Project acronym AQUAMS
Project Analysis of quantum many-body systems
Researcher (PI) Robert Seiringer
Host Institution (HI) INSTITUTE OF SCIENCE AND TECHNOLOGY AUSTRIA
Country Austria
Call Details Advanced Grant (AdG), PE1, ERC-2015-AdG
Summary The main focus of this project is the mathematical analysis of many-body quantum systems, in particular, interacting quantum gases at low temperature. The recent experimental advances in studying ultra-cold atomic gases have led to renewed interest in these systems. They display a rich variety of quantum phenomena, including, e.g., Bose–Einstein condensation and superfluidity, which makes them interesting both from a physical and a mathematical point of view.
The goal of this project is the development of new mathematical tools for dealing with complex problems in many-body quantum systems. New mathematical methods lead to different points of view and thus increase our understanding of physical systems. From the point of view of mathematical physics, there has been significant progress in the last few years in understanding the interesting phenomena occurring in quantum gases, and the goal of this project is to investigate some of the key issues that remain unsolved. Due to the complex nature of the problems, new mathematical ideas
and methods will have to be developed for this purpose. One of the main question addressed in this proposal is the validity of the Bogoliubov approximation for the excitation spectrum of many-body quantum systems. While its accuracy has been
successfully shown for the ground state energy of various models, its predictions concerning the excitation spectrum have so far only been verified in the Hartree limit, an extreme form of a mean-field limit where the interaction among the particles is very weak and ranges over the whole system. The central part of this project is concerned with the extension of these results to the case of short-range interactions. Apart from being mathematically much more challenging, the short-range case is the
one most relevant for the description of actual physical systems. Hence progress along these lines can be expected to yield valuable insight into the complex behavior of these many-body quantum systems.
Summary
The main focus of this project is the mathematical analysis of many-body quantum systems, in particular, interacting quantum gases at low temperature. The recent experimental advances in studying ultra-cold atomic gases have led to renewed interest in these systems. They display a rich variety of quantum phenomena, including, e.g., Bose–Einstein condensation and superfluidity, which makes them interesting both from a physical and a mathematical point of view.
The goal of this project is the development of new mathematical tools for dealing with complex problems in many-body quantum systems. New mathematical methods lead to different points of view and thus increase our understanding of physical systems. From the point of view of mathematical physics, there has been significant progress in the last few years in understanding the interesting phenomena occurring in quantum gases, and the goal of this project is to investigate some of the key issues that remain unsolved. Due to the complex nature of the problems, new mathematical ideas
and methods will have to be developed for this purpose. One of the main question addressed in this proposal is the validity of the Bogoliubov approximation for the excitation spectrum of many-body quantum systems. While its accuracy has been
successfully shown for the ground state energy of various models, its predictions concerning the excitation spectrum have so far only been verified in the Hartree limit, an extreme form of a mean-field limit where the interaction among the particles is very weak and ranges over the whole system. The central part of this project is concerned with the extension of these results to the case of short-range interactions. Apart from being mathematically much more challenging, the short-range case is the
one most relevant for the description of actual physical systems. Hence progress along these lines can be expected to yield valuable insight into the complex behavior of these many-body quantum systems.
Max ERC Funding
1 497 755 €
Duration
Start date: 2016-10-01, End date: 2022-03-31
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 CC-TOP
Project Cryosphere-Carbon on Top of the Earth (CC-Top):Decreasing Uncertainties of Thawing Permafrost and Collapsing Methane Hydrates in the Arctic
Researcher (PI) oerjan GUSTAFSSON
Host Institution (HI) STOCKHOLMS UNIVERSITET
Country Sweden
Call Details Advanced Grant (AdG), PE10, ERC-2015-AdG
Summary The enormous quantities of frozen carbon in the Arctic, held in shallow soils and sediments, act as “capacitors” of the global carbon system. Thawing permafrost (PF) and collapsing methane hydrates are top candidates to cause a net transfer of carbon from land/ocean to the atmosphere this century, yet uncertainties abound.
Our program targets the East Siberian Arctic Ocean (ESAO), the World’s largest shelf sea, as it holds 80% of coastal PF, 80% of subsea PF and 75% of shallow hydrates. Our initial findings (e.g., Science, 2010; Nature, 2012; PNAS; 2013; Nature Geoscience, 2013, 2014) are challenging earlier notions by showing complexities in terrestrial PF-Carbon remobilization and extensive venting of methane from subsea PF/hydrates. The objective of the CC-Top Program is to transform descriptive and data-lean pictures into quantitative understanding of the CC system, to pin down the present and predict future releases from these “Sleeping Giants” of the global carbon system.
The CC-Top program combines unique Arctic field capacities with powerful molecular-isotopic characterization of PF-carbon/methane to break through on:
The “awakening” of terrestrial PF-C pools: CC-Top will employ great pan-arctic rivers as natural integrators and by probing the δ13C/Δ14C and molecular fingerprints, apportion release fluxes of different PF-C pools.
The ESAO subsea cryosphere/methane: CC-Top will use recent spatially-extensive observations, deep sediment cores and gap-filling expeditions to (i) estimate distribution of subsea PF and hydrates; (ii) establish thermal state (thawing rate) of subsea PF-C; (iii) apportion sources of releasing methane btw subsea-PF, shallow hydrates vs seepage from the deep petroleum megapool using source-diagnostic triple-isotope fingerprinting.
Arctic Ocean slope hydrates: CC-Top will investigate sites (discovered by us 2008-2014) of collapsed hydrates venting methane, to characterize geospatial distribution and causes of destabilization.
