Project acronym LTDBud
Project Low Dimensional Topology in Budapest
Researcher (PI) Andras Istvan Stipsicz
Host Institution (HI) MAGYAR TUDOMANYOS AKADEMIA RENYI ALFRED MATEMATIKAI KUTATOINTEZET
Call Details Advanced Grant (AdG), PE1, ERC-2011-ADG_20110209
Summary "Heegaard Floer theory. In this project (in collaboration with P. Ozsváth and Z. Szabó) we plan to extend our earlier results computing various versions of Heegaard Floer homologies purely combinatorially. We also plan to find combinatorial definitions of these invariants (as graded groups). Such results will potentially lead to a combinatorial description of 4-dimensional Heegaard Floer (mixed) invariants, conjecturally equivalent to Seiberg-Witten invariants of smooth 4-manifolds. In particular, we hope to find a combinatorial proof of Donaldson’s diagonalizability theorem, and find relations between the Heegaard Floer and the fundamental groups of a 3-manifold.
Contact topology. Using Heegaard Floer theory and contact surgery, a systematic study of existence of tight contact structures on 3-manifolds is planned. Similar techniques also apply in studying Legendrian and transverse knots in contact 3-manifolds. In particular, the verification of the existence of tight structures on 3-manifolds given by surgery on a knot (with high enough framing) in the 3-sphere is proposed. Using the Legendrian invariant of knots, Legendrian and transverse simplicity can be conveniently studied. The ideas detailed in this part are planned to be carried out partly in collaboration with Paolo Lisca, Vera Vértesi and Hansjörg Geiges.
Exotic 4-manifolds. Extending our previous results, we plan to investigate the existence of exotic smooth structures on 4-manifolds with small Euler characteristics, such as the complex projective plane CP2, its blow-up CP2#CP2-bar, the product of two complex projective lines CP1×CP1 and ultimately the 4-dimensional sphere S4. We plan to investigate the effect of the Gluck transformation. Possible extensions of the rational blow down procedure (successful in producing exotic structures) will be also studied. We plan collaborations with Zoltán Szabó, Daniel Nash and Mohan Bhupal in these questions."
Summary
"Heegaard Floer theory. In this project (in collaboration with P. Ozsváth and Z. Szabó) we plan to extend our earlier results computing various versions of Heegaard Floer homologies purely combinatorially. We also plan to find combinatorial definitions of these invariants (as graded groups). Such results will potentially lead to a combinatorial description of 4-dimensional Heegaard Floer (mixed) invariants, conjecturally equivalent to Seiberg-Witten invariants of smooth 4-manifolds. In particular, we hope to find a combinatorial proof of Donaldson’s diagonalizability theorem, and find relations between the Heegaard Floer and the fundamental groups of a 3-manifold.
Contact topology. Using Heegaard Floer theory and contact surgery, a systematic study of existence of tight contact structures on 3-manifolds is planned. Similar techniques also apply in studying Legendrian and transverse knots in contact 3-manifolds. In particular, the verification of the existence of tight structures on 3-manifolds given by surgery on a knot (with high enough framing) in the 3-sphere is proposed. Using the Legendrian invariant of knots, Legendrian and transverse simplicity can be conveniently studied. The ideas detailed in this part are planned to be carried out partly in collaboration with Paolo Lisca, Vera Vértesi and Hansjörg Geiges.
Exotic 4-manifolds. Extending our previous results, we plan to investigate the existence of exotic smooth structures on 4-manifolds with small Euler characteristics, such as the complex projective plane CP2, its blow-up CP2#CP2-bar, the product of two complex projective lines CP1×CP1 and ultimately the 4-dimensional sphere S4. We plan to investigate the effect of the Gluck transformation. Possible extensions of the rational blow down procedure (successful in producing exotic structures) will be also studied. We plan collaborations with Zoltán Szabó, Daniel Nash and Mohan Bhupal in these questions."
