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 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: 2021-12-31
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 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
Project acronym LocomotorIntegration
Project Functional connectome of brainstem circuits that control locomotion
Researcher (PI) Ole Kiehn
Host Institution (HI) KAROLINSKA INSTITUTET
Country Sweden
Call Details Advanced Grant (AdG), LS5, ERC-2015-AdG
Summary Locomotion is a complex motor act that is used in many daily life activities and is the output measures of a plethora of brain behaviors. The planning and initiation of locomotion take place in the brain and brainstem, while the execution is accomplished by activity in neuronal networks in the spinal cord itself. Recent experiments have provided significant insight to the organization of the executive spinal locomotor networks. However, little is known about the brainstem control of these networks. Here, I propose to provide a unified understanding of the functional connectome of the key brainstem networks that control locomotion in mammals needed to select appropriate locomotor outputs. To obtain these goals we will develop a suite of transgenic mouse models with optogenetic or chemogenetic switches in defined populations of brainstem neurons combined with the possibility to use state-of-the-art cell-specific electrophysiological and anatomical connectivity studies. We will reveal the functional organization of ‘go’ and ‘stop’ command systems in the brainstem that are directly upstream from the spinal locomotor networks and the mechanisms for how spinal networks are selected. We will further functionally deconstruct the next network layer in midbrain structures that control the ‘go’ and ‘stop’ command systems. Our research takes a specific approach to provide mechanistic insight to the integrated movement function by building the motor matrix in a functional chain from the locomotor–related spinal cord neurons that have been identified to midbrain neurons. A segment of our research will link these networks to locomotor impairments after basal ganglia dysfunction. The work has the potential to make a breakthrough in our understanding of how complex movements are generated by the brain and has translational implications for patients with movement disorders. It will push boundaries in the universal effort that aims to comprehend how brain networks create behaviors.
Summary
Locomotion is a complex motor act that is used in many daily life activities and is the output measures of a plethora of brain behaviors. The planning and initiation of locomotion take place in the brain and brainstem, while the execution is accomplished by activity in neuronal networks in the spinal cord itself. Recent experiments have provided significant insight to the organization of the executive spinal locomotor networks. However, little is known about the brainstem control of these networks. Here, I propose to provide a unified understanding of the functional connectome of the key brainstem networks that control locomotion in mammals needed to select appropriate locomotor outputs. To obtain these goals we will develop a suite of transgenic mouse models with optogenetic or chemogenetic switches in defined populations of brainstem neurons combined with the possibility to use state-of-the-art cell-specific electrophysiological and anatomical connectivity studies. We will reveal the functional organization of ‘go’ and ‘stop’ command systems in the brainstem that are directly upstream from the spinal locomotor networks and the mechanisms for how spinal networks are selected. We will further functionally deconstruct the next network layer in midbrain structures that control the ‘go’ and ‘stop’ command systems. Our research takes a specific approach to provide mechanistic insight to the integrated movement function by building the motor matrix in a functional chain from the locomotor–related spinal cord neurons that have been identified to midbrain neurons. A segment of our research will link these networks to locomotor impairments after basal ganglia dysfunction. The work has the potential to make a breakthrough in our understanding of how complex movements are generated by the brain and has translational implications for patients with movement disorders. It will push boundaries in the universal effort that aims to comprehend how brain networks create behaviors.
Max ERC Funding
2 500 000 €
Duration
Start date: 2016-08-01, End date: 2021-07-31
Project acronym LoTGlasSy
Project Low Temperature Glassy Systems
Researcher (PI) Giorgio Parisi
Host Institution (HI) UNIVERSITA DEGLI STUDI DI ROMA LA SAPIENZA
Country Italy
Call Details Advanced Grant (AdG), PE2, ERC-2015-AdG
Summary Jamming of hard spheres is a new critical phenomenon whose exponents are different from those of the other known transitions. These exponents have been recently computed in a mean field approximation whose limits of validity are not known. Even if their values are in very good agreement with the ones obtained by accurate numerical simulations, the deep reasons for this success are not understood.
Trampolining from these results I plan to develop a theory of the large scale properties of the free energy landscape of glasses at low temperature. I will use techniques of statistical field theory and of renormalization group to identify and compute universal features. This proposal has the following goals.
• We will develop a complete analytic theory of the infinite pressure limit (jamming) of hard spheres in dimensions greater than the upper critical dimensions. We will first compute analytically the upper critical dimension. Numerical simulations suggest that the upper critical dimensions is equal to or smaller than 2: this result is puzzling and it would be very interesting to find out if this indication is supported by the theory. We will also investigate in detail the scaling properties and the conformal invariance of the correlation functions.
• Starting from these results we will derive universal properties of glassy materials in the low temperature regions in the classical and in the quantum regime. The properties of multiple equilibrium configurations are crucial; we will study the structure of small (localized or extended) oscillations around them, the classical and quantum tunneling barriers.
• We will analyze both equilibrium features and off-equilibrium features (like plasticity and the time dependence of the specific heat). The subject has been widely discussed and phenomenological laws have been derived. I aim to obtain these laws from first principles using the properties of the free energy landscape in glasses that will be derived analytically.
Summary
Jamming of hard spheres is a new critical phenomenon whose exponents are different from those of the other known transitions. These exponents have been recently computed in a mean field approximation whose limits of validity are not known. Even if their values are in very good agreement with the ones obtained by accurate numerical simulations, the deep reasons for this success are not understood.
Trampolining from these results I plan to develop a theory of the large scale properties of the free energy landscape of glasses at low temperature. I will use techniques of statistical field theory and of renormalization group to identify and compute universal features. This proposal has the following goals.
• We will develop a complete analytic theory of the infinite pressure limit (jamming) of hard spheres in dimensions greater than the upper critical dimensions. We will first compute analytically the upper critical dimension. Numerical simulations suggest that the upper critical dimensions is equal to or smaller than 2: this result is puzzling and it would be very interesting to find out if this indication is supported by the theory. We will also investigate in detail the scaling properties and the conformal invariance of the correlation functions.
• Starting from these results we will derive universal properties of glassy materials in the low temperature regions in the classical and in the quantum regime. The properties of multiple equilibrium configurations are crucial; we will study the structure of small (localized or extended) oscillations around them, the classical and quantum tunneling barriers.
• We will analyze both equilibrium features and off-equilibrium features (like plasticity and the time dependence of the specific heat). The subject has been widely discussed and phenomenological laws have been derived. I aim to obtain these laws from first principles using the properties of the free energy landscape in glasses that will be derived analytically.
Max ERC Funding
1 760 000 €
Duration
Start date: 2016-06-01, End date: 2021-05-31
