Project acronym AFRODITE
Project Advanced Fluid Research On Drag reduction In Turbulence Experiments
Researcher (PI) Jens Henrik Mikael Fransson
Host Institution (HI) KUNGLIGA TEKNISKA HOEGSKOLAN
Call Details Starting Grant (StG), PE8, ERC-2010-StG_20091028
Summary A hot topic in today's debate on global warming is drag reduction in aeronautics. The most beneficial concept for drag reduction is to maintain the major portion of the airfoil laminar. Estimations show that the potential drag reduction can be as much as 15%, which would give a significant reduction of NOx and CO emissions in the atmosphere considering that the number of aircraft take offs, only in the EU, is over 19 million per year. An important element for successful flow control, which can lead to a reduced aerodynamic drag, is enhanced physical understanding of the transition to turbulence process.
In previous wind tunnel measurements we have shown that roughness elements can be used to sensibly delay transition to turbulence. The result is revolutionary, since the common belief has been that surface roughness causes earlier transition and in turn increases the drag, and is a proof of concept of the passive control method per se. The beauty with a passive control technique is that no external energy has to be added to the flow system in order to perform the control, instead one uses the existing energy in the flow.
In this project proposal, AFRODITE, we will take this passive control method to the next level by making it twofold, more persistent and more robust. Transition prevention is the goal rather than transition delay and the method will be extended to simultaneously control separation, which is another unwanted flow phenomenon especially during airplane take offs. AFRODITE will be a catalyst for innovative research, which will lead to a cleaner sky.
Summary
A hot topic in today's debate on global warming is drag reduction in aeronautics. The most beneficial concept for drag reduction is to maintain the major portion of the airfoil laminar. Estimations show that the potential drag reduction can be as much as 15%, which would give a significant reduction of NOx and CO emissions in the atmosphere considering that the number of aircraft take offs, only in the EU, is over 19 million per year. An important element for successful flow control, which can lead to a reduced aerodynamic drag, is enhanced physical understanding of the transition to turbulence process.
In previous wind tunnel measurements we have shown that roughness elements can be used to sensibly delay transition to turbulence. The result is revolutionary, since the common belief has been that surface roughness causes earlier transition and in turn increases the drag, and is a proof of concept of the passive control method per se. The beauty with a passive control technique is that no external energy has to be added to the flow system in order to perform the control, instead one uses the existing energy in the flow.
In this project proposal, AFRODITE, we will take this passive control method to the next level by making it twofold, more persistent and more robust. Transition prevention is the goal rather than transition delay and the method will be extended to simultaneously control separation, which is another unwanted flow phenomenon especially during airplane take offs. AFRODITE will be a catalyst for innovative research, which will lead to a cleaner sky.
Max ERC Funding
1 418 399 €
Duration
Start date: 2010-11-01, End date: 2015-10-31
Project acronym BONEMECHBIO
Project Frontier research in bone mechanobiology during normal physiology, disease and for tissue regeneration
Researcher (PI) Laoise Maria Cunningham
Host Institution (HI) NATIONAL UNIVERSITY OF IRELAND GALWAY
Call Details Starting Grant (StG), PE8, ERC-2010-StG_20091028
Summary While previous studies have investigated cell-signalling pathways that facilitate mechanotransduction and have provided a wealth of data, to date, in vivo mechanobiology is not fully understood. In the research study proposed the applicant will embark upon frontier research to delineate these specific aspects of bone mechanotransduction during normal physiology, disease and for tissue regeneration purposes. If these quantities were better understood the proposed research program will deliver significant advances in the understanding of the mechanical regulation of bone remodelling during normal physiology and osteoporosis, and will enhance approaches for regeneration of bone tissue for treatment of bone pathologies. The primary objective is to delineate the normal mechanosensory and signalling mechanisms of bone cells. The secondary objective is to determine whether the regulatory role of bone cells is inhibited or impaired during bone diseases such as osteoporosis. The final objective of this project is to develop an in vitro mechanical loading device that can enhance bone tissue regeneration and thereby advance current treatment approaches for bone pathologies. To address these objectives, five hypotheses have been defined, each of which will underpin the research of five work packages. A combination of experimental studies, using animal models and in vitro cell culture, and computational modelling will be taken to test each of these hypotheses. Answering these hypotheses will bring us closer to an understanding of the origins of bone mechanobiology and diseases such as osteoporosis. Furthermore, the results of these studies will facilitate development of novel approaches to enhance bone regeneration in vitro.
