Project acronym ACTMECH
Project Emergent Active Mechanical Behaviour of the Actomyosin Cell Cortex
Researcher (PI) Stephan Wolfgang Grill
Host Institution (HI) TECHNISCHE UNIVERSITAET DRESDEN
Country Germany
Call Details Starting Grant (StG), LS3, ERC-2011-StG_20101109
Summary The cell cortex is a highly dynamic layer of crosslinked actin filaments and myosin molecular motors beneath the cell membrane. It plays a central role in large scale rearrangements that occur inside cells. Many molecular mechanisms contribute to cortex structure and dynamics. However, cell scale physical properties of the cortex are difficult to grasp. This is problematic because for large scale rearrangements inside a cell, such as coherent flow of the cell cortex, it is the cell scale emergent properties that are important for the realization of such events. I will investigate how the actomyosin cytoskeleton behaves at a coarse grained and cellular scale, and will study how this emergent active behaviour is influenced by molecular mechanisms. We will study the cell cortex in the one cell stage C. elegans embryo, which undergoes large scale cortical flow during polarization and cytokinesis. We will combine theory and experiment. We will characterize cortex structure and dynamics with biophysical techniques such as cortical laser ablation and quantitative photobleaching experiments. We will develop and employ novel theoretical approaches to describe the cell scale mechanical behaviour in terms of an active complex fluid. We will utilize genetic approaches to understand how these emergent mechanical properties are influenced by molecular activities. A central goal is to arrive at a coarse grained description of the cortex that can predict future dynamic behaviour from the past structure, which is conceptually similar to how weather forecasting is accomplished. To date, systematic approaches to link molecular scale physical mechanisms to those on cellular scales are missing. This work will open new opportunities for cell biological and cell biophysical research, by providing a methodological approach for bridging scales, for studying emergent and large-scale active mechanical behaviours and linking them to molecular mechanisms.
Summary
The cell cortex is a highly dynamic layer of crosslinked actin filaments and myosin molecular motors beneath the cell membrane. It plays a central role in large scale rearrangements that occur inside cells. Many molecular mechanisms contribute to cortex structure and dynamics. However, cell scale physical properties of the cortex are difficult to grasp. This is problematic because for large scale rearrangements inside a cell, such as coherent flow of the cell cortex, it is the cell scale emergent properties that are important for the realization of such events. I will investigate how the actomyosin cytoskeleton behaves at a coarse grained and cellular scale, and will study how this emergent active behaviour is influenced by molecular mechanisms. We will study the cell cortex in the one cell stage C. elegans embryo, which undergoes large scale cortical flow during polarization and cytokinesis. We will combine theory and experiment. We will characterize cortex structure and dynamics with biophysical techniques such as cortical laser ablation and quantitative photobleaching experiments. We will develop and employ novel theoretical approaches to describe the cell scale mechanical behaviour in terms of an active complex fluid. We will utilize genetic approaches to understand how these emergent mechanical properties are influenced by molecular activities. A central goal is to arrive at a coarse grained description of the cortex that can predict future dynamic behaviour from the past structure, which is conceptually similar to how weather forecasting is accomplished. To date, systematic approaches to link molecular scale physical mechanisms to those on cellular scales are missing. This work will open new opportunities for cell biological and cell biophysical research, by providing a methodological approach for bridging scales, for studying emergent and large-scale active mechanical behaviours and linking them to molecular mechanisms.
Max ERC Funding
1 500 000 €
Duration
Start date: 2011-12-01, End date: 2017-08-31
Project acronym Boom & Bust Cycles
Project Boom and Bust Cycles in Asset Prices: Real Implications and Monetary Policy Options
Researcher (PI) Klaus Adam
Host Institution (HI) UNIVERSITAET MANNHEIM
Country Germany
Call Details Starting Grant (StG), SH1, ERC-2011-StG_20101124
Summary I seek increasing our understanding of the origin of asset price booms and bust cycles and propose constructing structural dynamic equilibrium models that allow formalizing their interaction with the dynamics of consumption, hours worked, the current account, stock market trading activity, and monetary policy. For this purpose I propose developing macroeconomic models that relax the assumption of common knowledge of beliefs and preferences, incorporating instead subjective beliefs and learning about market behavior. These features allow for sustained deviations of asset prices from fundamentals in a setting where all agents behave individually rational.
