Project acronym AMYLOID
Project Identification and modulation of pathogenic Amyloid beta-peptide species
Researcher (PI) Christian Haass
Host Institution (HI) LUDWIG-MAXIMILIANS-UNIVERSITAET MUENCHEN
Call Details Advanced Grant (AdG), LS5, ERC-2012-ADG_20120314
Summary The frequency of Alzheimer's disease (AD) will dramatically increase in the ageing western society during the next decades. Currently, about 18 million people suffer worldwide from AD. Since no cure is available, this devastating disorder represents one of the most challenging socio-economical problems of our future. As onset and progression of AD is triggered by the amyloid cascade, I will put particular attention on amyloid ß-peptide (Aß). The reason for this approach is, that even though 20 years ago the Aß generating processing pathway was identified (Haass et al., Nature 1992a & b), the identity of the Aß species, which initiate the deadly cascade is still unknown. I will first tackle this challenge by investigating if a novel and so far completely overlooked proteolytic processing pathway is involved in the generation of Aß species capable to initiate spreading of pathology and neurotoxicity. I will then search for modulating proteins, which could affect generation of pathological Aß species. This includes a genome-wide screen for modifiers of gamma-secretase, one of the proteases involved in Aß generation as well as a targeted search for RNA binding proteins capable to posttranscriptionally regulate beta- and alpha-secretase. In a disease-crossing approach, RNA binding proteins, which were recently found not only to be deposited in Frontotemporal Lobar Degeneration and Amyotrophic Lateral Sclerosis but also in many AD cases, will be investigated for their potential to modulate Aß aggregation and AD pathology. Modifiers and novel antibodies specifically recognizing neurotoxic Aß assemblies will be validated for their potential not only to prevent amyloid plaque formation, but also spreading of pathology as well as neurotoxicity. In vivo validations include studies in innovative zebrafish models, which allow life imaging of neuronal cell death, as well as the establishment of microPET amyloid imaging for longitudinal studies in individual animals.
Summary
The frequency of Alzheimer's disease (AD) will dramatically increase in the ageing western society during the next decades. Currently, about 18 million people suffer worldwide from AD. Since no cure is available, this devastating disorder represents one of the most challenging socio-economical problems of our future. As onset and progression of AD is triggered by the amyloid cascade, I will put particular attention on amyloid ß-peptide (Aß). The reason for this approach is, that even though 20 years ago the Aß generating processing pathway was identified (Haass et al., Nature 1992a & b), the identity of the Aß species, which initiate the deadly cascade is still unknown. I will first tackle this challenge by investigating if a novel and so far completely overlooked proteolytic processing pathway is involved in the generation of Aß species capable to initiate spreading of pathology and neurotoxicity. I will then search for modulating proteins, which could affect generation of pathological Aß species. This includes a genome-wide screen for modifiers of gamma-secretase, one of the proteases involved in Aß generation as well as a targeted search for RNA binding proteins capable to posttranscriptionally regulate beta- and alpha-secretase. In a disease-crossing approach, RNA binding proteins, which were recently found not only to be deposited in Frontotemporal Lobar Degeneration and Amyotrophic Lateral Sclerosis but also in many AD cases, will be investigated for their potential to modulate Aß aggregation and AD pathology. Modifiers and novel antibodies specifically recognizing neurotoxic Aß assemblies will be validated for their potential not only to prevent amyloid plaque formation, but also spreading of pathology as well as neurotoxicity. In vivo validations include studies in innovative zebrafish models, which allow life imaging of neuronal cell death, as well as the establishment of microPET amyloid imaging for longitudinal studies in individual animals.