Summary
While previous studies have investigated cell-signalling pathways that facilitate mechanotransduction and have provided a wealth of data, to date, in vivo mechanobiology is not fully understood. In the research study proposed the applicant will embark upon frontier research to delineate these specific aspects of bone mechanotransduction during normal physiology, disease and for tissue regeneration purposes. If these quantities were better understood the proposed research program will deliver significant advances in the understanding of the mechanical regulation of bone remodelling during normal physiology and osteoporosis, and will enhance approaches for regeneration of bone tissue for treatment of bone pathologies. The primary objective is to delineate the normal mechanosensory and signalling mechanisms of bone cells. The secondary objective is to determine whether the regulatory role of bone cells is inhibited or impaired during bone diseases such as osteoporosis. The final objective of this project is to develop an in vitro mechanical loading device that can enhance bone tissue regeneration and thereby advance current treatment approaches for bone pathologies. To address these objectives, five hypotheses have been defined, each of which will underpin the research of five work packages. A combination of experimental studies, using animal models and in vitro cell culture, and computational modelling will be taken to test each of these hypotheses. Answering these hypotheses will bring us closer to an understanding of the origins of bone mechanobiology and diseases such as osteoporosis. Furthermore, the results of these studies will facilitate development of novel approaches to enhance bone regeneration in vitro.
Max ERC Funding
1 499 911 €
Duration
Start date: 2011-02-01, End date: 2016-01-31
Project acronym GAMETE RECOGNITION
Project Molecular Basis of Mammalian Egg-Sperm Interaction
Researcher (PI) Luca Vincenzo Luigi Jovine
Host Institution (HI) KAROLINSKA INSTITUTET
Call Details Starting Grant (StG), LS1, ERC-2010-StG_20091118
Summary At the dawn of the 21st century, our knowledge of the molecular mechanism of mammalian
fertilization remains very limited. Different lines of evidence indicate that initial gamete recognition
depends on interaction between a few distinct proteins on sperm and ZP3, a major component of the
extracellular coat of oocytes, the zona pellucida (ZP). On the other hand, recent findings suggest an
alternative mechanism in which cleavage of another ZP subunit, ZP2, regulates binding of gametes
by altering the global structure of the ZP. Progress in the field has been hindered by the paucity and
heterogeneity of native egg-sperm recognition proteins, so that novel approaches are needed to
reconcile all available data into a single consistent model of fertilization. Following our recent
determination of the structure of the most conserved domain of sperm receptor ZP3 by X-ray
crystallography, we will conclusively establish the basis of mammalian gamete recognition by
performing structural studies of homogeneous, biologically active recombinant proteins. First, we
will combine crystallographic studies of isolated ZP subunits with electron microscopy analysis of
their filaments to build a structural model of the ZP. Second, structures of key egg-sperm
recognition protein complexes will be determined. Third, we will investigate how proteolysis of
ZP2 triggers overall conformational changes of the ZP upon gamete fusion. Together with
functional analysis of mutant proteins, these studies will provide atomic resolution snapshots of the
most crucial step in the beginning of a new life, directly visualizing molecular determinants
responsible for species-restricted gamete interaction at fertilization. The progressive decrease of
births in the Western world and inadequacy of current contraceptive methods in developing
countries underscore an urgent need for a modern approach to reproductive welfare. This research
will not only shed light on a truly fundamental biological problem, but also constitute a solid
foundation for the reproductive medicine of the future.
