Project acronym 3D-JOINT
Project 3D Bioprinting of JOINT Replacements
Researcher (PI) Johannes Jos Malda
Host Institution (HI) UNIVERSITAIR MEDISCH CENTRUM UTRECHT
Call Details Consolidator Grant (CoG), LS7, ERC-2014-CoG
Summary The world has a significant medical challenge in repairing injured or diseased joints. Joint degeneration and its related pain is a major socio-economic burden that will increase over the next decade and is currently addressed by implanting a metal prosthesis. For the long term, the ideal solution to joint injury is to successfully regenerate rather than replace the damaged cartilage with synthetic implants. Recent advances in key technologies are now bringing this “holy grail” within reach; regenerative approaches, based on cell therapy, are already clinically available albeit only for smaller focal cartilage defects.
One of these key technologies is three-dimensional (3D) bio-printing, which provides a greatly controlled placement and organization of living constructs through the layer-by-layer deposition of materials and cells. These tissue constructs can be applied as tissue models for research and screening. However, the lack of biomechanical properties of these tissue constructs has hampered their application to the regeneration of damaged, degenerated or diseased tissue.
Having established a cartilage-focussed research laboratory in the University Medical Center Utrecht, I have addressed this biomechanical limitation of hydrogels through the use of hydrogel composites. Specifically, I have pioneered a 3D bio-printing technology that combines accurately printed small diameter thermoplast filaments with cell invasive hydrogels to form strong fibre-reinforced constructs. This, in combination with bioreactor technology, is the key to the generation of larger, complex tissue constructs with cartilage-like biomechanical resilience. With 3D-JOINT I will use my in-depth bio-printing and bioreactor knowledge and experience to develop a multi-phasic 3D-printed biological replacement of the joint.
Summary
The world has a significant medical challenge in repairing injured or diseased joints. Joint degeneration and its related pain is a major socio-economic burden that will increase over the next decade and is currently addressed by implanting a metal prosthesis. For the long term, the ideal solution to joint injury is to successfully regenerate rather than replace the damaged cartilage with synthetic implants. Recent advances in key technologies are now bringing this “holy grail” within reach; regenerative approaches, based on cell therapy, are already clinically available albeit only for smaller focal cartilage defects.
One of these key technologies is three-dimensional (3D) bio-printing, which provides a greatly controlled placement and organization of living constructs through the layer-by-layer deposition of materials and cells. These tissue constructs can be applied as tissue models for research and screening. However, the lack of biomechanical properties of these tissue constructs has hampered their application to the regeneration of damaged, degenerated or diseased tissue.
Having established a cartilage-focussed research laboratory in the University Medical Center Utrecht, I have addressed this biomechanical limitation of hydrogels through the use of hydrogel composites. Specifically, I have pioneered a 3D bio-printing technology that combines accurately printed small diameter thermoplast filaments with cell invasive hydrogels to form strong fibre-reinforced constructs. This, in combination with bioreactor technology, is the key to the generation of larger, complex tissue constructs with cartilage-like biomechanical resilience. With 3D-JOINT I will use my in-depth bio-printing and bioreactor knowledge and experience to develop a multi-phasic 3D-printed biological replacement of the joint.
Max ERC Funding
1 998 871 €
Duration
Start date: 2015-07-01, End date: 2020-06-30
Project acronym ABCvolume
Project The ABC of Cell Volume Regulation
Researcher (PI) Berend Poolman
Host Institution (HI) RIJKSUNIVERSITEIT GRONINGEN
Call Details Advanced Grant (AdG), LS1, ERC-2014-ADG
Summary Cell volume regulation is crucial for any living cell because changes in volume determine the metabolic activity through e.g. changes in ionic strength, pH, macromolecular crowding and membrane tension. These physical chemical parameters influence interaction rates and affinities of biomolecules, folding rates, and fold stabilities in vivo. Understanding of the underlying volume regulatory mechanisms has immediate application in biotechnology and health, yet these factors are generally ignored in systems analyses of cellular functions.
My team has uncovered a number of mechanisms and insights of cell volume regulation. The next step forward is to elucidate how the components of a cell volume regulatory circuit work together and control the physicochemical conditions of the cell.
