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 TGF-MEPPA
Project Terrestrial Gamma Flashes-the Most Energetic Photon Phenomenon in our Atmosphere
Researcher (PI) Nikolai oestgaard
Host Institution (HI) UNIVERSITETET I BERGEN
Country Norway
Call Details Advanced Grant (AdG), PE10, ERC-2012-ADG_20120216
Summary "Only 20 years after the discovery of Cosmic Gamma-ray Bursts from the universe another completely unknown phenomenon involving gamma-rays was discovered by coincidence the BATSE instrument on the Compton Gamma-Ray Observatory. Short-lived (~1 ms) and very energetic photon emissions (>1 MeV and later: >40 MeV) were found to originate from the Earth’s atmosphere and were named Terrestrial Gamma Flashes (TGFs). These flashes are the most energetic natural photon phenomenon that is known to exist on Earth, in which also anti-matter is produced. Based on the few datasets available to date we believe that TGFs are related to electric discharges in thunderstorm systems and that electrons accelerated to relativistic energies are involved to produce bremsstrahlung of such high energies. However, it is not known how frequent TGFs are, the altitude range and the spatial extent of their source region, to what kind of thunderstorms and lightning they are related or the implications of relativistic electrons and positrons ejected into space. There is no consensus on how TGFs are produced. All these questions need to be answered before we understand how important they are and how they may affect the Earth’s electrical circuit and atmosphere.
The goal of the TGF-MEPPA project is to attack these questions by combining modelling of electron acceleration in thunderstorm electric fields, X- and gamma-ray production and propagation, lightning development with unprecedented measurements of TGFs from three different altitudes: 350 km, 30 km and 20 km to obtain the most comprehensive and detailed dataset needed to make significant advances in the TGF research. I will also perform electric discharge experiments in the laboratory. The goal is to establish a consistent model for the TGF-production and answer the question ‘How common are TGFs?’ to determine their implications for the Earth’s electrical circuit, atmosphere and outer space."
Summary
"Only 20 years after the discovery of Cosmic Gamma-ray Bursts from the universe another completely unknown phenomenon involving gamma-rays was discovered by coincidence the BATSE instrument on the Compton Gamma-Ray Observatory. Short-lived (~1 ms) and very energetic photon emissions (>1 MeV and later: >40 MeV) were found to originate from the Earth’s atmosphere and were named Terrestrial Gamma Flashes (TGFs). These flashes are the most energetic natural photon phenomenon that is known to exist on Earth, in which also anti-matter is produced. Based on the few datasets available to date we believe that TGFs are related to electric discharges in thunderstorm systems and that electrons accelerated to relativistic energies are involved to produce bremsstrahlung of such high energies. However, it is not known how frequent TGFs are, the altitude range and the spatial extent of their source region, to what kind of thunderstorms and lightning they are related or the implications of relativistic electrons and positrons ejected into space. There is no consensus on how TGFs are produced. All these questions need to be answered before we understand how important they are and how they may affect the Earth’s electrical circuit and atmosphere.
The goal of the TGF-MEPPA project is to attack these questions by combining modelling of electron acceleration in thunderstorm electric fields, X- and gamma-ray production and propagation, lightning development with unprecedented measurements of TGFs from three different altitudes: 350 km, 30 km and 20 km to obtain the most comprehensive and detailed dataset needed to make significant advances in the TGF research. I will also perform electric discharge experiments in the laboratory. The goal is to establish a consistent model for the TGF-production and answer the question ‘How common are TGFs?’ to determine their implications for the Earth’s electrical circuit, atmosphere and outer space."
Max ERC Funding
2 492 811 €
Duration
Start date: 2013-03-01, End date: 2018-02-28