Summary
At the dawn of the 21st century, our knowledge of the molecular mechanism of mammalian
fertilization remains very limited. Different lines of evidence indicate that initial gamete recognition
depends on interaction between a few distinct proteins on sperm and ZP3, a major component of the
extracellular coat of oocytes, the zona pellucida (ZP). On the other hand, recent findings suggest an
alternative mechanism in which cleavage of another ZP subunit, ZP2, regulates binding of gametes
by altering the global structure of the ZP. Progress in the field has been hindered by the paucity and
heterogeneity of native egg-sperm recognition proteins, so that novel approaches are needed to
reconcile all available data into a single consistent model of fertilization. Following our recent
determination of the structure of the most conserved domain of sperm receptor ZP3 by X-ray
crystallography, we will conclusively establish the basis of mammalian gamete recognition by
performing structural studies of homogeneous, biologically active recombinant proteins. First, we
will combine crystallographic studies of isolated ZP subunits with electron microscopy analysis of
their filaments to build a structural model of the ZP. Second, structures of key egg-sperm
recognition protein complexes will be determined. Third, we will investigate how proteolysis of
ZP2 triggers overall conformational changes of the ZP upon gamete fusion. Together with
functional analysis of mutant proteins, these studies will provide atomic resolution snapshots of the
most crucial step in the beginning of a new life, directly visualizing molecular determinants
responsible for species-restricted gamete interaction at fertilization. The progressive decrease of
births in the Western world and inadequacy of current contraceptive methods in developing
countries underscore an urgent need for a modern approach to reproductive welfare. This research
will not only shed light on a truly fundamental biological problem, but also constitute a solid
foundation for the reproductive medicine of the future.
Max ERC Funding
1 499 282 €
Duration
Start date: 2011-01-01, End date: 2015-12-31
Project acronym MULTIMATE
Project A Research Platform Addressing Outstanding Research Challenges for Nanoscale Design and Engineering of Multifunctional Material
Researcher (PI) Johanna Rosen
Host Institution (HI) LINKOPINGS UNIVERSITET
Call Details Starting Grant (StG), PE8, ERC-2010-StG_20091028
Summary "Nanoscale engineering is a fascinating research field spawning extraordinary materials which revolutionize microelectronics, medicine,energy production, etc. Still, there is a need for new materials and synthesis methods to offer unprecedented properties for use in future applications.
In this research project, I will conduct fundamental science investigations focused towards the development of novel materials with tailor-made properties, achieved by precise control of the materials structure and compostition. The objectives are to: 1) Perform novel synthesis of graphene. 2) Explore nanoscale engineering of ""graphene-based"" materials, based on more than one atomic element. 3) Tailor uniquely combined metallic/ceramic/magnetic materials properties in so called MAX phases. 4) Provide proof of concept for thin film architectures in advanced applications that require specific mechanical, tribological, electronic, and magnetic properties.
This initative involves advanced materials design by a new and unique synthesis method based on cathodic arc. Research breakthroughs are envisioned: Functionalized graphene-based and fullerene-like compounds are expected to have a major impact on tribology and electronic applications. The MAX phases are expected to be a new candidate for applications within low friction contacts, electronics, as well as spintronics. In particular, single crystal devices are predicted through tuning of tunnel magnetoresistance (TMR) and anisotropic conductivity (from insulating to n-and p-type).
I can lead this innovative and interdisciplinary project, with a unique background combining relevant research areas: arc process development, plasma processing, materials synthesis and engineering, characterization, along with theory and modelling."
Summary
"Nanoscale engineering is a fascinating research field spawning extraordinary materials which revolutionize microelectronics, medicine,energy production, etc. Still, there is a need for new materials and synthesis methods to offer unprecedented properties for use in future applications.