I propose construction of a synthetic cell in which an osmoregulatory transporter and mechanosensitive channel form a minimal volume regulatory network. My group has developed the technology to reconstitute membrane proteins into lipid vesicles (synthetic cells). One of the challenges is to incorporate into the vesicles an efficient pathway for ATP production and maintain energy homeostasis while the load on the system varies. We aim to control the transmembrane flux of osmolytes, which requires elucidation of the molecular mechanism of gating of the osmoregulatory transporter. We will focus on the glycine betaine ABC importer, which is one of the most complex transporters known to date with ten distinct protein domains, transiently interacting with each other.
The proposed synthetic metabolic circuit constitutes a fascinating out-of-equilibrium system, allowing us to understand cell volume regulatory mechanisms in a context and at a level of complexity minimally needed for life. Analysis of this circuit will address many outstanding questions and eventually allow us to design more sophisticated vesicular systems with applications, for example as compartmentalized reaction networks.
Summary
Cell volume regulation is crucial for any living cell because changes in volume determine the metabolic activity through e.g. changes in ionic strength, pH, macromolecular crowding and membrane tension. These physical chemical parameters influence interaction rates and affinities of biomolecules, folding rates, and fold stabilities in vivo. Understanding of the underlying volume regulatory mechanisms has immediate application in biotechnology and health, yet these factors are generally ignored in systems analyses of cellular functions.
My team has uncovered a number of mechanisms and insights of cell volume regulation. The next step forward is to elucidate how the components of a cell volume regulatory circuit work together and control the physicochemical conditions of the cell.
I propose construction of a synthetic cell in which an osmoregulatory transporter and mechanosensitive channel form a minimal volume regulatory network. My group has developed the technology to reconstitute membrane proteins into lipid vesicles (synthetic cells). One of the challenges is to incorporate into the vesicles an efficient pathway for ATP production and maintain energy homeostasis while the load on the system varies. We aim to control the transmembrane flux of osmolytes, which requires elucidation of the molecular mechanism of gating of the osmoregulatory transporter. We will focus on the glycine betaine ABC importer, which is one of the most complex transporters known to date with ten distinct protein domains, transiently interacting with each other.
The proposed synthetic metabolic circuit constitutes a fascinating out-of-equilibrium system, allowing us to understand cell volume regulatory mechanisms in a context and at a level of complexity minimally needed for life. Analysis of this circuit will address many outstanding questions and eventually allow us to design more sophisticated vesicular systems with applications, for example as compartmentalized reaction networks.
Max ERC Funding
2 247 231 €
Duration
Start date: 2015-07-01, End date: 2020-06-30
Project acronym ActiveCortex
Project Active dendrites and cortical associations
Researcher (PI) Matthew Larkum
Host Institution (HI) HUMBOLDT-UNIVERSITAET ZU BERLIN
Call Details Advanced Grant (AdG), LS5, ERC-2014-ADG
Summary Converging studies from psychophysics in humans to single-cell recordings in monkeys and rodents indicate that most important cognitive processes depend on both feed-forward and feedback information interacting in the brain. Intriguingly, feedback to early cortical processing stages appears to play a causal role in these processes. Despite the central nature of this fact to understanding brain cognition, there is still no mechanistic explanation as to how this information could be so pivotal and what events take place that might be decisive. In this research program, we will test the hypothesis that the extraordinary performance of the cortex derives from an associative mechanism built into the basic neuronal unit: the pyramidal cell. The hypothesis is based on two important facts: (1) feedback information is conveyed predominantly to layer 1 and (2) the apical tuft dendrites that are the major recipient of this feedback information are highly electrogenic.
The research program is divided in to several workpackages to systematically investigate the hypothesis at every level. As a whole, we will investigate the causal link between intrinsic cellular activity and behaviour. To do this we will use eletrophysiological and optical techniques to record and influence cell the intrinsic properties of cells (in particular dendritic activity) in vivo and in vitro in rodents. In vivo experiments will have a specific focus on context driven behaviour and in vitro experiments on the impact of long-range (feedback-carrying) fibers on cell activity. The study will also focus on synaptic plasticity at the interface of feedback information and dendritic electrogenesis, namely synapses on to the tuft dendrite of pyramidal neurons. The proposed program will not only address a long-standing and important hypothesis but also provide a transformational contribution towards understanding the operation of the cerebral cortex.
