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 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 bECOMiNG
Project spontaneous Evolution and Clonal heterOgeneity in MoNoclonal Gammopathies: from mechanisms of progression to clinical management
Researcher (PI) Niccolo Bolli
Host Institution (HI) UNIVERSITA DEGLI STUDI DI MILANO
Call Details Consolidator Grant (CoG), LS7, ERC-2018-COG
Summary As an onco-hematologist with a strong expertise in genomics, I significantly contributed to the understanding of multiple myeloma (MM) heterogeneity and its evolution over time, driven by genotypic and phenotypic features carried by different subpopulations of cells. MM is preceded by prevalent, asymptomatic stages that may evolve with variable frequency, not accurately captured by current clinical prognostic scores. Supported by preliminary data, my hypothesis is that the same heterogeneity is present early on the disease course, and identification of the biological determinants of evolution at this stage will allow better prediction of its evolutionary trajectory, if not its control. In this proposal I will therefore make a sharp change from conventional approaches and move to early stages of MM using unique retrospective sample cohorts and ambitious prospective sampling. To identify clonal MM cells in the elderly before a monoclonal gammopathy can be detected, I will collect bone marrow (BM) from hundreds of hip replacement specimens, and analyze archive peripheral blood samples of thousands of healthy individuals with years of annotated clinical follow-up. This will identify early genomic alterations that are permissive to disease initiation/evolution and may serve as biomarkers for clinical screening. Through innovative, integrated single-cell genotyping and phenotyping of hundreds of asymptomatic MMs, I will functionally dissect heterogeneity and characterize the BM microenvironment to look for determinants of disease progression. Correlation with clinical outcome and mini-invasive serial sampling of circulating cell-free DNA will identify candidate biological markers to better predict evolution. Last, aggressive modelling of candidate early lesions and modifier screens will offer a list of vulnerabilities that could be exploited for rationale therapies. These methodologies will deliver a paradigm for the use of molecularly-driven precision medicine in cancer.
Summary
As an onco-hematologist with a strong expertise in genomics, I significantly contributed to the understanding of multiple myeloma (MM) heterogeneity and its evolution over time, driven by genotypic and phenotypic features carried by different subpopulations of cells. MM is preceded by prevalent, asymptomatic stages that may evolve with variable frequency, not accurately captured by current clinical prognostic scores. Supported by preliminary data, my hypothesis is that the same heterogeneity is present early on the disease course, and identification of the biological determinants of evolution at this stage will allow better prediction of its evolutionary trajectory, if not its control. In this proposal I will therefore make a sharp change from conventional approaches and move to early stages of MM using unique retrospective sample cohorts and ambitious prospective sampling. To identify clonal MM cells in the elderly before a monoclonal gammopathy can be detected, I will collect bone marrow (BM) from hundreds of hip replacement specimens, and analyze archive peripheral blood samples of thousands of healthy individuals with years of annotated clinical follow-up. This will identify early genomic alterations that are permissive to disease initiation/evolution and may serve as biomarkers for clinical screening. Through innovative, integrated single-cell genotyping and phenotyping of hundreds of asymptomatic MMs, I will functionally dissect heterogeneity and characterize the BM microenvironment to look for determinants of disease progression. Correlation with clinical outcome and mini-invasive serial sampling of circulating cell-free DNA will identify candidate biological markers to better predict evolution. Last, aggressive modelling of candidate early lesions and modifier screens will offer a list of vulnerabilities that could be exploited for rationale therapies. These methodologies will deliver a paradigm for the use of molecularly-driven precision medicine in cancer.
Max ERC Funding
1 998 781 €
Duration
Start date: 2019-03-01, End date: 2024-02-29
Project acronym BIOINOHYB
Project Smart Bioinorganic Hybrids for Nanomedicine
Researcher (PI) Cristiana Di Valentin
Host Institution (HI) UNIVERSITA' DEGLI STUDI DI MILANO-BICOCCA
Call Details Consolidator Grant (CoG), PE5, ERC-2014-CoG
Summary The use of bioinorganic nanohybrids (nanoscaled systems based on an inorganic and a biological component) has already resulted in several innovative medical breakthroughs for drug delivery, therapeutics, imaging, diagnosis and biocompatibility. However, researchers still know relatively little about the structure, function and mechanism of these nanodevices. Theoretical investigations of bioinorganic interfaces are mostly limited to force-field approaches which cannot grasp the details of the physicochemical mechanisms. The BIOINOHYB project proposes to capitalize on recent massively parallelized codes to investigate bioinorganic nanohybrids by advanced quantum chemical methods. This approach will allow to master the chemical and electronic interplay between the bio and the inorganic components in the first part of the project, and the interaction of the hybrid systems with light in the second part. The ultimate goal is to provide the design principles for novel, unconventional assemblies with unprecedented functionalities and strong impact potential in nanomedicine.
More specifically, in this project the traditional metallic nanoparticle will be substituted by emerging semiconducting metal oxide nanostructures with photocatalytic or magnetic properties capable of opening totally new horizons in nanomedicine (e.g. photocatalytic therapy, a new class of contrast agents, magnetically guided drug delivery). Potentially efficient linkers will be screened regarding their ability both to anchor surfaces and to bind biomolecules. Different kinds of biomolecules (from oligopeptides and oligonucleotides to small drugs) will be tethered to the activated surface according to the desired functionality. The key computational challenge, requiring the recourse to more sophisticated methods, will be the investigation of the photo-response to light of the assembled bioinorganic systems, also with specific reference to their labelling with fluorescent markers and contrast agents.
Summary
The use of bioinorganic nanohybrids (nanoscaled systems based on an inorganic and a biological component) has already resulted in several innovative medical breakthroughs for drug delivery, therapeutics, imaging, diagnosis and biocompatibility. However, researchers still know relatively little about the structure, function and mechanism of these nanodevices. Theoretical investigations of bioinorganic interfaces are mostly limited to force-field approaches which cannot grasp the details of the physicochemical mechanisms. The BIOINOHYB project proposes to capitalize on recent massively parallelized codes to investigate bioinorganic nanohybrids by advanced quantum chemical methods. This approach will allow to master the chemical and electronic interplay between the bio and the inorganic components in the first part of the project, and the interaction of the hybrid systems with light in the second part. The ultimate goal is to provide the design principles for novel, unconventional assemblies with unprecedented functionalities and strong impact potential in nanomedicine.
