strategies was the production of florilegia, i.e. anthologies that they used to excerpt and reinvent the patristic canon, a corpus of Greek Christian works of the 2nd–6th centuries shared by European and Middle Eastern Christian cultures. A Greco-centric bias has prevented scholars from viewing these florilegia as laboratories of cultural creativity. FLOS will reverse the state of the art through two groundbreaking endeavours: 1) open-access digital editions of a set of Syriac florilegia of the 8th–10th centuries; 2) a study of many neglected writings of Syriac and Christian Arabic authors of the 8th–11th centuries. These tremendously important writings drew from Syriac patristic florilegia to pinpoint topics like incarnation and the Trinity against other Christians or Islam, showing how patristic sources were used to create new knowledge for the entangled environment of the Abbasid era. FLOS will thus dramatically improve our understanding of the cultural dynamics of Late Antiquity; patristic Christianity will emerge as a bridge between the intellectual history of Europe and of the Middle East. By studying how this shared patrimony was transformed in situations of interreligious interaction, especially with Islam, FLOS will facilitate the comprehension of Europe’s current religious discourses, and the preservation of the endangered cultural heritage of the Syriac Christians.
Max ERC Funding
1 343 175 €
Duration
Start date: 2018-03-01, End date: 2023-02-28
Project acronym HISTANTARTSI
Project Historical memory, Antiquarian Culture and Artistic Patronage: Social Identities in the Centres of Southern Italy between the Medieval and Early Modern Period
Researcher (PI) Bianca De Divitiis
Host Institution (HI) UNIVERSITA DEGLI STUDI DI NAPOLI FEDERICO II
Call Details Starting Grant (StG), SH5, ERC-2010-StG_20091209
Summary From the 12th-century southern Italy was overrun by foreign rulers and their houses and saw fierce dynastic struggles for succession. In attempting to cope with these sudden changes and upheavels, the local urban communities continually found themselves faced by the need to legitimize and reconfirm their status through actual negotiations with the king, and eventually with the baron. In this context the procedures and methods used to construct specific
local identities take on particular importance, as do those used by individuals and families to affirm their social position. Through an interdisciplinary team the project seeks to identify the conscious and strategic use of archival and literary sources, and of local antiquities, in methods of self-representation adopted by the elite and by the local communities in the Regno di Napoli between the medieval and early modern period beginning with Campania and then extending to Puglia, Calabria, Lucania, Molise and Abruzzo. The aim of the project is to establish a balanced view of southern continental Italy and to create new instruments which will improve not only
international academic knowledge but can benefit civil society as a whole, as well as institutions in laying the foundations for a new conservation strategy to protect and manage the cultural patrimony of southern Italy, a region which has contributed significantly to the formation of a European identity. An accessible database on the Internet will be specifically designed and programmed to gather together all the data from this research pre-requisite for studying such themes, and will provide a new instrument and new prospects of research for scholars world-wide.
Summary
From the 12th-century southern Italy was overrun by foreign rulers and their houses and saw fierce dynastic struggles for succession. In attempting to cope with these sudden changes and upheavels, the local urban communities continually found themselves faced by the need to legitimize and reconfirm their status through actual negotiations with the king, and eventually with the baron. In this context the procedures and methods used to construct specific
local identities take on particular importance, as do those used by individuals and families to affirm their social position. Through an interdisciplinary team the project seeks to identify the conscious and strategic use of archival and literary sources, and of local antiquities, in methods of self-representation adopted by the elite and by the local communities in the Regno di Napoli between the medieval and early modern period beginning with Campania and then extending to Puglia, Calabria, Lucania, Molise and Abruzzo. The aim of the project is to establish a balanced view of southern continental Italy and to create new instruments which will improve not only
international academic knowledge but can benefit civil society as a whole, as well as institutions in laying the foundations for a new conservation strategy to protect and manage the cultural patrimony of southern Italy, a region which has contributed significantly to the formation of a European identity. An accessible database on the Internet will be specifically designed and programmed to gather together all the data from this research pre-requisite for studying such themes, and will provide a new instrument and new prospects of research for scholars world-wide.
