Project acronym 321
Project from Cubic To Linear complexity in computational electromagnetics
Researcher (PI) Francesco Paolo ANDRIULLI
Host Institution (HI) POLITECNICO DI TORINO
Country Italy
Call Details Consolidator Grant (CoG), PE7, ERC-2016-COG
Summary Computational Electromagnetics (CEM) is the scientific field at the origin of all new modeling and simulation tools required by the constantly arising design challenges of emerging and future technologies in applied electromagnetics. As in many other technological fields, however, the trend in all emerging technologies in electromagnetic engineering is going towards miniaturized, higher density and multi-scale scenarios. Computationally speaking this translates in the steep increase of the number of degrees of freedom. Given that the design cost (the cost of a multi-right-hand side problem dominated by matrix inversion) can scale as badly as cubically with these degrees of freedom, this fact, as pointed out by many, will sensibly compromise the practical impact of CEM on future and emerging technologies.
For this reason, the CEM scientific community has been looking for years for a FFT-like paradigm shift: a dynamic fast direct solver providing a design cost that would scale only linearly with the degrees of freedom. Such a fast solver is considered today a Holy Grail of the discipline.
The Grand Challenge of 321 will be to tackle this Holy Grail in Computational Electromagnetics by investigating a dynamic Fast Direct Solver for Maxwell Problems that would run in a linear-instead-of-cubic complexity for an arbitrary number and configuration of degrees of freedom.
The failure of all previous attempts will be overcome by a game-changing transformation of the CEM classical problem that will leverage on a recent breakthrough of the PI. Starting from this, the project will investigate an entire new paradigm for impacting algorithms to achieve this grand challenge.
The impact of the FFT’s quadratic-to-linear paradigm shift shows how computational complexity reductions can be groundbreaking on applications. The cubic-to-linear paradigm shift, which the 321 project will aim for, will have such a rupturing impact on electromagnetic science and technology.
Summary
Computational Electromagnetics (CEM) is the scientific field at the origin of all new modeling and simulation tools required by the constantly arising design challenges of emerging and future technologies in applied electromagnetics. As in many other technological fields, however, the trend in all emerging technologies in electromagnetic engineering is going towards miniaturized, higher density and multi-scale scenarios. Computationally speaking this translates in the steep increase of the number of degrees of freedom. Given that the design cost (the cost of a multi-right-hand side problem dominated by matrix inversion) can scale as badly as cubically with these degrees of freedom, this fact, as pointed out by many, will sensibly compromise the practical impact of CEM on future and emerging technologies.
For this reason, the CEM scientific community has been looking for years for a FFT-like paradigm shift: a dynamic fast direct solver providing a design cost that would scale only linearly with the degrees of freedom. Such a fast solver is considered today a Holy Grail of the discipline.
The Grand Challenge of 321 will be to tackle this Holy Grail in Computational Electromagnetics by investigating a dynamic Fast Direct Solver for Maxwell Problems that would run in a linear-instead-of-cubic complexity for an arbitrary number and configuration of degrees of freedom.
The failure of all previous attempts will be overcome by a game-changing transformation of the CEM classical problem that will leverage on a recent breakthrough of the PI. Starting from this, the project will investigate an entire new paradigm for impacting algorithms to achieve this grand challenge.
The impact of the FFT’s quadratic-to-linear paradigm shift shows how computational complexity reductions can be groundbreaking on applications. The cubic-to-linear paradigm shift, which the 321 project will aim for, will have such a rupturing impact on electromagnetic science and technology.
