Project acronym BrainBIT
Project All-optical brain-to-brain behaviour and information transfer
Researcher (PI) Francesco PAVONE
Host Institution (HI) UNIVERSITA DEGLI STUDI DI FIRENZE
Country Italy
Call Details Advanced Grant (AdG), PE2, ERC-2015-AdG
Summary Exchange of information between different brains usually takes place through the interaction between bodies and the external environment. The ultimate goal of this project is to establish a novel paradigm of brain-to-brain communication based on direct full-optical recording and controlled stimulation of neuronal activity in different subjects. To pursue this challenging objective, we propose to develop optical technologies well beyond the state of the art for simultaneous neuronal “reading” and “writing” across large volumes and with high spatial and temporal resolution, targeted to the transfer of advantageous behaviour in physiological and pathological conditions.
We will perform whole-brain high-resolution imaging in zebrafish larvae to disentangle the activity patterns related to different tasks. We will then use these patterns as stimulation templates in other larvae to investigate spatio-temporal subject-invariant signatures of specific behavioural states. This ‘pump and probe’ strategy will allow gaining deep insights into the complex relationship between neuronal activity and subject behaviour.
To move towards clinics-oriented studies on brain stimulation therapies, we will complement whole-brain experiments in zebrafish with large area functional imaging and optostimulation in mammals. We will investigate all-optical brain-to-brain information transfer to boost an advantageous behaviour, i.e. motor recovery, in a mouse model of stroke. Mice showing more effective responses to rehabilitation will provide neuronal activity templates to be elicited in other animals, in order to increase rehabilitation efficiency.
We strongly believe that the implementation of new technologies for all-optical transfer of behaviour between different subjects will offer unprecedented views of neuronal activity in healthy and injured brain, paving the way to more effective brain stimulation therapies.
Summary
Exchange of information between different brains usually takes place through the interaction between bodies and the external environment. The ultimate goal of this project is to establish a novel paradigm of brain-to-brain communication based on direct full-optical recording and controlled stimulation of neuronal activity in different subjects. To pursue this challenging objective, we propose to develop optical technologies well beyond the state of the art for simultaneous neuronal “reading” and “writing” across large volumes and with high spatial and temporal resolution, targeted to the transfer of advantageous behaviour in physiological and pathological conditions.
We will perform whole-brain high-resolution imaging in zebrafish larvae to disentangle the activity patterns related to different tasks. We will then use these patterns as stimulation templates in other larvae to investigate spatio-temporal subject-invariant signatures of specific behavioural states. This ‘pump and probe’ strategy will allow gaining deep insights into the complex relationship between neuronal activity and subject behaviour.
To move towards clinics-oriented studies on brain stimulation therapies, we will complement whole-brain experiments in zebrafish with large area functional imaging and optostimulation in mammals. We will investigate all-optical brain-to-brain information transfer to boost an advantageous behaviour, i.e. motor recovery, in a mouse model of stroke. Mice showing more effective responses to rehabilitation will provide neuronal activity templates to be elicited in other animals, in order to increase rehabilitation efficiency.
We strongly believe that the implementation of new technologies for all-optical transfer of behaviour between different subjects will offer unprecedented views of neuronal activity in healthy and injured brain, paving the way to more effective brain stimulation therapies.
Max ERC Funding
2 370 250 €
Duration
Start date: 2016-12-01, End date: 2022-05-31
Project acronym CDK6-DrugOpp
Project CDK6 in transcription - turning a foe in a friend
Researcher (PI) Veronika SEXL
Host Institution (HI) VETERINAERMEDIZINISCHE UNIVERSITAET WIEN
Country Austria
Call Details Advanced Grant (AdG), LS7, ERC-2015-AdG
Summary "Translational research aims at applying mechanistic understanding in the development of "precision medicine", which depends on precise diagnostic tools and therapeutic approaches. Cancer therapy is experiencing a switch from non-specific, cytotoxic agents towards molecularly targeted and rationally designed compounds with the promise of greater efficacy and fewer side effects.