Summary
Converging studies from psychophysics in humans to single-cell recordings in monkeys and rodents indicate that most important cognitive processes depend on both feed-forward and feedback information interacting in the brain. Intriguingly, feedback to early cortical processing stages appears to play a causal role in these processes. Despite the central nature of this fact to understanding brain cognition, there is still no mechanistic explanation as to how this information could be so pivotal and what events take place that might be decisive. In this research program, we will test the hypothesis that the extraordinary performance of the cortex derives from an associative mechanism built into the basic neuronal unit: the pyramidal cell. The hypothesis is based on two important facts: (1) feedback information is conveyed predominantly to layer 1 and (2) the apical tuft dendrites that are the major recipient of this feedback information are highly electrogenic.
The research program is divided in to several workpackages to systematically investigate the hypothesis at every level. As a whole, we will investigate the causal link between intrinsic cellular activity and behaviour. To do this we will use eletrophysiological and optical techniques to record and influence cell the intrinsic properties of cells (in particular dendritic activity) in vivo and in vitro in rodents. In vivo experiments will have a specific focus on context driven behaviour and in vitro experiments on the impact of long-range (feedback-carrying) fibers on cell activity. The study will also focus on synaptic plasticity at the interface of feedback information and dendritic electrogenesis, namely synapses on to the tuft dendrite of pyramidal neurons. The proposed program will not only address a long-standing and important hypothesis but also provide a transformational contribution towards understanding the operation of the cerebral cortex.
Max ERC Funding
2 386 304 €
Duration
Start date: 2016-01-01, End date: 2020-12-31
Project acronym AdaptoSCOPE
Project Using cis-regulatory mutations to highlight polygenic adaptation in natural plant systems
Researcher (PI) Juliette de Meaux
Host Institution (HI) UNIVERSITAET ZU KOELN
Call Details Consolidator Grant (CoG), LS8, ERC-2014-CoG
Summary The goal of this project is to demonstrate that novel aspects of the molecular basis of Darwinian adaptation can be discovered if the polygenic basis of adaptation is taken into account. This project will use the genome-wide distribution of cis-regulatory variants to discover the molecular pathways that are optimized during adaptation via accumulation of small effect mutations. Current approaches include scans for outlier genes with strong population genetics signatures of selection, or large effect QTL associating with fitness. They can only reveal a small subset of the molecular changes recruited along adaptive paths. Here, instead, the distribution of small effect mutations will be used to make inferences on the targets of polygenic adaptation across divergent populations in each of the two closely related species, A. thaliana and A. lyrata. These species are both found at diverse latitudes and show sign of local adaptation to climatic differences. Mutations affecting cis-regulation will be identified in leaves of plants exposed to various temperature regimes triggering phenotypic responses of adaptive relevance. Their distribution in clusters of functionally connected genes will be quantified. The phylogeographic differences in the distribution of the mutations will be used to disentangle neutral from adaptive clusters of functionally connected genes in each of the two species. This project will identify the molecular pathways subjected collectively to natural selection and provide a completely novel view on adaptive landscapes. It will further examine whether local adaptation occurs by convergent evolution of molecular systems in plants. This approach has the potential to find broad applications in ecology and agriculture.
Summary
The goal of this project is to demonstrate that novel aspects of the molecular basis of Darwinian adaptation can be discovered if the polygenic basis of adaptation is taken into account. This project will use the genome-wide distribution of cis-regulatory variants to discover the molecular pathways that are optimized during adaptation via accumulation of small effect mutations. Current approaches include scans for outlier genes with strong population genetics signatures of selection, or large effect QTL associating with fitness. They can only reveal a small subset of the molecular changes recruited along adaptive paths. Here, instead, the distribution of small effect mutations will be used to make inferences on the targets of polygenic adaptation across divergent populations in each of the two closely related species, A. thaliana and A. lyrata. These species are both found at diverse latitudes and show sign of local adaptation to climatic differences. Mutations affecting cis-regulation will be identified in leaves of plants exposed to various temperature regimes triggering phenotypic responses of adaptive relevance. Their distribution in clusters of functionally connected genes will be quantified. The phylogeographic differences in the distribution of the mutations will be used to disentangle neutral from adaptive clusters of functionally connected genes in each of the two species. This project will identify the molecular pathways subjected collectively to natural selection and provide a completely novel view on adaptive landscapes. It will further examine whether local adaptation occurs by convergent evolution of molecular systems in plants. This approach has the potential to find broad applications in ecology and agriculture.