Max ERC Funding
2 000 000 €
Duration
Start date: 2017-09-01, End date: 2023-08-31
Project acronym A-FRO
Project Actively Frozen - contextual modulation of freezing and its neuronal basis
Researcher (PI) Marta de Aragao Pacheco Moita
Host Institution (HI) FUNDACAO D. ANNA SOMMER CHAMPALIMAUD E DR. CARLOS MONTEZ CHAMPALIMAUD
Country Portugal
Call Details Consolidator Grant (CoG), LS5, ERC-2018-COG
Summary When faced with a threat, an animal must decide whether to freeze, reducing its chances of being noticed, or to flee to the safety of a refuge. Animals from fish to primates choose between these two alternatives when confronted by an attacking predator, a choice that largely depends on the context in which the threat occurs. Recent work has made strides identifying the pre-motor circuits, and their inputs, which control freezing behavior in rodents, but how contextual information is integrated to guide this choice is still far from understood. We recently found that fruit flies in response to visual looming stimuli, simulating a large object on collision course, make rapid freeze/flee choices that depend on the social and spatial environment, and the fly’s internal state. Further, identification of looming detector neurons was recently reported and we identified the descending command neurons, DNp09, responsible for freezing in the fly. Knowing the sensory input and descending output for looming-evoked freezing, two environmental factors that modulate its expression, and using a genetically tractable system affording the use of large sample sizes, places us in an unique position to understand how a information about a threat is integrated with cues from the environment to guide the choice of whether to freeze (our goal). To assess how social information impinges on the circuit for freezing, we will examine the sensory inputs and neuromodulators that mediate this process, mapping their connections to DNp09 neurons (Aim 1). We ask whether learning is required for the spatial modulation of freezing, which cues flies are using to discriminate different places and which brain circuits mediate this process (Aim 2). Finally, we will study how activity of DNp09 neurons drives freezing (Aim 3). This project will provide a comprehensive understanding of the mechanism of freezing and its modulation by the environment, from single neurons to behaviour.
Summary
When faced with a threat, an animal must decide whether to freeze, reducing its chances of being noticed, or to flee to the safety of a refuge. Animals from fish to primates choose between these two alternatives when confronted by an attacking predator, a choice that largely depends on the context in which the threat occurs. Recent work has made strides identifying the pre-motor circuits, and their inputs, which control freezing behavior in rodents, but how contextual information is integrated to guide this choice is still far from understood. We recently found that fruit flies in response to visual looming stimuli, simulating a large object on collision course, make rapid freeze/flee choices that depend on the social and spatial environment, and the fly’s internal state. Further, identification of looming detector neurons was recently reported and we identified the descending command neurons, DNp09, responsible for freezing in the fly. Knowing the sensory input and descending output for looming-evoked freezing, two environmental factors that modulate its expression, and using a genetically tractable system affording the use of large sample sizes, places us in an unique position to understand how a information about a threat is integrated with cues from the environment to guide the choice of whether to freeze (our goal). To assess how social information impinges on the circuit for freezing, we will examine the sensory inputs and neuromodulators that mediate this process, mapping their connections to DNp09 neurons (Aim 1). We ask whether learning is required for the spatial modulation of freezing, which cues flies are using to discriminate different places and which brain circuits mediate this process (Aim 2). Finally, we will study how activity of DNp09 neurons drives freezing (Aim 3). This project will provide a comprehensive understanding of the mechanism of freezing and its modulation by the environment, from single neurons to behaviour.
Max ERC Funding
1 969 750 €
Duration
Start date: 2019-02-01, End date: 2024-01-31
Project acronym ADHESWITCHES
Project Adhesion switches in cancer and development: from in vivo to synthetic biology
Researcher (PI) Mari Johanna Ivaska
Host Institution (HI) TURUN YLIOPISTO
Country Finland
Call Details Consolidator Grant (CoG), LS3, ERC-2013-CoG
Summary Integrins are transmembrane cell adhesion receptors controlling cell proliferation and migration. Our objective is to gain fundamentally novel mechanistic insight into the emerging new roles of integrins in cancer and to generate a road map of integrin dependent pathways critical in mammary gland development and integrin signalling thus opening new targets for therapeutic interventions. We will combine an in vivo based translational approach with cell and molecular biological studies aiming to identify entirely novel concepts in integrin function using cutting edge techniques and synthetic-biology tools.