Max ERC Funding
1 500 000 €
Duration
Start date: 2011-01-01, End date: 2016-05-31
Project acronym IEMTX
Project Therapies for inborn errors of metabolism
Researcher (PI) Nicola Brunetti-Pierri
Host Institution (HI) FONDAZIONE TELETHON
Call Details Starting Grant (StG), LS7, ERC-2012-StG_20111109
Summary We discovered that phenylbutyrate, prevents both in vitro and in vivo the inactivation by phosphorylation of the branched chain ketoacid dehydrogenase complex (BCKDC) and pyruvate dehydrogenase complex (PDHC). We show that phenylbutyrate is effective for treatment of maple syrup urine disease (MSUD) due to deficiency of branched chain ketoacid dehydrogenase complex (BCKDC), and has potential for therapy of deficiency of pyruvate dehydrogenase complex (PDHC). We propose to investigate phenylbutyrate for PDHC deficiency in a zebrafish model and in PDHC-deficient patients. We have recently developed a systems biology tool for prediction of drug mode of action starting from their gene expression profiles. This tool has a significant potential for drug discovery and repositioning. Through this approach, we found several FDA-approved drugs sharing with phenylbutyrate a similar mode of action. We propose to investigate the efficacy of these drugs for increasing the enzymatic activity of both BCKDC and PDHC and their therapeutic potential. While useful for proof-of-concept studies animal models are not suited to predict patient response to drugs which depends upon multiple factors including type of mutation and affected enzyme subunit. We propose to develop PDHC deficient neurons and MSUD hepatocytes from induced pluripotent stem cells (iPSCs) derived from patients’ fibroblasts. Drug response in these disease-relevant cell types will better predict clinical response of patients. Human iPSCs will be generated through a novel system based on high cloning capacity, non-integrating helper-dependent adenoviral (HDAd) vector expressing a combination of reprogramming factors. We will investigate altered metabolic pathways in PDHC deficient neurons and MSUD hepatocytes to search for effective drugs by an innovative systems biology approach. In summary, the results of the proposed study have the potential to provide novel and effective treatments for MSUD and PDHC deficiency.
Summary
We discovered that phenylbutyrate, prevents both in vitro and in vivo the inactivation by phosphorylation of the branched chain ketoacid dehydrogenase complex (BCKDC) and pyruvate dehydrogenase complex (PDHC). We show that phenylbutyrate is effective for treatment of maple syrup urine disease (MSUD) due to deficiency of branched chain ketoacid dehydrogenase complex (BCKDC), and has potential for therapy of deficiency of pyruvate dehydrogenase complex (PDHC). We propose to investigate phenylbutyrate for PDHC deficiency in a zebrafish model and in PDHC-deficient patients. We have recently developed a systems biology tool for prediction of drug mode of action starting from their gene expression profiles. This tool has a significant potential for drug discovery and repositioning. Through this approach, we found several FDA-approved drugs sharing with phenylbutyrate a similar mode of action. We propose to investigate the efficacy of these drugs for increasing the enzymatic activity of both BCKDC and PDHC and their therapeutic potential. While useful for proof-of-concept studies animal models are not suited to predict patient response to drugs which depends upon multiple factors including type of mutation and affected enzyme subunit. We propose to develop PDHC deficient neurons and MSUD hepatocytes from induced pluripotent stem cells (iPSCs) derived from patients’ fibroblasts. Drug response in these disease-relevant cell types will better predict clinical response of patients. Human iPSCs will be generated through a novel system based on high cloning capacity, non-integrating helper-dependent adenoviral (HDAd) vector expressing a combination of reprogramming factors. We will investigate altered metabolic pathways in PDHC deficient neurons and MSUD hepatocytes to search for effective drugs by an innovative systems biology approach. In summary, the results of the proposed study have the potential to provide novel and effective treatments for MSUD and PDHC deficiency.
Max ERC Funding
1 491 520 €
Duration
Start date: 2012-11-01, End date: 2018-10-31
Project acronym INCOMMON
Project In praise of community: shared creativity in arts and politics in Italy (1959-1979)
Researcher (PI) Annalisa Sacchi
Host Institution (HI) UNIVERSITA IUAV DI VENEZIA
Call Details Starting Grant (StG), SH5, ERC-2015-STG
Summary INCOMMON will be the first study to systematically analyse the field of performing arts as resulting from the practice of commonality both theorized and experienced over the 1960s and the 1970s.In particular, the project is aimed to study the history of the ‘laboratory Italy’ as the place where artistic counterculture expressed by performing arts arose in a milieu characterized by a profound relation between philosophy, politics, and revolutionary practices.