Max ERC Funding
2 497 020 €
Duration
Start date: 2013-03-01, End date: 2018-02-28
Project acronym ATMMACHINE
Project Structural mechanism of recognition, signaling and resection of DNA double-strand breaks
Researcher (PI) Karl-Peter Hopfner
Host Institution (HI) LUDWIG-MAXIMILIANS-UNIVERSITAET MUENCHEN
Call Details Advanced Grant (AdG), LS1, ERC-2012-ADG_20120314
Summary DNA double-strand breaks are perhaps the most harmful DNA damages and result in carcinogenic chromosome aberrations. Cells protect their genome by activating a complex signaling and repair network, collectively denoted DNA damage response (DDR). A key initial step of the DDR is the activation of the 360 kDa checkpoint kinase ATM (ataxia telangiectasia mutated) by the multifunctional DSB repair factor Mre11-Rad50-Nbs1 (MRN). MRN senses and tethers DSBs, processes DSBs for further resection, and recruits and activates ATM to trigger the DDR. A mechanistic basis for the activities of the core DDR sensor MRN has not been established, despite intense research over the past decade. Our recent breakthroughs on structures of core Mre11-Rad50 and Mre11-Nbs1 complexes enable us now address three central questions to finally clarify the mechanism of MRN in the DDR:
- How does MRN interact with DNA or DNA ends in an ATP dependent manner?
- How do MRN and associated factors such as CtIP process blocked DNA ends?
- How do MRN and DNA activate ATM?
We will employ an innovative structural biology hybrid methods approach by combining X-ray crystallography, electron microscopy and small angle scattering with crosslink mass spectrometry and combine the structure-oriented techniques with validating in vitro and in vivo functional studies. The anticipated outcome will clarify the structural mechanism of one of the most important but enigmatic molecular machineries in maintaining genome stability and also help understand the molecular defects associated with several prominent cancer predisposition and neurodegenerative disorders.
Summary
DNA double-strand breaks are perhaps the most harmful DNA damages and result in carcinogenic chromosome aberrations. Cells protect their genome by activating a complex signaling and repair network, collectively denoted DNA damage response (DDR). A key initial step of the DDR is the activation of the 360 kDa checkpoint kinase ATM (ataxia telangiectasia mutated) by the multifunctional DSB repair factor Mre11-Rad50-Nbs1 (MRN). MRN senses and tethers DSBs, processes DSBs for further resection, and recruits and activates ATM to trigger the DDR. A mechanistic basis for the activities of the core DDR sensor MRN has not been established, despite intense research over the past decade. Our recent breakthroughs on structures of core Mre11-Rad50 and Mre11-Nbs1 complexes enable us now address three central questions to finally clarify the mechanism of MRN in the DDR:
- How does MRN interact with DNA or DNA ends in an ATP dependent manner?
- How do MRN and associated factors such as CtIP process blocked DNA ends?
- How do MRN and DNA activate ATM?
We will employ an innovative structural biology hybrid methods approach by combining X-ray crystallography, electron microscopy and small angle scattering with crosslink mass spectrometry and combine the structure-oriented techniques with validating in vitro and in vivo functional studies. The anticipated outcome will clarify the structural mechanism of one of the most important but enigmatic molecular machineries in maintaining genome stability and also help understand the molecular defects associated with several prominent cancer predisposition and neurodegenerative disorders.
Max ERC Funding
2 498 019 €
Duration
Start date: 2013-05-01, End date: 2018-04-30
Project acronym BIOSENSORIMAGING
Project Hyperpolarized Biosensors in Molecular Imaging
Researcher (PI) Leif Schröder
Host Institution (HI) FORSCHUNGSVERBUND BERLIN EV
Call Details Starting Grant (StG), LS7, ERC-2009-StG
Summary Xenon biosensors have an outstanding potential to increase the significance of magnetic resonance imaging (MRI) in molecular imaging and to combine the advantages of MRI with the high sensitivity of hyperpolarized Xe-129 and the specificity of a functionalized contrast agent. Based on new detection schemes (Hyper-CEST method) in Xe MRI, this novel concept in molecular diagnostics will be made available for biomedical applications. The advancement focuses on high-sensitivity in vitro diagnostics for localization of tumour cells in cell cultures and first demonstrations on animal models based on a transferrin-functionalized biosensor. Such a sensor will enable detection of subcutaneous tumours at high sensitivity without any background signal. More detailed work on the different available Hyper-CEST contrast parameters focuses on an absolute quantification of new molecular markers that will improve non-invasive tumour diagnostics significantly. NMR detection of functionalized Xe biosensors have the potential to close the sensitivity gap between modalities of nuclear medicine like PET/SPECT and MRI without using ionizing radiation or making compromises in penetration depth like in optical methods.