Max ERC Funding
1 683 120 €
Duration
Start date: 2015-09-01, End date: 2020-08-31
Project acronym AdLibYeast
Project Synthetic platforms for ad libitum remodelling of yeast central metabolism
Researcher (PI) Pascale Andrée Simone Lapujade Daran
Host Institution (HI) TECHNISCHE UNIVERSITEIT DELFT
Call Details Consolidator Grant (CoG), LS9, ERC-2014-CoG
Summary Replacement of petrochemistry by bio-based processes is key to sustainable development and requires microbes equipped with novel-to-nature capabilities. The efficiency of such engineered microbes strongly depends on their native metabolic networks. However, aeons of evolution have optimized these networks for fitness in nature rather than for industrial performance. As a result, central metabolic networks are complex and encoded by mosaic microbial genomes in which genes, irrespective of their function, are scattered over the genome and chromosomes. This absence of a modular organization tremendously restricts genetic accessibility and presents a major hurdle for fundamental understanding and rational engineering of central metabolism. To conquer this limitation, I introduce the concept of ‘pathway swapping’, which will enable experimenters to remodel the core machinery of microbes at will.
Using the yeast Saccharomyces cerevisiae, an industrial biotechnology work horse and model eukaryotic cell, I propose to design and construct a microbial chassis in which all genes encoding enzymes in central carbon metabolism are relocated to a specialized synthetic chromosome, from which they can be easily swapped by any – homologous or heterologous – synthetic pathway. This challenging and innovative project paves the way for a modular approach to engineering of central metabolism.
Beyond providing a ground-breaking enabling technology, the ultimate goal of the pathway swapping technology is to address hitherto unanswered fundamental questions. Access to a sheer endless variety of configurations of central metabolism offers unique, new possibilities to study the fundamental design of metabolic pathways, the constraints that have shaped them and unifying principles for their structure and regulation. Moreover, this technology enables fast, combinatorial optimization studies on central metabolism to optimize its performance in biotechnological purposes.
Summary
Replacement of petrochemistry by bio-based processes is key to sustainable development and requires microbes equipped with novel-to-nature capabilities. The efficiency of such engineered microbes strongly depends on their native metabolic networks. However, aeons of evolution have optimized these networks for fitness in nature rather than for industrial performance. As a result, central metabolic networks are complex and encoded by mosaic microbial genomes in which genes, irrespective of their function, are scattered over the genome and chromosomes. This absence of a modular organization tremendously restricts genetic accessibility and presents a major hurdle for fundamental understanding and rational engineering of central metabolism. To conquer this limitation, I introduce the concept of ‘pathway swapping’, which will enable experimenters to remodel the core machinery of microbes at will.
Using the yeast Saccharomyces cerevisiae, an industrial biotechnology work horse and model eukaryotic cell, I propose to design and construct a microbial chassis in which all genes encoding enzymes in central carbon metabolism are relocated to a specialized synthetic chromosome, from which they can be easily swapped by any – homologous or heterologous – synthetic pathway. This challenging and innovative project paves the way for a modular approach to engineering of central metabolism.
Beyond providing a ground-breaking enabling technology, the ultimate goal of the pathway swapping technology is to address hitherto unanswered fundamental questions. Access to a sheer endless variety of configurations of central metabolism offers unique, new possibilities to study the fundamental design of metabolic pathways, the constraints that have shaped them and unifying principles for their structure and regulation. Moreover, this technology enables fast, combinatorial optimization studies on central metabolism to optimize its performance in biotechnological purposes.
Max ERC Funding
2 149 718 €
Duration
Start date: 2015-09-01, End date: 2020-08-31
Project acronym ALLEGRO
Project unrAvelLing sLow modE travelinG and tRaffic: with innOvative data to a new transportation and traffic theory for pedestrians and bicycles
Researcher (PI) Serge Hoogendoorn
Host Institution (HI) TECHNISCHE UNIVERSITEIT DELFT
Call Details Advanced Grant (AdG), SH3, ERC-2014-ADG
Summary A major challenge in contemporary traffic and transportation theory is having a comprehensive understanding of pedestrians and cyclists behaviour. This is notoriously hard to observe, since sensors providing abundant and detailed information about key variables characterising this behaviour have not been available until very recently. The behaviour is also far more complex than that of the much better understood fast mode. This is due to the many degrees of freedom in decision-making, the interactions among slow traffic participants that are more involved and far less guided by traffic rules and regulations than those between car-drivers, and the many fascinating but complex phenomena in slow traffic flows (self-organised patterns, turbulence, spontaneous phase transitions, herding, etc.) that are very hard to predict accurately.