The overall objectives of INCOMMON are i) to study, collect and contextualize those encounters between theatre, music, visual arts, cinema and video art that assumed the form of performances, especially those created as collaborations between artists; ii) to apply the concept of ‘will-to-the-common’ to the art field of the counterculture; iii) to underline the significance of artistic communities in the local and international scene; iv) to create a digital archive of the performances of the Italian artists of the period.
The project will connect historical, philosophical and artistic debates to those in other sciences, sociology and in particular Social Network Theory,in order to reveal significant structures of meanings in the artistic community and to reveal the peculiar characteristics of shared creative processes.The methodology that will be developed is meant 1) to produce new ways of modelling the knowledge and interpretation of performing arts and 2) to create an innovative form of digital archive visualization, where rich interfaces will sustain and improve the understanding of the context and relationships analysed.
INCOMMON will produce a comprehensive approach, oriented toward collection, digitization, restoration and dissemination of direct documentation and related materials of the Italian performing arts production of the great creative, political, existential wave of the counterculture, preserving and making accessible a patrimony that otherwise will continue to be lost to future generations.
Summary
INCOMMON will be the first study to systematically analyse the field of performing arts as resulting from the practice of commonality both theorized and experienced over the 1960s and the 1970s.In particular, the project is aimed to study the history of the ‘laboratory Italy’ as the place where artistic counterculture expressed by performing arts arose in a milieu characterized by a profound relation between philosophy, politics, and revolutionary practices.
The overall objectives of INCOMMON are i) to study, collect and contextualize those encounters between theatre, music, visual arts, cinema and video art that assumed the form of performances, especially those created as collaborations between artists; ii) to apply the concept of ‘will-to-the-common’ to the art field of the counterculture; iii) to underline the significance of artistic communities in the local and international scene; iv) to create a digital archive of the performances of the Italian artists of the period.
The project will connect historical, philosophical and artistic debates to those in other sciences, sociology and in particular Social Network Theory,in order to reveal significant structures of meanings in the artistic community and to reveal the peculiar characteristics of shared creative processes.The methodology that will be developed is meant 1) to produce new ways of modelling the knowledge and interpretation of performing arts and 2) to create an innovative form of digital archive visualization, where rich interfaces will sustain and improve the understanding of the context and relationships analysed.
INCOMMON will produce a comprehensive approach, oriented toward collection, digitization, restoration and dissemination of direct documentation and related materials of the Italian performing arts production of the great creative, political, existential wave of the counterculture, preserving and making accessible a patrimony that otherwise will continue to be lost to future generations.
Max ERC Funding
1 452 686 €
Duration
Start date: 2016-06-01, End date: 2021-05-31
Project acronym MINDTRAVEL
Project Travels of the Mind: Modes of brain functioning in complex dynamic environments
Researcher (PI) Emiliano Macaluso
Host Institution (HI) FONDAZIONE SANTA LUCIA
Call Details Starting Grant (StG), LS5, ERC-2009-StG
Summary Subjective everyday experience entails a well-structured and continuous flow of sensory signals, actions, thoughts and emotions. How does the brain build such a coherent representation of space and time despite the vast amount and confusing nature of the input? Furthermore, what are the physiological constraints preventing simultaneous awareness of multiple spatial and temporal instances? Here I propose a novel approach ("brain modes") to investigate these issues within life-like experimental settings. I will investigate how the brain selects and integrates relevant information using complex dynamic environments that includes space, time and multisensorial inputs. Combining model-free and model-driven analyses of functional imaging data I will examine: 1. How signals in different sensory modalities and same/different locations interact in complex environments; 2. How contextual information influences memory encoding and retrieval and the ability to integrate current sensory signals with events in the past. 3. How prospective goals and expectancies arising from the temporal dynamic of the context influence on-line processing. My expectation is that the results will reveal novel mechanisms underlying the ability to organise information in an orderly manner, on a time-line spanning the past, the present and the future; and how we can direct our thoughts along this time-line. My investigation will provide new evidence on the capacity limitations of this selection process and how integration and competition interact to form a representation of the external world that evolves as a coherent flow through space and time. Potential practical implications are foreseen for the design of brain-machine interfaces and for understanding the abnormal perceptions of mental illness.
