Project acronym CASAA
Project Catalytic asymmetric synthesis of amines and amides
Researcher (PI) Jeffrey William Bode
Host Institution (HI) EIDGENOESSISCHE TECHNISCHE HOCHSCHULE ZUERICH
Country Switzerland
Call Details Starting Grant (StG), PE5, ERC-2012-StG_20111012
Summary "Amines and their acylated derivatives – amides – are among the most common chemical functional groups found in modern pharmaceuticals. Despite this there are few methods for their efficient, environmentally sustainable production in enantiomerically pure form. This proposal seeks to provide new catalytic chemical methods including 1) the catalytic, enantioselective synthesis of peptides and 2) catalytic methods for the preparation of enantiopure nitrogen-containing heterocycles. The proposed work features innovative chemistry including novel reaction mechanism and catalysts. These methods have far reaching applications for the sustainable production of valuable compounds as well as fundamental science."
Summary
"Amines and their acylated derivatives – amides – are among the most common chemical functional groups found in modern pharmaceuticals. Despite this there are few methods for their efficient, environmentally sustainable production in enantiomerically pure form. This proposal seeks to provide new catalytic chemical methods including 1) the catalytic, enantioselective synthesis of peptides and 2) catalytic methods for the preparation of enantiopure nitrogen-containing heterocycles. The proposed work features innovative chemistry including novel reaction mechanism and catalysts. These methods have far reaching applications for the sustainable production of valuable compounds as well as fundamental science."
Max ERC Funding
1 500 000 €
Duration
Start date: 2012-12-01, End date: 2017-11-30
Project acronym CYTRIX
Project Engineering Cytokines for Super-Affinity Binding to Matrix in Regenerative Medicine
Researcher (PI) Jeffrey Alan Hubbell
Host Institution (HI) ECOLE POLYTECHNIQUE FEDERALE DE LAUSANNE
Country Switzerland
Call Details Advanced Grant (AdG), LS7, ERC-2013-ADG
Summary In physiological situations, the extracellular matrix (ECM) sequesters cytokines, localizes them, and modulates their signaling. Thus, physiological signaling from cytokines occurs primarily when the cytokines are interacting with the ECM. In therapeutic use of cytokines, however, this interaction and balance have not been respected; rather the growth factors are merely injected or applied as soluble molecules, perhaps in controlled release forms. This has led to modest efficacy and substantial concerns on safety. Here, we will develop a protein engineering design for second-generation cytokines to lead to their super-affinity binding to ECM molecules in the targeted tissues; this would allow application to a tissue site to yield a tight association with ECM molecules there, turning the tissue itself into a reservoir for cytokine sequestration and presentation. To accomplish this, we have undertaken preliminary work screening a library of cytokines for extraordinarily high affinity binding to a library of ECM molecules. We have thereby identified a small peptide domain within placental growth factor-2 (PlGF-2), namely PlGF-2123-144, that displays super-affinity for a number of ECM proteins. Also in preliminary work, we have demonstrated that recombinant fusion of this domain to low-affinity binding cytokines, namely VEGF-A, PDGF-BB and BMP-2, confers super-affinity binding to ECM molecules and accentuates their functionality in vivo in regenerative medicine models. In the proposed project, based on this preliminary data, we will push forward this protein engineering design, pursuing super-affinity variants of VEGF-A and PDGF-BB in chronic wounds, TGF-beta3 and CXCL11 in skin scar reduction, FGF-18 in osteoarthritic cartilage repair and CXCL12 in stem cell recruitment to ischemic cardiac muscle. Thus, we seek to demonstrate a fundamentally new concept and platform for second-generation growth factor protein engineering.