With slow traffic modes gaining ground in terms of mode share in many cities, lack of empirical insights, behavioural theories, predictively valid analytical and simulation models, and tools to support planning, design, management and control is posing a major societal problem as well: examples of major accidents due to bad planning, organisation and management of events are manifold, as are locations where safety of slow modes is a serious issue due to interactions with fast modes.
This programme is geared towards establishing a comprehensive theory of slow mode traffic behaviour, considering the different behavioural levels relevant for understanding, reproducing and predicting slow mode traffic flows in cities. The levels deal with walking and cycling operations, activity scheduling and travel behaviour, and knowledge representation and learning. Major scientific breakthroughs are expected at each of these levels, in terms of theory and modelling, by using innovative (big) data collection and experimentation, analysis and fusion techniques, including social media data analytics, using augmented reality, and remote and crowd sensing.
Summary
A major challenge in contemporary traffic and transportation theory is having a comprehensive understanding of pedestrians and cyclists behaviour. This is notoriously hard to observe, since sensors providing abundant and detailed information about key variables characterising this behaviour have not been available until very recently. The behaviour is also far more complex than that of the much better understood fast mode. This is due to the many degrees of freedom in decision-making, the interactions among slow traffic participants that are more involved and far less guided by traffic rules and regulations than those between car-drivers, and the many fascinating but complex phenomena in slow traffic flows (self-organised patterns, turbulence, spontaneous phase transitions, herding, etc.) that are very hard to predict accurately.
With slow traffic modes gaining ground in terms of mode share in many cities, lack of empirical insights, behavioural theories, predictively valid analytical and simulation models, and tools to support planning, design, management and control is posing a major societal problem as well: examples of major accidents due to bad planning, organisation and management of events are manifold, as are locations where safety of slow modes is a serious issue due to interactions with fast modes.
This programme is geared towards establishing a comprehensive theory of slow mode traffic behaviour, considering the different behavioural levels relevant for understanding, reproducing and predicting slow mode traffic flows in cities. The levels deal with walking and cycling operations, activity scheduling and travel behaviour, and knowledge representation and learning. Major scientific breakthroughs are expected at each of these levels, in terms of theory and modelling, by using innovative (big) data collection and experimentation, analysis and fusion techniques, including social media data analytics, using augmented reality, and remote and crowd sensing.
Max ERC Funding
2 458 700 €
Duration
Start date: 2015-11-01, End date: 2020-10-31
Project acronym Angiolnc
Project Endothelial long non-coding RNAs
Researcher (PI) Stefanie Dimmeler
Host Institution (HI) JOHANN WOLFGANG GOETHE-UNIVERSITATFRANKFURT AM MAIN
Call Details Advanced Grant (AdG), LS4, ERC-2014-ADG
Summary Endothelial cells comprise the inner cellular cover of the vasculature, which delivers metabolites and oxygen to the tissue. Dysfunction of endothelial cells as it occurs during aging or metabolic syndromes can result in atherosclerosis, which can lead to myocardial infarction or stroke, whereas pathological angiogenesis contributes to tumor growth and diabetic retinopathy. Thus, endothelial cells play central roles in pathophysiological processes of many diseases including cardiovascular diseases and cancer. Many studies explored the regulation of endothelial cell functions by growth factors, but the impact of epigenetic mechanisms and particularly the role of novel non-coding RNAs is largely unknown. More than 70 % of the human genome encodes for non-coding RNAs (ncRNAs) and increasing evidence suggests that a significant portion of these ncRNAs are functionally active as RNA molecules. Angiolnc aims to explore the function of long ncRNAs (lncRNAs) and particular circular RNAs (circRNAs) in the endothelium. LncRNAs comprise a heterogenic class of RNAs with a length of > 200 nucleotides and circRNAs are generated by back splicing.
Angiolnc is based on the discovery of novel endothelial hypoxia-regulated lncRNAs and circRNAs by next generation sequencing. To begin to understand the potential functions of lncRNAs in the endothelium, we will study two lncRNAs, named Angiolnc1 und Angiolnc2, as prototypical examples of endothelial cell-enriched lncRNAs that are regulated by oxygen levels. We will further dissect the epigenetic mechanisms, by which these lncRNAs regulate endothelial cell function. In the second part of the application, we will determine the regulation and function of circRNAs, which may act as molecular sponges in the cytoplasm. Finally, we will study the function of identified lncRNAs and circRNAs in mouse models and measure their expression in human specimens in order to determine their role as therapeutic targets or diagnostic tools.