Max ERC Funding
1 208 980 €
Duration
Start date: 2012-04-01, End date: 2017-03-31
Project acronym MOLECMAP
Project Quantitative Molecular Map of the Neuronal Surface
Researcher (PI) Zoltan Jozsef Nusser
Host Institution (HI) INSTITUTE OF EXPERIMENTAL MEDICINE - HUNGARIAN ACADEMY OF SCIENCES
Call Details Advanced Grant (AdG), LS5, ERC-2011-ADG_20110310
Summary The most fundamental roles of nerve cells are the detection of chemical neurotransmitters to generate synaptic potentials; the summation of these potentials to create their output signals; and the consequent release of their own neurotransmitter molecules. All of these functions require the orchestrated work of hundreds of molecules targeted to specialized regions of the cells. In nerve cells, more than in any other cell type, a single molecule could fulfill very different functional roles depending on its subcellular location. For example, dendritic voltage-gated Ca2+ channels play a role in the integration and plasticity of synaptic inputs, whereas the same channels when concentrated in presynaptic active zones are essential for neurotransmitter release. Thus, the function of a protein in nerve cells cannot be understood from its expression or lack of it, but its precise subcellular location, density and molecular environment needs to be determined. The major aim of the present proposal is to create a quantitative molecular map of the surface of hippocampal pyramidal cells (PCs). We will start by examining voltage-gated ion channels due to their pivotal roles in input summation, output generation and neurotransmitter release. We will apply high resolution quantitative molecular neuroanatomical techniques to reveal their densities in 19 different axo-somato-dendritic plasma membrane compartments of CA1 PCs. Functional predictions will be generated using detailed, morphologically realistic multicompartmental PC models with experimentally determined ion channel distributions and densities. Such predictions will be tested by combining in vitro patch-clamp electrophysiology and imaging techniques with correlated light- and electron microscopy. Our results will provide the first quantitative molecular map of the neuronal surface and will reveal new mechanisms that increase the computational power and the functional diversity of nerve cells.
Summary
The most fundamental roles of nerve cells are the detection of chemical neurotransmitters to generate synaptic potentials; the summation of these potentials to create their output signals; and the consequent release of their own neurotransmitter molecules. All of these functions require the orchestrated work of hundreds of molecules targeted to specialized regions of the cells. In nerve cells, more than in any other cell type, a single molecule could fulfill very different functional roles depending on its subcellular location. For example, dendritic voltage-gated Ca2+ channels play a role in the integration and plasticity of synaptic inputs, whereas the same channels when concentrated in presynaptic active zones are essential for neurotransmitter release. Thus, the function of a protein in nerve cells cannot be understood from its expression or lack of it, but its precise subcellular location, density and molecular environment needs to be determined. The major aim of the present proposal is to create a quantitative molecular map of the surface of hippocampal pyramidal cells (PCs). We will start by examining voltage-gated ion channels due to their pivotal roles in input summation, output generation and neurotransmitter release. We will apply high resolution quantitative molecular neuroanatomical techniques to reveal their densities in 19 different axo-somato-dendritic plasma membrane compartments of CA1 PCs. Functional predictions will be generated using detailed, morphologically realistic multicompartmental PC models with experimentally determined ion channel distributions and densities. Such predictions will be tested by combining in vitro patch-clamp electrophysiology and imaging techniques with correlated light- and electron microscopy. Our results will provide the first quantitative molecular map of the neuronal surface and will reveal new mechanisms that increase the computational power and the functional diversity of nerve cells.
Max ERC Funding
2 494 446 €
Duration
Start date: 2012-02-01, End date: 2017-01-31
Project acronym MOLINFLAM
Project Molecular dissection of inflammatory pathways
Researcher (PI) Attila Mocsai
Host Institution (HI) SEMMELWEIS EGYETEM
Call Details Starting Grant (StG), LS3, ERC-2007-StG
Summary Inflammatory diseases are highly prevalent, often chronic diseases that cause diminished quality of life and are connected with major causes of death in Western societies. Despite their societal impact, their pathomechanism is incompletely understood, hindering development of novel therapeutic strategies. In particular, little is known about the intracellular signal transduction processes involved in the tissue destruction phase of aggressive autoimmune diseases such as rheumatoid arthritis. The present proposal aims to clarify this issue using in vivo and in vitro studies on genetically manipulated mice. During the proposed studies, mice deficient in various signal transduction molecules such as Syk, PLCg2, Gab2 and p190 RhoGAPs will be used to test their contribution to inflammatory responses. In vitro studies will test the activation of major effector cells of inflammation (neutrophils, macrophages and osteoclasts) while in vivo studies will utilize mouse models such as autoantibody- and cytokine-induced inflammatory arthritis or autoantibody-induced glomerulonephritis. Further studies will be performed to test the contribution of the above signaling molecules to disease pathogenesis in a lineage-restricted manner, using the Cre-lox approach. Finally, wild type and mutant versions of the signaling molecules tested will be retrovirally re-expressed into the relevant knockout hematopoietic stem cells in vivo to allow structure-function studies during in vivo inflammation. Two novel transgenic strains and a knock-in (floxed) mutant will also be generated during the course of the project. Using state-of-the-art approaches and techniques, this project will provide information at unprecedented molecular detail on signal transduction mechanisms involved in inflammatory diseases, and is expected to point to possible future targets of novel anti-inflammatory therapies.