In this research project, I will conduct fundamental science investigations focused towards the development of novel materials with tailor-made properties, achieved by precise control of the materials structure and compostition. The objectives are to: 1) Perform novel synthesis of graphene. 2) Explore nanoscale engineering of ""graphene-based"" materials, based on more than one atomic element. 3) Tailor uniquely combined metallic/ceramic/magnetic materials properties in so called MAX phases. 4) Provide proof of concept for thin film architectures in advanced applications that require specific mechanical, tribological, electronic, and magnetic properties.
This initative involves advanced materials design by a new and unique synthesis method based on cathodic arc. Research breakthroughs are envisioned: Functionalized graphene-based and fullerene-like compounds are expected to have a major impact on tribology and electronic applications. The MAX phases are expected to be a new candidate for applications within low friction contacts, electronics, as well as spintronics. In particular, single crystal devices are predicted through tuning of tunnel magnetoresistance (TMR) and anisotropic conductivity (from insulating to n-and p-type).
I can lead this innovative and interdisciplinary project, with a unique background combining relevant research areas: arc process development, plasma processing, materials synthesis and engineering, characterization, along with theory and modelling."
Max ERC Funding
1 484 700 €
Duration
Start date: 2010-09-01, End date: 2015-08-31
Project acronym REPMIT
Project THE ENZYMATIC MACHINERY OF HUMAN MITOCHONDRIAL DNA MAINTENANCE
Researcher (PI) Maria Gustafsson Falkenberg
Host Institution (HI) GOETEBORGS UNIVERSITET
Call Details Starting Grant (StG), LS1, ERC-2010-StG_20091118
Summary SUMMARY
Mitochondria are required to convert food into usable energy forms and every cell contains thousands of them. Unlike most other cellular compartments, mitochondria have their own genomes (mtDNA) that encode for 13 of the about 90 proteins present in the respiratory chain. All proteins necessary for mtDNA replication, as well as transcription and translation of mtDNA-encoded genes, are encoded in the nucleus. Mutations in nuclear-encoded proteins required for mtDNA maintenance is an important cause of neurodegeneration and muscle diseases. The common result of these defects is either mtDNA depletion or accumulation of multiple deletions of mtDNA in postmitotic tissues.
Research in my laboratory will elucidate the molecular mechanisms and regulation of mitochondrial DNA replication in human cells. We will establish how mtDNA is packaged into nucleoprotein complexes, a.k.a. nucleoids and establish how these nucleoids are selected for mtDNA replication. We will elucidate the molecular mechanisms by which specific mutations in the mtDNA replication machinery affect mtDNA maintenance and cause human disease.
Mitochondrial dysfunction is not limited to rare, genetic disorders, but also associated with age-associated common diseases as well as with the normal aging process. I will use my biochemical insights in combination with mouse genetics to address the hypothesis that increased mtDNA mutation load may be an important cause of normal aging.
My specific aims will be:
Aim 1. To define how initiation of mtDNA replication at OriH is regulated.
Aim 2. To identify and characterize regulators of mtDNA replication.
Aim 3. To characterize the structure and function of the mtDNA nucleoid in DNA replication.
Aim 4. To address the mitochondrial theory of ageing
Summary
SUMMARY
Mitochondria are required to convert food into usable energy forms and every cell contains thousands of them. Unlike most other cellular compartments, mitochondria have their own genomes (mtDNA) that encode for 13 of the about 90 proteins present in the respiratory chain. All proteins necessary for mtDNA replication, as well as transcription and translation of mtDNA-encoded genes, are encoded in the nucleus. Mutations in nuclear-encoded proteins required for mtDNA maintenance is an important cause of neurodegeneration and muscle diseases. The common result of these defects is either mtDNA depletion or accumulation of multiple deletions of mtDNA in postmitotic tissues.
Research in my laboratory will elucidate the molecular mechanisms and regulation of mitochondrial DNA replication in human cells. We will establish how mtDNA is packaged into nucleoprotein complexes, a.k.a. nucleoids and establish how these nucleoids are selected for mtDNA replication. We will elucidate the molecular mechanisms by which specific mutations in the mtDNA replication machinery affect mtDNA maintenance and cause human disease.