Summary
The enormous quantities of frozen carbon in the Arctic, held in shallow soils and sediments, act as “capacitors” of the global carbon system. Thawing permafrost (PF) and collapsing methane hydrates are top candidates to cause a net transfer of carbon from land/ocean to the atmosphere this century, yet uncertainties abound.
Our program targets the East Siberian Arctic Ocean (ESAO), the World’s largest shelf sea, as it holds 80% of coastal PF, 80% of subsea PF and 75% of shallow hydrates. Our initial findings (e.g., Science, 2010; Nature, 2012; PNAS; 2013; Nature Geoscience, 2013, 2014) are challenging earlier notions by showing complexities in terrestrial PF-Carbon remobilization and extensive venting of methane from subsea PF/hydrates. The objective of the CC-Top Program is to transform descriptive and data-lean pictures into quantitative understanding of the CC system, to pin down the present and predict future releases from these “Sleeping Giants” of the global carbon system.
The CC-Top program combines unique Arctic field capacities with powerful molecular-isotopic characterization of PF-carbon/methane to break through on:
The “awakening” of terrestrial PF-C pools: CC-Top will employ great pan-arctic rivers as natural integrators and by probing the δ13C/Δ14C and molecular fingerprints, apportion release fluxes of different PF-C pools.
The ESAO subsea cryosphere/methane: CC-Top will use recent spatially-extensive observations, deep sediment cores and gap-filling expeditions to (i) estimate distribution of subsea PF and hydrates; (ii) establish thermal state (thawing rate) of subsea PF-C; (iii) apportion sources of releasing methane btw subsea-PF, shallow hydrates vs seepage from the deep petroleum megapool using source-diagnostic triple-isotope fingerprinting.
Arctic Ocean slope hydrates: CC-Top will investigate sites (discovered by us 2008-2014) of collapsed hydrates venting methane, to characterize geospatial distribution and causes of destabilization.
Max ERC Funding
2 499 756 €
Duration
Start date: 2016-11-01, End date: 2021-10-31
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 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 FIRSTORM
Project Modeling first-order Mott transitions
Researcher (PI) Michele FABRIZIO
Host Institution (HI) SCUOLA INTERNAZIONALE SUPERIORE DI STUDI AVANZATI DI TRIESTE
Country Italy
Call Details Advanced Grant (AdG), PE3, ERC-2015-AdG
Summary Mott insulators are “unsuccessful metals”, where conduction is impeded by strong Coulomb repulsion. Their use in microelectronics started to be seriously considered in the 1990s, when first reports of field-effect switches appeared. These attempts were motivated by the expectation that the dielectric breakdown in Mott insulators could suddenly release all formerly localized carriers, a significant potential for nanometer scaling. Over the very last years striking experimental data on narrow-gap Mott insulators have finally materialized that expectation disclosing an unprecedented scenario where the metal phase actually stabilized was only metastable at equilibrium, which foreshadows exciting potential applications. These new data call for an urgent theoretical understanding so far missing. In fact, the conventional portrait of Mott insulators has overlooked that Mott transitions are mostly 1st order, implying an extended insulator-metal coexistence. As a result, bias or light may nucleate long-lived metastable metal droplets within the stable insulator, as indeed seen in experiments. The unexpected 1st order nature of dielectric breakdown in Mott insulators and its poorly explored but important conceptual and practical consequences are the scope of my theoretical project. I will model known Mott insulators identifying the variety of mechanisms (Coulomb, lattice distortions) that support and boost the 1st order character of the Mott transition. I will model and study insulator-metal coexistence and associated novel phenomena such as those related to nucleation and wetting at the interface, including possible unexplored role of quantum fluctuations. I will then simulate in model calculations the spatially inhomogeneous dynamics and non-equilibrium pathways across the 1st order Mott transition, relating the results to ongoing experiments in top groups. The outcome of this project is expected to yield immediate conceptual as well as later technological consequences.
Summary
Mott insulators are “unsuccessful metals”, where conduction is impeded by strong Coulomb repulsion. Their use in microelectronics started to be seriously considered in the 1990s, when first reports of field-effect switches appeared. These attempts were motivated by the expectation that the dielectric breakdown in Mott insulators could suddenly release all formerly localized carriers, a significant potential for nanometer scaling. Over the very last years striking experimental data on narrow-gap Mott insulators have finally materialized that expectation disclosing an unprecedented scenario where the metal phase actually stabilized was only metastable at equilibrium, which foreshadows exciting potential applications. These new data call for an urgent theoretical understanding so far missing. In fact, the conventional portrait of Mott insulators has overlooked that Mott transitions are mostly 1st order, implying an extended insulator-metal coexistence. As a result, bias or light may nucleate long-lived metastable metal droplets within the stable insulator, as indeed seen in experiments. The unexpected 1st order nature of dielectric breakdown in Mott insulators and its poorly explored but important conceptual and practical consequences are the scope of my theoretical project. I will model known Mott insulators identifying the variety of mechanisms (Coulomb, lattice distortions) that support and boost the 1st order character of the Mott transition. I will model and study insulator-metal coexistence and associated novel phenomena such as those related to nucleation and wetting at the interface, including possible unexplored role of quantum fluctuations. I will then simulate in model calculations the spatially inhomogeneous dynamics and non-equilibrium pathways across the 1st order Mott transition, relating the results to ongoing experiments in top groups. The outcome of this project is expected to yield immediate conceptual as well as later technological consequences.
Max ERC Funding
1 422 684 €
Duration
Start date: 2016-09-01, End date: 2022-02-28
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