The first research project derives the derivative price implications of asset price models with learning agents and determines the limits to arbitrage required so that learning models are consistent with the existence of only weak incentives for improving forecasts and beliefs. The second project introduces housing, collateral constraints and open economy features into existing asset pricing models under learning to explain a range of cross-sectional facts about the behavior of the current account that have been observed in the recent housing boom and bust cycle. The third project constructs quantitatively plausible macro asset pricing models that can explain the dynamics of consumption and hours worked jointly with the occurrence of asset price boom and busts cycles. The forth project develops a set of monetary policy models allowing to study the interaction between monetary policies, the real economy and asset prices, and determines how monetary policy should optimally react to asset price movements. The last project explains the aggregate trading patterns on stock exchanges over boom and bust cycles and improves our understanding of the forces supporting the large cross-sectional heterogeneity in return expectations revealed in survey data.
Summary
I seek increasing our understanding of the origin of asset price booms and bust cycles and propose constructing structural dynamic equilibrium models that allow formalizing their interaction with the dynamics of consumption, hours worked, the current account, stock market trading activity, and monetary policy. For this purpose I propose developing macroeconomic models that relax the assumption of common knowledge of beliefs and preferences, incorporating instead subjective beliefs and learning about market behavior. These features allow for sustained deviations of asset prices from fundamentals in a setting where all agents behave individually rational.
The first research project derives the derivative price implications of asset price models with learning agents and determines the limits to arbitrage required so that learning models are consistent with the existence of only weak incentives for improving forecasts and beliefs. The second project introduces housing, collateral constraints and open economy features into existing asset pricing models under learning to explain a range of cross-sectional facts about the behavior of the current account that have been observed in the recent housing boom and bust cycle. The third project constructs quantitatively plausible macro asset pricing models that can explain the dynamics of consumption and hours worked jointly with the occurrence of asset price boom and busts cycles. The forth project develops a set of monetary policy models allowing to study the interaction between monetary policies, the real economy and asset prices, and determines how monetary policy should optimally react to asset price movements. The last project explains the aggregate trading patterns on stock exchanges over boom and bust cycles and improves our understanding of the forces supporting the large cross-sectional heterogeneity in return expectations revealed in survey data.
Max ERC Funding
769 440 €
Duration
Start date: 2011-09-01, End date: 2017-04-30
Project acronym CARDIOSPLICE
Project A systems and targeted approach to alternative splicing in the developing and diseased heart: Translating basic cell biology to improved cardiac function
Researcher (PI) Michael Gotthardt
Host Institution (HI) MAX DELBRUECK CENTRUM FUER MOLEKULARE MEDIZIN IN DER HELMHOLTZ-GEMEINSCHAFT (MDC)
Country Germany
Call Details Starting Grant (StG), LS4, ERC-2011-StG_20101109
Summary Cardiovascular disease keeps the top spot in mortality statistics in Europe with 2 million deaths annually and although prevention and therapy have continuously been improved, the prevalence of heart failure continues to rise. While contractile (systolic) dysfunction is readily accessible to pharmacological treatment, there is a lack of therapeutic options for reduced ventricular filling (diastolic dysfunction). The diastolic properties of the heart are largely determined by the giant sarcomeric protein titin, which is alternatively spliced to adjust the elastic properties of the cardiomyocyte. We have recently identified a titin splice factor that plays a parallel role in cardiac disease and postnatal development. It targets a subset of genes that concertedly affect biomechanics, electrical activity, and signal transduction and suggests alternative splicing as a novel therapeutic target in heart disease. Here we will build on the titin splice factor to identify regulatory principles and cofactors that adjust cardiac isoform expression. In a complementary approach we will investigate titin mRNA binding proteins to provide a comprehensive analysis of factors governing titin’s differential splicing in cardiac development, health, and disease. Based on its distinctive role in ventricular filling we will evaluate titin splicing as a therapeutic target in diastolic heart failure and use a titin based reporter assay to identify small molecules to interfere with titin isoform expression. Finally, we will evaluate the effects of altered alternative splicing on diastolic dysfunction in vivo utilizing the splice deficient mutant and our available animal models for diastolic dysfunction.
