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 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 HBAR12
Project Spectroscopy of Trapped Antihydrogen
Researcher (PI) Jeffrey Scott Hangst
Host Institution (HI) AARHUS UNIVERSITET
Country Denmark
Call Details Advanced Grant (AdG), PE2, ERC-2012-ADG_20120216
Summary Antihydrogen is the only stable, neutral antimatter system available for laboratory study. Recently, the ALPHA Collaboration at CERN has succeeded in synthesizing and trapping antihydrogen atoms, storing them for up to 1000 s, and performing the first resonant spectroscopy, using microwaves, on trapped antihydrogen. This last, historic result paves the way for precision microwave and laser spectroscopic measurements using small numbers of trapped antihydrogen atoms. Because of the breakthroughs made in our collaboration, it is now possible, for the first time, to design antimatter spectroscopic experiments that have achievable milestones of precision. These measurements require a next-generation apparatus, known as ALPHA-2, which is the subject of this proposal. The items sought are hardware components and radiation sources to help us to test CPT (charge conjugation, parity, time reversal) symmetry invariance by comparing the spectrum of antihydrogen to that of hydrogen. More generally, we will address the very fundamental question: do matter and antimatter obey the same laws of physics? The Standard Model says that they must, but mystery continues to cloud our understanding of antimatter - as evidenced by the unexplained baryon asymmetry in the universe. ALPHA's experiments offer a unique, high precision, model-independent view into the internal workings of antimatter.
Summary
Antihydrogen is the only stable, neutral antimatter system available for laboratory study. Recently, the ALPHA Collaboration at CERN has succeeded in synthesizing and trapping antihydrogen atoms, storing them for up to 1000 s, and performing the first resonant spectroscopy, using microwaves, on trapped antihydrogen. This last, historic result paves the way for precision microwave and laser spectroscopic measurements using small numbers of trapped antihydrogen atoms. Because of the breakthroughs made in our collaboration, it is now possible, for the first time, to design antimatter spectroscopic experiments that have achievable milestones of precision. These measurements require a next-generation apparatus, known as ALPHA-2, which is the subject of this proposal. The items sought are hardware components and radiation sources to help us to test CPT (charge conjugation, parity, time reversal) symmetry invariance by comparing the spectrum of antihydrogen to that of hydrogen. More generally, we will address the very fundamental question: do matter and antimatter obey the same laws of physics? The Standard Model says that they must, but mystery continues to cloud our understanding of antimatter - as evidenced by the unexplained baryon asymmetry in the universe. ALPHA's experiments offer a unique, high precision, model-independent view into the internal workings of antimatter.
Max ERC Funding
2 136 888 €
Duration
Start date: 2013-05-01, End date: 2018-12-31
Project acronym M4D
Project Metal Microstructures in Four Dimensions
Researcher (PI) Dorte JUUL JENSEN
Host Institution (HI) DANMARKS TEKNISKE UNIVERSITET
Country Denmark
Call Details Advanced Grant (AdG), PE8, ERC-2017-ADG
Summary The goals are:
1) to develop a universal laboratory-based 4D X-ray microscope with potentials in the broad field of materials science and beyond;
2) to advance metal research by quantifying local microstructural variations using the new 4D tool and by including the effects hereof in the understanding and modelling of industrially relevant metals.
Today, high resolution 4D (x,y,z,time) crystallographic characterization of materials is possible only at large international facilities. This is a serious limitation preventing the common use. The new technique will allow such 4D characterization to be carried out at home laboratories, thereby wide spreading this powerful tool.
Whereas current metal research mainly focuses on average properties, local microstructural variations are present in all metals on several length scales, and are often of critical importance for the properties and performance of the metal. In this project, the new technique will be the cornerstone in studies of such variations in three types of metallic materials: 3D printed, multilayered and micrometre-scale metals. Effects of local variations on the subsequent microstructural evolution will be followed during deformation and annealing, i.e. during processes typical for manufacturing, and occurring during in-service operation.
Current models largely ignore the presence of local microstructural variations and lack predictive power. Based on the new experimental data, three models operating on different length scales will be improved and combined, namely crystal plasticity finite element, phase field and molecular dynamics models. The main novelty here relates to the full 4D validation of the models, which has not been possible hitherto because of lack of sufficient experimental data.
The resulting fundamental understanding of the inherent microstructural variations and the new models are foreseen to be an integral part of the future design of metallic materials for high performance applications.
Summary
The goals are:
1) to develop a universal laboratory-based 4D X-ray microscope with potentials in the broad field of materials science and beyond;
2) to advance metal research by quantifying local microstructural variations using the new 4D tool and by including the effects hereof in the understanding and modelling of industrially relevant metals.
Today, high resolution 4D (x,y,z,time) crystallographic characterization of materials is possible only at large international facilities. This is a serious limitation preventing the common use. The new technique will allow such 4D characterization to be carried out at home laboratories, thereby wide spreading this powerful tool.
Whereas current metal research mainly focuses on average properties, local microstructural variations are present in all metals on several length scales, and are often of critical importance for the properties and performance of the metal. In this project, the new technique will be the cornerstone in studies of such variations in three types of metallic materials: 3D printed, multilayered and micrometre-scale metals. Effects of local variations on the subsequent microstructural evolution will be followed during deformation and annealing, i.e. during processes typical for manufacturing, and occurring during in-service operation.
Current models largely ignore the presence of local microstructural variations and lack predictive power. Based on the new experimental data, three models operating on different length scales will be improved and combined, namely crystal plasticity finite element, phase field and molecular dynamics models. The main novelty here relates to the full 4D validation of the models, which has not been possible hitherto because of lack of sufficient experimental data.
The resulting fundamental understanding of the inherent microstructural variations and the new models are foreseen to be an integral part of the future design of metallic materials for high performance applications.
Max ERC Funding
2 496 519 €
Duration
Start date: 2018-10-01, End date: 2023-09-30
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