More specifically, in this project the traditional metallic nanoparticle will be substituted by emerging semiconducting metal oxide nanostructures with photocatalytic or magnetic properties capable of opening totally new horizons in nanomedicine (e.g. photocatalytic therapy, a new class of contrast agents, magnetically guided drug delivery). Potentially efficient linkers will be screened regarding their ability both to anchor surfaces and to bind biomolecules. Different kinds of biomolecules (from oligopeptides and oligonucleotides to small drugs) will be tethered to the activated surface according to the desired functionality. The key computational challenge, requiring the recourse to more sophisticated methods, will be the investigation of the photo-response to light of the assembled bioinorganic systems, also with specific reference to their labelling with fluorescent markers and contrast agents.
Max ERC Funding
1 748 125 €
Duration
Start date: 2016-02-01, End date: 2021-01-31
Project acronym BIT-ACT
Project Bottom-up initiatives and anti-corruption technologies: how citizens use ICTs to fight corruption
Researcher (PI) Alice Mattoni
Host Institution (HI) ALMA MATER STUDIORUM - UNIVERSITA DI BOLOGNA
Call Details Starting Grant (StG), SH2, ERC-2018-STG
Summary Corruption is a global challenge that affects the lives of millions of citizens. In the past decade, Information and Communication Technologies (ICTs) have become indispensable tools in the fight to reduce corruption, especially when employed from the bottom-up by civil society organizations. While pioneering initiatives in this direction have flourished, to date we only have unsystematic and descriptive evidence regarding how they work and the associated consequences. With the objective of significantly advancing knowledge on this topic, BIT-ACT will open a new line of inquiry by investigating what I call anti-corruption technologies (ACTs) to: (1) assess how civil society organizations engage with ACTs to counter corruption, (2) appraise how ACTs enable intersections between bottom-up and top-down efforts against corruption, and (3) evaluate how ACTs blend with the transnational dimension in the struggle against corruption. Based on an interdisciplinary framework that combines corruption studies, science and technology studies and social movement studies, BIT-ACT will use the constructivist grounded theory method to analyze a combination of textual and visual data in a comparative and transnational research design including nine countries – Algeria, Bangladesh, Brazil, Estonia, India, Italy, Spain, Ukraine, Uruguay. BIT-ACT will be groundbreaking in three ways. At the theoretical level, it will expand the debate on anti-corruption providing grounded concepts and models to explain ACTs; at the empirical level, it will advance knowledge on how the usage of ACTs is changing the relationship between citizens and democratic institutions; at the methodological level, it will innovate in the use of grounded theory assessing a new standard for cross-national comparative grounded theory. Finally, BIT-ACT will produce sound and useful knowledge for the stakeholders involved in the fight against corruption worldwide by suggesting how to best employ ICTs from the bottom-up.
Summary
Corruption is a global challenge that affects the lives of millions of citizens. In the past decade, Information and Communication Technologies (ICTs) have become indispensable tools in the fight to reduce corruption, especially when employed from the bottom-up by civil society organizations. While pioneering initiatives in this direction have flourished, to date we only have unsystematic and descriptive evidence regarding how they work and the associated consequences. With the objective of significantly advancing knowledge on this topic, BIT-ACT will open a new line of inquiry by investigating what I call anti-corruption technologies (ACTs) to: (1) assess how civil society organizations engage with ACTs to counter corruption, (2) appraise how ACTs enable intersections between bottom-up and top-down efforts against corruption, and (3) evaluate how ACTs blend with the transnational dimension in the struggle against corruption. Based on an interdisciplinary framework that combines corruption studies, science and technology studies and social movement studies, BIT-ACT will use the constructivist grounded theory method to analyze a combination of textual and visual data in a comparative and transnational research design including nine countries – Algeria, Bangladesh, Brazil, Estonia, India, Italy, Spain, Ukraine, Uruguay. BIT-ACT will be groundbreaking in three ways. At the theoretical level, it will expand the debate on anti-corruption providing grounded concepts and models to explain ACTs; at the empirical level, it will advance knowledge on how the usage of ACTs is changing the relationship between citizens and democratic institutions; at the methodological level, it will innovate in the use of grounded theory assessing a new standard for cross-national comparative grounded theory. Finally, BIT-ACT will produce sound and useful knowledge for the stakeholders involved in the fight against corruption worldwide by suggesting how to best employ ICTs from the bottom-up.
Max ERC Funding
1 489 115 €
Duration
Start date: 2019-07-01, End date: 2024-06-30
Project acronym BORDERLANDS
Project Borderlands: Expanding Boundaries, Governance, and Power in the European Union's Relations with North Africa and the Middle East
Researcher (PI) Raffaella Alessandra Del Sarto
Host Institution (HI) EUROPEAN UNIVERSITY INSTITUTE
Call Details Starting Grant (StG), SH2, ERC-2010-StG_20091209
Summary Challenging the notion of Fortress Europe , the research investigates relations between the European Union and its southern periphery through the concept of borderlands . The concept emphasises the disaggregation of the triple function of borders demarcating state territory, authority, and national identity inherent in the Westphalian model of statehood. This process is most visible in (although not limited to) Europe, where integration has led to supranational areas of sovereignty, an internal market, a common currency, and a zone of free movement of people, each with a different territorial span. The project explores the complex and differentiated process by which the EU extends its unbundled functional and legal borders to the so-called southern Mediterranean (North Africa and parts of the Middle East), thereby transforming it into borderlands . They connect the European core with the periphery through various legal and functional border regimes, governance patterns, and the selective outsourcing of some EU border control duties. The overarching questions informing this research is whether, first, the borderland policies of the EU, described by some as a neo-medieval empire, is a functional consequence of the specific integration model pursued inside the EU, a matter of foreign policy choice or a local manifestation of a broader global phenomenon. Second, the project addresses the question of power dynamics that underwrite borderland governance, presuming a growing leverage of third country governments resulting from their co-optation as gatekeepers. Thus, while adopting an innovative approach, the project will enhance our understanding of EU-Mediterranean relations while also addressing crucial theoretical questions in international relations.