Summary
Endothelial cells comprise the inner cellular cover of the vasculature, which delivers metabolites and oxygen to the tissue. Dysfunction of endothelial cells as it occurs during aging or metabolic syndromes can result in atherosclerosis, which can lead to myocardial infarction or stroke, whereas pathological angiogenesis contributes to tumor growth and diabetic retinopathy. Thus, endothelial cells play central roles in pathophysiological processes of many diseases including cardiovascular diseases and cancer. Many studies explored the regulation of endothelial cell functions by growth factors, but the impact of epigenetic mechanisms and particularly the role of novel non-coding RNAs is largely unknown. More than 70 % of the human genome encodes for non-coding RNAs (ncRNAs) and increasing evidence suggests that a significant portion of these ncRNAs are functionally active as RNA molecules. Angiolnc aims to explore the function of long ncRNAs (lncRNAs) and particular circular RNAs (circRNAs) in the endothelium. LncRNAs comprise a heterogenic class of RNAs with a length of > 200 nucleotides and circRNAs are generated by back splicing.
Angiolnc is based on the discovery of novel endothelial hypoxia-regulated lncRNAs and circRNAs by next generation sequencing. To begin to understand the potential functions of lncRNAs in the endothelium, we will study two lncRNAs, named Angiolnc1 und Angiolnc2, as prototypical examples of endothelial cell-enriched lncRNAs that are regulated by oxygen levels. We will further dissect the epigenetic mechanisms, by which these lncRNAs regulate endothelial cell function. In the second part of the application, we will determine the regulation and function of circRNAs, which may act as molecular sponges in the cytoplasm. Finally, we will study the function of identified lncRNAs and circRNAs in mouse models and measure their expression in human specimens in order to determine their role as therapeutic targets or diagnostic tools.
Max ERC Funding
2 497 398 €
Duration
Start date: 2016-01-01, End date: 2020-12-31
Project acronym ApoptoMDS
Project Hematopoietic stem cell Apoptosis in bone marrow failure and MyeloDysplastic Syndromes: Friend or foe?
Researcher (PI) Miriam Erlacher
Host Institution (HI) UNIVERSITAETSKLINIKUM FREIBURG
Call Details Starting Grant (StG), LS4, ERC-2014-STG
Summary Deregulated apoptotic signaling in hematopoietic stem and progenitor cells (HSPCs) strongly contributes to the pathogenesis and phenotypes of congenital bone marrow failure and myelodysplastic syndromes (MDS) and their progression to acute myeloid leukemia (AML). HSPCs are highly susceptible to apoptosis during bone marrow failure and early MDS, but AML evolution selects for apoptosis resistance. Little is known about the main apoptotic players and their regulators. ApoptoMDS will investigate the impact of apoptotic deregulation for pathogenesis, correlate apoptotic susceptibility with the kinetics of disease progression and characterize the mechanism by which apoptotic susceptibility turns into resistance. ApoptoMDS will draw on a large collection of patient-derived samples and genetically engineered mouse models to investigate disease progression in serially transplanted and xenotransplanted mice. How activated DNA damage checkpoint signaling contributes to syndrome phenotypes and HSPC hypersusceptibility to apoptosis will be assessed. Checkpoint activation confers a competitive disadvantage, and HSPCs undergoing malignant transformation are under high selective pressure to inactivate it. Checkpoint abrogation mitigates the hematological phenotype, but increases the risk of AML evolution. ApoptoMDS aims to analyze if inhibiting apoptosis in HSPCs from bone marrow failure and early-stage MDS can overcome the dilemma of checkpoint abrogation. Whether inhibiting apoptosis is sufficient to improve HSPC function will be tested on several levels and validated in patient-derived samples. How inhibiting apoptosis in the presence of functional checkpoint signaling influences malignant transformation kinetics will be assessed. If, as hypothesized, inhibiting apoptosis both mitigates hematological symptoms and delays AML evolution, ApoptoMDS will pave the way for novel therapeutic approaches to expand the less severe symptomatic period for patients with these syndromes.