Summary
Subjective everyday experience entails a well-structured and continuous flow of sensory signals, actions, thoughts and emotions. How does the brain build such a coherent representation of space and time despite the vast amount and confusing nature of the input? Furthermore, what are the physiological constraints preventing simultaneous awareness of multiple spatial and temporal instances? Here I propose a novel approach ("brain modes") to investigate these issues within life-like experimental settings. I will investigate how the brain selects and integrates relevant information using complex dynamic environments that includes space, time and multisensorial inputs. Combining model-free and model-driven analyses of functional imaging data I will examine: 1. How signals in different sensory modalities and same/different locations interact in complex environments; 2. How contextual information influences memory encoding and retrieval and the ability to integrate current sensory signals with events in the past. 3. How prospective goals and expectancies arising from the temporal dynamic of the context influence on-line processing. My expectation is that the results will reveal novel mechanisms underlying the ability to organise information in an orderly manner, on a time-line spanning the past, the present and the future; and how we can direct our thoughts along this time-line. My investigation will provide new evidence on the capacity limitations of this selection process and how integration and competition interact to form a representation of the external world that evolves as a coherent flow through space and time. Potential practical implications are foreseen for the design of brain-machine interfaces and for understanding the abnormal perceptions of mental illness.
Max ERC Funding
1 219 597 €
Duration
Start date: 2010-07-01, End date: 2015-06-30
Project acronym MULTIJEDI
Project Multilingual Joint Word Sense Disambiguation
Researcher (PI) Roberto Navigli
Host Institution (HI) UNIVERSITA DEGLI STUDI DI ROMA LA SAPIENZA
Call Details Starting Grant (StG), PE6, ERC-2010-StG_20091028
Summary In the information society the language barrier represents one of the main obstacles to the automatic use, integration and manipulation of knowledge, and this is manifested in the lack of intelligent systems able to perform unified semantic processing of textual resources in a multitude of different languages. To create such systems, a necessary step is to assign the appropriate meanings to the words in documents, a task referred to as Word Sense Disambiguation (WSD). But while WSD is typically performed in a monolingual setting, in order to enable multilingual processing, the semantic connections between word senses (i.e. meanings) in different languages need to be exploited. However, current state-of-the-art systems mainly rely on the existence of bilingual aligned text collections or limited-coverage multilingual resources to perform cross-lingual disambiguation, an unrealistic requirement when working with an arbitrary number of language pairs.
Here we propose a research program that will investigate radically new directions for performing multilingual WSD. The key intuition underlying our proposal is that WSD can be performed globally to exploit at the same time knowledge available in many languages. The first stage will involve the development of a methodology for automatically creating a large-scale, multilingual knowledge base. In a second stage, using this lexical resource, novel graph-based algorithms for jointly performing disambiguation across different languages will be designed and experimented. Crucially, we aim to show that these two tasks are mutually beneficial for going beyond current state-of-the-art WSD systems. The proposed project will have an impact not only on WSD research, but also on related areas such as Information Retrieval and Machine Translation.
Summary
In the information society the language barrier represents one of the main obstacles to the automatic use, integration and manipulation of knowledge, and this is manifested in the lack of intelligent systems able to perform unified semantic processing of textual resources in a multitude of different languages. To create such systems, a necessary step is to assign the appropriate meanings to the words in documents, a task referred to as Word Sense Disambiguation (WSD). But while WSD is typically performed in a monolingual setting, in order to enable multilingual processing, the semantic connections between word senses (i.e. meanings) in different languages need to be exploited. However, current state-of-the-art systems mainly rely on the existence of bilingual aligned text collections or limited-coverage multilingual resources to perform cross-lingual disambiguation, an unrealistic requirement when working with an arbitrary number of language pairs.
Here we propose a research program that will investigate radically new directions for performing multilingual WSD. The key intuition underlying our proposal is that WSD can be performed globally to exploit at the same time knowledge available in many languages. The first stage will involve the development of a methodology for automatically creating a large-scale, multilingual knowledge base. In a second stage, using this lexical resource, novel graph-based algorithms for jointly performing disambiguation across different languages will be designed and experimented. Crucially, we aim to show that these two tasks are mutually beneficial for going beyond current state-of-the-art WSD systems. The proposed project will have an impact not only on WSD research, but also on related areas such as Information Retrieval and Machine Translation.