Summary
Xenon biosensors have an outstanding potential to increase the significance of magnetic resonance imaging (MRI) in molecular imaging and to combine the advantages of MRI with the high sensitivity of hyperpolarized Xe-129 and the specificity of a functionalized contrast agent. Based on new detection schemes (Hyper-CEST method) in Xe MRI, this novel concept in molecular diagnostics will be made available for biomedical applications. The advancement focuses on high-sensitivity in vitro diagnostics for localization of tumour cells in cell cultures and first demonstrations on animal models based on a transferrin-functionalized biosensor. Such a sensor will enable detection of subcutaneous tumours at high sensitivity without any background signal. More detailed work on the different available Hyper-CEST contrast parameters focuses on an absolute quantification of new molecular markers that will improve non-invasive tumour diagnostics significantly. NMR detection of functionalized Xe biosensors have the potential to close the sensitivity gap between modalities of nuclear medicine like PET/SPECT and MRI without using ionizing radiation or making compromises in penetration depth like in optical methods.
Max ERC Funding
1 848 600 €
Duration
Start date: 2009-12-01, End date: 2014-11-30
Project acronym CHROMDECON
Project analysis of postmitotic chromatin decondensation
Researcher (PI) Wolfram Antonin
Host Institution (HI) UNIVERSITAETSKLINIKUM AACHEN
Call Details Starting Grant (StG), LS1, ERC-2012-StG_20111109
Summary Chromatin undergoes fascinating structural and functional changes during the metazoan cell cycle. It massively condenses at the beginning of mitosis with a degree of compaction up to fiftyfold higher than in interphase. At the end of mitosis, mitotic chromosomes decondense to re-establish their interphase chromatin structure. This process is indispensable for reinitiating transcription and treplication, and is thus of central importance in the cellular life cycle. Despite its significance to basic research as well as its potential medical implications, postmitotic chromatin decondensation is only poorly understood. It has been well described cytologically, but we lack an understanding of the underlying molecular events. We are ignorant about the proteins that mediate chromatin decondensation, the distinct steps in this multi-step procedure and their regulation.
Using a novel in vitro assay, which recapitulates the process in the simplicity of a cell free reaction, we will identify the molecular machinery mediating postmitotic chromatin decondensation and define the different steps of the process. The cell free assay offers the unique possibility to isolate and purify activities responsible for individual steps in chromatin decondensation, to identify their molecular composition and to analyse the molecular changes they induce on chromatin. Accompanied by live cell imaging in mammalian tissue culture cells, the proposed approach will not only facilitate the elucidation of the factors involved in chromatin decondensation, but will also provide insight into how this process is integrated into mitotic exit and nuclear reformation and linked to other concomitant processes such as nuclear envelope assembly or nuclear body formation.
Thus, using an unprecedented approach to study the ill-defined but important cell biological process of postmitotic chromatin decondensation, we aim to expand the frontiers in our knowledge on this topic.
Summary
Chromatin undergoes fascinating structural and functional changes during the metazoan cell cycle. It massively condenses at the beginning of mitosis with a degree of compaction up to fiftyfold higher than in interphase. At the end of mitosis, mitotic chromosomes decondense to re-establish their interphase chromatin structure. This process is indispensable for reinitiating transcription and treplication, and is thus of central importance in the cellular life cycle. Despite its significance to basic research as well as its potential medical implications, postmitotic chromatin decondensation is only poorly understood. It has been well described cytologically, but we lack an understanding of the underlying molecular events. We are ignorant about the proteins that mediate chromatin decondensation, the distinct steps in this multi-step procedure and their regulation.
Using a novel in vitro assay, which recapitulates the process in the simplicity of a cell free reaction, we will identify the molecular machinery mediating postmitotic chromatin decondensation and define the different steps of the process. The cell free assay offers the unique possibility to isolate and purify activities responsible for individual steps in chromatin decondensation, to identify their molecular composition and to analyse the molecular changes they induce on chromatin. Accompanied by live cell imaging in mammalian tissue culture cells, the proposed approach will not only facilitate the elucidation of the factors involved in chromatin decondensation, but will also provide insight into how this process is integrated into mitotic exit and nuclear reformation and linked to other concomitant processes such as nuclear envelope assembly or nuclear body formation.