Summary
In physiological situations, the extracellular matrix (ECM) sequesters cytokines, localizes them, and modulates their signaling. Thus, physiological signaling from cytokines occurs primarily when the cytokines are interacting with the ECM. In therapeutic use of cytokines, however, this interaction and balance have not been respected; rather the growth factors are merely injected or applied as soluble molecules, perhaps in controlled release forms. This has led to modest efficacy and substantial concerns on safety. Here, we will develop a protein engineering design for second-generation cytokines to lead to their super-affinity binding to ECM molecules in the targeted tissues; this would allow application to a tissue site to yield a tight association with ECM molecules there, turning the tissue itself into a reservoir for cytokine sequestration and presentation. To accomplish this, we have undertaken preliminary work screening a library of cytokines for extraordinarily high affinity binding to a library of ECM molecules. We have thereby identified a small peptide domain within placental growth factor-2 (PlGF-2), namely PlGF-2123-144, that displays super-affinity for a number of ECM proteins. Also in preliminary work, we have demonstrated that recombinant fusion of this domain to low-affinity binding cytokines, namely VEGF-A, PDGF-BB and BMP-2, confers super-affinity binding to ECM molecules and accentuates their functionality in vivo in regenerative medicine models. In the proposed project, based on this preliminary data, we will push forward this protein engineering design, pursuing super-affinity variants of VEGF-A and PDGF-BB in chronic wounds, TGF-beta3 and CXCL11 in skin scar reduction, FGF-18 in osteoarthritic cartilage repair and CXCL12 in stem cell recruitment to ischemic cardiac muscle. Thus, we seek to demonstrate a fundamentally new concept and platform for second-generation growth factor protein engineering.
Max ERC Funding
2 368 170 €
Duration
Start date: 2014-05-01, End date: 2019-04-30
Project acronym ESSOG
Project Extracting science from surveys of our Galaxy
Researcher (PI) James Jeffrey Binney
Host Institution (HI) THE CHANCELLOR, MASTERS AND SCHOLARS OF THE UNIVERSITY OF OXFORD
Country United Kingdom
Call Details Advanced Grant (AdG), PE9, ERC-2012-ADG_20120216
Summary "The goal is to put in place the infrastructure required to extract the promised science for large surveys of our Galaxy that are underway and will culminate in ESA's Cornerstone Mission Gaia. Dynamical models are fundamental to this process because surveys are heavily biased by the Sun's location in the Galaxy. Novel dynamical models will be built and novel methods of fitting them to the data developed. With their help we will be able to constrain the distribution of dark matter in the Galaxy. By modelling the chemical and dynamical evolution of the Galaxy we expect to be able to infer much information about how the Galaxy was assembled, and thus test the prevailing cosmological paradigm. During the grant period we will be applying our tools to ground-based surveys, but the first version of the Gaia Catalogue will become available at the end of the grant period, and our goal is to have everything ready and tested for its prompt exploitation."
Summary
"The goal is to put in place the infrastructure required to extract the promised science for large surveys of our Galaxy that are underway and will culminate in ESA's Cornerstone Mission Gaia. Dynamical models are fundamental to this process because surveys are heavily biased by the Sun's location in the Galaxy. Novel dynamical models will be built and novel methods of fitting them to the data developed. With their help we will be able to constrain the distribution of dark matter in the Galaxy. By modelling the chemical and dynamical evolution of the Galaxy we expect to be able to infer much information about how the Galaxy was assembled, and thus test the prevailing cosmological paradigm. During the grant period we will be applying our tools to ground-based surveys, but the first version of the Gaia Catalogue will become available at the end of the grant period, and our goal is to have everything ready and tested for its prompt exploitation."