The two cell-cycle kinases CDK4 and CDK6 normally facilitate cell-cycle progression but are abnormally activated in certain cancers. CDK6 is up-regulated in hematopoietic malignancies, where it is the predominant cell-cycle kinase. The importance of CDK4/6 for tumor development is underscored by the fact that the US FDA selected inhibitors of the kinase activity of CDK4/6 as "breakthrough of the year 2013". Our recent findings suggest that the effects of the inhibitors may be limited as CDK6 is not only involved in cell-cycle progression: ground-breaking research in my group and others has shown that CDK6 is involved in regulation of transcription in a kinase-independent manner thereby driving the proliferation of leukemic stem cells and tumor formation. We have now identified mutations in CDK6 that convert it from a tumor promoter into a tumor suppressor. This unexpected outcome is accompanied by a distinct transcriptional profile. Separating the tumor-promoting from the tumor suppressive functions may open a novel therapeutic avenue for drug development. We aim at understanding which domains and residues of CDK6 are involved in rewiring the transcriptional landscape to pave the way for sophisticated inhibitors. The idea of turning a cancer cell's own most potent weapon against itself is novel and would represent a new paradigm for drug design. Finally, the understanding of CDK6 functions in tumor promotion and maintenance will also result in better patient stratification and improved treatment decisions for a broad spectrum of cancer types."
Summary
"Translational research aims at applying mechanistic understanding in the development of "precision medicine", which depends on precise diagnostic tools and therapeutic approaches. Cancer therapy is experiencing a switch from non-specific, cytotoxic agents towards molecularly targeted and rationally designed compounds with the promise of greater efficacy and fewer side effects.
The two cell-cycle kinases CDK4 and CDK6 normally facilitate cell-cycle progression but are abnormally activated in certain cancers. CDK6 is up-regulated in hematopoietic malignancies, where it is the predominant cell-cycle kinase. The importance of CDK4/6 for tumor development is underscored by the fact that the US FDA selected inhibitors of the kinase activity of CDK4/6 as "breakthrough of the year 2013". Our recent findings suggest that the effects of the inhibitors may be limited as CDK6 is not only involved in cell-cycle progression: ground-breaking research in my group and others has shown that CDK6 is involved in regulation of transcription in a kinase-independent manner thereby driving the proliferation of leukemic stem cells and tumor formation. We have now identified mutations in CDK6 that convert it from a tumor promoter into a tumor suppressor. This unexpected outcome is accompanied by a distinct transcriptional profile. Separating the tumor-promoting from the tumor suppressive functions may open a novel therapeutic avenue for drug development. We aim at understanding which domains and residues of CDK6 are involved in rewiring the transcriptional landscape to pave the way for sophisticated inhibitors. The idea of turning a cancer cell's own most potent weapon against itself is novel and would represent a new paradigm for drug design. Finally, the understanding of CDK6 functions in tumor promotion and maintenance will also result in better patient stratification and improved treatment decisions for a broad spectrum of cancer types."