The specific objectives are:
1) Integrin inactivation in branching morphogenesis and cancer invasion. Integrins regulate mammary gland development and cancer invasion but the role of integrin inactivating proteins in these processes is currently completely unknown. We will investigate this using genetically modified mice, ex-vivo organoid models and human tissues with the aim to identify beneficial combinational treatments against cancer invasion.
2) Endosomal adhesomes – cross-talk between integrin activity and integrin “inside-in signaling”. We hypothesize that endocytosed active integrins engage in specialized endosomal signaling that governs cell survival especially in cancer. RNAi cell arrays, super-resolution STED imaging and endosomal proteomics will be used to investigate integrin signaling in endosomes.
3) Spatio-temporal co-ordination of adhesion and endocytosis. Several cytosolic proteins compete for integrin binding to regulate activation, endocytosis and recycling. Photoactivatable protein-traps and predefined matrix micropatterns will be employed to mechanistically dissect the spatio-temporal dynamics and hierarchy of their recruitment.
We will employ innovative and unconventional techniques to address three major unanswered questions in the field and significantly advance our understanding of integrin function in development and cancer.
Summary
Integrins are transmembrane cell adhesion receptors controlling cell proliferation and migration. Our objective is to gain fundamentally novel mechanistic insight into the emerging new roles of integrins in cancer and to generate a road map of integrin dependent pathways critical in mammary gland development and integrin signalling thus opening new targets for therapeutic interventions. We will combine an in vivo based translational approach with cell and molecular biological studies aiming to identify entirely novel concepts in integrin function using cutting edge techniques and synthetic-biology tools.
The specific objectives are:
1) Integrin inactivation in branching morphogenesis and cancer invasion. Integrins regulate mammary gland development and cancer invasion but the role of integrin inactivating proteins in these processes is currently completely unknown. We will investigate this using genetically modified mice, ex-vivo organoid models and human tissues with the aim to identify beneficial combinational treatments against cancer invasion.
2) Endosomal adhesomes – cross-talk between integrin activity and integrin “inside-in signaling”. We hypothesize that endocytosed active integrins engage in specialized endosomal signaling that governs cell survival especially in cancer. RNAi cell arrays, super-resolution STED imaging and endosomal proteomics will be used to investigate integrin signaling in endosomes.
3) Spatio-temporal co-ordination of adhesion and endocytosis. Several cytosolic proteins compete for integrin binding to regulate activation, endocytosis and recycling. Photoactivatable protein-traps and predefined matrix micropatterns will be employed to mechanistically dissect the spatio-temporal dynamics and hierarchy of their recruitment.
We will employ innovative and unconventional techniques to address three major unanswered questions in the field and significantly advance our understanding of integrin function in development and cancer.
Max ERC Funding
1 887 910 €
Duration
Start date: 2014-05-01, End date: 2019-04-30
Project acronym AMI
Project Animals Make identities. The Social Bioarchaeology of Late Mesolithic and Early Neolithic Cemeteries in North-East Europe
Researcher (PI) Kristiina MANNERMAA
Host Institution (HI) HELSINGIN YLIOPISTO
Country Finland
Call Details Consolidator Grant (CoG), SH6, ERC-2019-COG
Summary AMI aims to provide a novel interpretation of social links between humans and animals in hunter-gatherer cemeteries in North-East Europe, c. 9000–7500 years ago. AMI brings together cutting-edge developments in bioarchaeological science and the latest understanding of how people’s identities form in order to study the relationships between humans and animals. Grave materials and human remains will be studied from the viewpoint of process rather than as isolated objects, and will be interpreted through their histories.
The main objectives are
1) Synthesize the animal related bioarchaeological materials in mortuary contexts in North-East Europe,
2) Conduct a systematic multimethodological analysis of the animal-derived artefacts and to study them as actors in human social identity construction,
3) Reconstruct the individual life histories of humans, animals, and animal-derived artefacts in the cemeteries, and
4) Produce models for the reconstruction of social identities based on the data from the bioanalyses, literature, and GIS.