Max ERC Funding
1 954 460 €
Duration
Start date: 2013-04-01, End date: 2018-03-31
Project acronym GENEWELL
Project Genetics and epigenetics of animal welfare
Researcher (PI) Per Ole Stokmann Jensen
Host Institution (HI) LINKOPINGS UNIVERSITET
Country Sweden
Call Details Advanced Grant (AdG), LS9, ERC-2012-ADG_20120314
Summary Animal welfare is a topic of highest societal and scientific priority. Here, I propose to use genomic and epigenetic tools to provide a new perspective on the biology of animal welfare. This will reveal mechanisms involved in modulating stress responses. Groundbreaking aspects include new insights into how environmental conditions shape the orchestration of the genome by means of epigenetic mechanisms, and how this in turn modulates coping patterns of animals. The flexible epigenome comprises the interface between the environment and the genome. It is involved in both short- and long-term, including transgenerational, adaptations of animals. Hence, populations may adapt to environmental conditions over generations, using epigenetic mechanisms. The project will primarily be based on chickens, but will also be extended to a novel species, the dog. We will generate congenic chicken strains, where interesting alleles and epialleles will be fixed against a common background of either RJF or domestic genotypes. In these, we will apply a broad phenotyping strategy, to characterize the effects on different welfare relevant behaviors. Furthermore, we will characterize how environmental stress affects the epigenome of birds, and tissue samples from more than 500 birds from an intercross between RJF and White Leghorn layers will be used to perform an extensive meth-QTL-analysis. This will reveal environmental and genetic mechanisms affecting gene-specific methylation. The dog is another highly interesting species in the context of behavior genetics, because of its high inter-breed variation in behavior, and its compact and sequenced genome. We will set up a large-scale F2-intercross experiment and phenotype about 400 dogs in standardized behavioral tests. All individuals will be genotyped on about 1000 genetic markers, and this will be used for performing an extensive QTL-analysis in order to find new loci and alleles associated with personalities and coping patterns.
Summary
Animal welfare is a topic of highest societal and scientific priority. Here, I propose to use genomic and epigenetic tools to provide a new perspective on the biology of animal welfare. This will reveal mechanisms involved in modulating stress responses. Groundbreaking aspects include new insights into how environmental conditions shape the orchestration of the genome by means of epigenetic mechanisms, and how this in turn modulates coping patterns of animals. The flexible epigenome comprises the interface between the environment and the genome. It is involved in both short- and long-term, including transgenerational, adaptations of animals. Hence, populations may adapt to environmental conditions over generations, using epigenetic mechanisms. The project will primarily be based on chickens, but will also be extended to a novel species, the dog. We will generate congenic chicken strains, where interesting alleles and epialleles will be fixed against a common background of either RJF or domestic genotypes. In these, we will apply a broad phenotyping strategy, to characterize the effects on different welfare relevant behaviors. Furthermore, we will characterize how environmental stress affects the epigenome of birds, and tissue samples from more than 500 birds from an intercross between RJF and White Leghorn layers will be used to perform an extensive meth-QTL-analysis. This will reveal environmental and genetic mechanisms affecting gene-specific methylation. The dog is another highly interesting species in the context of behavior genetics, because of its high inter-breed variation in behavior, and its compact and sequenced genome. We will set up a large-scale F2-intercross experiment and phenotype about 400 dogs in standardized behavioral tests. All individuals will be genotyped on about 1000 genetic markers, and this will be used for performing an extensive QTL-analysis in order to find new loci and alleles associated with personalities and coping patterns.
Max ERC Funding
2 499 828 €
Duration
Start date: 2013-03-01, End date: 2018-02-28
Project acronym HETMAT
Project Heterogeneity That Matters for Trade and Welfare
Researcher (PI) Thierry Mayer
Host Institution (HI) FONDATION NATIONALE DES SCIENCES POLITIQUES
Country France
Call Details Starting Grant (StG), SH1, ERC-2012-StG_20111124
Summary Accounting for firms' heterogeneity in trade patterns is probably one of the key innovations of international trade that occurred during the last decade. The impact of initial papers such as Melitz (2003) and Bernard and Jensen (1999) is so large in the field that it is considered to have introduced a new paradigm. Apart from providing a convincing framework for a set of empirical facts, the main motivation of this literature was that there are new gains to be expected from trade liberalization. Those come from a selection process, raising aggregate productivity through the reallocation of output among heterogeneous firms. It initially seemed that the information requirements for trade policy evaluations had become much more demanding, in particular requiring detailed micro data. However, the recent work of Arkolakis et al. (2011) suggests that two aggregate ``sufficient statistics'' may be all that is needed to compute the welfare changes associated with trade liberalization. More, they show that those statistics are the same when evaluating welfare changes in representative firm models. The project has three parts. The first one starts by showing that the sufficient statistics approach relies crucially on a specific distributional assumption on heterogeneity, the Pareto distribution. When distributed non-Pareto, heterogeneity does matter, i.e. aggregate statistics are not sufficient to evaluate welfare changes and predict trade patterns. The second part of the project specifies which type of firm-level heterogeneity matters. It shows how to identify which sectors are characterized by ``productivity sorting'' and in which ones ``quality sorting'' is more relevant. Extending the analysis to multiple product firms, the third part shows that heterogeneity inside the firm also matters for welfare changes following trade shocks. It considers how the change in the product mix of the firm following trade liberalization alters the measured productivity of the firm.
