Project acronym BTVI
Project First Biodegradable Biocatalytic VascularTherapeutic Implants
Researcher (PI) Alexander Zelikin
Host Institution (HI) AARHUS UNIVERSITET
Country Denmark
Call Details Consolidator Grant (CoG), PE8, ERC-2013-CoG
Summary "We aim to perform academic development of a novel biomedical opportunity: localized synthesis of drugs within biocatalytic therapeutic vascular implants (BVI) for site-specific drug delivery to target organs and tissues. Primary envisioned targets for therapeutic intervention using BVI are atherosclerosis, viral hepatitis, and hepatocellular carcinoma: three of the most prevalent and debilitating conditions which affect hundreds of millions worldwide and which continue to increase in their importance in the era of increasingly aging population. For hepatic applications, we aim to develop drug eluting beads which are equipped with tools of enzyme-prodrug therapy (EPT) and are administered to the liver via trans-arterial catheter embolization. Therein, the beads perform localized synthesis of drugs and imaging reagents for anticancer combination therapy and theranostics, antiviral and anti-inflammatory agents for the treatment of hepatitis. Further, we conceive vascular therapeutic inserts (VTI) as a novel type of implantable biomaterials for treatment of atherosclerosis and re-endothelialization of vascular stents and grafts. Using EPT, inserts will tame “the guardian of cardiovascular grafts”, nitric oxide, for which localized, site specific synthesis and delivery spell success of therapeutic intervention and/or aided tissue regeneration. This proposal is positioned on the forefront of biomedical engineering and its success requires excellence in polymer chemistry, materials design, medicinal chemistry, and translational medicine. Each part of this proposal - design of novel types of vascular implants, engineering novel biomaterials, developing innovative fabrication and characterization techniques – is of high value for fundamental biomedical sciences. The project is target-oriented and once successful, will be of highest practical value and contribute to increased quality of life of millions of people worldwide."
Summary
"We aim to perform academic development of a novel biomedical opportunity: localized synthesis of drugs within biocatalytic therapeutic vascular implants (BVI) for site-specific drug delivery to target organs and tissues. Primary envisioned targets for therapeutic intervention using BVI are atherosclerosis, viral hepatitis, and hepatocellular carcinoma: three of the most prevalent and debilitating conditions which affect hundreds of millions worldwide and which continue to increase in their importance in the era of increasingly aging population. For hepatic applications, we aim to develop drug eluting beads which are equipped with tools of enzyme-prodrug therapy (EPT) and are administered to the liver via trans-arterial catheter embolization. Therein, the beads perform localized synthesis of drugs and imaging reagents for anticancer combination therapy and theranostics, antiviral and anti-inflammatory agents for the treatment of hepatitis. Further, we conceive vascular therapeutic inserts (VTI) as a novel type of implantable biomaterials for treatment of atherosclerosis and re-endothelialization of vascular stents and grafts. Using EPT, inserts will tame “the guardian of cardiovascular grafts”, nitric oxide, for which localized, site specific synthesis and delivery spell success of therapeutic intervention and/or aided tissue regeneration. This proposal is positioned on the forefront of biomedical engineering and its success requires excellence in polymer chemistry, materials design, medicinal chemistry, and translational medicine. Each part of this proposal - design of novel types of vascular implants, engineering novel biomaterials, developing innovative fabrication and characterization techniques – is of high value for fundamental biomedical sciences. The project is target-oriented and once successful, will be of highest practical value and contribute to increased quality of life of millions of people worldwide."
Max ERC Funding
1 996 126 €
Duration
Start date: 2014-04-01, End date: 2019-03-31
Project acronym DDRegulation
Project Regulation of DNA damage responses at the replication fork
Researcher (PI) Niels Mailand
Host Institution (HI) KOBENHAVNS UNIVERSITET
Country Denmark
Call Details Consolidator Grant (CoG), LS1, ERC-2013-CoG
Summary This project aims at delineating the regulatory signaling processes that enable cells to overcome DNA damage during DNA replication, a major challenge to the integrity of the genome as the normal replication machinery is unable to replicate past DNA lesions. This may result in collapse of the replication fork, potentially giving rise to gross genomic alterations. To mitigate this threat, all cells have evolved DNA damage bypass strategies such as translesion DNA synthesis (TLS), involving low fidelity DNA polymerases that can replicate damaged DNA, albeit in an error-prone manner, offering a trade-off between limited mutagenesis and gross chromosomal instability. How DNA damage bypass pathways are regulated and integrated with DNA replication and repair remain poorly resolved questions fundamental to understanding genome stability maintenance and disease onset. Regulatory signaling mediated by the small modifier protein ubiquitin has a prominent role in orchestrating the reorganization of the replication fork necessary for overcoming DNA lesions, but this involvement has not been systematically explored. To remedy these gaps in our knowledge, I propose to implement a series of innovative complementary strategies to isolate and identify the regulatory factors and ubiquitin-dependent processes that promote DNA damage responses at the replication fork, allowing for subsequent in-depth characterization of their roles in protecting genome integrity by targeted functional studies. This project will enable an advanced level of mechanistic insight into key regulatory processes underlying replication-associated DNA damage responses that has not been feasible to achieve with exisiting methodologies, providing a realistic outlook for groundbreaking discoveries that will open up many new avenues for further research into mechanisms and biological functions of regulatory signaling processes in the DNA damage response and beyond.