Summary
Inflammatory diseases are highly prevalent, often chronic diseases that cause diminished quality of life and are connected with major causes of death in Western societies. Despite their societal impact, their pathomechanism is incompletely understood, hindering development of novel therapeutic strategies. In particular, little is known about the intracellular signal transduction processes involved in the tissue destruction phase of aggressive autoimmune diseases such as rheumatoid arthritis. The present proposal aims to clarify this issue using in vivo and in vitro studies on genetically manipulated mice. During the proposed studies, mice deficient in various signal transduction molecules such as Syk, PLCg2, Gab2 and p190 RhoGAPs will be used to test their contribution to inflammatory responses. In vitro studies will test the activation of major effector cells of inflammation (neutrophils, macrophages and osteoclasts) while in vivo studies will utilize mouse models such as autoantibody- and cytokine-induced inflammatory arthritis or autoantibody-induced glomerulonephritis. Further studies will be performed to test the contribution of the above signaling molecules to disease pathogenesis in a lineage-restricted manner, using the Cre-lox approach. Finally, wild type and mutant versions of the signaling molecules tested will be retrovirally re-expressed into the relevant knockout hematopoietic stem cells in vivo to allow structure-function studies during in vivo inflammation. Two novel transgenic strains and a knock-in (floxed) mutant will also be generated during the course of the project. Using state-of-the-art approaches and techniques, this project will provide information at unprecedented molecular detail on signal transduction mechanisms involved in inflammatory diseases, and is expected to point to possible future targets of novel anti-inflammatory therapies.
Max ERC Funding
1 200 000 €
Duration
Start date: 2008-10-01, End date: 2014-03-31
Project acronym NETWORK EVOLUTION
Project Integrated evolutionary analyses of genetic and drug interaction networks in yeast
Researcher (PI) Csaba Pal
Host Institution (HI) MAGYAR TUDOMANYOS AKADEMIA SZEGEDIBIOLOGIAI KUTATOKOZPONT
Call Details Starting Grant (StG), LS5, ERC-2007-StG
Summary The ability of cellular systems to adapt to genetic and environmental perturbations is a fundamental but poorly understood process both at the molecular and evolutionary level. There are both physiological and evolutionary reasonings why mutations often have limited impact on cellular growth. First, perturbations that hit one target often have no effect on the overall performance of a complex system (such as metabolic networks), as perturbations can be adjusted by reorganizing fluxes in metabolic networks, or changing regulation and expression of genes. Second, due to the fast evolvability of microbes, the effect of a perturbation can readily be alleviated by the evolution of compensatory mutations at other sites of the network. Understanding the extent of intrinsic and evolved robustness in cellular systems demands integrated analyses that combine functional genomics and computational systems biology with microbial evolutionary experiments. In collaboration with several leading research teams in the field, we plan to investigate the following issues. First, we will ask how accurately genome-scale metabolic network models can predict the impact of genetic deletions and other non-heritable perturbations. Second, to understand how the impact of genetic and drug perturbations can be mitigated during evolution, we will pursue a large-scale lab evolutionary protocol, and compare the results with predictions of computational models. Our work may suggest avenues of research on the general rules of acquired drug resistance in microbes.