The overall scientific goal of the proposed work is to investigate the regulation of cardiac alternative splicing in development and disease and to evaluate if splice directed therapy can be used to improve diastolic function and specifically the elastic properties of the heart.
Summary
Cardiovascular disease keeps the top spot in mortality statistics in Europe with 2 million deaths annually and although prevention and therapy have continuously been improved, the prevalence of heart failure continues to rise. While contractile (systolic) dysfunction is readily accessible to pharmacological treatment, there is a lack of therapeutic options for reduced ventricular filling (diastolic dysfunction). The diastolic properties of the heart are largely determined by the giant sarcomeric protein titin, which is alternatively spliced to adjust the elastic properties of the cardiomyocyte. We have recently identified a titin splice factor that plays a parallel role in cardiac disease and postnatal development. It targets a subset of genes that concertedly affect biomechanics, electrical activity, and signal transduction and suggests alternative splicing as a novel therapeutic target in heart disease. Here we will build on the titin splice factor to identify regulatory principles and cofactors that adjust cardiac isoform expression. In a complementary approach we will investigate titin mRNA binding proteins to provide a comprehensive analysis of factors governing titin’s differential splicing in cardiac development, health, and disease. Based on its distinctive role in ventricular filling we will evaluate titin splicing as a therapeutic target in diastolic heart failure and use a titin based reporter assay to identify small molecules to interfere with titin isoform expression. Finally, we will evaluate the effects of altered alternative splicing on diastolic dysfunction in vivo utilizing the splice deficient mutant and our available animal models for diastolic dysfunction.
The overall scientific goal of the proposed work is to investigate the regulation of cardiac alternative splicing in development and disease and to evaluate if splice directed therapy can be used to improve diastolic function and specifically the elastic properties of the heart.
Max ERC Funding
1 499 191 €
Duration
Start date: 2012-01-01, End date: 2017-06-30
Project acronym CHIRALMICROBOTS
Project Chiral Nanostructured Surfaces and Colloidal Microbots
Researcher (PI) Peer Fischer
Host Institution (HI) Klinik Max Planck Institut für Psychiatrie
Country Germany
Call Details Starting Grant (StG), PE4, ERC-2011-StG_20101014
Summary "From scientific publications to the popular media, there have been numerous speculations about wirelessly controlled microrobots (microbots) navigating the human body. Microbots have the potential to revolutionize analytics, targeted drug delivery, and microsurgery, but until now there has not been any untethered microscopic system that could be properly moved let alone controlled in fluidic environments. Using glancing angle (physical vapor deposition) we will grow billions of micron-sized colloidal screw-propellers on a wafer. These chiral mesoscopic screws can be magnetized and moved through solution under computer control. The screw-propellers resemble artificial flagella and are the only ‘microbots’ to date that can be fully controlled in solution at micron length scales. The proposed work will advance the fabrication so that active microbots can be applied in rheological measurements and analytics. We will use these novel probes in bio-microrheology with the potential to probe the viscoelastic properties of membranes and tissues, and to explore questions of micro-hydrodynamics. At the same time we will develop these structures as ""colloidal molecules"" and grow asymmetric mesoscopic particles with tailored shapes and properties. We propose experiments that allow the observation of fundamental effects, such as chiral Brownian motion, something that exist at the molecular scale, but has never been observed to date. Similarly, we will be able to demonstrate for the first time chiral separations based purely on physical fields. The proposed technical advances of the growth of nanostructured surfaces will at the same time permit wafer-scale 3-D nano-structuring for photonic and plasmonic applications, which we plan to demonstrate. We will develop a system for targeted drug delivery, study the interaction of swarms of microbots and devise techniques to control and image these swarms."