Summary
This project aims at delineating the regulatory signaling processes that enable cells to overcome DNA damage during DNA replication, a major challenge to the integrity of the genome as the normal replication machinery is unable to replicate past DNA lesions. This may result in collapse of the replication fork, potentially giving rise to gross genomic alterations. To mitigate this threat, all cells have evolved DNA damage bypass strategies such as translesion DNA synthesis (TLS), involving low fidelity DNA polymerases that can replicate damaged DNA, albeit in an error-prone manner, offering a trade-off between limited mutagenesis and gross chromosomal instability. How DNA damage bypass pathways are regulated and integrated with DNA replication and repair remain poorly resolved questions fundamental to understanding genome stability maintenance and disease onset. Regulatory signaling mediated by the small modifier protein ubiquitin has a prominent role in orchestrating the reorganization of the replication fork necessary for overcoming DNA lesions, but this involvement has not been systematically explored. To remedy these gaps in our knowledge, I propose to implement a series of innovative complementary strategies to isolate and identify the regulatory factors and ubiquitin-dependent processes that promote DNA damage responses at the replication fork, allowing for subsequent in-depth characterization of their roles in protecting genome integrity by targeted functional studies. This project will enable an advanced level of mechanistic insight into key regulatory processes underlying replication-associated DNA damage responses that has not been feasible to achieve with exisiting methodologies, providing a realistic outlook for groundbreaking discoveries that will open up many new avenues for further research into mechanisms and biological functions of regulatory signaling processes in the DNA damage response and beyond.
Max ERC Funding
1 996 356 €
Duration
Start date: 2014-07-01, End date: 2019-06-30
Project acronym MalOnco
Project Targeting cancer using evolutionary refined pathogen derived antigens
Researcher (PI) Ali Salanti
Host Institution (HI) KOBENHAVNS UNIVERSITET
Country Denmark
Call Details Consolidator Grant (CoG), LS7, ERC-2013-CoG
Summary We have recently discovered a malaria protein which has shown a high potential in cancer treatment. In pregnant women, malaria infected red blood cells express a protein that binds to a distinct carbohydrate structure present only on cells of the maternal side of the placental circulation, but not elsewhere in the vasculature. This highly evolved binding system enables the parasite to evade clearance and infect placental tissue, causing pregnancy-associated malaria. This malaria protein binds to most cancer cells with a highly specific and strong interaction. It is apparent that cancer cells commonly express this modified glycoprotein, also found on placental cells, but rarely on normal somatic cells. The carbohydrate structures enable cancer cells to migrate and invade surrounding normal tissue, and to play a role in metastatic spread of the primary lesion.
I have preliminary data showing that (1) the malaria protein binds specifically to a wide range of cancer cells and patient cancer tissues including melanoma, lymphoma, carcinomas and sarcomas, whereas no binding is detected to normal healthy cells or tissue, and (2) cancer cells treated with the malaria protein have markedly reduced growth and migration capacity.
This raises the intriguing possibility that we can use this naturally refined parasite-host interaction mechanism as a tool to specifically target cancer and inhibit the metastatic potential. Furthermore, as the malaria protein binds strongly to patient-derived cancer tissues, the malaria protein could be used to differentiate between specific subtypes of cancers and possibly advance the diagnostic process in clinical settings. The proposed project augments a novel strategy of targeting a wide range of receptors involved in human disease using pathogen derived evolutionary refined ligands. I expect this project to pioneer the use of inherently refined parasite-host interactions as a tool to combat human malignant disease.
Summary
We have recently discovered a malaria protein which has shown a high potential in cancer treatment. In pregnant women, malaria infected red blood cells express a protein that binds to a distinct carbohydrate structure present only on cells of the maternal side of the placental circulation, but not elsewhere in the vasculature. This highly evolved binding system enables the parasite to evade clearance and infect placental tissue, causing pregnancy-associated malaria. This malaria protein binds to most cancer cells with a highly specific and strong interaction. It is apparent that cancer cells commonly express this modified glycoprotein, also found on placental cells, but rarely on normal somatic cells. The carbohydrate structures enable cancer cells to migrate and invade surrounding normal tissue, and to play a role in metastatic spread of the primary lesion.