Mitochondrial dysfunction is not limited to rare, genetic disorders, but also associated with age-associated common diseases as well as with the normal aging process. I will use my biochemical insights in combination with mouse genetics to address the hypothesis that increased mtDNA mutation load may be an important cause of normal aging.
My specific aims will be:
Aim 1. To define how initiation of mtDNA replication at OriH is regulated.
Aim 2. To identify and characterize regulators of mtDNA replication.
Aim 3. To characterize the structure and function of the mtDNA nucleoid in DNA replication.
Aim 4. To address the mitochondrial theory of ageing
Max ERC Funding
1 492 684 €
Duration
Start date: 2011-04-01, End date: 2016-03-31
Project acronym RNANTIBIOTICS
Project RNA-mediated virulence gene regulation: Identification of novel antibacterial compounds
Researcher (PI) Jan Jörgen Johansson
Host Institution (HI) UMEA UNIVERSITET
Call Details Starting Grant (StG), LS6, ERC-2010-StG_20091118
Summary All kingdoms possess a large fraction of RNA-based regulation. We identified several small non-coding regulatory RNAs (ncRNAs) in the human bacterial pathogen Listeria monocytogenes that controlled virulence by a direct RNA:RNA interaction. My group have also identified several 5´-untranslated RNAs (5´-UTRs) known to control expression of their downstream mRNA by a switch mechanism triggered by certain metabolites, specific compartments of the host or by different temperatures.
In the suggested project, we will analyze the mechanism by how various RNA-species function on a molecular level by biochemical and genetic approaches. By constructing mutations (deletion and base-substitutions), the role of the regulatory RNAs and their targets during pathogenesis will be pin-pointed using different virulence model organisms. For 5´-UTRs binding specific metabolites, we will add non-metabolic analogs to examine if such molecules can block the function of the 5´-UTRs and hence infection. The core structure of one identified ncRNA will be used as a scaffold to develop an RNA interference system in bacteria.
At least one RNA-helicase has been shown to be essential for bacterial motility and growth at 4°C. It is being purified to test its in vitro properties at mRNA targets and at different temperatures. Its in vivo role will be analyzed by genetic techniques.
Bacterial resistance against different antibiotics is an increasing problem worldwide. We have identified one pyridine molecule specifically targeting listerial virulence gene expression and its mechanism of action will be revealed by genetic and biochemical techniques. A diffusible, although yet unknown molecule, with bacteriostatic activity was observed and its nature and mechanism will be revealed mainly by biochemical experiments.
Our work will give important knowledge of how the bacterium uses RNA to sense its surroundings, but will also identifiy new types of antibacterial agents.
Summary
All kingdoms possess a large fraction of RNA-based regulation. We identified several small non-coding regulatory RNAs (ncRNAs) in the human bacterial pathogen Listeria monocytogenes that controlled virulence by a direct RNA:RNA interaction. My group have also identified several 5´-untranslated RNAs (5´-UTRs) known to control expression of their downstream mRNA by a switch mechanism triggered by certain metabolites, specific compartments of the host or by different temperatures.
In the suggested project, we will analyze the mechanism by how various RNA-species function on a molecular level by biochemical and genetic approaches. By constructing mutations (deletion and base-substitutions), the role of the regulatory RNAs and their targets during pathogenesis will be pin-pointed using different virulence model organisms. For 5´-UTRs binding specific metabolites, we will add non-metabolic analogs to examine if such molecules can block the function of the 5´-UTRs and hence infection. The core structure of one identified ncRNA will be used as a scaffold to develop an RNA interference system in bacteria.
At least one RNA-helicase has been shown to be essential for bacterial motility and growth at 4°C. It is being purified to test its in vitro properties at mRNA targets and at different temperatures. Its in vivo role will be analyzed by genetic techniques.