Summary
Deregulated apoptotic signaling in hematopoietic stem and progenitor cells (HSPCs) strongly contributes to the pathogenesis and phenotypes of congenital bone marrow failure and myelodysplastic syndromes (MDS) and their progression to acute myeloid leukemia (AML). HSPCs are highly susceptible to apoptosis during bone marrow failure and early MDS, but AML evolution selects for apoptosis resistance. Little is known about the main apoptotic players and their regulators. ApoptoMDS will investigate the impact of apoptotic deregulation for pathogenesis, correlate apoptotic susceptibility with the kinetics of disease progression and characterize the mechanism by which apoptotic susceptibility turns into resistance. ApoptoMDS will draw on a large collection of patient-derived samples and genetically engineered mouse models to investigate disease progression in serially transplanted and xenotransplanted mice. How activated DNA damage checkpoint signaling contributes to syndrome phenotypes and HSPC hypersusceptibility to apoptosis will be assessed. Checkpoint activation confers a competitive disadvantage, and HSPCs undergoing malignant transformation are under high selective pressure to inactivate it. Checkpoint abrogation mitigates the hematological phenotype, but increases the risk of AML evolution. ApoptoMDS aims to analyze if inhibiting apoptosis in HSPCs from bone marrow failure and early-stage MDS can overcome the dilemma of checkpoint abrogation. Whether inhibiting apoptosis is sufficient to improve HSPC function will be tested on several levels and validated in patient-derived samples. How inhibiting apoptosis in the presence of functional checkpoint signaling influences malignant transformation kinetics will be assessed. If, as hypothesized, inhibiting apoptosis both mitigates hematological symptoms and delays AML evolution, ApoptoMDS will pave the way for novel therapeutic approaches to expand the less severe symptomatic period for patients with these syndromes.
Max ERC Funding
1 372 525 €
Duration
Start date: 2015-06-01, End date: 2020-05-31
Project acronym ASICA
Project New constraints on the Amazonian carbon balance from airborne observations of the stable isotopes of CO2
Researcher (PI) Wouter Peters
Host Institution (HI) WAGENINGEN UNIVERSITY
Call Details Consolidator Grant (CoG), PE10, ERC-2014-CoG
Summary Severe droughts in Amazonia in 2005 and 2010 caused widespread loss of carbon from the terrestrial biosphere. This loss, almost twice the annual fossil fuel CO2 emissions in the EU, suggests a large sensitivity of the Amazonian carbon balance to a predicted more intense drought regime in the next decades. This is a dangerous inference though, as there is no scientific consensus on the most basic metrics of Amazonian carbon exchange: the gross primary production (GPP) and its response to moisture deficits in the soil and atmosphere. Measuring them on scales that span the whole Amazon forest was thus far impossible, but in this project I aim to deliver the first observation-based estimate of pan-Amazonian GPP and its drought induced variations.
My program builds on two recent breakthroughs in our use of stable isotopes (13C, 17O, 18O) in atmospheric CO2: (1) Our discovery that observed δ¹³C in CO2 in the atmosphere is a quantitative measure for vegetation water-use efficiency over millions of square kilometers, integrating the drought response of individual plants. (2) The possibility to precisely measure the relative ratios of 18O/16O and 17O/16O in CO2, called Δ17O. Anomalous Δ17O values are present in air coming down from the stratosphere, but this anomaly is removed upon contact of CO2 with leaf water inside plant stomata. Hence, observed Δ17O values depend directly on the magnitude of GPP. Both δ¹³C and Δ17O measurements are scarce over the Amazon-basin, and I propose more than 7000 new measurements leveraging an established aircraft monitoring program in Brazil. Quantitative interpretation of these observations will break new ground in our use of stable isotopes to understand climate variations, and is facilitated by our renowned numerical modeling system “CarbonTracker”. My program will answer two burning question in carbon cycle science today: (a) What is the magnitude of GPP in Amazonia? And (b) How does it vary over different intensities of drought?
Summary
Severe droughts in Amazonia in 2005 and 2010 caused widespread loss of carbon from the terrestrial biosphere. This loss, almost twice the annual fossil fuel CO2 emissions in the EU, suggests a large sensitivity of the Amazonian carbon balance to a predicted more intense drought regime in the next decades. This is a dangerous inference though, as there is no scientific consensus on the most basic metrics of Amazonian carbon exchange: the gross primary production (GPP) and its response to moisture deficits in the soil and atmosphere. Measuring them on scales that span the whole Amazon forest was thus far impossible, but in this project I aim to deliver the first observation-based estimate of pan-Amazonian GPP and its drought induced variations.