I have preliminary data showing that (1) the malaria protein binds specifically to a wide range of cancer cells and patient cancer tissues including melanoma, lymphoma, carcinomas and sarcomas, whereas no binding is detected to normal healthy cells or tissue, and (2) cancer cells treated with the malaria protein have markedly reduced growth and migration capacity.
This raises the intriguing possibility that we can use this naturally refined parasite-host interaction mechanism as a tool to specifically target cancer and inhibit the metastatic potential. Furthermore, as the malaria protein binds strongly to patient-derived cancer tissues, the malaria protein could be used to differentiate between specific subtypes of cancers and possibly advance the diagnostic process in clinical settings. The proposed project augments a novel strategy of targeting a wide range of receptors involved in human disease using pathogen derived evolutionary refined ligands. I expect this project to pioneer the use of inherently refined parasite-host interactions as a tool to combat human malignant disease.
Max ERC Funding
1 998 800 €
Duration
Start date: 2014-09-01, End date: 2019-08-31
Project acronym stardust2asteroids
Project Stardust to asteroids: Unravelling the formation and earliest evolution of a habitable solar system
Researcher (PI) Martin Bizzarro
Host Institution (HI) KOBENHAVNS UNIVERSITET
Country Denmark
Call Details Consolidator Grant (CoG), PE10, ERC-2013-CoG
Summary As far as we know, our solar system is unique. It could, in principle, be the only planetary system in the Universe to harbor intelligent life or, indeed, life at all. As such, attempting to reconstruct its history is one of the most fundamental pursuits in the natural sciences. Whereas astronomical observations of star- forming regions provide a framework for understanding the formation of low-mass stars and the early evolution of planetary systems in general, direct information about the earliest solar system can only come from primitive meteorites and their components and some differentiated meteorites that record the birth of the solar system. The main objective of this proposal is to investigate the timescales and processes – including the role of supernovas – leading to the formation of the solar system by measurement of isotopic variations in meteorites. To achieve our objectives, we will integrate long-lived and short-lived radioisotope chronometers with the presence/absence of nucleosynthetic anomalies in various meteorites and meteoritic components. Our isotopic measurements will be obtained using state-of-the-art technologies such as second-generation mass spectrometers housed in laboratories directed by the PI and fully dedicated to cosmochemistry. This will allow us to: 1) define the mechanism and timescale for the collapse of the protosolar molecular cloud and emergence of the protoplanetary disk, 2) constrain the source and locale of chondrule-forming event(s) as well as the nature of the mechanism(s) required to transport chondrules to the accretion regions of chondrites, and 3) provide robust estimates of the timing and mechanism of asteroidal differentiation. We aim to understand how the variable initial conditions imposed by the range of possible stellar environments and protoplanetary disk properties regulated the formation and assemblage of disk solids into asteroidal and planetary bodies comprising our solar system.
Summary
As far as we know, our solar system is unique. It could, in principle, be the only planetary system in the Universe to harbor intelligent life or, indeed, life at all. As such, attempting to reconstruct its history is one of the most fundamental pursuits in the natural sciences. Whereas astronomical observations of star- forming regions provide a framework for understanding the formation of low-mass stars and the early evolution of planetary systems in general, direct information about the earliest solar system can only come from primitive meteorites and their components and some differentiated meteorites that record the birth of the solar system. The main objective of this proposal is to investigate the timescales and processes – including the role of supernovas – leading to the formation of the solar system by measurement of isotopic variations in meteorites. To achieve our objectives, we will integrate long-lived and short-lived radioisotope chronometers with the presence/absence of nucleosynthetic anomalies in various meteorites and meteoritic components. Our isotopic measurements will be obtained using state-of-the-art technologies such as second-generation mass spectrometers housed in laboratories directed by the PI and fully dedicated to cosmochemistry. This will allow us to: 1) define the mechanism and timescale for the collapse of the protosolar molecular cloud and emergence of the protoplanetary disk, 2) constrain the source and locale of chondrule-forming event(s) as well as the nature of the mechanism(s) required to transport chondrules to the accretion regions of chondrites, and 3) provide robust estimates of the timing and mechanism of asteroidal differentiation. We aim to understand how the variable initial conditions imposed by the range of possible stellar environments and protoplanetary disk properties regulated the formation and assemblage of disk solids into asteroidal and planetary bodies comprising our solar system.
Max ERC Funding
1 910 889 €
Duration
Start date: 2014-02-01, End date: 2019-01-31