Summary
Challenging the notion of Fortress Europe , the research investigates relations between the European Union and its southern periphery through the concept of borderlands . The concept emphasises the disaggregation of the triple function of borders demarcating state territory, authority, and national identity inherent in the Westphalian model of statehood. This process is most visible in (although not limited to) Europe, where integration has led to supranational areas of sovereignty, an internal market, a common currency, and a zone of free movement of people, each with a different territorial span. The project explores the complex and differentiated process by which the EU extends its unbundled functional and legal borders to the so-called southern Mediterranean (North Africa and parts of the Middle East), thereby transforming it into borderlands . They connect the European core with the periphery through various legal and functional border regimes, governance patterns, and the selective outsourcing of some EU border control duties. The overarching questions informing this research is whether, first, the borderland policies of the EU, described by some as a neo-medieval empire, is a functional consequence of the specific integration model pursued inside the EU, a matter of foreign policy choice or a local manifestation of a broader global phenomenon. Second, the project addresses the question of power dynamics that underwrite borderland governance, presuming a growing leverage of third country governments resulting from their co-optation as gatekeepers. Thus, while adopting an innovative approach, the project will enhance our understanding of EU-Mediterranean relations while also addressing crucial theoretical questions in international relations.
Max ERC Funding
1 353 920 €
Duration
Start date: 2011-10-01, End date: 2017-03-31
Project acronym CARBONANOBRIDGE
Project Neuron Networking with Nano Bridges via the Synthesis and Integration of Functionalized Carbon Nanotubes
Researcher (PI) Maurizio Prato
Host Institution (HI) UNIVERSITA DEGLI STUDI DI TRIESTE
Call Details Advanced Grant (AdG), PE5, ERC-2008-AdG
Summary We propose the development of novel nanodevices, such as nanoscale bridges and nanovectors, based on functionalized carbon nanotubes (CNT) for manipulating neurons and neuronal network activity in vitro. The main aim is to put forward innovative solutions that have the potential to circumvent the problems currently faced by spinal cord lesions or by neurodegenerative diseases. The unifying theme is to use recent advances in chemistry and nanotechnology to gain insight into the functioning of hybrid neuronal/CNT networks, relevant for the development of novel implantable devices to control neuronal signaling and improve synapse formation in a controlled fashion. The proposal s core strategy is to exploit the expertise of the PI in the chemical control of CNT properties to develop devices reaching various degrees of functional integration with the physiological electrical activity of cells and their networks, and to understand how such global dynamics are orchestrated when integrated by different substrates. An unconventional strategy will be represented by the electrical characterization of micro and nano patterned substrates by AFM and conductive tip AFM, both before and after neurons have grown on the substrates. We will also use the capability of AFM to identify critical positions in the neuronal network, while delivering time-dependent chemical stimulations. We will apply nanotechnology to contemporary neuroscience in the perspective of novel neuro-implantable devices and drug nanovectors, engineered to treat neurological and neurodegenerative lesions. The scientific strategy at the core of the proposal is the convergence between nanotechnology, chemistry and neurobiology. Such convergence, beyond helping understand the functioning and malfunctioning of the brain, can stimulate further research in this area and may ultimately lead to a new generation of nanomedicine applications in neurology and to new opportunities for the health care industry.
Summary
We propose the development of novel nanodevices, such as nanoscale bridges and nanovectors, based on functionalized carbon nanotubes (CNT) for manipulating neurons and neuronal network activity in vitro. The main aim is to put forward innovative solutions that have the potential to circumvent the problems currently faced by spinal cord lesions or by neurodegenerative diseases. The unifying theme is to use recent advances in chemistry and nanotechnology to gain insight into the functioning of hybrid neuronal/CNT networks, relevant for the development of novel implantable devices to control neuronal signaling and improve synapse formation in a controlled fashion. The proposal s core strategy is to exploit the expertise of the PI in the chemical control of CNT properties to develop devices reaching various degrees of functional integration with the physiological electrical activity of cells and their networks, and to understand how such global dynamics are orchestrated when integrated by different substrates. An unconventional strategy will be represented by the electrical characterization of micro and nano patterned substrates by AFM and conductive tip AFM, both before and after neurons have grown on the substrates. We will also use the capability of AFM to identify critical positions in the neuronal network, while delivering time-dependent chemical stimulations. We will apply nanotechnology to contemporary neuroscience in the perspective of novel neuro-implantable devices and drug nanovectors, engineered to treat neurological and neurodegenerative lesions. The scientific strategy at the core of the proposal is the convergence between nanotechnology, chemistry and neurobiology. Such convergence, beyond helping understand the functioning and malfunctioning of the brain, can stimulate further research in this area and may ultimately lead to a new generation of nanomedicine applications in neurology and to new opportunities for the health care industry.
Max ERC Funding
2 500 000 €
Duration
Start date: 2009-02-01, End date: 2014-01-31
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 CoCEAL
Project The Common Core of European Administrative Law
Researcher (PI) Giacinto DELLA CANANEA
Host Institution (HI) UNIVERSITA COMMERCIALE LUIGI BOCCONI
Call Details Advanced Grant (AdG), SH2, ERC-2015-AdG
Summary The European dimension of administrative law is the focus of a flurry of initiatives aiming to investigate similarities and differences, and to shape common legal scenarios. A codification of the administrative procedures of the EU has been envisaged by the European Parliament in its resolution of February 2013. A broader proposal of codification, including rule-making and contractual procedures, has been elaborated by ReNEUAL and has been discussed in a series of workshops in 2015.