Thus, using an unprecedented approach to study the ill-defined but important cell biological process of postmitotic chromatin decondensation, we aim to expand the frontiers in our knowledge on this topic.
Max ERC Funding
1 499 880 €
Duration
Start date: 2013-03-01, End date: 2018-02-28
Project acronym CiliTransport
Project Structural Studies and Regulation of Intraflagellar Transport Complexes
Researcher (PI) Esben Lorentzen
Host Institution (HI) MAX-PLANCK-GESELLSCHAFT ZUR FORDERUNG DER WISSENSCHAFTEN EV
Call Details Starting Grant (StG), LS1, ERC-2012-StG_20111109
Summary The cilium is an organelle that protrudes from the cell body and is responsible for the motility of unicellular organisms and of vertebrate cell types such as sperm cells. In addition, most vertebrate cells have primary non-motile cilia important for sensory reception and signalling. The assembly and function of cilia rely on intraflagellar transport (IFT), the bi-directional movement of macromolecules between the cell body and the cilium. As cilia do not contain ribosomes, IFT is required to move the approximately 600 different ciliary proteins from their site of synthesis in the cell body to their site of function in the cilium. IFT is powered by kinesin and dynein motors, which move cargoes along the microtubule-based axoneme of the cilium. The interaction between motors and cargoes is mediated by the IFT complex, a 1.6 MDa complex formed by 20 different proteins. Despite the importance of the IFT complex, very little is known about its architecture and how it is regulated. In this proposal, we want to address both aspects using a combination of structural and functional studies. The structural analysis of the IFT complex is daunting given its size and complexity. We are proceeding with the biochemical reconstitution of the core subcomplexes, which we plan to analyze using X-ray crystallography and electron microscopy. To date, we have solved the X-ray structure of a dimeric complex between an IFT GTPase and its binding factor, and have reconstituted one of the two core complexes (the 8-subunit IFT-B complex) in amounts and purity suitable for structural studies. While these studies are progressing, we plan to use similar approaches to tackle the other core complex (IFT-A) and the plethora of ciliary GTPases, with the ambitious goal of understanding the architecture and regulation of the the entire IFT complex. This will shed light on the molecular basis of ciliogenesis and the pathological consequences of its disruption.
Summary
The cilium is an organelle that protrudes from the cell body and is responsible for the motility of unicellular organisms and of vertebrate cell types such as sperm cells. In addition, most vertebrate cells have primary non-motile cilia important for sensory reception and signalling. The assembly and function of cilia rely on intraflagellar transport (IFT), the bi-directional movement of macromolecules between the cell body and the cilium. As cilia do not contain ribosomes, IFT is required to move the approximately 600 different ciliary proteins from their site of synthesis in the cell body to their site of function in the cilium. IFT is powered by kinesin and dynein motors, which move cargoes along the microtubule-based axoneme of the cilium. The interaction between motors and cargoes is mediated by the IFT complex, a 1.6 MDa complex formed by 20 different proteins. Despite the importance of the IFT complex, very little is known about its architecture and how it is regulated. In this proposal, we want to address both aspects using a combination of structural and functional studies. The structural analysis of the IFT complex is daunting given its size and complexity. We are proceeding with the biochemical reconstitution of the core subcomplexes, which we plan to analyze using X-ray crystallography and electron microscopy. To date, we have solved the X-ray structure of a dimeric complex between an IFT GTPase and its binding factor, and have reconstituted one of the two core complexes (the 8-subunit IFT-B complex) in amounts and purity suitable for structural studies. While these studies are progressing, we plan to use similar approaches to tackle the other core complex (IFT-A) and the plethora of ciliary GTPases, with the ambitious goal of understanding the architecture and regulation of the the entire IFT complex. This will shed light on the molecular basis of ciliogenesis and the pathological consequences of its disruption.