Summary
Accounting for firms' heterogeneity in trade patterns is probably one of the key innovations of international trade that occurred during the last decade. The impact of initial papers such as Melitz (2003) and Bernard and Jensen (1999) is so large in the field that it is considered to have introduced a new paradigm. Apart from providing a convincing framework for a set of empirical facts, the main motivation of this literature was that there are new gains to be expected from trade liberalization. Those come from a selection process, raising aggregate productivity through the reallocation of output among heterogeneous firms. It initially seemed that the information requirements for trade policy evaluations had become much more demanding, in particular requiring detailed micro data. However, the recent work of Arkolakis et al. (2011) suggests that two aggregate ``sufficient statistics'' may be all that is needed to compute the welfare changes associated with trade liberalization. More, they show that those statistics are the same when evaluating welfare changes in representative firm models. The project has three parts. The first one starts by showing that the sufficient statistics approach relies crucially on a specific distributional assumption on heterogeneity, the Pareto distribution. When distributed non-Pareto, heterogeneity does matter, i.e. aggregate statistics are not sufficient to evaluate welfare changes and predict trade patterns. The second part of the project specifies which type of firm-level heterogeneity matters. It shows how to identify which sectors are characterized by ``productivity sorting'' and in which ones ``quality sorting'' is more relevant. Extending the analysis to multiple product firms, the third part shows that heterogeneity inside the firm also matters for welfare changes following trade shocks. It considers how the change in the product mix of the firm following trade liberalization alters the measured productivity of the firm.
Max ERC Funding
1 119 040 €
Duration
Start date: 2012-11-01, End date: 2018-07-31
Project acronym MatMech
Project Live Tapings of Material Formation: Unravelling formation mechanisms in materials chemistry through Multimodal X-ray total scattering studies
Researcher (PI) Kirsten Marie oernsbjerg Jensen
Host Institution (HI) KOBENHAVNS UNIVERSITET
Country Denmark
Call Details Starting Grant (StG), PE5, ERC-2018-STG
Summary With this proposal, I want to develop a new, multimodal approach to in situ X-ray scattering studies to unravel formation mechanisms of the solid state. The aim of the project is to develop a unified view of metal oxide nucleation processes on the atomic scale: From precursor complexes over pre-nucelation clusters to the final crystalline particle.
The development of new materials relies on our understanding of the relation between material structure, properties and synthesis. While the intense focus on ‘materials by design’ have made it possible to predict the properties of many materials given an atomic arrangement, actually knowing how to synthesize it is a completely different story. Material synthesis methods are to a large degree developed by extensive parameter studies based on trial-and-error experiments. Specifically, our knowledge of particle nucleation is lacking, as even non-classical views on nucleation such as the concept of pre-nucleation clusters do not apply an atomistic view of the formation process. Here, I want to use new methods in X-ray total scattering and Pair Distribution Function analysis to follow nucleation processes to establish the framework needed for predictive material synthesis. One of the large challenges in studying nucleation is the lack of a characterization method that can give structural information on materials without long-range order. I have demonstrated that time-resolved X-ray total scattering gives new possibilities for following structural changes in a synthesis, and the use of total scattering has opened for a new view on material formation. However, the complexity of the structures involved in nucleation processes is too large to obtain sufficient information from X-ray total scattering alone. Here, I will combine X-ray total scattering data with complementary techniques using a new multimodal approach for complex modelling analysis, providing a unifying view on material nucleation.