Max ERC Funding
2 497 520 €
Duration
Start date: 2016-09-01, End date: 2021-08-31
Project acronym CoCEAL
Project The Common Core of European Administrative Law
Researcher (PI) Giacinto DELLA CANANEA
Host Institution (HI) UNIVERSITA COMMERCIALE LUIGI BOCCONI
Country Italy
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: 2022-08-31
Project acronym CohesinMolMech
Project Molecular mechanisms of cohesin-mediated sister chromatid cohesion and chromatin organization
Researcher (PI) Jan-Michael Peters
Host Institution (HI) FORSCHUNGSINSTITUT FUR MOLEKULARE PATHOLOGIE GESELLSCHAFT MBH
Country Austria
Call Details Advanced Grant (AdG), LS1, ERC-2015-AdG
Summary During S-phase newly synthesized “sister” DNA molecules become physically connected. This sister chromatid cohesion resists the pulling forces of the mitotic spindle and thereby enables the bi-orientation and subsequent symmetrical segregation of chromosomes. Cohesion is mediated by ring-shaped cohesin complexes, which are thought to entrap sister DNA molecules topologically. In mammalian cells, cohesin is loaded onto DNA at the end of mitosis by the Scc2-Scc4 complex, becomes acetylated during S-phase, and is stably “locked” on DNA during S- and G2-phase by sororin. Sororin stabilizes cohesin on DNA by inhibiting Wapl, which can otherwise release cohesin from DNA again. In addition to mediating cohesion, cohesin also has important roles in organizing higher-order chromatin structures and in gene regulation. Cohesin performs the latter functions in both proliferating and post-mitotic cells and mediates at least some of these together with the sequence-specific DNA-binding protein CTCF, which co-localizes with cohesin at many genomic sites. Although cohesin and CTCF perform essential functions in mammalian cells, it is poorly understood how cohesin is loaded onto DNA by Scc2-Scc4, how cohesin is positioned in the genome, how cohesin is released from DNA again by Wapl, and how Wapl is inhibited by sororin. Likewise, it is not known how cohesin establishes cohesion during DNA replication and how cohesin cooperates with CTCF to organize chromatin structure. Here we propose to address these questions by combining biochemical reconstitution, single-molecule TIRF microscopy, genetic and cell biological approaches. We expect that the results of these studies will advance our understanding of cell division, chromatin structure and gene regulation, and may also provide insight into the etiology of disorders that are caused by cohesin dysfunction, such as Down syndrome and “cohesinopathies” or cancers, in which cohesin mutations have been found to occur frequently.
Summary
During S-phase newly synthesized “sister” DNA molecules become physically connected. This sister chromatid cohesion resists the pulling forces of the mitotic spindle and thereby enables the bi-orientation and subsequent symmetrical segregation of chromosomes. Cohesion is mediated by ring-shaped cohesin complexes, which are thought to entrap sister DNA molecules topologically. In mammalian cells, cohesin is loaded onto DNA at the end of mitosis by the Scc2-Scc4 complex, becomes acetylated during S-phase, and is stably “locked” on DNA during S- and G2-phase by sororin. Sororin stabilizes cohesin on DNA by inhibiting Wapl, which can otherwise release cohesin from DNA again. In addition to mediating cohesion, cohesin also has important roles in organizing higher-order chromatin structures and in gene regulation. Cohesin performs the latter functions in both proliferating and post-mitotic cells and mediates at least some of these together with the sequence-specific DNA-binding protein CTCF, which co-localizes with cohesin at many genomic sites. Although cohesin and CTCF perform essential functions in mammalian cells, it is poorly understood how cohesin is loaded onto DNA by Scc2-Scc4, how cohesin is positioned in the genome, how cohesin is released from DNA again by Wapl, and how Wapl is inhibited by sororin. Likewise, it is not known how cohesin establishes cohesion during DNA replication and how cohesin cooperates with CTCF to organize chromatin structure. Here we propose to address these questions by combining biochemical reconstitution, single-molecule TIRF microscopy, genetic and cell biological approaches. We expect that the results of these studies will advance our understanding of cell division, chromatin structure and gene regulation, and may also provide insight into the etiology of disorders that are caused by cohesin dysfunction, such as Down syndrome and “cohesinopathies” or cancers, in which cohesin mutations have been found to occur frequently.
Max ERC Funding
2 500 000 €
Duration
Start date: 2016-10-01, End date: 2021-09-30
Project acronym DisCont
Project Discontinuities in Household and Family Formation
Researcher (PI) Francesco Candeloro Billari
Host Institution (HI) UNIVERSITA COMMERCIALE LUIGI BOCCONI
Country Italy
Call Details Advanced Grant (AdG), SH3, ERC-2015-AdG
Summary Household, family and fertility changes are key drivers of population dynamics. Discovering and explaining the velocity of these changes is essential to understand the current situation and to provide scientific evidence on our demographic future. DisCont will provide seminal contributions by studying the impact of macro-level discontinuities on household and family formation (including fertility) in post-industrial contemporary societies. In the past decade, two macro-level discontinuities have radically transformed lives: the Great Recession and the digitalization of life and of the life course. Although their short-term and long-term impacts are likely to be fundamental, they have not yet been systematically analysed. Through a coordinated series of theoretically-founded empirical studies based on linked macro- and micro-level data, and using a comparative perspective, DisCont will argue that macro-level discontinuities are crucial in explaining broad changes in household and family formation, and that their effects can be persistent either for the population as a whole, or for specific cohorts. DisCont will contribute to five areas: 1) it will make theoretical advances by showing the importance of macro-level discontinuities in the explanation of changes in household and family formation in particular, and in population dynamics in general; 2) it will substantially advance our knowledge of household and family formation in post-industrial contemporary societies; 3) it will contribute in a systematic and path-breaking way to research on the broader societal impact of digitalization and of the Great Recession; 4) it will bring a paradigm shift in Age-Period-Cohort modelling; 5) it will make ground-breaking contributions on the demographic use of “big data” and on the use of agent-based models for the population-level implications of household and family change.