The issues that arise are both practical and theoretical:
- it is important to understand whether the method traditionally followed by the European Court of Justice in order to identify the principles that are general and common to national legal systems, only applies when all those systems recognize such principles;
- whether national systems of public law share the same idea of what an administrative procedure is is another question;
whether the specific principles governing administrative procedures, such as the right to be heard and the duty to give reasons, are the same is still another question;
- finally, if any commonality exists, the question that arises is whether it is limited to the level of general principles of law or it includes the which govern procedures.
The research project is innovative on grounds of method, because:
- it aims at ascertaining whether, and the extent to that, the well-established methodology developed under the ‘Common Core of European Private Law’ project can be applied to EU administrative law;
- it permits to distinguish between ‘operative rules’, ‘descriptive formants’, and ‘meta-legal formants’;
- it also allows to understand whether the specific nature of the interests recognized and protected by the rules of public law require legal methodologies that are distinct and distant from those of private law.
Summary
The European dimension of administrative law is the focus of a flurry of initiatives aiming to investigate similarities and differences, and to shape common legal scenarios. A codification of the administrative procedures of the EU has been envisaged by the European Parliament in its resolution of February 2013. A broader proposal of codification, including rule-making and contractual procedures, has been elaborated by ReNEUAL and has been discussed in a series of workshops in 2015.
The issues that arise are both practical and theoretical:
- it is important to understand whether the method traditionally followed by the European Court of Justice in order to identify the principles that are general and common to national legal systems, only applies when all those systems recognize such principles;
- whether national systems of public law share the same idea of what an administrative procedure is is another question;
whether the specific principles governing administrative procedures, such as the right to be heard and the duty to give reasons, are the same is still another question;
- finally, if any commonality exists, the question that arises is whether it is limited to the level of general principles of law or it includes the which govern procedures.
The research project is innovative on grounds of method, because:
- it aims at ascertaining whether, and the extent to that, the well-established methodology developed under the ‘Common Core of European Private Law’ project can be applied to EU administrative law;
- it permits to distinguish between ‘operative rules’, ‘descriptive formants’, and ‘meta-legal formants’;
- it also allows to understand whether the specific nature of the interests recognized and protected by the rules of public law require legal methodologies that are distinct and distant from those of private law.
Max ERC Funding
1 254 105 €
Duration
Start date: 2016-09-01, End date: 2021-08-31
Project acronym COD
Project The economic, social and political consequences of democratic reforms. A quantitative and qualitative comparative analysis
Researcher (PI) Giovanni Marco Carbone
Host Institution (HI) UNIVERSITA DEGLI STUDI DI MILANO
Call Details Starting Grant (StG), SH2, ERC-2010-StG_20091209
Summary The latter part of the twentieth century was a period of rapid democratisation on a global scale. The attention of comparative politics scholars followed the progression of so-called Third Wave democracies, and gradually progressed from the study of the causes of and the transitions to democracy to the problems of democratic consolidation, and then to more recent issues relating to the quality of democracy. A further, frontier step may now be added to such research path by focusing on a subject that has remained largely under-researched, if at all, namely the political, social and economic consequences that emerged in countries where real democratic change took place. The question of what democracy has been able to deliver will become ever more relevant to the future prospects of recent democratisation processes and of democracy at large.
In the study of the consequences of democratisation, the advent of democracy is thus no longer observed as an endpoint, or a dependent variable to be explained, but as a starting point, or an independent variable that allegedly contributes to the explanation of a wide range of political, economic and social effects. The question of the corollaries of democratisation also has crucial policy implications.
The goals of the proposed research are:
a) the definition of a theoretical framework that articulates, integrates and interrelates the different existing hypotheses and arguments on the consequences of democratization processes
b) the empirical investigation, through a combination and integration of quantitative and qualitative methods, of the validity of three specific such hypotheses, namely:
i. democratisation favours the consolidation of the state (as a political effect)
ii. democratisation favours economic liberalization (as an economic effect)
iii. democratisation improves social welfare (as a social effect)
c) the analysis of the specific forms that the effects of democratization assume in different world regions
Summary
The latter part of the twentieth century was a period of rapid democratisation on a global scale. The attention of comparative politics scholars followed the progression of so-called Third Wave democracies, and gradually progressed from the study of the causes of and the transitions to democracy to the problems of democratic consolidation, and then to more recent issues relating to the quality of democracy. A further, frontier step may now be added to such research path by focusing on a subject that has remained largely under-researched, if at all, namely the political, social and economic consequences that emerged in countries where real democratic change took place. The question of what democracy has been able to deliver will become ever more relevant to the future prospects of recent democratisation processes and of democracy at large.
In the study of the consequences of democratisation, the advent of democracy is thus no longer observed as an endpoint, or a dependent variable to be explained, but as a starting point, or an independent variable that allegedly contributes to the explanation of a wide range of political, economic and social effects. The question of the corollaries of democratisation also has crucial policy implications.
The goals of the proposed research are:
a) the definition of a theoretical framework that articulates, integrates and interrelates the different existing hypotheses and arguments on the consequences of democratization processes
b) the empirical investigation, through a combination and integration of quantitative and qualitative methods, of the validity of three specific such hypotheses, namely:
i. democratisation favours the consolidation of the state (as a political effect)
ii. democratisation favours economic liberalization (as an economic effect)
iii. democratisation improves social welfare (as a social effect)
c) the analysis of the specific forms that the effects of democratization assume in different world regions
Max ERC Funding
322 284 €
Duration
Start date: 2010-11-01, End date: 2015-10-31
Project acronym CompuLaw
Project Computable Law
Researcher (PI) Giovanni Sartor
Host Institution (HI) ALMA MATER STUDIORUM - UNIVERSITA DI BOLOGNA
Call Details Advanced Grant (AdG), SH2, ERC-2018-ADG
Summary The project addresses the regulation of computations (processes and systems) through an innovative legal & technological framework: it provides epistemic, technical and normative guidance for the de-velopment of computable laws and law compliant computations.