Summary
With this proposal, I want to develop a new, multimodal approach to in situ X-ray scattering studies to unravel formation mechanisms of the solid state. The aim of the project is to develop a unified view of metal oxide nucleation processes on the atomic scale: From precursor complexes over pre-nucelation clusters to the final crystalline particle.
The development of new materials relies on our understanding of the relation between material structure, properties and synthesis. While the intense focus on ‘materials by design’ have made it possible to predict the properties of many materials given an atomic arrangement, actually knowing how to synthesize it is a completely different story. Material synthesis methods are to a large degree developed by extensive parameter studies based on trial-and-error experiments. Specifically, our knowledge of particle nucleation is lacking, as even non-classical views on nucleation such as the concept of pre-nucleation clusters do not apply an atomistic view of the formation process. Here, I want to use new methods in X-ray total scattering and Pair Distribution Function analysis to follow nucleation processes to establish the framework needed for predictive material synthesis. One of the large challenges in studying nucleation is the lack of a characterization method that can give structural information on materials without long-range order. I have demonstrated that time-resolved X-ray total scattering gives new possibilities for following structural changes in a synthesis, and the use of total scattering has opened for a new view on material formation. However, the complexity of the structures involved in nucleation processes is too large to obtain sufficient information from X-ray total scattering alone. Here, I will combine X-ray total scattering data with complementary techniques using a new multimodal approach for complex modelling analysis, providing a unifying view on material nucleation.
Max ERC Funding
1 493 269 €
Duration
Start date: 2019-02-01, End date: 2024-01-31
Project acronym StemHealth
Project Foetal Intestinal Stem Cells in Biology and Health
Researcher (PI) Kim Bak Jensen
Host Institution (HI) KOBENHAVNS UNIVERSITET
Country Denmark
Call Details Consolidator Grant (CoG), LS7, ERC-2015-CoG
Summary There is currently no medical cure for the millions of individuals affected by inflammatory bowel disease (IBD). These patients suffer from bleeding along the gastrointestinal tract due to epithelial ulceration, which causes severe abdominal pain, diarrhoea and malnutrition. This is due to the severely compromised integrity of the intestinal epithelium. I propose that patients with IBD will benefit from an intestinal epithelial transplant.
The objectives of this research programme are two fold. Firstly, I propose to perform preclinical testing of human intestinal epithelium to pave the way for their inclusion in clinical trials for IBD patients. This will be based on a combination of state-of-the-art cell culture methods with novel transplantation methodology. By combining analysis of intestinal epithelial cells from various developmental stages, I will be able to identify the most suitable source for transplantation and define how adult stem cells are specified in the tissue. Secondly, I will utilise an in vitro culture system to identify the transcriptional networks responsible for the maturation of the foetal intestinal epithelium. Tissue maturation currently constitutes a major roadblock in regenerative medicine as cells derived from foetal and pluripotent stem cells have foetal properties. Understanding this process will therefore improve our ability to generate sustainable sources of cells for transplantation, which is pivotal for future therapies relying on regenerative medicine and in vitro modelling of disease
The proposed research programme will have significant clinical and biological impact. Clinically, it provides the framework for initiating clinical trials for patients with IBD and protocols to obtain mature adult epithelium for in vitro disease modelling. From a biological perspective, we will gain insights into how specific signalling networks maintain specific cell states and dictate tissue maturation.
Summary
There is currently no medical cure for the millions of individuals affected by inflammatory bowel disease (IBD). These patients suffer from bleeding along the gastrointestinal tract due to epithelial ulceration, which causes severe abdominal pain, diarrhoea and malnutrition. This is due to the severely compromised integrity of the intestinal epithelium. I propose that patients with IBD will benefit from an intestinal epithelial transplant.