Max ERC Funding
1 498 650 €
Duration
Start date: 2012-09-01, End date: 2017-08-31
Project acronym CORTEX SIMPLEX
Project Function and computation in three-layer cortex
Researcher (PI) Gilles Jean Laurent
Host Institution (HI) MAX-PLANCK-GESELLSCHAFT ZUR FORDERUNG DER WISSENSCHAFTEN EV
Call Details Advanced Grant (AdG), LS5, ERC-2012-ADG_20120314
Summary "Understanding brain function is one of the outstanding challenges of modern biology. Many studies focus on mammalian neocortex, a modular and versatile structure that operates equally well with different sensory inputs and for perception, planning as well as action. Neocortex, however, is remarkably complex. It contains many cell types, six layers, networks with local and long-range connections, and its study is technically challenging. We propose here to address central issues of cortical computation using a simpler experimental system. Neocortex evolved from a more primitive cortex, likely present in the ancestors of all amniotes. Extant reptiles are closest to this putative ancestor: their cortex contains only three layers, two of which are nearly exclusively neuropilar. Reptilian cortex is also closest to mammals’ old cortices (piriform and hippocampus). Like in mammals, reptilian cortex is modular. Its design, however, is considerably simpler and more ubiquitous than in mammals. Indeed, so far as we know, reptilian primary olfactory and visual cortices are very similar to one another. Finally, certain reptiles such as turtles have evolved biochemical and metabolic adaptations to resist long periods of anoxia. Thus, their brains can be studied ex vivo over long periods, giving experimenters access to the entire brain with an intact retina or nasal epithelium. We will use this system to study cortical computation, primarily in visual and olfactory areas. Using electrophysiological, imaging, molecular, behavioral and computational methods, we will discover the representational strategies of these two cortices in vivo, the functional architecture of their microcircuits and the computations that they carry out. This understanding of generic and ancient units of cortical computation will illuminate our studies of more complex and sophisticated cortical circuits."
Summary
"Understanding brain function is one of the outstanding challenges of modern biology. Many studies focus on mammalian neocortex, a modular and versatile structure that operates equally well with different sensory inputs and for perception, planning as well as action. Neocortex, however, is remarkably complex. It contains many cell types, six layers, networks with local and long-range connections, and its study is technically challenging. We propose here to address central issues of cortical computation using a simpler experimental system. Neocortex evolved from a more primitive cortex, likely present in the ancestors of all amniotes. Extant reptiles are closest to this putative ancestor: their cortex contains only three layers, two of which are nearly exclusively neuropilar. Reptilian cortex is also closest to mammals’ old cortices (piriform and hippocampus). Like in mammals, reptilian cortex is modular. Its design, however, is considerably simpler and more ubiquitous than in mammals. Indeed, so far as we know, reptilian primary olfactory and visual cortices are very similar to one another. Finally, certain reptiles such as turtles have evolved biochemical and metabolic adaptations to resist long periods of anoxia. Thus, their brains can be studied ex vivo over long periods, giving experimenters access to the entire brain with an intact retina or nasal epithelium. We will use this system to study cortical computation, primarily in visual and olfactory areas. Using electrophysiological, imaging, molecular, behavioral and computational methods, we will discover the representational strategies of these two cortices in vivo, the functional architecture of their microcircuits and the computations that they carry out. This understanding of generic and ancient units of cortical computation will illuminate our studies of more complex and sophisticated cortical circuits."
Max ERC Funding
2 496 111 €
Duration
Start date: 2013-02-01, End date: 2018-01-31
Project acronym DAMAGE BYPASS
Project Mechanistic analysis of DNA damage bypass in the context of chromatin and genome replication
Researcher (PI) Helle Doerte Ulrich
Host Institution (HI) INSTITUT FUR MOLEKULARE BIOLOGIE GGMBH
Call Details Advanced Grant (AdG), LS1, ERC-2012-ADG_20120314
Summary During its duplication, DNA, the carrier of our genetic information, is particularly vulnerable to decay, and the capacity of cells to deal with replication stress has been recognised as a major factor protecting us from genome instability and cancer. A major pathway that allows cells to overcome or bypass DNA lesions during replication is activated by posttranslational modifications of the sliding clamp protein PCNA. Whereas monoubiquitylation of PCNA allows mutagenic translesion synthesis by damage-tolerant DNA polymerases, polyubiquitylation is required for an error-free pathway that involves template switching to the undamaged sister chromatid, involving a recombination-like mechanism. Hence, damage bypass contributes to genome maintenance, but can itself be a source of genomic instability. It is therefore not surprising that PRR is a highly regulated process whose activity is limited to the appropriate situations by stringent control mechanisms.