Max ERC Funding
1 288 400 €
Duration
Start date: 2011-02-01, End date: 2016-01-31
Project acronym NATURE NANODEVICES
Project "Nature-inspired theranostic nanodevices for tumor imaging, early diagnosis and targeted drug-release"
Researcher (PI) Francesco Ricci
Host Institution (HI) UNIVERSITA DEGLI STUDI DI ROMA TOR VERGATA
Call Details Starting Grant (StG), LS7, ERC-2013-StG
Summary "Late diagnosis and difficult treatment represent major obstacles in the fight against cancer. I propose here the development of self-regulated theranostic nanodevices supporting both early cancer diagnosis and targeted, tumor-cell-specific drug-release. Specifically, I will exploit the “designability” of nucleic acids to design and optimize molecular nanodevices that undergo binding-induced conformational changes upon target binding and, in doing so, signal the presence of a specific tumor marker or release a toxic therapeutic cargo. The inspiration behind my approach is derived from nature, which employs similar nanometer-scale protein and nucleic-acid-based “switches” as devices to detect –and respond to- specific molecules even against the complex background “noise” of the physiological environment. Furthering on this “nature-inspired” synthetic biology view I will also exploit naturally occurring regulatory mechanisms (e.g., allostery, cooperativity, etc.) to tune and edit the dose-response curve of these nanodevices, improve their analytical sensitivity, and optimize drug-release efficiency. In summary, I will use biomimetic “tricks’ taken directly from nature to move beyond the state-of-the-art of sensor design, with the goal being improved diagnostics and “smarter,” more effective drug delivery. Achieving these goals will require multidisciplinary expertise in the field of analytical chemistry, biophysics, electrochemistry, bioengineering, computational chemistry and synthetic biology. In my career I have demonstrated skills and expertise in similarly complex projects and in each of these challenging fields. Finally, the development of the proposed nanodevices will significantly impact the safety, compliance and efficacy of therapies and medical procedures bringing to scientific, technological and socio-economic benefits."
Summary
"Late diagnosis and difficult treatment represent major obstacles in the fight against cancer. I propose here the development of self-regulated theranostic nanodevices supporting both early cancer diagnosis and targeted, tumor-cell-specific drug-release. Specifically, I will exploit the “designability” of nucleic acids to design and optimize molecular nanodevices that undergo binding-induced conformational changes upon target binding and, in doing so, signal the presence of a specific tumor marker or release a toxic therapeutic cargo. The inspiration behind my approach is derived from nature, which employs similar nanometer-scale protein and nucleic-acid-based “switches” as devices to detect –and respond to- specific molecules even against the complex background “noise” of the physiological environment. Furthering on this “nature-inspired” synthetic biology view I will also exploit naturally occurring regulatory mechanisms (e.g., allostery, cooperativity, etc.) to tune and edit the dose-response curve of these nanodevices, improve their analytical sensitivity, and optimize drug-release efficiency. In summary, I will use biomimetic “tricks’ taken directly from nature to move beyond the state-of-the-art of sensor design, with the goal being improved diagnostics and “smarter,” more effective drug delivery. Achieving these goals will require multidisciplinary expertise in the field of analytical chemistry, biophysics, electrochemistry, bioengineering, computational chemistry and synthetic biology. In my career I have demonstrated skills and expertise in similarly complex projects and in each of these challenging fields. Finally, the development of the proposed nanodevices will significantly impact the safety, compliance and efficacy of therapies and medical procedures bringing to scientific, technological and socio-economic benefits."
Max ERC Funding
1 458 600 €
Duration
Start date: 2014-04-01, End date: 2019-03-31
Project acronym NEGOTIATINGMODERNITY
Project “Negotiating Modernity”: History of Modern Political Thought in East-Central Europe
Researcher (PI) Balázs Trencsényi
Host Institution (HI) CENTRE FOR ADVANCED STUDY SOFIA
Call Details Starting Grant (StG), SH5, ERC-2007-StG
Summary The principal aim of the Project is an unprecedented synthetic volume on the history of modern political thought in East Central Europe. It is not meant to be compartmentalized according to national sub-chapters but based on a diachronic analysis especially sensitive to transnational discursive phenomena (e.g. the ideological traditions transcending national borders such as liberalism, socialism, conservatism, federalism), and being equally open to supra-national and sub-national (regional) frameworks, where different national projects were interacting. The project entails the task of “redescription” and conceptual transfer, i.e. finding a regional and trans-culturally acceptable set of analytical categories, as well as new knowledge-production – answering questions about the basic components of European political thought, formulated on the basis of a regional and trans-regional comparative analysis. It also necessitates the “trading” of concepts: both in the direction of inserting specific historical experiences and analytical categories into European circulation, and also testing the value of the interpretative models linked to such notions as “populism”. The project thus aims neither at a compendium of case-studies nor at a deductive Area Studies-type of approach that tends to eliminate differences to forge a general narrative. What it seeks to produce instead is a cross-cultural “synthesis”– the work of a compact team of multi-national composition, skilled in comparative research and drawing on the recent upsurge of transnational historiography. By shifting the reference point of historical thinking from the “West” to the cross-European experience with a special emphasis on East-Central Europe, in other words, the project seeks to rethink the history of the “negotiation of political modernity,” moving from “moral ethnocentrism” and oversimplification towards a more encompassing notion of what constitutes the European intellectual heritage.