The context is the ongoing transformation of the social world into a hybrid infosphere, populated by a huge and growing number of increasingly pervasive, autonomous and intelligent computational enti-ties. The scale, speed, ubiquity and autonomy of computations make it impossible for humans to di-rectly monitor them and anticipate all possible illegal computational behaviours. The law can hold the hybrid infosphere under its rule – providing protection, security and trust – only if it be-comes computation-oriented: legal and ethical requirements must be integrated with, mapped onto, and partially translated into, computable representations of legal knowledge and reasoning.
Current legal culture still has not adequately addressed risks and potentials of computable law. My project will fill this gap, providing concepts, principles, methods and techniques and normative guide-lines to support law-abiding computations. It has the normative purpose to uphold the principle of rule of law, translating legal norms and legal values into requirements for computable laws and legally-responsive computational agents. My project will provide major methodological and substantive breakthroughs. On the one hand, it pro-poses a socio-technical methodology for regulatory design and evaluation, integrating three discipli-nary clusters: a social-legal one, a philosophical-logical one and a computing-AI one. On the other hand, it develops a framework including: (a) norms, legal values and principles for developers, de-ployers and users; (b) languages and methods to specify requirements of computations and norms directed to them; (c) cognitive architectures for legally-responsive computational agents.
Summary
The project addresses the regulation of computations (processes and systems) through an innovative legal & technological framework: it provides epistemic, technical and normative guidance for the de-velopment of computable laws and law compliant computations.
The context is the ongoing transformation of the social world into a hybrid infosphere, populated by a huge and growing number of increasingly pervasive, autonomous and intelligent computational enti-ties. The scale, speed, ubiquity and autonomy of computations make it impossible for humans to di-rectly monitor them and anticipate all possible illegal computational behaviours. The law can hold the hybrid infosphere under its rule – providing protection, security and trust – only if it be-comes computation-oriented: legal and ethical requirements must be integrated with, mapped onto, and partially translated into, computable representations of legal knowledge and reasoning.
Current legal culture still has not adequately addressed risks and potentials of computable law. My project will fill this gap, providing concepts, principles, methods and techniques and normative guide-lines to support law-abiding computations. It has the normative purpose to uphold the principle of rule of law, translating legal norms and legal values into requirements for computable laws and legally-responsive computational agents. My project will provide major methodological and substantive breakthroughs. On the one hand, it pro-poses a socio-technical methodology for regulatory design and evaluation, integrating three discipli-nary clusters: a social-legal one, a philosophical-logical one and a computing-AI one. On the other hand, it develops a framework including: (a) norms, legal values and principles for developers, de-ployers and users; (b) languages and methods to specify requirements of computations and norms directed to them; (c) cognitive architectures for legally-responsive computational agents.
Max ERC Funding
2 273 550 €
Duration
Start date: 2019-11-01, End date: 2024-10-31
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 DENDROWORLD
Project Mucosal dendritic cells in intestinal homeostasis and bacteria-related diseases
Researcher (PI) Maria Rescigno
Host Institution (HI) ISTITUTO EUROPEO DI ONCOLOGIA SRL
Call Details Starting Grant (StG), LS3, ERC-2007-StG
Summary The bacterial microflora has always been regarded as beneficial for the host but recent studies have shown that this symbiosis has risks as well as benefits. Although active mechanisms allow tolerating the commensal flora, the physiological stress that is associated with the symbionts’ metabolism can exhaust the intestinal barrier resulting in serious effects on the health of the host. Protracted immune deregulations can lead to severe disorders including diabetes, cancer and inflammatory bowel disease (IBD). Several mechanisms and players are involved in the maintenance of intestinal immune homeostasis, including T regulatory cells and Immunoglobulin (Ig)-A. In this proposal we focus our attention on dendritic cells (DCs) for their ability to induce both tolerance and immunity by regulating B and T cell responses. We have recently shown that DC function is controlled by intestinal epithelial cell (EC) derived factors and in particular by Thymic stromal lymphopoietin (TSLP). EC-conditioned DCs acquire a ‘mucosal’ phenotype as they are prone to activate T regulatory cells and IgA responses. Three major issues related to the maintenance and disruption of intestinal immune homeostasis will be explored in this project: 1) What are the mediators and mechanisms that regulate the interaction between intestinal epithelial cells and dendritic cells? What is the function of TSLP? 2) Which are the sites and players for the activation of an IgA response to pathogenic and commensal bacteria? Can we visualize them in vivo? 3) Can prolonged infections or bacterial products promote intestinal tumour development? Are there different bacterial constituents acting as inducers or protectors of carcinogenesis? What is the role of Toll-like receptors?
Summary
The bacterial microflora has always been regarded as beneficial for the host but recent studies have shown that this symbiosis has risks as well as benefits. Although active mechanisms allow tolerating the commensal flora, the physiological stress that is associated with the symbionts’ metabolism can exhaust the intestinal barrier resulting in serious effects on the health of the host. Protracted immune deregulations can lead to severe disorders including diabetes, cancer and inflammatory bowel disease (IBD). Several mechanisms and players are involved in the maintenance of intestinal immune homeostasis, including T regulatory cells and Immunoglobulin (Ig)-A. In this proposal we focus our attention on dendritic cells (DCs) for their ability to induce both tolerance and immunity by regulating B and T cell responses. We have recently shown that DC function is controlled by intestinal epithelial cell (EC) derived factors and in particular by Thymic stromal lymphopoietin (TSLP). EC-conditioned DCs acquire a ‘mucosal’ phenotype as they are prone to activate T regulatory cells and IgA responses. Three major issues related to the maintenance and disruption of intestinal immune homeostasis will be explored in this project: 1) What are the mediators and mechanisms that regulate the interaction between intestinal epithelial cells and dendritic cells? What is the function of TSLP? 2) Which are the sites and players for the activation of an IgA response to pathogenic and commensal bacteria? Can we visualize them in vivo? 3) Can prolonged infections or bacterial products promote intestinal tumour development? Are there different bacterial constituents acting as inducers or protectors of carcinogenesis? What is the role of Toll-like receptors?