Summary
Household, family and fertility changes are key drivers of population dynamics. Discovering and explaining the velocity of these changes is essential to understand the current situation and to provide scientific evidence on our demographic future. DisCont will provide seminal contributions by studying the impact of macro-level discontinuities on household and family formation (including fertility) in post-industrial contemporary societies. In the past decade, two macro-level discontinuities have radically transformed lives: the Great Recession and the digitalization of life and of the life course. Although their short-term and long-term impacts are likely to be fundamental, they have not yet been systematically analysed. Through a coordinated series of theoretically-founded empirical studies based on linked macro- and micro-level data, and using a comparative perspective, DisCont will argue that macro-level discontinuities are crucial in explaining broad changes in household and family formation, and that their effects can be persistent either for the population as a whole, or for specific cohorts. DisCont will contribute to five areas: 1) it will make theoretical advances by showing the importance of macro-level discontinuities in the explanation of changes in household and family formation in particular, and in population dynamics in general; 2) it will substantially advance our knowledge of household and family formation in post-industrial contemporary societies; 3) it will contribute in a systematic and path-breaking way to research on the broader societal impact of digitalization and of the Great Recession; 4) it will bring a paradigm shift in Age-Period-Cohort modelling; 5) it will make ground-breaking contributions on the demographic use of “big data” and on the use of agent-based models for the population-level implications of household and family change.
Max ERC Funding
2 400 555 €
Duration
Start date: 2017-02-01, End date: 2022-07-31
Project acronym EYEGET
Project Gene therapy of inherited retinal diseases
Researcher (PI) Alberto AURICCHIO
Host Institution (HI) FONDAZIONE TELETHON
Country Italy
Call Details Advanced Grant (AdG), LS7, ERC-2015-AdG
Summary Inherited retinal degenerations (IRDs) are a major cause of blindness worldwide. IRD patients witness inexorable progressive vision loss as no therapy is currently available. In the last decade my group has significantly contributed to a change of this scenario by developing efficient adeno-associated viral (AAV) vectors for retinal gene therapy that are safe and effective in humans. The objective of EYEGET (EYE GEne Therapy) is to overcome some of the current major limitations in the field of retinal gene therapy to expand initial therapeutic successes to a larger number of IRDs. To achieve this, we propose to use four parallel, highly innovative and complementary approaches: i. expansion of the limited AAV cargo capacity by a novel methodology based on co-administration of multiple AAVs that reassemble in target retinal cells and reconstitute large genes; ii. targeting of frequent dominant gain-of-function mutations that cause RP using state-of-the-art AAV-mediated genome editing technologies; iii. induction of retinal cells clearance of toxic IRD products by AAV-mediated activation of autophagy and lysosomal function; iv. development of methodologies to directly convert fibroblasts to photoreceptors that can be transplanted in retinas from IRD patients with advanced PR loss and for whom in vivo gene therapy is no longer an option. We will use a combination of in vitro and in vivo state-of-the-art technologies including novel AAV vector design, high content screening of drugs that enhance AAV transduction, genome editing, and advanced in vivo retinal phenotyping to obtain proof-of-concept for each of these therapeutic strategies. The results from this study may impact the quality of life of millions of people worldwide by providing a cure based on gene and/or cell therapy for a large group of IRDs.