Summary
The ability of cellular systems to adapt to genetic and environmental perturbations is a fundamental but poorly understood process both at the molecular and evolutionary level. There are both physiological and evolutionary reasonings why mutations often have limited impact on cellular growth. First, perturbations that hit one target often have no effect on the overall performance of a complex system (such as metabolic networks), as perturbations can be adjusted by reorganizing fluxes in metabolic networks, or changing regulation and expression of genes. Second, due to the fast evolvability of microbes, the effect of a perturbation can readily be alleviated by the evolution of compensatory mutations at other sites of the network. Understanding the extent of intrinsic and evolved robustness in cellular systems demands integrated analyses that combine functional genomics and computational systems biology with microbial evolutionary experiments. In collaboration with several leading research teams in the field, we plan to investigate the following issues. First, we will ask how accurately genome-scale metabolic network models can predict the impact of genetic deletions and other non-heritable perturbations. Second, to understand how the impact of genetic and drug perturbations can be mitigated during evolution, we will pursue a large-scale lab evolutionary protocol, and compare the results with predictions of computational models. Our work may suggest avenues of research on the general rules of acquired drug resistance in microbes.
Max ERC Funding
1 280 000 €
Duration
Start date: 2008-07-01, End date: 2013-06-30
Project acronym SERRACO
Project Modulation of cortical activity by median raphe neuronal assemblies with identified behavioural effects
Researcher (PI) Tamás Freund
Host Institution (HI) INSTITUTE OF EXPERIMENTAL MEDICINE - HUNGARIAN ACADEMY OF SCIENCES
Call Details Advanced Grant (AdG), LS5, ERC-2011-ADG_20110310
Summary Cortical operations are built up from states associated with distinct behaviour-dependent network activity patterns that subserve information aquisition, encoding, memory consolidation and retrieval. Thus, they can be considered as manifestations of different processing modes. Groups of modulatory, largely monoaminergic neurons located in subcortical nuclei innervating all forebrain areas are indispensable for the generation, stabilization and termination of cortical activity states. In recent years the concept of subcortical modulation has been expanded by the discovery of a fast type of modulatory action driving the rapid readjustment of cortical activity and associated behaviours. Thus, cortical networks are under the influence of a tonic, slow, as well as a phasic, rapid component of subcortical modulation that are acting in parallel. Results from our laboratory revealed that the median raphe (MR) nucleus, one of the main sources of serotonergic innervation of the limbic system , besides the non-synaptic diffuse action, also exerts a fast type of modulation via the selective innervation of cortical GABAergic interneurons. This selective effect on local inhibition may be ideal for the synchronous resetting of the target principal cell circuits, or for the continuous tuning of their activity. These discoveries, together with the methodological advances of recent years, enable us to map the neuronal network mechanisms behind transitions of brain states, as well as associated behaviours, induced by subcortical inputs. We will focus on the MR – limbic connection with the aim to unravel the physiological, pharmacological and anatomical features of MR neuronal assemblies, both the slow- and fast-acting, as well as the serotonergic and glutamatergic components (together with their cortical target circuits) that will have been shown - using optic stimulation of ChR2/eGFP virus-infected MR neurons - to evoke characteristic behaviours, such as anxiety and conditioned fear.
Summary
Cortical operations are built up from states associated with distinct behaviour-dependent network activity patterns that subserve information aquisition, encoding, memory consolidation and retrieval. Thus, they can be considered as manifestations of different processing modes. Groups of modulatory, largely monoaminergic neurons located in subcortical nuclei innervating all forebrain areas are indispensable for the generation, stabilization and termination of cortical activity states. In recent years the concept of subcortical modulation has been expanded by the discovery of a fast type of modulatory action driving the rapid readjustment of cortical activity and associated behaviours. Thus, cortical networks are under the influence of a tonic, slow, as well as a phasic, rapid component of subcortical modulation that are acting in parallel. Results from our laboratory revealed that the median raphe (MR) nucleus, one of the main sources of serotonergic innervation of the limbic system , besides the non-synaptic diffuse action, also exerts a fast type of modulation via the selective innervation of cortical GABAergic interneurons. This selective effect on local inhibition may be ideal for the synchronous resetting of the target principal cell circuits, or for the continuous tuning of their activity. These discoveries, together with the methodological advances of recent years, enable us to map the neuronal network mechanisms behind transitions of brain states, as well as associated behaviours, induced by subcortical inputs. We will focus on the MR – limbic connection with the aim to unravel the physiological, pharmacological and anatomical features of MR neuronal assemblies, both the slow- and fast-acting, as well as the serotonergic and glutamatergic components (together with their cortical target circuits) that will have been shown - using optic stimulation of ChR2/eGFP virus-infected MR neurons - to evoke characteristic behaviours, such as anxiety and conditioned fear.
Max ERC Funding
2 700 000 €
Duration
Start date: 2012-03-01, End date: 2017-02-28