Max ERC Funding
1 195 680 €
Duration
Start date: 2008-07-01, End date: 2013-06-30
Project acronym DIDO
Project Innovative drugs targeting IDO molecular dynamics in autoimmunity and neoplasia
Researcher (PI) Ursula Grohmann
Host Institution (HI) UNIVERSITA DEGLI STUDI DI PERUGIA
Call Details Advanced Grant (AdG), LS7, ERC-2013-ADG
Summary "Catabolism of amino acids is an ancient survival strategy that also controls immune responses in mammals. Indoleamine 2,3-dioxygenase (IDO), a tryptophan catabolizing enzyme, is recognized as an authentic regulator of immunity in several physiopathologic conditions, including autoimmune diseases, in which it is often defective, and neoplasia, in which it promotes immune unresponsiveness. The PI’s group recently revealed that IDO does not merely degrade tryptophan and produce immunoregulatory kynurenines but also acts as a signal-transducing molecule independently of its enzyme activity. IDO’s signaling function relies on the presence of phosphorylable motifs in a region (small IDO domain) distant from the catalytic site (large IDO domain). Preliminary data indicate that IDO, depending on microenvironmental conditions, can move among distinct cellular compartments. Thus IDO may be considered a ‘moonligthing’ protein, i.e., an ancestral metabolic molecule that, during evolution, has acquired the DYNAMIC feature of moving intracellularly and switching among distinct functions by changing its conformational state. By means of computational studies, Macchiarulo’s group (team member) has identified distinct conformations of IDO, some of which are associated with optimal catalytic activity of the enzyme whereas others may favor tyrosine phosphorylation of IDO’s small domain. A switch between distinct conformations can be induced by the use of ligands that bind either the catalytic site or an accessory pocket outside the IDO catalytic site. The first aim of DIDO is to decipher the relationships between IDO conformations and multiple functions of the enzyme. A second aim is to identify small molecules with drug-like properties capable of modulating distinct IDO’s molecular conformations in order to either potentiate (a new therapeutic approach in autoimmune diseases) or inhibit (more efficient anti-tumor therapeutic strategy) immunoregulatory signaling ability of IDO."
Summary
"Catabolism of amino acids is an ancient survival strategy that also controls immune responses in mammals. Indoleamine 2,3-dioxygenase (IDO), a tryptophan catabolizing enzyme, is recognized as an authentic regulator of immunity in several physiopathologic conditions, including autoimmune diseases, in which it is often defective, and neoplasia, in which it promotes immune unresponsiveness. The PI’s group recently revealed that IDO does not merely degrade tryptophan and produce immunoregulatory kynurenines but also acts as a signal-transducing molecule independently of its enzyme activity. IDO’s signaling function relies on the presence of phosphorylable motifs in a region (small IDO domain) distant from the catalytic site (large IDO domain). Preliminary data indicate that IDO, depending on microenvironmental conditions, can move among distinct cellular compartments. Thus IDO may be considered a ‘moonligthing’ protein, i.e., an ancestral metabolic molecule that, during evolution, has acquired the DYNAMIC feature of moving intracellularly and switching among distinct functions by changing its conformational state. By means of computational studies, Macchiarulo’s group (team member) has identified distinct conformations of IDO, some of which are associated with optimal catalytic activity of the enzyme whereas others may favor tyrosine phosphorylation of IDO’s small domain. A switch between distinct conformations can be induced by the use of ligands that bind either the catalytic site or an accessory pocket outside the IDO catalytic site. The first aim of DIDO is to decipher the relationships between IDO conformations and multiple functions of the enzyme. A second aim is to identify small molecules with drug-like properties capable of modulating distinct IDO’s molecular conformations in order to either potentiate (a new therapeutic approach in autoimmune diseases) or inhibit (more efficient anti-tumor therapeutic strategy) immunoregulatory signaling ability of IDO."
Max ERC Funding
2 442 078 €
Duration
Start date: 2014-02-01, End date: 2019-01-31
Project acronym DISEASEAVATARS
Project Modeling Disease through Cell Reprogramming: a Translational Approach to the Pathogenesis of Syndromes Caused by Symmetrical Gene Dosage Imbalances
Researcher (PI) Giuseppe Testa
Host Institution (HI) UNIVERSITA DEGLI STUDI DI MILANO
Call Details Consolidator Grant (CoG), LS7, ERC-2013-CoG
Summary The fundamental limitation in our ability to dissect human diseases is the scarce availability of human tissues at relevant disease stages, which is particularly salient for neural disorders. Somatic cell reprogramming is overcoming this limitation through the derivation of patient-specific induced pluripotent stem cells (iPSC) that can be differentiated into disease-relevant cell-types. Despite these tantalizing possibilities, there are critical issues to be addressed in order to secure iPSC-modeling as a robust platform for the interrogation of disease aetiology and the development of new therapies. These concern the taming of human genetic variation, the identification of differentiation stages in which to uncover and validate phenotypes, and finally their translational into drug discovery assays. This project confronts these challenges focusing on the paradigmatic case of two rare but uniquely informative disorders caused by symmetric gene dosage imbalances at 7q11.23: Williams Beuren Syndrome and the subset of autism spectrum disorders associated to 7q11.23 microduplication. The hallmark of WBS is a unique behavioral-cognitive profile characterized by hypersociability and intellectual disability in the face of comparatively well-preserved language abilities. Hence, the striking symmetry in genotype and phenotype between WBS and 7dupASD points to the 7q11.23 cluster as a surprisingly small subset of dosage-sensitive genes affecting social behaviour and cognition. We build on a large panel of iPSC lines that we already reprogrammed from a unique cohort of WBS and 7dupASD patients and whose characterization points to specific derangements at the level of transcriptional/epigenetic control, protein synthesis and synaptic dysfunction. Through the integration of transcriptomic and epigenomic profiling with targeted mass spectrometry and gene network prediction we propose an innovative drug discovery pipeline for the identification of new therapeutic leads.