Summary
Inherited retinal degenerations (IRDs) are a major cause of blindness worldwide. IRD patients witness inexorable progressive vision loss as no therapy is currently available. In the last decade my group has significantly contributed to a change of this scenario by developing efficient adeno-associated viral (AAV) vectors for retinal gene therapy that are safe and effective in humans. The objective of EYEGET (EYE GEne Therapy) is to overcome some of the current major limitations in the field of retinal gene therapy to expand initial therapeutic successes to a larger number of IRDs. To achieve this, we propose to use four parallel, highly innovative and complementary approaches: i. expansion of the limited AAV cargo capacity by a novel methodology based on co-administration of multiple AAVs that reassemble in target retinal cells and reconstitute large genes; ii. targeting of frequent dominant gain-of-function mutations that cause RP using state-of-the-art AAV-mediated genome editing technologies; iii. induction of retinal cells clearance of toxic IRD products by AAV-mediated activation of autophagy and lysosomal function; iv. development of methodologies to directly convert fibroblasts to photoreceptors that can be transplanted in retinas from IRD patients with advanced PR loss and for whom in vivo gene therapy is no longer an option. We will use a combination of in vitro and in vivo state-of-the-art technologies including novel AAV vector design, high content screening of drugs that enhance AAV transduction, genome editing, and advanced in vivo retinal phenotyping to obtain proof-of-concept for each of these therapeutic strategies. The results from this study may impact the quality of life of millions of people worldwide by providing a cure based on gene and/or cell therapy for a large group of IRDs.
Max ERC Funding
2 499 564 €
Duration
Start date: 2017-01-01, End date: 2022-12-31
Project acronym GameofGates
Project Solute carrier proteins as the gates managing chemical access to cells
Researcher (PI) Giulio SUPERTI-FURGA
Host Institution (HI) CEMM - FORSCHUNGSZENTRUM FUER MOLEKULARE MEDIZIN GMBH
Country Austria
Call Details Advanced Grant (AdG), LS2, ERC-2015-AdG
Summary Chemical exchange between cells and their environment occurs at cellular membranes, the interface where biology meets chemistry. Studying mechanisms of drug resistance, I realized that SoLute Carrier proteins (SLCs), not only represent the major class of small molecule transporters, but that they are encoded by one of the most neglected group of human genes. I identified a case where an SLC controls the activity of mTOR, suggesting that other SLCs may be involved in signalling. This formed the basis for the GameofGates project proposal. The name refers to SLCs as a metaphor for cellular gates coordinating access to resources following game rules that are largely unknown but worth learning, as the acquired knowledge could impact our understanding of cellular physiology and open avenues for innovative treatment of human diseases.
GameofGates (GoG) plans the investigation of SLC function by comprehensively and deeply charting the genetic and protein interaction landscape of SLCs in a human cell line, while monitoring fitness, drug sensitivity and metabolic state. GoG aims at functionally de-orphanize many SLCs by assessing hundreds of thousands of genetic interactions as well as thousands protein and drug interactions. I hypothesize that SLC action is linked to signalling pathways and plays an important role in integration of metabolism and cell regulation for successful homeostasis. I propose that whole circuits of SLCs may be linked to particular nutrient auxotrophy states and that knowledge of these dependencies could instruct assessment of vulnerabilities in cancer cells. In turn, these could be pharmacologically exploited using existing or future drugs. Overall, GoG should position enough pieces into functional and regulatory networks in the SLC puzzle game to facilitate future work and motivate the community to embrace investigation of SLCs as conveyers of metabolic and chemical integration of cell biology with physiology and, in a wider scope, ecology.
Summary
Chemical exchange between cells and their environment occurs at cellular membranes, the interface where biology meets chemistry. Studying mechanisms of drug resistance, I realized that SoLute Carrier proteins (SLCs), not only represent the major class of small molecule transporters, but that they are encoded by one of the most neglected group of human genes. I identified a case where an SLC controls the activity of mTOR, suggesting that other SLCs may be involved in signalling. This formed the basis for the GameofGates project proposal. The name refers to SLCs as a metaphor for cellular gates coordinating access to resources following game rules that are largely unknown but worth learning, as the acquired knowledge could impact our understanding of cellular physiology and open avenues for innovative treatment of human diseases.