Summary
The principal aim of the Project is an unprecedented synthetic volume on the history of modern political thought in East Central Europe. It is not meant to be compartmentalized according to national sub-chapters but based on a diachronic analysis especially sensitive to transnational discursive phenomena (e.g. the ideological traditions transcending national borders such as liberalism, socialism, conservatism, federalism), and being equally open to supra-national and sub-national (regional) frameworks, where different national projects were interacting. The project entails the task of “redescription” and conceptual transfer, i.e. finding a regional and trans-culturally acceptable set of analytical categories, as well as new knowledge-production – answering questions about the basic components of European political thought, formulated on the basis of a regional and trans-regional comparative analysis. It also necessitates the “trading” of concepts: both in the direction of inserting specific historical experiences and analytical categories into European circulation, and also testing the value of the interpretative models linked to such notions as “populism”. The project thus aims neither at a compendium of case-studies nor at a deductive Area Studies-type of approach that tends to eliminate differences to forge a general narrative. What it seeks to produce instead is a cross-cultural “synthesis”– the work of a compact team of multi-national composition, skilled in comparative research and drawing on the recent upsurge of transnational historiography. By shifting the reference point of historical thinking from the “West” to the cross-European experience with a special emphasis on East-Central Europe, in other words, the project seeks to rethink the history of the “negotiation of political modernity,” moving from “moral ethnocentrism” and oversimplification towards a more encompassing notion of what constitutes the European intellectual heritage.
Max ERC Funding
689 579 €
Duration
Start date: 2008-04-01, End date: 2013-04-30
Project acronym NeMoSanctI
Project New Models of Sanctity in Italy (1960s-2010s).A Semiotic Analysis of Norms, Causes of Saints, Hagiography, and Narratives
Researcher (PI) Jenny PONZO
Host Institution (HI) UNIVERSITA DEGLI STUDI DI TORINO
Call Details Starting Grant (StG), SH5, ERC-2017-STG
Summary In cultures with a strong Catholic tradition saints represent models of life perfection, dialectically elaborated by a plurality of subjects and expressed in a thick intertextual network. Since the Second Vatican Council (1962-1965), when the Church promoted a policy of adaptation of her tradition to the modern world, the modeling of sanctity has undergone a deep transformation. In a context of global change, new models of sanctity have assumed a central role in guiding the faithful by proposing a renewed religious alternative to growing secularization.
NeMoSanctI intends to study how models of sanctity have changed after the Second Vatican Council and their relationship with the culture of a country exemplum of strong Catholicism: Italy. To this end, it will apply a pioneering semiotic method based on the study of values, which will allow the comparative analysis of a corpus of texts of different genres:
- normative texts regulating sanctity emanating from the Church;
- judicial texts, i.e. causes of canonization of three famous Italian saints (Padre Pio, Gianna Beretta Molla, and Gerardo Maiella), with a focus on the dialectics between the models proposed by laic witnesses and by ecclesiastic inquirers;
- narrative texts, i.e. a sample of popular hagiography about the three saints, of official hagiographic collections, and of Italian literary texts, where the theme of sanctity tends to be unconventionally elaborated and dissociated from Catholic values.
Despite its relevance for a deeper understanding of the role of religion in today’s culture, a systematic research on new models of sanctity and on their intertextual codification is still missing. By carrying out this research and by proposing an innovative semiotic method for the analysis of models of life perfection, NeMoSanctI will have a significant impact on numerous disciplines, especially semiotics, religious and cultural studies, critical studies of hagiography and canon law, literary and Italian studies.