My program builds on two recent breakthroughs in our use of stable isotopes (13C, 17O, 18O) in atmospheric CO2: (1) Our discovery that observed δ¹³C in CO2 in the atmosphere is a quantitative measure for vegetation water-use efficiency over millions of square kilometers, integrating the drought response of individual plants. (2) The possibility to precisely measure the relative ratios of 18O/16O and 17O/16O in CO2, called Δ17O. Anomalous Δ17O values are present in air coming down from the stratosphere, but this anomaly is removed upon contact of CO2 with leaf water inside plant stomata. Hence, observed Δ17O values depend directly on the magnitude of GPP. Both δ¹³C and Δ17O measurements are scarce over the Amazon-basin, and I propose more than 7000 new measurements leveraging an established aircraft monitoring program in Brazil. Quantitative interpretation of these observations will break new ground in our use of stable isotopes to understand climate variations, and is facilitated by our renowned numerical modeling system “CarbonTracker”. My program will answer two burning question in carbon cycle science today: (a) What is the magnitude of GPP in Amazonia? And (b) How does it vary over different intensities of drought?
Max ERC Funding
2 269 689 €
Duration
Start date: 2015-09-01, End date: 2020-08-31
Project acronym AUROMYC
Project N-Myc and Aurora A: From Protein Stability to Chromosome TopologyN-Myc and Aurora A: From Protein Stability to Chromosome TopologyMyc and Aurora A: From Protein Stability to Chromosome Topology
Researcher (PI) Martin Eilers
Host Institution (HI) JULIUS-MAXIMILIANS-UNIVERSITAT WURZBURG
Call Details Advanced Grant (AdG), LS4, ERC-2014-ADG
Summary There is an intense interest in the function of human Myc proteins that stems from their pervasive role in the genesis of human tumors. A large body of evidence has established that expression levels of one of three closely related Myc proteins are enhanced in the majority of all human tumors and that multiple tumor entities depend on elevated Myc function, arguing that targeting Myc will have significant therapeutic efficacy. This hope awaits clinical confirmation, since the strategies that are currently under investigation to target Myc function or expression have yet to enter the clinic. Myc proteins are global regulators of transcription, but their mechanism of action is poorly understood.
Myc proteins are highly unstable in normal cells and rapidly turned over by the ubiquitin/proteasome system. In contrast, they are stabilized in tumor cells. Work by us and by others has shown that stabilization of Myc is required for tumorigenesis and has identified strategies to destabilize Myc for tumor therapy. This work has also led to the surprising observation that the N-Myc protein, which drives neuroendocrine tumorigenesis, is stabilized by association with the Aurora-A kinase and that clinically available Aurora-A inhibitors can dissociate the complex and destabilize N-Myc. Aurora-A has not previously been implicated in transcription, prompting us to use protein crystallography, proteomics and shRNA screening to understand its interaction with N-Myc. We have now identified a novel protein complex of N-Myc and Aurora-A that provides an unexpected and potentially groundbreaking insight into Myc function. We have also solved the crystal structure of the N-Myc/Aurora-A complex. Collectively, both findings open new strategies to target Myc function for tumor therapy.
Summary
There is an intense interest in the function of human Myc proteins that stems from their pervasive role in the genesis of human tumors. A large body of evidence has established that expression levels of one of three closely related Myc proteins are enhanced in the majority of all human tumors and that multiple tumor entities depend on elevated Myc function, arguing that targeting Myc will have significant therapeutic efficacy. This hope awaits clinical confirmation, since the strategies that are currently under investigation to target Myc function or expression have yet to enter the clinic. Myc proteins are global regulators of transcription, but their mechanism of action is poorly understood.
Myc proteins are highly unstable in normal cells and rapidly turned over by the ubiquitin/proteasome system. In contrast, they are stabilized in tumor cells. Work by us and by others has shown that stabilization of Myc is required for tumorigenesis and has identified strategies to destabilize Myc for tumor therapy. This work has also led to the surprising observation that the N-Myc protein, which drives neuroendocrine tumorigenesis, is stabilized by association with the Aurora-A kinase and that clinically available Aurora-A inhibitors can dissociate the complex and destabilize N-Myc. Aurora-A has not previously been implicated in transcription, prompting us to use protein crystallography, proteomics and shRNA screening to understand its interaction with N-Myc. We have now identified a novel protein complex of N-Myc and Aurora-A that provides an unexpected and potentially groundbreaking insight into Myc function. We have also solved the crystal structure of the N-Myc/Aurora-A complex. Collectively, both findings open new strategies to target Myc function for tumor therapy.
Max ERC Funding
2 455 180 €
Duration
Start date: 2015-08-01, End date: 2020-07-31