GameofGates (GoG) plans the investigation of SLC function by comprehensively and deeply charting the genetic and protein interaction landscape of SLCs in a human cell line, while monitoring fitness, drug sensitivity and metabolic state. GoG aims at functionally de-orphanize many SLCs by assessing hundreds of thousands of genetic interactions as well as thousands protein and drug interactions. I hypothesize that SLC action is linked to signalling pathways and plays an important role in integration of metabolism and cell regulation for successful homeostasis. I propose that whole circuits of SLCs may be linked to particular nutrient auxotrophy states and that knowledge of these dependencies could instruct assessment of vulnerabilities in cancer cells. In turn, these could be pharmacologically exploited using existing or future drugs. Overall, GoG should position enough pieces into functional and regulatory networks in the SLC puzzle game to facilitate future work and motivate the community to embrace investigation of SLCs as conveyers of metabolic and chemical integration of cell biology with physiology and, in a wider scope, ecology.
Max ERC Funding
2 389 782 €
Duration
Start date: 2016-10-01, End date: 2021-09-30
Project acronym GIANTSYN
Project Biophysics and circuit function of a giant cortical glutamatergic synapse
Researcher (PI) Peter Jonas
Host Institution (HI) INSTITUTE OF SCIENCE AND TECHNOLOGY AUSTRIA
Country Austria
Call Details Advanced Grant (AdG), LS5, ERC-2015-AdG
Summary A fundamental question in neuroscience is how the biophysical properties of synapses shape higher network
computations. The hippocampal mossy fiber synapse, formed between axons of dentate gyrus granule cells
and dendrites of CA3 pyramidal neurons, is the ideal synapse to address this question. This synapse is accessible
to presynaptic recording, due to its large size, allowing a rigorous investigation of the biophysical
mechanisms of transmission and plasticity. Furthermore, this synapse is placed in the center of a memory
circuit, and several hypotheses about its network function have been generated. However, even basic properties
of this key communication element remain enigmatic. The ambitious goal of the current proposal, GIANTSYN,
is to understand the hippocampal mossy fiber synapse at all levels of complexity. At the subcellular
level, we want to elucidate the biophysical mechanisms of transmission and synaptic plasticity in the
same depth as previously achieved at peripheral and brainstem synapses, classical synaptic models. At the
network level, we want to unravel the connectivity rules and the in vivo network function of this synapse,
particularly its role in learning and memory. To reach these objectives, we will combine functional and
structural approaches. For the analysis of synaptic transmission and plasticity, we will combine direct preand
postsynaptic patch-clamp recording and high-pressure freezing electron microscopy. For the analysis of
connectivity and network function, we will use transsynaptic labeling and in vivo electrophysiology. Based
on the proposed interdisciplinary research, the hippocampal mossy fiber synapse could become the first synapse
in the history of neuroscience in which we reach complete insight into both synaptic biophysics and
network function. In the long run, the results may open new perspectives for the diagnosis and treatment of
brain diseases in which mossy fiber transmission, plasticity, or connectivity are impaired.