Summary
The fundamental limitation in our ability to dissect human diseases is the scarce availability of human tissues at relevant disease stages, which is particularly salient for neural disorders. Somatic cell reprogramming is overcoming this limitation through the derivation of patient-specific induced pluripotent stem cells (iPSC) that can be differentiated into disease-relevant cell-types. Despite these tantalizing possibilities, there are critical issues to be addressed in order to secure iPSC-modeling as a robust platform for the interrogation of disease aetiology and the development of new therapies. These concern the taming of human genetic variation, the identification of differentiation stages in which to uncover and validate phenotypes, and finally their translational into drug discovery assays. This project confronts these challenges focusing on the paradigmatic case of two rare but uniquely informative disorders caused by symmetric gene dosage imbalances at 7q11.23: Williams Beuren Syndrome and the subset of autism spectrum disorders associated to 7q11.23 microduplication. The hallmark of WBS is a unique behavioral-cognitive profile characterized by hypersociability and intellectual disability in the face of comparatively well-preserved language abilities. Hence, the striking symmetry in genotype and phenotype between WBS and 7dupASD points to the 7q11.23 cluster as a surprisingly small subset of dosage-sensitive genes affecting social behaviour and cognition. We build on a large panel of iPSC lines that we already reprogrammed from a unique cohort of WBS and 7dupASD patients and whose characterization points to specific derangements at the level of transcriptional/epigenetic control, protein synthesis and synaptic dysfunction. Through the integration of transcriptomic and epigenomic profiling with targeted mass spectrometry and gene network prediction we propose an innovative drug discovery pipeline for the identification of new therapeutic leads.
Max ERC Funding
1 997 804 €
Duration
Start date: 2014-09-01, End date: 2019-08-31
Project acronym DissectPcG
Project Dissecting the Function of Multiple Polycomb Group Complexes in Establishing Transcriptional Identity
Researcher (PI) Diego PASINI
Host Institution (HI) UNIVERSITA DEGLI STUDI DI MILANO
Call Details Consolidator Grant (CoG), LS3, ERC-2016-COG
Summary The activities of the Polycomb group (PcG) of repressive chromatin modifiers are required to maintain correct transcriptional identity during development and differentiation. These activities are altered in a variety of tumours by gain- or loss-of-function mutations, whose mechanistic aspects still remain unclear.
PcGs can be classified in two major repressive complexes (PRC1 and PRC2) with common pathways but distinct biochemical activities. PRC1 catalyses histone H2A ubiquitination of lysine 119, and PRC2 tri-methylation of histone H3 lysine 27. However, PRC1 has a more heterogeneous composition than PRC2, with six mutually exclusive PCGF subunits (PCGF1–6) essential for assembling distinct PRC1 complexes that differ in subunit composition but share the same catalytic core.
While up to six different PRC1 forms can co-exist in a given cell, the molecular mechanisms regulating their activities and their relative contributions to general PRC1 function in any tissue/cell type remain largely unknown. In line with this biochemical heterogeneity, PRC1 retains broader biological functions than PRC2. Critically, however, no molecular analysis has yet been published that dissects the contribution of each PRC1 complex in regulating transcriptional identity.
We will take advantage of newly developed reagents and unpublished genetic models to target each of the six Pcgf genes in either embryonic stem cells or mouse adult tissues. This will systematically dissect the contributions of the different PRC1 complexes to chromatin profiles, gene expression programs, and cellular phenotypes during stem cell self-renewal, differentiation and adult tissue homeostasis. Overall, this will elucidate some of the fundamental mechanisms underlying the establishment and maintenance of cellular identity and will allow us to further determine the molecular links between PcG deregulation and cancer development in a tissue- and/or cell type–specific manner.
Summary
The activities of the Polycomb group (PcG) of repressive chromatin modifiers are required to maintain correct transcriptional identity during development and differentiation. These activities are altered in a variety of tumours by gain- or loss-of-function mutations, whose mechanistic aspects still remain unclear.
PcGs can be classified in two major repressive complexes (PRC1 and PRC2) with common pathways but distinct biochemical activities. PRC1 catalyses histone H2A ubiquitination of lysine 119, and PRC2 tri-methylation of histone H3 lysine 27. However, PRC1 has a more heterogeneous composition than PRC2, with six mutually exclusive PCGF subunits (PCGF1–6) essential for assembling distinct PRC1 complexes that differ in subunit composition but share the same catalytic core.
While up to six different PRC1 forms can co-exist in a given cell, the molecular mechanisms regulating their activities and their relative contributions to general PRC1 function in any tissue/cell type remain largely unknown. In line with this biochemical heterogeneity, PRC1 retains broader biological functions than PRC2. Critically, however, no molecular analysis has yet been published that dissects the contribution of each PRC1 complex in regulating transcriptional identity.
We will take advantage of newly developed reagents and unpublished genetic models to target each of the six Pcgf genes in either embryonic stem cells or mouse adult tissues. This will systematically dissect the contributions of the different PRC1 complexes to chromatin profiles, gene expression programs, and cellular phenotypes during stem cell self-renewal, differentiation and adult tissue homeostasis. Overall, this will elucidate some of the fundamental mechanisms underlying the establishment and maintenance of cellular identity and will allow us to further determine the molecular links between PcG deregulation and cancer development in a tissue- and/or cell type–specific manner.
Max ERC Funding
2 000 000 €
Duration
Start date: 2017-11-01, End date: 2022-10-31
Project acronym DomEQUAL
Project A Global Approach to Paid Domestic Work and Social Inequalities
Researcher (PI) Sabrina Marchetti
Host Institution (HI) UNIVERSITA CA' FOSCARI VENEZIA
Call Details Starting Grant (StG), SH2, ERC-2015-STG
Summary How does globalisation impact the construction of social inequality? DomEQUAL tackles this question through a study on paid domestic work (PDW). Of the 52.6 million PDWs in the world today, 43 million are women and 7 million are children. The multidimensional transformations brought about by globalisation with the intensification of international migration, the urbanisation of rural and indigenous populations, and changes in household organisation and welfare regimes have a massive impact on PDWs at the global level.