Various contextual, qualitative and quantitative biodata from animals and humans will be analysed and compared. Correlations and differences will be explored. Intra-site spatial analyses and data already published on cemeteries will contribute significantly to the research. Ethnographic information about recent hunter-gatherers from circumpolar regions gathered from literature will support the interpretation of the results from these analyses.
The research material derives from almost 300 burials from eight sites in North-East Europe and includes, for example, unique materials from Russia that have not previously been available for modern multidisciplinary research. The project will make a significant contribution to our understanding of how humans living in the forests of North-East Europe adapted the animals they shared their environment with into their social and ideological realities and practices.
Summary
AMI aims to provide a novel interpretation of social links between humans and animals in hunter-gatherer cemeteries in North-East Europe, c. 9000–7500 years ago. AMI brings together cutting-edge developments in bioarchaeological science and the latest understanding of how people’s identities form in order to study the relationships between humans and animals. Grave materials and human remains will be studied from the viewpoint of process rather than as isolated objects, and will be interpreted through their histories.
The main objectives are
1) Synthesize the animal related bioarchaeological materials in mortuary contexts in North-East Europe,
2) Conduct a systematic multimethodological analysis of the animal-derived artefacts and to study them as actors in human social identity construction,
3) Reconstruct the individual life histories of humans, animals, and animal-derived artefacts in the cemeteries, and
4) Produce models for the reconstruction of social identities based on the data from the bioanalyses, literature, and GIS.
Various contextual, qualitative and quantitative biodata from animals and humans will be analysed and compared. Correlations and differences will be explored. Intra-site spatial analyses and data already published on cemeteries will contribute significantly to the research. Ethnographic information about recent hunter-gatherers from circumpolar regions gathered from literature will support the interpretation of the results from these analyses.
The research material derives from almost 300 burials from eight sites in North-East Europe and includes, for example, unique materials from Russia that have not previously been available for modern multidisciplinary research. The project will make a significant contribution to our understanding of how humans living in the forests of North-East Europe adapted the animals they shared their environment with into their social and ideological realities and practices.
Max ERC Funding
1 992 839 €
Duration
Start date: 2020-04-01, End date: 2025-03-31
Project acronym ANTILEAK
Project Development of antagonists of vascular leakage
Researcher (PI) Pipsa SAHARINEN
Host Institution (HI) HELSINGIN YLIOPISTO
Country Finland
Call Details Consolidator Grant (CoG), LS4, ERC-2017-COG
Summary Dysregulation of capillary permeability is a severe problem in critically ill patients, but the mechanisms involved are poorly understood. Further, there are no targeted therapies to stabilize leaky vessels in various common, potentially fatal diseases, such as systemic inflammation and sepsis, which affect millions of people annually. Although a multitude of signals that stimulate opening of endothelial cell-cell junctions leading to permeability have been characterized using cellular and in vivo models, approaches to reverse the harmful process of capillary leakage in disease conditions are yet to be identified. I propose to explore a novel autocrine endothelial permeability regulatory system as a potentially universal mechanism that antagonizes vascular stabilizing ques and sustains vascular leakage in inflammation. My group has identified inflammation-induced mechanisms that switch vascular stabilizing factors into molecules that destabilize vascular barriers, and identified tools to prevent the barrier disruption. Building on these discoveries, my group will use mouse genetics, structural biology and innovative, systematic antibody development coupled with gene editing and gene silencing technology, in order to elucidate mechanisms of vascular barrier breakdown and repair in systemic inflammation. The expected outcomes include insights into endothelial cell signaling and permeability regulation, and preclinical proof-of-concept antibodies to control endothelial activation and vascular leakage in systemic inflammation and sepsis models. Ultimately, the new knowledge and preclinical tools developed in this project may facilitate future development of targeted approaches against vascular leakage.