Summary
A fundamental question in neuroscience is how the biophysical properties of synapses shape higher network
computations. The hippocampal mossy fiber synapse, formed between axons of dentate gyrus granule cells
and dendrites of CA3 pyramidal neurons, is the ideal synapse to address this question. This synapse is accessible
to presynaptic recording, due to its large size, allowing a rigorous investigation of the biophysical
mechanisms of transmission and plasticity. Furthermore, this synapse is placed in the center of a memory
circuit, and several hypotheses about its network function have been generated. However, even basic properties
of this key communication element remain enigmatic. The ambitious goal of the current proposal, GIANTSYN,
is to understand the hippocampal mossy fiber synapse at all levels of complexity. At the subcellular
level, we want to elucidate the biophysical mechanisms of transmission and synaptic plasticity in the
same depth as previously achieved at peripheral and brainstem synapses, classical synaptic models. At the
network level, we want to unravel the connectivity rules and the in vivo network function of this synapse,
particularly its role in learning and memory. To reach these objectives, we will combine functional and
structural approaches. For the analysis of synaptic transmission and plasticity, we will combine direct preand
postsynaptic patch-clamp recording and high-pressure freezing electron microscopy. For the analysis of
connectivity and network function, we will use transsynaptic labeling and in vivo electrophysiology. Based
on the proposed interdisciplinary research, the hippocampal mossy fiber synapse could become the first synapse
in the history of neuroscience in which we reach complete insight into both synaptic biophysics and
network function. In the long run, the results may open new perspectives for the diagnosis and treatment of
brain diseases in which mossy fiber transmission, plasticity, or connectivity are impaired.
Max ERC Funding
2 677 500 €
Duration
Start date: 2017-03-01, End date: 2022-02-28
Project acronym IFAMID
Project Institutional Family Demography
Researcher (PI) Arnstein AASSVE
Host Institution (HI) UNIVERSITA COMMERCIALE LUIGI BOCCONI
Country Italy
Call Details Advanced Grant (AdG), SH2, ERC-2015-AdG
Summary "IFAMID presents a new framework for the analysis of family demography. Drawing on recent theoretical developments, and exploiting cognitive and methodological insights from a wide range of disciplines, most importantly from sociology and political science, it is argued that trends in family formation (and its dynamics) not only derive from broad global forces, but also from institutional ""quality"" and cultural traits, and, critically important, from the interaction between the two. Whereas the framework is general, the empirical side of the project focuses on explaining 1) fertility trends and differentials in OECD countries, 2) the transition to adulthood, and 3) the global perspective of fertility change. An important aspect of this approach is that policies contained within existing welfare constellations, often taken as explanatory factors for family outcomes, are necessarily endogenous, and its evolution depends on the underlying quality of relevant institutions and cultural traits, which may react very differently with respect to the onset of global trends, and therefore give different patterns of family formation. With this project, a series of hypotheses will be developed and empirically tested. The World Values Surveys will serve as an important data source, but the unit of analysis will be in large part at the regional level since it is impossible to account fully for the complex interaction of culture and institutions from a cross-country perspective only. This implies collecting a chronology of regional variables on cultural traits, institutions and demographic outcomes. Working closely with Gosta Esping-Andesen and with a team of historical demographers led by Guido Alfani (Bocconi), and drawing heavily on the statistical modeling skills of the PI, the aim is to devise a set of state-of-the-art techniques including instrumental variables, spatial econometrics and epidemiological approaches that deal with the endogeneity of culture and institutions."
Summary
"IFAMID presents a new framework for the analysis of family demography. Drawing on recent theoretical developments, and exploiting cognitive and methodological insights from a wide range of disciplines, most importantly from sociology and political science, it is argued that trends in family formation (and its dynamics) not only derive from broad global forces, but also from institutional ""quality"" and cultural traits, and, critically important, from the interaction between the two. Whereas the framework is general, the empirical side of the project focuses on explaining 1) fertility trends and differentials in OECD countries, 2) the transition to adulthood, and 3) the global perspective of fertility change. An important aspect of this approach is that policies contained within existing welfare constellations, often taken as explanatory factors for family outcomes, are necessarily endogenous, and its evolution depends on the underlying quality of relevant institutions and cultural traits, which may react very differently with respect to the onset of global trends, and therefore give different patterns of family formation. With this project, a series of hypotheses will be developed and empirically tested. The World Values Surveys will serve as an important data source, but the unit of analysis will be in large part at the regional level since it is impossible to account fully for the complex interaction of culture and institutions from a cross-country perspective only. This implies collecting a chronology of regional variables on cultural traits, institutions and demographic outcomes. Working closely with Gosta Esping-Andesen and with a team of historical demographers led by Guido Alfani (Bocconi), and drawing heavily on the statistical modeling skills of the PI, the aim is to devise a set of state-of-the-art techniques including instrumental variables, spatial econometrics and epidemiological approaches that deal with the endogeneity of culture and institutions."