Summary
"From scientific publications to the popular media, there have been numerous speculations about wirelessly controlled microrobots (microbots) navigating the human body. Microbots have the potential to revolutionize analytics, targeted drug delivery, and microsurgery, but until now there has not been any untethered microscopic system that could be properly moved let alone controlled in fluidic environments. Using glancing angle (physical vapor deposition) we will grow billions of micron-sized colloidal screw-propellers on a wafer. These chiral mesoscopic screws can be magnetized and moved through solution under computer control. The screw-propellers resemble artificial flagella and are the only ‘microbots’ to date that can be fully controlled in solution at micron length scales. The proposed work will advance the fabrication so that active microbots can be applied in rheological measurements and analytics. We will use these novel probes in bio-microrheology with the potential to probe the viscoelastic properties of membranes and tissues, and to explore questions of micro-hydrodynamics. At the same time we will develop these structures as ""colloidal molecules"" and grow asymmetric mesoscopic particles with tailored shapes and properties. We propose experiments that allow the observation of fundamental effects, such as chiral Brownian motion, something that exist at the molecular scale, but has never been observed to date. Similarly, we will be able to demonstrate for the first time chiral separations based purely on physical fields. The proposed technical advances of the growth of nanostructured surfaces will at the same time permit wafer-scale 3-D nano-structuring for photonic and plasmonic applications, which we plan to demonstrate. We will develop a system for targeted drug delivery, study the interaction of swarms of microbots and devise techniques to control and image these swarms."
Max ERC Funding
1 479 760 €
Duration
Start date: 2012-02-01, End date: 2018-01-31
Project acronym COMBIPATTERNING
Project Combinatorial Patterning of Particles for High Density Peptide Arrays
Researcher (PI) Alexander Nesterov-Mueller
Host Institution (HI) KARLSRUHER INSTITUT FUER TECHNOLOGIE
Country Germany
Call Details Starting Grant (StG), PE8, ERC-2011-StG_20101014
Summary We want to use selective laser melting to pattern a substrate with different solid micro particles at a density of 1 million spots per cm2. First, a homogeneous particle layer is deposited on a substrate and a pattern of micro spots of melted matrix is generated by laser radiation. Then, non-melted particles are blown away. Embedded within the particles are different chemically reactive amino acid derivatives that will start coupling to very small synthesis sites upon melting the particle pattern in an oven. This is done once all of the 20 different amino acid particles have been glued by laser patterning to the surface. Washing away uncoupled material, removing Fmoc protecting group, and repeating the patterning steps according to standard Merrifield synthesis, leads to the combinatorial synthesis of very high-density peptide arrays. The main objective of this proposal is to develop this method up to the level of a semi-automated synthesis machine. In addition, we will use the manufactured very high-density peptide arrays to readout the information that is deposited in the immune system, i.e. find a peptide binder for every one of the 200-500 antibody species that patrol the serum of an individual in elevated levels. These experiments might lead to novel tools to find out the causes of hitherto enigmatic diseases because then we might be able to correlate antibody patterns with disease status without knowing in advance the disease-specific antibodies. Beyond the life sciences, we want to embed 10.000 peptides per cm2 within an insulating layer of alkane thiols, each on a different gold pad of a specially designed screening chip. Then, we could readout I/V characteristics of individual peptide species, and eventually find peptide-based diodes. These could be modified in their sequence and screened again for better performance. This evolution-inspired screening approach might lead to novel materials that could be used in fuel cells.
Summary
We want to use selective laser melting to pattern a substrate with different solid micro particles at a density of 1 million spots per cm2. First, a homogeneous particle layer is deposited on a substrate and a pattern of micro spots of melted matrix is generated by laser radiation. Then, non-melted particles are blown away. Embedded within the particles are different chemically reactive amino acid derivatives that will start coupling to very small synthesis sites upon melting the particle pattern in an oven. This is done once all of the 20 different amino acid particles have been glued by laser patterning to the surface. Washing away uncoupled material, removing Fmoc protecting group, and repeating the patterning steps according to standard Merrifield synthesis, leads to the combinatorial synthesis of very high-density peptide arrays. The main objective of this proposal is to develop this method up to the level of a semi-automated synthesis machine. In addition, we will use the manufactured very high-density peptide arrays to readout the information that is deposited in the immune system, i.e. find a peptide binder for every one of the 200-500 antibody species that patrol the serum of an individual in elevated levels. These experiments might lead to novel tools to find out the causes of hitherto enigmatic diseases because then we might be able to correlate antibody patterns with disease status without knowing in advance the disease-specific antibodies. Beyond the life sciences, we want to embed 10.000 peptides per cm2 within an insulating layer of alkane thiols, each on a different gold pad of a specially designed screening chip. Then, we could readout I/V characteristics of individual peptide species, and eventually find peptide-based diodes. These could be modified in their sequence and screened again for better performance. This evolution-inspired screening approach might lead to novel materials that could be used in fuel cells.