The proposed project aims at understanding DNA damage bypass in its cellular context. Using a combination of new and established technology, we will address the role of chromatin dynamics in the reaction, its spatial and temporal control in relation to genome replication, and its coordination with other PCNA-dependent processes in the cell. To this end, we will establish technology to isolate and analyse the composition of damage bypass tracts, develop and implement novel methods to induce lesions and image damage processing in live cells, and exploit a spectrum of biochemical and biophysical techniques to investigate the role of PCNA as a molecular tool-belt in the coordination of its interaction partners. In combination, these approaches will give important insight into how the replication of damaged DNA is managed with high efficiency and accuracy within the cell.
Summary
During its duplication, DNA, the carrier of our genetic information, is particularly vulnerable to decay, and the capacity of cells to deal with replication stress has been recognised as a major factor protecting us from genome instability and cancer. A major pathway that allows cells to overcome or bypass DNA lesions during replication is activated by posttranslational modifications of the sliding clamp protein PCNA. Whereas monoubiquitylation of PCNA allows mutagenic translesion synthesis by damage-tolerant DNA polymerases, polyubiquitylation is required for an error-free pathway that involves template switching to the undamaged sister chromatid, involving a recombination-like mechanism. Hence, damage bypass contributes to genome maintenance, but can itself be a source of genomic instability. It is therefore not surprising that PRR is a highly regulated process whose activity is limited to the appropriate situations by stringent control mechanisms.
The proposed project aims at understanding DNA damage bypass in its cellular context. Using a combination of new and established technology, we will address the role of chromatin dynamics in the reaction, its spatial and temporal control in relation to genome replication, and its coordination with other PCNA-dependent processes in the cell. To this end, we will establish technology to isolate and analyse the composition of damage bypass tracts, develop and implement novel methods to induce lesions and image damage processing in live cells, and exploit a spectrum of biochemical and biophysical techniques to investigate the role of PCNA as a molecular tool-belt in the coordination of its interaction partners. In combination, these approaches will give important insight into how the replication of damaged DNA is managed with high efficiency and accuracy within the cell.
Max ERC Funding
2 476 388 €
Duration
Start date: 2013-03-01, End date: 2018-02-28
Project acronym DMD
Project Dynamic Mechanism Design: Theory and Applications
Researcher (PI) Benedict Moldovanu
Host Institution (HI) RHEINISCHE FRIEDRICH-WILHELMS-UNIVERSITAT BONN
Call Details Advanced Grant (AdG), SH1, ERC-2009-AdG
Summary We plan to construct a theoretical bridge between classical dynamic allocation models used in Operations Research/Management Science, and between the modern theory of mechanism design. Our theoretical results will generate insights for the construction of applied pricing schemes and testable implications about the pattern of observed prices. The Economics literature has focused on information and incentive issues in static models, whereas the Operations Research/Management Science literature has looked at dynamic models that were often lacking strategic/ informational aspects. There is an increased recent interest in combining these bodies of knowledge, spurred by studies of yield management, and of decentralized platforms for interaction/ communication among agents. A general mechanism design analysis starts with the characterization of all dynamically implementable allocation policies. Variational arguments can be used then to characterize optimal policies. The research will focus on models with multidimensional incomplete information, such as: 1) Add incomplete information to the dynamic & stochastic knapsack problem; 2) Allow for strategic purchase time in dynamic pricing models; 3)Allow for competing mechanism designers. The ensuing control problems are often not standard and require special tools. An additional attack line will be devoted to models that combine design with learning about the environment. The information revealed by an agent affects then both the value of the current allocation, and the option value of future allocations. We plan to: 1) Derive the properties of learning processes that allow efficient, dynamic implementation; 2) Characterize second-best mechanism in cases where adaptive learning and efficiency are not compatible with each other.