Summary
In cultures with a strong Catholic tradition saints represent models of life perfection, dialectically elaborated by a plurality of subjects and expressed in a thick intertextual network. Since the Second Vatican Council (1962-1965), when the Church promoted a policy of adaptation of her tradition to the modern world, the modeling of sanctity has undergone a deep transformation. In a context of global change, new models of sanctity have assumed a central role in guiding the faithful by proposing a renewed religious alternative to growing secularization.
NeMoSanctI intends to study how models of sanctity have changed after the Second Vatican Council and their relationship with the culture of a country exemplum of strong Catholicism: Italy. To this end, it will apply a pioneering semiotic method based on the study of values, which will allow the comparative analysis of a corpus of texts of different genres:
- normative texts regulating sanctity emanating from the Church;
- judicial texts, i.e. causes of canonization of three famous Italian saints (Padre Pio, Gianna Beretta Molla, and Gerardo Maiella), with a focus on the dialectics between the models proposed by laic witnesses and by ecclesiastic inquirers;
- narrative texts, i.e. a sample of popular hagiography about the three saints, of official hagiographic collections, and of Italian literary texts, where the theme of sanctity tends to be unconventionally elaborated and dissociated from Catholic values.
Despite its relevance for a deeper understanding of the role of religion in today’s culture, a systematic research on new models of sanctity and on their intertextual codification is still missing. By carrying out this research and by proposing an innovative semiotic method for the analysis of models of life perfection, NeMoSanctI will have a significant impact on numerous disciplines, especially semiotics, religious and cultural studies, critical studies of hagiography and canon law, literary and Italian studies.
Max ERC Funding
1 051 590 €
Duration
Start date: 2018-03-01, End date: 2023-02-28
Project acronym NeuroTRACK
Project Tracking and predicting neurodegeneration spreading across the brain connectome
Researcher (PI) Federica Agosta
Host Institution (HI) OSPEDALE SAN RAFFAELE SRL
Call Details Starting Grant (StG), LS7, ERC-2016-STG
Summary Current knowledge of neurodegenerative diseases is limited by poor understanding of how they progress through the central nervous system (CNS). It has recently been hypothesized that clinical progression in these conditions involves the systematic spreading of protein misfolding along neuronal pathways. Protein aggregates would trigger misfolding of adjacent homologue proteins in newly-affected regions, and this would propagate in a “prion-like” fashion across anatomical connections. This proposal seeks to decipher the mechanisms of network-based neurodegeneration by understanding how the complex architecture of brain networks (the connectome) shapes the evolving pathology of neurodegenerative diseases, and to develop tools for monitoring disease progression from presymptomatic to later stages of the disease.
NeuroTRACK will apply emerging network science tools to longitudinal, structural and functional brain connectivity 3T magnetic resonance imaging data from patients with frontotemporal lobar degeneration (FTLD) – a devastating, relentlessly progressive, young onset, neurodegenerative disorder. The study will involve both sporadic and familial cases, including presymptomatic gene mutation carriers. The proposal addresses the following fundamental questions: i) How and where does pathological protein propagation occur in the FTLD phenotypes? ii) Can pathological spreading be predicted from brain connectome fingerprinting? iii) How do different protein abnormalities translate into large-scale network degeneration? iv) How early are brain network changes detectable in the (even presymptomatic) course of the disease?
The ground-breaking nature of the experiments planned in this proposal will pave the way to the development of novel tools for understanding the biological underpinnings of other CNS proteinopathies such as Alzheimer’s disease and Parkinson’s disease, and to identifying individualized, early interventions to modify disease progression.
Summary
Current knowledge of neurodegenerative diseases is limited by poor understanding of how they progress through the central nervous system (CNS). It has recently been hypothesized that clinical progression in these conditions involves the systematic spreading of protein misfolding along neuronal pathways. Protein aggregates would trigger misfolding of adjacent homologue proteins in newly-affected regions, and this would propagate in a “prion-like” fashion across anatomical connections. This proposal seeks to decipher the mechanisms of network-based neurodegeneration by understanding how the complex architecture of brain networks (the connectome) shapes the evolving pathology of neurodegenerative diseases, and to develop tools for monitoring disease progression from presymptomatic to later stages of the disease.