Max ERC Funding
1 494 600 €
Duration
Start date: 2011-11-01, End date: 2016-10-31
Project acronym COMPLEXNMD
Project NMD Complexes: Eukaryotic mRNA Quality Control
Researcher (PI) Christiane Helene Berger-Schaffitzel
Host Institution (HI) EUROPEAN MOLECULAR BIOLOGY LABORATORY
Country Germany
Call Details Starting Grant (StG), LS1, ERC-2011-StG_20101109
Summary Nonsense-mediated mRNA decay (NMD) is an essential mechanism controlling translation in the eukaryotic cell. NMD ascertains accurate expression of the genetic information by quality controlling messenger RNA (mRNA). During translation, NMD factors recognize and target to degradation aberrant mRNAs that have a premature stop codon (PTC) and that would otherwise lead to the production of truncated proteins which could be harmful for the cell. A wide range of genetic diseases have their origin in the mechanisms of NMD. Discrimination of a PTC from a correct termination codon depends on splicing and translation, and it is the first and foremost step in human NMD. The molecular mechanism of this process remains elusive to date.
In the research proposed, I will undertake to elucidate the molecular basis of translation termination and induction of NMD. I will study complexes involved in human translation termination at a normal stop codon and involved in NMD. I will employ an array of innovative techniques including recombinant production of human protein complexes by the MultiBac system, mammalian in vitro translation, mass spectrometry for detecting relevant protein modifications, biophysical techniques, mutational analyses and RNA-interference experiments. Stable ribosomal complexes with termination factors and complexes of NMD factors will be used for structure determination by cryo-electron microscopy. State-of-the-art image processing will be applied to address the inherent heterogeneity of the complexes. Hybrid approaches will allow the combination of cryo-EM structures with existing high-resolution structures of factors involved for generation of quasi-atomic models thereby visualizing molecular mechanisms of NMD action. This interdisciplinary work will foster our understanding at a molecular level of a paramount step in mRNA quality control, which is a vital prerequisite for the development of new treatment strategies in NMD-related diseases.
Summary
Nonsense-mediated mRNA decay (NMD) is an essential mechanism controlling translation in the eukaryotic cell. NMD ascertains accurate expression of the genetic information by quality controlling messenger RNA (mRNA). During translation, NMD factors recognize and target to degradation aberrant mRNAs that have a premature stop codon (PTC) and that would otherwise lead to the production of truncated proteins which could be harmful for the cell. A wide range of genetic diseases have their origin in the mechanisms of NMD. Discrimination of a PTC from a correct termination codon depends on splicing and translation, and it is the first and foremost step in human NMD. The molecular mechanism of this process remains elusive to date.
In the research proposed, I will undertake to elucidate the molecular basis of translation termination and induction of NMD. I will study complexes involved in human translation termination at a normal stop codon and involved in NMD. I will employ an array of innovative techniques including recombinant production of human protein complexes by the MultiBac system, mammalian in vitro translation, mass spectrometry for detecting relevant protein modifications, biophysical techniques, mutational analyses and RNA-interference experiments. Stable ribosomal complexes with termination factors and complexes of NMD factors will be used for structure determination by cryo-electron microscopy. State-of-the-art image processing will be applied to address the inherent heterogeneity of the complexes. Hybrid approaches will allow the combination of cryo-EM structures with existing high-resolution structures of factors involved for generation of quasi-atomic models thereby visualizing molecular mechanisms of NMD action. This interdisciplinary work will foster our understanding at a molecular level of a paramount step in mRNA quality control, which is a vital prerequisite for the development of new treatment strategies in NMD-related diseases.