New research possibilities are open since PDW has become an object of global governance. The ILO Convention 189 is the most evident sign of this. For researchers, this has the important effect of making new data and tools for analysis available. DomEQUAL profits from this opportunity to provide a global comparison of PDWs’ social positions, especially in the socio-economic and legal fields. It also provides the opportunity to experiment an ‘intersectionality’ approach to PDW on a large scale. Finally, it analyses which type of global/local actor is more effective in improving the legal framework for PDWs. In so doing, it aims at a theoretical and methodological contribution that goes beyond PDW and addresses the construction of social inequalities within globalisation more generally.
This is done through a diachronic comparison (1950s-now) of the changing situation of PDWs in the following countries: Spain, Italy and Germany in Europe; Colombia, Ecuador and Brazil in South America; and India, the Philippines and Taiwan in Asia. These nine countries are interesting cases for comparison because of their different positions within the process of globalisation, the specificities of their socio-cultural contexts, and also because they have all experienced mobilisations for PDWs’ rights. The project will be carried out by the PI and two senior post-doc researchers based in Italy, with the support of nine experts in the selected countries.
Summary
How does globalisation impact the construction of social inequality? DomEQUAL tackles this question through a study on paid domestic work (PDW). Of the 52.6 million PDWs in the world today, 43 million are women and 7 million are children. The multidimensional transformations brought about by globalisation with the intensification of international migration, the urbanisation of rural and indigenous populations, and changes in household organisation and welfare regimes have a massive impact on PDWs at the global level.
New research possibilities are open since PDW has become an object of global governance. The ILO Convention 189 is the most evident sign of this. For researchers, this has the important effect of making new data and tools for analysis available. DomEQUAL profits from this opportunity to provide a global comparison of PDWs’ social positions, especially in the socio-economic and legal fields. It also provides the opportunity to experiment an ‘intersectionality’ approach to PDW on a large scale. Finally, it analyses which type of global/local actor is more effective in improving the legal framework for PDWs. In so doing, it aims at a theoretical and methodological contribution that goes beyond PDW and addresses the construction of social inequalities within globalisation more generally.
This is done through a diachronic comparison (1950s-now) of the changing situation of PDWs in the following countries: Spain, Italy and Germany in Europe; Colombia, Ecuador and Brazil in South America; and India, the Philippines and Taiwan in Asia. These nine countries are interesting cases for comparison because of their different positions within the process of globalisation, the specificities of their socio-cultural contexts, and also because they have all experienced mobilisations for PDWs’ rights. The project will be carried out by the PI and two senior post-doc researchers based in Italy, with the support of nine experts in the selected countries.
Max ERC Funding
1 199 976 €
Duration
Start date: 2016-09-01, End date: 2020-08-31
Project acronym DREAMS
Project Development of a Research Environment for Advanced Modelling of Soft matter
Researcher (PI) Vincenzo Barone
Host Institution (HI) SCUOLA NORMALE SUPERIORE
Call Details Advanced Grant (AdG), PE5, ERC-2012-ADG_20120216
Summary "DREAMS aims at developing an integrated theoretical-computational approach for the efficient description of linear and non-linear spectroscopies of several classes of organic probes, dispersed in polymeric matrices that range in complexity from simple polyolefins all the way to large biomolecules (proteins and polysaccharides).
In order to reach this objective, developments along the following lines are required: (i) elaboration of new theoretical models, to expand the scope of currently available treatments; (ii) definition of specific treatments for intermediate regions / regimes in the context of space- and time-multiscale descriptions; (iii) algorithmic implementation of the developed models / protocols in computational codes and, (iv) their efficient integration allowing for seamless flow of information and easy use by non-specialists.
A crucial asset for the success of the planned theoretical-computational developments is represented by an extensive network of solid collaborations with leading experimental groups, that will be involved in the synthesis and characterization of the different chromophore / matrix systems, as well as in the in-depth characterization of their spectroscopic responses. These interactions will thus allow for a stringent and exhaustive validation of the capabilities required of a general and versatile computational tool; at the same time, the experimental groups will make full use of advanced theoretical interpretations in the context of a real-world technological problem.
In summary, DREAMS relies on a carefully planned combination of theoretical developments, computational implementations, and interactions with experimentalists, in order to achieve a novel and cutting-edge result, namely to provide the scientific community with a set of computational tools that will make possible the simulation and prediction of response and spectroscopic properties of multi-component materials."
Summary
"DREAMS aims at developing an integrated theoretical-computational approach for the efficient description of linear and non-linear spectroscopies of several classes of organic probes, dispersed in polymeric matrices that range in complexity from simple polyolefins all the way to large biomolecules (proteins and polysaccharides).
In order to reach this objective, developments along the following lines are required: (i) elaboration of new theoretical models, to expand the scope of currently available treatments; (ii) definition of specific treatments for intermediate regions / regimes in the context of space- and time-multiscale descriptions; (iii) algorithmic implementation of the developed models / protocols in computational codes and, (iv) their efficient integration allowing for seamless flow of information and easy use by non-specialists.
A crucial asset for the success of the planned theoretical-computational developments is represented by an extensive network of solid collaborations with leading experimental groups, that will be involved in the synthesis and characterization of the different chromophore / matrix systems, as well as in the in-depth characterization of their spectroscopic responses. These interactions will thus allow for a stringent and exhaustive validation of the capabilities required of a general and versatile computational tool; at the same time, the experimental groups will make full use of advanced theoretical interpretations in the context of a real-world technological problem.
In summary, DREAMS relies on a carefully planned combination of theoretical developments, computational implementations, and interactions with experimentalists, in order to achieve a novel and cutting-edge result, namely to provide the scientific community with a set of computational tools that will make possible the simulation and prediction of response and spectroscopic properties of multi-component materials."
Max ERC Funding
2 152 600 €
Duration
Start date: 2013-02-01, End date: 2018-01-31