Bacterial resistance against different antibiotics is an increasing problem worldwide. We have identified one pyridine molecule specifically targeting listerial virulence gene expression and its mechanism of action will be revealed by genetic and biochemical techniques. A diffusible, although yet unknown molecule, with bacteriostatic activity was observed and its nature and mechanism will be revealed mainly by biochemical experiments.
Our work will give important knowledge of how the bacterium uses RNA to sense its surroundings, but will also identifiy new types of antibacterial agents.
Max ERC Funding
999 996 €
Duration
Start date: 2010-10-01, End date: 2015-09-30
Project acronym STEMREPAIR
Project Novel mesenchymal stem cell based therapies for articular cartilage repair
Researcher (PI) Daniel John Kelly
Host Institution (HI) THE PROVOST, FELLOWS, FOUNDATION SCHOLARS & THE OTHER MEMBERS OF BOARD OF THE COLLEGE OF THE HOLY & UNDIVIDED TRINITY OF QUEEN ELIZABETH NEAR DUBLIN
Call Details Starting Grant (StG), PE8, ERC-2010-StG_20091028
Summary Once damaged articular cartilage has a limited reparative capacity and thus lesions often progress to arthritis. This has motivated the development of cell based therapies for the repair of cartilage defects such as autologous chondrocyte implantation (ACI). Such therapies are limited in two ways. Firstly, they do not result in the regeneration of hyaline cartilage and hence the repair is temporary. Secondly, widespread adaptation into the clinical setting is impeded by practical issues such as the high fiscal cost and time required for culture expansion of chondrocytes. The applicant is of the belief that both issues cannot currently be addressed by a single new therapy. Therefore the proposed project will put forward separate solutions to both issues. The first theme of the project will determine whether freshly isolated (not culture expanded) infrapatellar fat pad derived cells, embedded in a hydrogel containing microbead-encapsulated growth factors, can used to engineer functional cartilage tissue. A component of this theme will involve magnetic microbead enrichment for cells with surface markers associated with highly chondrogenic cells. Theme 2 of the proposed project will explore an alternative therapy for cartilage defect repair. Specifically, the objective is to tissue engineer in vitro a functional tissue with a zonal structure mimicking that of normal articular cartilage using mesenchymal stem cells. It is hypothesised that such a zonal structure can be generated by controlling the oxygen tension and mechanical environment within the developing tissue. The final theme of the project will be to determine if repairing high-load bearing cartilage defects using either tissue engineering therapies will result in significantly improved repair compared to ACI in a cartilage defect model.
Summary
Once damaged articular cartilage has a limited reparative capacity and thus lesions often progress to arthritis. This has motivated the development of cell based therapies for the repair of cartilage defects such as autologous chondrocyte implantation (ACI). Such therapies are limited in two ways. Firstly, they do not result in the regeneration of hyaline cartilage and hence the repair is temporary. Secondly, widespread adaptation into the clinical setting is impeded by practical issues such as the high fiscal cost and time required for culture expansion of chondrocytes. The applicant is of the belief that both issues cannot currently be addressed by a single new therapy. Therefore the proposed project will put forward separate solutions to both issues. The first theme of the project will determine whether freshly isolated (not culture expanded) infrapatellar fat pad derived cells, embedded in a hydrogel containing microbead-encapsulated growth factors, can used to engineer functional cartilage tissue. A component of this theme will involve magnetic microbead enrichment for cells with surface markers associated with highly chondrogenic cells. Theme 2 of the proposed project will explore an alternative therapy for cartilage defect repair. Specifically, the objective is to tissue engineer in vitro a functional tissue with a zonal structure mimicking that of normal articular cartilage using mesenchymal stem cells. It is hypothesised that such a zonal structure can be generated by controlling the oxygen tension and mechanical environment within the developing tissue. The final theme of the project will be to determine if repairing high-load bearing cartilage defects using either tissue engineering therapies will result in significantly improved repair compared to ACI in a cartilage defect model.
Max ERC Funding
1 499 770 €
Duration
Start date: 2010-09-01, End date: 2015-08-31