Max ERC Funding
1 176 825 €
Duration
Start date: 2012-02-01, End date: 2016-11-30
Project acronym COMPNET
Project Dynamics and Self-organisation in Complex Cytoskeletal Networks
Researcher (PI) Andreas Bausch
Host Institution (HI) TECHNISCHE UNIVERSITAET MUENCHEN
Country Germany
Call Details Starting Grant (StG), PE3, ERC-2011-StG_20101014
Summary The requirements on the eukaryotic cytoskeleton are not only of high complexity, but include demands that are actually contradictory in the first place: While the dynamic character of cytoskeletal structures is essential for the motility of cells, their ability for morphological reorganisations and cell division, the structural integrity of cells relies on the stability of cytoskeletal structures. From a biophysical point of view, this dynamic structure formation and stabilization stems from a self-organisation process that is tightly controlled by the simultaneous and competing function of a plethora of actin binding proteins (ABPs). To understand the self-organisation phenomena observed in the cytoskeleton it is therefore indispensable to first shed light on the functional role of ABPs and their underlying molecular mechanisms. Hereby development of reliable reconstituted model systems as has been proven by the great progress achieved in our understanding of individual crosslinking proteins that turn the cytoskeleton into a viscoelastic physical gel. The advantage of such reconstituted systems is that the biological complexity is decreased to an accessible level that the physical principles can be explored and identified.
It is the aim of the present proposal to successively increase the complexity in a well defined manner to further progress in understanding the functional units of a cell. On the way to a sound physical understanding of cellular self organizing principles, the planned major step comprises the incorporation of active processes like the active (de-)polymerisation of filaments and motor mediated active reorganisation and contraction. We plan to develop new tools and approaches to address how the different kinds of ABPs are interacting with each other and how the structure, dynamics and function of the cytoskeleton is locally governed by the competition and interplay between them.
Summary
The requirements on the eukaryotic cytoskeleton are not only of high complexity, but include demands that are actually contradictory in the first place: While the dynamic character of cytoskeletal structures is essential for the motility of cells, their ability for morphological reorganisations and cell division, the structural integrity of cells relies on the stability of cytoskeletal structures. From a biophysical point of view, this dynamic structure formation and stabilization stems from a self-organisation process that is tightly controlled by the simultaneous and competing function of a plethora of actin binding proteins (ABPs). To understand the self-organisation phenomena observed in the cytoskeleton it is therefore indispensable to first shed light on the functional role of ABPs and their underlying molecular mechanisms. Hereby development of reliable reconstituted model systems as has been proven by the great progress achieved in our understanding of individual crosslinking proteins that turn the cytoskeleton into a viscoelastic physical gel. The advantage of such reconstituted systems is that the biological complexity is decreased to an accessible level that the physical principles can be explored and identified.
It is the aim of the present proposal to successively increase the complexity in a well defined manner to further progress in understanding the functional units of a cell. On the way to a sound physical understanding of cellular self organizing principles, the planned major step comprises the incorporation of active processes like the active (de-)polymerisation of filaments and motor mediated active reorganisation and contraction. We plan to develop new tools and approaches to address how the different kinds of ABPs are interacting with each other and how the structure, dynamics and function of the cytoskeleton is locally governed by the competition and interplay between them.
Max ERC Funding
1 495 196 €
Duration
Start date: 2011-10-01, End date: 2012-03-31
Project acronym DYNACOM
Project From Genome Integrity to Genome Plasticity:
Dynamic Complexes Controlling Once per Cell Cycle Replication
Researcher (PI) Zoi Lygerou
Host Institution (HI) PANEPISTIMIO PATRON
Country Greece
Call Details Starting Grant (StG), LS3, ERC-2011-StG_20101109
Summary Accurate genome duplication is controlled by multi-subunit protein complexes which associate with chromatin and dictate when and where replication should take place. Dynamic changes in these complexes lie at the heart of their ability to ensure the maintenance of genomic integrity. Defects in origin bound complexes lead to re-replication of the genome across evolution, have been linked to DNA-replication stress and may predispose for gene amplification events. Such genomic aberrations are central to malignant transformation.
We wish to understand how once per cell cycle replication is normally controlled within the context of the living cell and how defects in this control may result in loss of genome integrity and provide genome plasticity. To this end, live cell imaging in human cells in culture will be combined with genetic studies in fission yeast and modelling and in silico analysis.
The proposed research aims to:
1. Decipher the regulatory mechanisms which act in time and space to ensure once per cell cycle replication within living cells and how they may be affected by system aberrations, using functional live cell imaging.