Summary
Dysregulation of capillary permeability is a severe problem in critically ill patients, but the mechanisms involved are poorly understood. Further, there are no targeted therapies to stabilize leaky vessels in various common, potentially fatal diseases, such as systemic inflammation and sepsis, which affect millions of people annually. Although a multitude of signals that stimulate opening of endothelial cell-cell junctions leading to permeability have been characterized using cellular and in vivo models, approaches to reverse the harmful process of capillary leakage in disease conditions are yet to be identified. I propose to explore a novel autocrine endothelial permeability regulatory system as a potentially universal mechanism that antagonizes vascular stabilizing ques and sustains vascular leakage in inflammation. My group has identified inflammation-induced mechanisms that switch vascular stabilizing factors into molecules that destabilize vascular barriers, and identified tools to prevent the barrier disruption. Building on these discoveries, my group will use mouse genetics, structural biology and innovative, systematic antibody development coupled with gene editing and gene silencing technology, in order to elucidate mechanisms of vascular barrier breakdown and repair in systemic inflammation. The expected outcomes include insights into endothelial cell signaling and permeability regulation, and preclinical proof-of-concept antibodies to control endothelial activation and vascular leakage in systemic inflammation and sepsis models. Ultimately, the new knowledge and preclinical tools developed in this project may facilitate future development of targeted approaches against vascular leakage.
Max ERC Funding
1 999 770 €
Duration
Start date: 2018-05-01, End date: 2023-04-30
Project acronym ArmEn
Project Armenia Entangled: Connectivity and Cultural Encounters in Medieval Eurasia
Researcher (PI) Zaroui POGOSSIAN
Host Institution (HI) UNIVERSITA DEGLI STUDI DI FIRENZE
Country Italy
Call Details Consolidator Grant (CoG), SH6, ERC-2019-COG
Summary ArmEn seeks to establish a new framework for studying the southern Caucasus, eastern Anatolia and northern Mesopotamia (CAM) as a space of cultural entanglements between the 9th to 14th centuries. It argues that this region is key to understanding the history of medieval Eurasia but has so far been completely neglected by the burgeoning field of Global Middle Ages. The CAM was on the crossroads of expanding Eurasian empires and population movements, but was removed from major hubs of power. Poly-centrism; political, ethno-linguistic, and religious heterogeneity; frequently shifting hegemonic hierarchies were key aspects of its, nevertheless, inter-connected landscape. This fluidity and complexity left its mark on the cultural products – textual and material – created in the CAM. ArmEn aims to trace shared features in the multi-lingual textual and artistic production of CAM and correlate them to the circulation of ideas and concepts, as well as to real-life interactions, between multiple groups, identifying the locations and agents of entanglements. The large but under-utilised body of Armenian sources to be explored together with those in Arabic, Georgian, Greek, Persian, Syriac, and Turkish, will illuminate cultural entanglements between Muslim and Christian Arabs, Byzantines, Syriac Christians, Georgians, Caucasian Albanians, Turko-Muslim dynasties, Kurds, Iranians, Western Europeans, and Mongols, that inhabited, conquered, or passed through and produced cultural goods in CAM. Evidence from manuscript illuminations and numismatics will provide a material cultural dimension to the analysis. ArmEn will create a trans-cultural vision of the CAM, bridging area studies into a unifying framework, bringing together various disciplinary approaches (philology, literary criticism, religious studies, art history, numismatics, etc.), to build a narrative synthesis in which the dynamics of cross-cultural entanglements in the CAM emerge in their spatial and temporal dimensions.