Summary
We plan to construct a theoretical bridge between classical dynamic allocation models used in Operations Research/Management Science, and between the modern theory of mechanism design. Our theoretical results will generate insights for the construction of applied pricing schemes and testable implications about the pattern of observed prices. The Economics literature has focused on information and incentive issues in static models, whereas the Operations Research/Management Science literature has looked at dynamic models that were often lacking strategic/ informational aspects. There is an increased recent interest in combining these bodies of knowledge, spurred by studies of yield management, and of decentralized platforms for interaction/ communication among agents. A general mechanism design analysis starts with the characterization of all dynamically implementable allocation policies. Variational arguments can be used then to characterize optimal policies. The research will focus on models with multidimensional incomplete information, such as: 1) Add incomplete information to the dynamic & stochastic knapsack problem; 2) Allow for strategic purchase time in dynamic pricing models; 3)Allow for competing mechanism designers. The ensuing control problems are often not standard and require special tools. An additional attack line will be devoted to models that combine design with learning about the environment. The information revealed by an agent affects then both the value of the current allocation, and the option value of future allocations. We plan to: 1) Derive the properties of learning processes that allow efficient, dynamic implementation; 2) Characterize second-best mechanism in cases where adaptive learning and efficiency are not compatible with each other.
Max ERC Funding
1 123 200 €
Duration
Start date: 2010-05-01, End date: 2016-04-30
Project acronym FUTUREGENES
Project Gene transfer techniques in the treatment of cardiovascular diseases and malignant glioma
Researcher (PI) Seppo Yla-Herttuala
Host Institution (HI) ITA-SUOMEN YLIOPISTO
Call Details Advanced Grant (AdG), LS7, ERC-2009-AdG
Summary Background: Poor angiogenesis and collateral vessel formation lead to coronary heart disease, claudication, infarctions and amputations while malignant glioma is one of the most aggressive proangiogenic tumors leading to death in a few months. For these diseases either stimulation or blocking, respectively, of angiogenesis may provide novel treatment options. Advancing State-of-the-Art: Our hypothesis is that in ischemia it will be possible to support natural growth of blood vessels with Therapeutic angiogenesis and lymphangiogenesis by using local gene transfer of the new members of vascular endothelial growth factor (VEGF) family and their receptors. New co-receptors, designer mutants and PCR suffling products of VEGFs will be used. New vector technology will be used to achieve long-lasting effects of VEGFs. We aim to develop novel site-specifically integrating, targeted, regulated vectors to precisely express the new VEGFs, their soluble decoy receptors and single-chain therapeutic antibodies (scFv) for pro- and anti-angiogenic purposes. As novel approaches, we have developed metabolically biotinylated lenti- and adenoviruses suitable for targeting and Epigenetherapy where siRNA/miRNAs and short nuclear RNAs regulate endogenous gene expression at the VEGF promoter level via modification of histone code. scFv library for endothelial cells and lentivirus-siRNA library directed to all human and mouse kinases will be screened to identify new mediators of angiogenesis in order to develop next generation pro- and antiangiogenic therapies. Based on our strong track record in Clinical applications, the best new pro- and antiangiogenic approaches will be taken to phase I clinical studies in myocardial ischemia and malignant glioma. Significance: This work should lead to significant advances and new therapies for severe ischemia and malignant glioma. Epigenetherapy and new site-specifically integrating, regulated vectors should be widely applicable in medicine.
Summary
Background: Poor angiogenesis and collateral vessel formation lead to coronary heart disease, claudication, infarctions and amputations while malignant glioma is one of the most aggressive proangiogenic tumors leading to death in a few months. For these diseases either stimulation or blocking, respectively, of angiogenesis may provide novel treatment options. Advancing State-of-the-Art: Our hypothesis is that in ischemia it will be possible to support natural growth of blood vessels with Therapeutic angiogenesis and lymphangiogenesis by using local gene transfer of the new members of vascular endothelial growth factor (VEGF) family and their receptors. New co-receptors, designer mutants and PCR suffling products of VEGFs will be used. New vector technology will be used to achieve long-lasting effects of VEGFs. We aim to develop novel site-specifically integrating, targeted, regulated vectors to precisely express the new VEGFs, their soluble decoy receptors and single-chain therapeutic antibodies (scFv) for pro- and anti-angiogenic purposes. As novel approaches, we have developed metabolically biotinylated lenti- and adenoviruses suitable for targeting and Epigenetherapy where siRNA/miRNAs and short nuclear RNAs regulate endogenous gene expression at the VEGF promoter level via modification of histone code. scFv library for endothelial cells and lentivirus-siRNA library directed to all human and mouse kinases will be screened to identify new mediators of angiogenesis in order to develop next generation pro- and antiangiogenic therapies. Based on our strong track record in Clinical applications, the best new pro- and antiangiogenic approaches will be taken to phase I clinical studies in myocardial ischemia and malignant glioma. Significance: This work should lead to significant advances and new therapies for severe ischemia and malignant glioma. Epigenetherapy and new site-specifically integrating, regulated vectors should be widely applicable in medicine.