2. Test whether aberrations in the licensing system may provide a selective advantage, through amplification of multiple genomic loci. To this end, a natural selection experiment will be set up in fission yeast .
3. Investigate how rereplication takes place along the genome in single cells. Is there heterogeneity amongst a population, leading to a plethora of different genotypes? In silico analysis of full genome DNA rereplication will be combined to single cell analysis in fission yeast.
4. Assess the relevance of our findings for gene amplification events in cancer. Does ectopic expression of human Cdt1/Cdc6 in cancer cells enhance drug resistance through gene amplification?
Our findings are expected to offer novel insight into mechanisms underlying cancer development and progression.
Summary
Accurate genome duplication is controlled by multi-subunit protein complexes which associate with chromatin and dictate when and where replication should take place. Dynamic changes in these complexes lie at the heart of their ability to ensure the maintenance of genomic integrity. Defects in origin bound complexes lead to re-replication of the genome across evolution, have been linked to DNA-replication stress and may predispose for gene amplification events. Such genomic aberrations are central to malignant transformation.
We wish to understand how once per cell cycle replication is normally controlled within the context of the living cell and how defects in this control may result in loss of genome integrity and provide genome plasticity. To this end, live cell imaging in human cells in culture will be combined with genetic studies in fission yeast and modelling and in silico analysis.
The proposed research aims to:
1. Decipher the regulatory mechanisms which act in time and space to ensure once per cell cycle replication within living cells and how they may be affected by system aberrations, using functional live cell imaging.
2. Test whether aberrations in the licensing system may provide a selective advantage, through amplification of multiple genomic loci. To this end, a natural selection experiment will be set up in fission yeast .
3. Investigate how rereplication takes place along the genome in single cells. Is there heterogeneity amongst a population, leading to a plethora of different genotypes? In silico analysis of full genome DNA rereplication will be combined to single cell analysis in fission yeast.
4. Assess the relevance of our findings for gene amplification events in cancer. Does ectopic expression of human Cdt1/Cdc6 in cancer cells enhance drug resistance through gene amplification?
Our findings are expected to offer novel insight into mechanisms underlying cancer development and progression.
Max ERC Funding
1 531 000 €
Duration
Start date: 2012-02-01, End date: 2017-01-31
Project acronym DYNAMOM
Project New magnetic resonance techniques to determine the dynamic structure of mitochondrial outer membrane proteins and their complexes
Researcher (PI) Markus Heinz-Georg Sebastian Zweckstetter
Host Institution (HI) DEUTSCHES ZENTRUM FUR NEURODEGENERATIVE ERKRANKUNGEN EV
Country Germany
Call Details Starting Grant (StG), LS1, ERC-2011-StG_20101109
Summary Membrane proteins are coded by about 30% of the genes in the human genome and are primary targets for the action of drugs. I propose an interdisciplinary approach that will provide insight into the dynamic structure of membrane proteins of the outer mitochondrial membrane at unprecedented detail with respect to spatial resolution and time scale separation. Analysis of the dynamics and structure of membrane proteins is one of the biggest challenges in structural biology. I propose several new techniques mainly for solution NMR spectroscopy but also for solid-state NMR and electron paramagnetic resonance that go far beyond the state of art and enrich the sparse information from each of the individual techniques. The integration of complementary experimental information together with molecular dynamics simulations will push the description of the dynamic structure of membrane proteins to a new level. This new level is characterized by the possibility to determine structural ensembles of higher structural complexity and by access to dynamic time scales ranging from picoseconds to milliseconds. The characterization of motion is expected to establish the essential link between structure and function. The chosen outer mitochondrial membrane proteins are linked to several human pathologies that cannot be treated because structural and dynamic information at atomic resolution is missing. I expect that the novel insight into the dynamic structure of mitochondrial proteins will be critical to lay the basis for the development of novel, selective and improved therapies for cancer and age-related neurodegeneration.