NeuroTRACK will apply emerging network science tools to longitudinal, structural and functional brain connectivity 3T magnetic resonance imaging data from patients with frontotemporal lobar degeneration (FTLD) – a devastating, relentlessly progressive, young onset, neurodegenerative disorder. The study will involve both sporadic and familial cases, including presymptomatic gene mutation carriers. The proposal addresses the following fundamental questions: i) How and where does pathological protein propagation occur in the FTLD phenotypes? ii) Can pathological spreading be predicted from brain connectome fingerprinting? iii) How do different protein abnormalities translate into large-scale network degeneration? iv) How early are brain network changes detectable in the (even presymptomatic) course of the disease?
The ground-breaking nature of the experiments planned in this proposal will pave the way to the development of novel tools for understanding the biological underpinnings of other CNS proteinopathies such as Alzheimer’s disease and Parkinson’s disease, and to identifying individualized, early interventions to modify disease progression.
Max ERC Funding
1 496 994 €
Duration
Start date: 2017-04-01, End date: 2022-03-31
Project acronym NEVAI
Project Neurovascular Interactions and Pathfinding in the Spinal Motor System
Researcher (PI) Dario Bonanomi
Host Institution (HI) OSPEDALE SAN RAFFAELE SRL
Call Details Starting Grant (StG), LS5, ERC-2013-StG
Summary "Neurons and blood vessels rely on common guidance signals to wire into elaborate neural and vascular networks that are closely juxtaposed and interdependent: vascular supply of oxygen and nutrients is essential to sustain the high metabolic rate of the nervous system, and conversely neural control of vascular tone is crucial for circulatory homeostasis. However, it remains unclear how the nervous and vascular systems establish an intimate physical and functional relationship. This proposal seeks to reveal the developmental mechanisms that link neuronal connectivity and vascularization of the nervous system, focusing on the interactions between vascular endothelial cells and spinal motor neurons that control locomotion, respiration and autonomic responses. Motor neuron diseases and a variety of other neurodegenerative conditions are precipitated by vascular abnormalities. Thus, understanding the molecular basis of neurovascular crosstalk may offer novel therapeutic opportunities.
My group will use mutagenesis-based forward genetics in reporter mice combined with gene profiling of motor neurons and endothelial cells to screen for novel regulators of neurovascular interactions and pathfinding. Candidate genes will be further characterized using in vivo mouse and chick models, in addition to in vitro studies to uncover the mechanisms of action. Through this multi-disciplinary approach, the proposal will address these fundamental questions: (i) Do neurovascular interactions instruct the assembly of neural and vascular networks? (ii) What signaling pathways connect region-specific vascularization of the CNS to the local metabolic and functional demand of neuronal tissues? (iii) What mechanisms account for specificity, spatiotemporal control and integration of guidance signaling? In addition, this research plan will generate comprehensive transcriptional/proteomic datasets and novel mouse mutants for future studies of neurovascular communication and patterning."
Summary
"Neurons and blood vessels rely on common guidance signals to wire into elaborate neural and vascular networks that are closely juxtaposed and interdependent: vascular supply of oxygen and nutrients is essential to sustain the high metabolic rate of the nervous system, and conversely neural control of vascular tone is crucial for circulatory homeostasis. However, it remains unclear how the nervous and vascular systems establish an intimate physical and functional relationship. This proposal seeks to reveal the developmental mechanisms that link neuronal connectivity and vascularization of the nervous system, focusing on the interactions between vascular endothelial cells and spinal motor neurons that control locomotion, respiration and autonomic responses. Motor neuron diseases and a variety of other neurodegenerative conditions are precipitated by vascular abnormalities. Thus, understanding the molecular basis of neurovascular crosstalk may offer novel therapeutic opportunities.
My group will use mutagenesis-based forward genetics in reporter mice combined with gene profiling of motor neurons and endothelial cells to screen for novel regulators of neurovascular interactions and pathfinding. Candidate genes will be further characterized using in vivo mouse and chick models, in addition to in vitro studies to uncover the mechanisms of action. Through this multi-disciplinary approach, the proposal will address these fundamental questions: (i) Do neurovascular interactions instruct the assembly of neural and vascular networks? (ii) What signaling pathways connect region-specific vascularization of the CNS to the local metabolic and functional demand of neuronal tissues? (iii) What mechanisms account for specificity, spatiotemporal control and integration of guidance signaling? In addition, this research plan will generate comprehensive transcriptional/proteomic datasets and novel mouse mutants for future studies of neurovascular communication and patterning."
Max ERC Funding
1 653 000 €
Duration
Start date: 2015-01-01, End date: 2019-12-31