Max ERC Funding
2 200 000 €
Duration
Start date: 2010-06-01, End date: 2015-05-31
Project acronym GABACELLSANDMEMORY
Project Linking GABAergic neurones to hippocampal-entorhinal system functions
Researcher (PI) Hannelore Monyer
Host Institution (HI) UNIVERSITATSKLINIKUM HEIDELBERG
Call Details Advanced Grant (AdG), LS5, ERC-2009-AdG
Summary GABAergic interneurones can effectively synchronize the activity of principal cells giving rise to distinct oscillatory patterns. A particular rhythm, hippocampal theta oscillations (6-10Hz), links two ways of coding by which pyramidal cells in the hippocampus represent space, namely rate and phase coding. Thus, the theta cycle provides a clock against which the increased firing rate of pyramidal cells in the hippocampus and entorhinal cortex is measured. Furthermore, hippocampal theta is believed to constitute a link to episodic memory. Recent evidence from our lab indicates that recruitment of GABAergic interneurones critically affects certain aspects of hippocampus-dependent spatial memory in mice. We have established genetic tools that allow us to manipulate GABAergic interneurones in a cell type and region-specific manner. In combination with in vivo electrophysiology in the hippocampus/entorhinal cortex and behavioural studies, we will investigate how GABAergic interneurones regulate the activity in neuronal networks and contribute to behaviour. Specifically, we will address the following questions: 1) How does reduced recruitment of GABAergic interneurones affect network activity (theta oscillations)? 2) How does altered activity of GABAergic interneurones affect spatial representation (activity of place cells in the hippocampus and grid cells in the entorhinal cortex)? 3) How does modified activity in the hippocampus affect activity in the entorhinal cortex (and vice versa)? 4) How does modified network activity and spatial representation translate into spatial memory? The interdisciplinary approach will enable us to provide better insight into how cellular activity of GABAergic interneurones relates to network activity and ultimately to behaviour.
Summary
GABAergic interneurones can effectively synchronize the activity of principal cells giving rise to distinct oscillatory patterns. A particular rhythm, hippocampal theta oscillations (6-10Hz), links two ways of coding by which pyramidal cells in the hippocampus represent space, namely rate and phase coding. Thus, the theta cycle provides a clock against which the increased firing rate of pyramidal cells in the hippocampus and entorhinal cortex is measured. Furthermore, hippocampal theta is believed to constitute a link to episodic memory. Recent evidence from our lab indicates that recruitment of GABAergic interneurones critically affects certain aspects of hippocampus-dependent spatial memory in mice. We have established genetic tools that allow us to manipulate GABAergic interneurones in a cell type and region-specific manner. In combination with in vivo electrophysiology in the hippocampus/entorhinal cortex and behavioural studies, we will investigate how GABAergic interneurones regulate the activity in neuronal networks and contribute to behaviour. Specifically, we will address the following questions: 1) How does reduced recruitment of GABAergic interneurones affect network activity (theta oscillations)? 2) How does altered activity of GABAergic interneurones affect spatial representation (activity of place cells in the hippocampus and grid cells in the entorhinal cortex)? 3) How does modified activity in the hippocampus affect activity in the entorhinal cortex (and vice versa)? 4) How does modified network activity and spatial representation translate into spatial memory? The interdisciplinary approach will enable us to provide better insight into how cellular activity of GABAergic interneurones relates to network activity and ultimately to behaviour.
Max ERC Funding
1 872 000 €
Duration
Start date: 2010-07-01, End date: 2015-06-30