Summary
Membrane proteins are coded by about 30% of the genes in the human genome and are primary targets for the action of drugs. I propose an interdisciplinary approach that will provide insight into the dynamic structure of membrane proteins of the outer mitochondrial membrane at unprecedented detail with respect to spatial resolution and time scale separation. Analysis of the dynamics and structure of membrane proteins is one of the biggest challenges in structural biology. I propose several new techniques mainly for solution NMR spectroscopy but also for solid-state NMR and electron paramagnetic resonance that go far beyond the state of art and enrich the sparse information from each of the individual techniques. The integration of complementary experimental information together with molecular dynamics simulations will push the description of the dynamic structure of membrane proteins to a new level. This new level is characterized by the possibility to determine structural ensembles of higher structural complexity and by access to dynamic time scales ranging from picoseconds to milliseconds. The characterization of motion is expected to establish the essential link between structure and function. The chosen outer mitochondrial membrane proteins are linked to several human pathologies that cannot be treated because structural and dynamic information at atomic resolution is missing. I expect that the novel insight into the dynamic structure of mitochondrial proteins will be critical to lay the basis for the development of novel, selective and improved therapies for cancer and age-related neurodegeneration.
Max ERC Funding
1 496 200 €
Duration
Start date: 2011-11-01, End date: 2017-10-31
Project acronym E3
Project E3 - Extreme Event Ecology
Researcher (PI) Annette Menzel
Host Institution (HI) TECHNISCHE UNIVERSITAET MUENCHEN
Country Germany
Call Details Starting Grant (StG), LS9, ERC-2011-StG_20101109
Summary With anthropogenic warming, extreme events have already increased in magnitude and frequency and are likely to continue to do so in the near future. These extreme events play decisive roles in climate change impacts. Natural and managed systems, such as agriculture and forestry, are more strongly affected by extremes than by a change in average conditions. Classical parameters considered have included temperature, precipitation and wind speed, but here we will concentrate on multi-factorial complex situations, such as drought, and subsequent ecological events, such as pests. Novel methods from finance mathematics and statistics will be transferred for application to natural systems in order to assess risks of extremes in past, present and future conditions. Special emphasis will be given to deriving critical thresholds and prediction for when they will be crossed. Here, analyses of long-term ecoclimatological data from dendrology, phenology, seed quality, as well as both manipulated experiments and simulations are needed to provide information on the effects stemming from multiple stressors and extremes. In contrast, real data, no matter how long-term, cannot model the risk of new threatening combinations of climatological and ecological parameters. Adaptation should therefore focus not only on retrospective but also on new extremes, in other words, should look forward to the future. In particular, low probabilities and high risk scenarios have to be taken into account. Adaptation measures can range from breeding, and selection of suitable species and varieties to management options, such as sanitation and forest protection. Insurance also needs to adapt to changes in climate and ecology and accurate forecasting becomes more critical in the face of unforeseen extremes and calamities. Thus, future risk management must be based on both adaptation and insurance, with new products, such as index insurance, facilitating the handling of customer claims.
Summary
With anthropogenic warming, extreme events have already increased in magnitude and frequency and are likely to continue to do so in the near future. These extreme events play decisive roles in climate change impacts. Natural and managed systems, such as agriculture and forestry, are more strongly affected by extremes than by a change in average conditions. Classical parameters considered have included temperature, precipitation and wind speed, but here we will concentrate on multi-factorial complex situations, such as drought, and subsequent ecological events, such as pests. Novel methods from finance mathematics and statistics will be transferred for application to natural systems in order to assess risks of extremes in past, present and future conditions. Special emphasis will be given to deriving critical thresholds and prediction for when they will be crossed. Here, analyses of long-term ecoclimatological data from dendrology, phenology, seed quality, as well as both manipulated experiments and simulations are needed to provide information on the effects stemming from multiple stressors and extremes. In contrast, real data, no matter how long-term, cannot model the risk of new threatening combinations of climatological and ecological parameters. Adaptation should therefore focus not only on retrospective but also on new extremes, in other words, should look forward to the future. In particular, low probabilities and high risk scenarios have to be taken into account. Adaptation measures can range from breeding, and selection of suitable species and varieties to management options, such as sanitation and forest protection. Insurance also needs to adapt to changes in climate and ecology and accurate forecasting becomes more critical in the face of unforeseen extremes and calamities. Thus, future risk management must be based on both adaptation and insurance, with new products, such as index insurance, facilitating the handling of customer claims.
Max ERC Funding
1 487 000 €
Duration
Start date: 2012-01-01, End date: 2016-12-31