The objectives of this research programme are two fold. Firstly, I propose to perform preclinical testing of human intestinal epithelium to pave the way for their inclusion in clinical trials for IBD patients. This will be based on a combination of state-of-the-art cell culture methods with novel transplantation methodology. By combining analysis of intestinal epithelial cells from various developmental stages, I will be able to identify the most suitable source for transplantation and define how adult stem cells are specified in the tissue. Secondly, I will utilise an in vitro culture system to identify the transcriptional networks responsible for the maturation of the foetal intestinal epithelium. Tissue maturation currently constitutes a major roadblock in regenerative medicine as cells derived from foetal and pluripotent stem cells have foetal properties. Understanding this process will therefore improve our ability to generate sustainable sources of cells for transplantation, which is pivotal for future therapies relying on regenerative medicine and in vitro modelling of disease
The proposed research programme will have significant clinical and biological impact. Clinically, it provides the framework for initiating clinical trials for patients with IBD and protocols to obtain mature adult epithelium for in vitro disease modelling. From a biological perspective, we will gain insights into how specific signalling networks maintain specific cell states and dictate tissue maturation.
Max ERC Funding
2 000 000 €
Duration
Start date: 2016-08-01, End date: 2022-07-31
Project acronym WATERUNDERTHEICE
Project Where is the water under the Greenland ice sheet?
Researcher (PI) Dorthe Dahl-Jensen
Host Institution (HI) KOBENHAVNS UNIVERSITET
Country Denmark
Call Details Advanced Grant (AdG), PE10, ERC-2009-AdG
Summary Recent analysis of radar-depth sounder data has shown that many areas of the Greenland ice sheet have melt water under the base. The extent of the wet base and distribution of melt water are poorly known. Also lakes under the ice have not been discovered in contrast with those in Antarctica. The effect of the water beneath the ice, however, is well documented: it lubricates the bed and removes the friction between the basal ice and underlying bedrock. The ice with a wet bed flows faster, reacts rapidly to changes in climate and the basal-melt water contributes to the fresh-water supply to the ocean from the Greenland ice sheet. The primary objectives of the project are to map melt water extent of the Greenland ice sheet and its impact by tracing internal layers and analyzing bedrock returns from airborne radio-echo sounding data, and use mapping results in conjunction with ice-sheet and hydrostatic models for the movement of the basal water to predict the ice-sheet s response to climate change. The information derived from deep ice-cores that reach the bed will be used to constrain models. We will also study the basal material (dust, DNA and microbiological material) and bedrock properties from the deep-ice core sites. This will add a further dimension to the study and provide opportunities to look for life under the ice and constrain the age of the Greenland ice sheet. The proposed research is a high risk project because of the difficulty in accessing basal conditions under 3-km of ice with a potential for high payoff science. The team will consist of scientists and engineers with expertise in the palaeoclimate, radar sounding and signal processing, and ice-sheet models.
Summary
Recent analysis of radar-depth sounder data has shown that many areas of the Greenland ice sheet have melt water under the base. The extent of the wet base and distribution of melt water are poorly known. Also lakes under the ice have not been discovered in contrast with those in Antarctica. The effect of the water beneath the ice, however, is well documented: it lubricates the bed and removes the friction between the basal ice and underlying bedrock. The ice with a wet bed flows faster, reacts rapidly to changes in climate and the basal-melt water contributes to the fresh-water supply to the ocean from the Greenland ice sheet. The primary objectives of the project are to map melt water extent of the Greenland ice sheet and its impact by tracing internal layers and analyzing bedrock returns from airborne radio-echo sounding data, and use mapping results in conjunction with ice-sheet and hydrostatic models for the movement of the basal water to predict the ice-sheet s response to climate change. The information derived from deep ice-cores that reach the bed will be used to constrain models. We will also study the basal material (dust, DNA and microbiological material) and bedrock properties from the deep-ice core sites. This will add a further dimension to the study and provide opportunities to look for life under the ice and constrain the age of the Greenland ice sheet. The proposed research is a high risk project because of the difficulty in accessing basal conditions under 3-km of ice with a potential for high payoff science. The team will consist of scientists and engineers with expertise in the palaeoclimate, radar sounding and signal processing, and ice-sheet models.
Max ERC Funding
2 499 999 €
Duration
Start date: 2010-01-01, End date: 2015-12-31