Summary
ArmEn seeks to establish a new framework for studying the southern Caucasus, eastern Anatolia and northern Mesopotamia (CAM) as a space of cultural entanglements between the 9th to 14th centuries. It argues that this region is key to understanding the history of medieval Eurasia but has so far been completely neglected by the burgeoning field of Global Middle Ages. The CAM was on the crossroads of expanding Eurasian empires and population movements, but was removed from major hubs of power. Poly-centrism; political, ethno-linguistic, and religious heterogeneity; frequently shifting hegemonic hierarchies were key aspects of its, nevertheless, inter-connected landscape. This fluidity and complexity left its mark on the cultural products – textual and material – created in the CAM. ArmEn aims to trace shared features in the multi-lingual textual and artistic production of CAM and correlate them to the circulation of ideas and concepts, as well as to real-life interactions, between multiple groups, identifying the locations and agents of entanglements. The large but under-utilised body of Armenian sources to be explored together with those in Arabic, Georgian, Greek, Persian, Syriac, and Turkish, will illuminate cultural entanglements between Muslim and Christian Arabs, Byzantines, Syriac Christians, Georgians, Caucasian Albanians, Turko-Muslim dynasties, Kurds, Iranians, Western Europeans, and Mongols, that inhabited, conquered, or passed through and produced cultural goods in CAM. Evidence from manuscript illuminations and numismatics will provide a material cultural dimension to the analysis. ArmEn will create a trans-cultural vision of the CAM, bridging area studies into a unifying framework, bringing together various disciplinary approaches (philology, literary criticism, religious studies, art history, numismatics, etc.), to build a narrative synthesis in which the dynamics of cross-cultural entanglements in the CAM emerge in their spatial and temporal dimensions.
Max ERC Funding
1 999 994 €
Duration
Start date: 2020-10-01, End date: 2025-09-30
Project acronym AutoRecon
Project Molecular mechanisms of autophagosome formation during selective autophagy
Researcher (PI) Sascha Martens
Host Institution (HI) UNIVERSITAT WIEN
Country Austria
Call Details Consolidator Grant (CoG), LS3, ERC-2014-CoG
Summary I propose to study how eukaryotic cells generate autophagosomes, organelles bounded by a double membrane. These are formed during autophagy and mediate the degradation of cytoplasmic substances within the lysosomal compartment. Autophagy thereby protects the organism from pathological conditions such as neurodegeneration, cancer and infections. Many core factors required for autophagosome formation have been identified but the order in which they act and their mode of action is still unclear. We will use a combination of biochemical and cell biological approaches to elucidate the choreography and mechanism of these core factors. In particular, we will focus on selective autophagy and determine how the autophagic machinery generates an autophagosome that selectively contains the cargo.
To this end we will focus on the cytoplasm-to-vacuole-targeting pathway in S. cerevisiae that mediates the constitutive delivery of the prApe1 enzyme into the vacuole. We will use cargo mimetics or prApe1 complexes in combination with purified autophagy proteins and vesicles to reconstitute the process and so determine which factors are both necessary and sufficient for autophagosome formation, as well as elucidating their mechanism of action.
In parallel we will study selective autophagosome formation in human cells. This will reveal common principles and special adaptations. In particular, we will use cell lysates from genome-edited cells in combination with purified autophagy proteins to reconstitute selective autophagosome formation around ubiquitin-positive cargo material. The insights and hypotheses obtained from these reconstituted systems will be validated using cell biological approaches.
Taken together, our experiments will allow us to delineate the major steps of autophagosome formation during selective autophagy. Our results will yield detailed insights into how cells form and shape organelles in a de novo manner, which is major question in cell- and developmental biology.
Summary
I propose to study how eukaryotic cells generate autophagosomes, organelles bounded by a double membrane. These are formed during autophagy and mediate the degradation of cytoplasmic substances within the lysosomal compartment. Autophagy thereby protects the organism from pathological conditions such as neurodegeneration, cancer and infections. Many core factors required for autophagosome formation have been identified but the order in which they act and their mode of action is still unclear. We will use a combination of biochemical and cell biological approaches to elucidate the choreography and mechanism of these core factors. In particular, we will focus on selective autophagy and determine how the autophagic machinery generates an autophagosome that selectively contains the cargo.