Max ERC Funding
1 850 820 €
Duration
Start date: 2016-10-01, End date: 2022-03-31
Project acronym IMMUNOALZHEIMER
Project The role of immune cells in Alzheimer's disease
Researcher (PI) Gabriela CONSTANTIN
Host Institution (HI) UNIVERSITA DEGLI STUDI DI VERONA
Country Italy
Call Details Advanced Grant (AdG), LS6, ERC-2015-AdG
Summary "Alzheimer’s disease is the most common form of dementia affecting more than 35 million people worldwide and its prevalence is projected to nearly double every 20 years with tremendous social and economical impact on the society. There is no cure for Alzheimer's disease and current drugs only temporarily improve disease symptoms.
Alzheimer's disease is characterized by a progressive deterioration of cognitive functions, and the neuropathological features include amyloid beta deposition, aggregates of hyperphosphorylated tau protein, and the loss of neurons in the central nervous system (CNS). Research efforts in the past decades have been focused on neurons and other CNS resident cells, but this "neurocentric" view has not resulted in disease-modifying therapies.
Growing evidence suggests that inflammation mechanisms are involved in Alzheimer's disease and our team has recently shown an unexpected role for neutrophils in Alzheimer's disease, supporting the innovative idea that circulating leukocytes contribute to disease pathogenesis.
The main goal of this project is to study the role of immune cells in animal models of Alzheimer's disease focusing on neutrophils and T cells. We will first study leukocyte-endothelial interactions in CNS microcirculation in intravital microscopy experiments. Leukocyte trafficking will be then studied inside the brain parenchyma by using two-photon microscopy, which will allow us to characterize leukocyte dynamic behaviour and the crosstalk between migrating leukocytes and CNS cells. The effect of therapeutic blockade of leukocyte-dependent inflammation mechanisms will be determined in animal models of Alzheimer's disease. Finally, the presence of immune cells will be studied on brain samples from Alzheimer's disease patients. Overall, IMMUNOALZHEIMER will generate fundamental knowledge to the understanding of the role of immune cells in neurodegeneration and will unveil novel therapeutic strategies to address Alzheimer’s disease."
Summary
"Alzheimer’s disease is the most common form of dementia affecting more than 35 million people worldwide and its prevalence is projected to nearly double every 20 years with tremendous social and economical impact on the society. There is no cure for Alzheimer's disease and current drugs only temporarily improve disease symptoms.
Alzheimer's disease is characterized by a progressive deterioration of cognitive functions, and the neuropathological features include amyloid beta deposition, aggregates of hyperphosphorylated tau protein, and the loss of neurons in the central nervous system (CNS). Research efforts in the past decades have been focused on neurons and other CNS resident cells, but this "neurocentric" view has not resulted in disease-modifying therapies.
Growing evidence suggests that inflammation mechanisms are involved in Alzheimer's disease and our team has recently shown an unexpected role for neutrophils in Alzheimer's disease, supporting the innovative idea that circulating leukocytes contribute to disease pathogenesis.
The main goal of this project is to study the role of immune cells in animal models of Alzheimer's disease focusing on neutrophils and T cells. We will first study leukocyte-endothelial interactions in CNS microcirculation in intravital microscopy experiments. Leukocyte trafficking will be then studied inside the brain parenchyma by using two-photon microscopy, which will allow us to characterize leukocyte dynamic behaviour and the crosstalk between migrating leukocytes and CNS cells. The effect of therapeutic blockade of leukocyte-dependent inflammation mechanisms will be determined in animal models of Alzheimer's disease. Finally, the presence of immune cells will be studied on brain samples from Alzheimer's disease patients. Overall, IMMUNOALZHEIMER will generate fundamental knowledge to the understanding of the role of immune cells in neurodegeneration and will unveil novel therapeutic strategies to address Alzheimer’s disease."
Max ERC Funding
2 500 000 €
Duration
Start date: 2016-09-01, End date: 2021-08-31