To this end we will focus on the cytoplasm-to-vacuole-targeting pathway in S. cerevisiae that mediates the constitutive delivery of the prApe1 enzyme into the vacuole. We will use cargo mimetics or prApe1 complexes in combination with purified autophagy proteins and vesicles to reconstitute the process and so determine which factors are both necessary and sufficient for autophagosome formation, as well as elucidating their mechanism of action.
In parallel we will study selective autophagosome formation in human cells. This will reveal common principles and special adaptations. In particular, we will use cell lysates from genome-edited cells in combination with purified autophagy proteins to reconstitute selective autophagosome formation around ubiquitin-positive cargo material. The insights and hypotheses obtained from these reconstituted systems will be validated using cell biological approaches.
Taken together, our experiments will allow us to delineate the major steps of autophagosome formation during selective autophagy. Our results will yield detailed insights into how cells form and shape organelles in a de novo manner, which is major question in cell- and developmental biology.
Max ERC Funding
1 999 640 €
Duration
Start date: 2016-03-01, End date: 2021-02-28
Project acronym BabyRhythm
Project Tuned to the Rhythm: How Prenatally and Postnatally Heard Speech Prosody Lays the Foundations for Language Learning
Researcher (PI) Judit Gervain
Host Institution (HI) UNIVERSITA DEGLI STUDI DI PADOVA
Country Italy
Call Details Consolidator Grant (CoG), SH4, ERC-2017-COG
Summary The role of experience in language acquisition has been the focus of heated theoretical debates, between proponents of nativist views according to whom experience plays a minimal role and advocates of empiricist positions holding that experience, be it linguistic, social or other, is sufficient to account for language acquisition. Despite more than a half century of dedicated research efforts, the problem is not solved.
The present project brings a novel perspective to this debate, combining hitherto unconnected research in language acquisition with recent advances in the neurophysiology of hearing and speech processing. Specifically, it claims that prenatal experience with speech, which mainly consists of prosody due to the filtering effects of the womb, is what shapes the speech perception system, laying the foundations of subsequent language learning. Prosody is thus the cue that links genetically endowed predispositions present in the initial state with language experience. The proposal links the behavioral and neural levels, arguing that the hierarchy of the neural oscillations corresponds to a unique developmental chronology in human infants’ experience with speech and language.
The project uses state-of-the-art brain imaging techniques, EEG & NIRS, with monolingual full term newborns, as well as full-term bilingual, preterm and deaf newborns to investigate the link between prenatal experience and subsequent language acquisition. It proposes to follow the developmental trajectories of these four populations from birth to 6 and 9 months of age.
Summary
The role of experience in language acquisition has been the focus of heated theoretical debates, between proponents of nativist views according to whom experience plays a minimal role and advocates of empiricist positions holding that experience, be it linguistic, social or other, is sufficient to account for language acquisition. Despite more than a half century of dedicated research efforts, the problem is not solved.
The present project brings a novel perspective to this debate, combining hitherto unconnected research in language acquisition with recent advances in the neurophysiology of hearing and speech processing. Specifically, it claims that prenatal experience with speech, which mainly consists of prosody due to the filtering effects of the womb, is what shapes the speech perception system, laying the foundations of subsequent language learning. Prosody is thus the cue that links genetically endowed predispositions present in the initial state with language experience. The proposal links the behavioral and neural levels, arguing that the hierarchy of the neural oscillations corresponds to a unique developmental chronology in human infants’ experience with speech and language.
The project uses state-of-the-art brain imaging techniques, EEG & NIRS, with monolingual full term newborns, as well as full-term bilingual, preterm and deaf newborns to investigate the link between prenatal experience and subsequent language acquisition. It proposes to follow the developmental trajectories of these four populations from birth to 6 and 9 months of age.
Max ERC Funding
1 621 250 €
Duration
Start date: 2018-06-01, End date: 2023-05-31
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
Country Italy
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
Country Italy
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
