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 EURECA
Project Eukaryotic Regulated RNA Catabolism
Researcher (PI) Torben Heick Jensen
Host Institution (HI) AARHUS UNIVERSITET
Country Denmark
Call Details Advanced Grant (AdG), LS1, ERC-2013-ADG
Summary "Regulation and fidelity of gene expression is fundamental to the differentiation and maintenance of all living organisms. While historically attention has been focused on the process of transcriptional activation, we predict that RNA turnover pathways are equally important for gene expression regulation. This has been implied for selected protein-coding RNAs (mRNAs) but is virtually unexplored for non-protein-coding RNAs (ncRNAs).
The intention of the EURECA proposal is to establish cutting-edge research to characterize mammalian nuclear RNA turnover; its factor utility, substrate specificity and regulatory capacity. We foresee that RNA turnover is at the core of gene expression regulation - forming intricate connection to RNA productive systems – thus, being centrally placed to determine RNA fate. EURECA seeks to dramatically improve our understanding of cellular decision processes impacting RNA levels and to establish models for how regulated RNA turnover helps control key biological processes.
The realization that the number of ncRNA producing genes was previously grossly underestimated foretells that ncRNA regulation will impact on most aspects of cell biology. Consistently, aberrant ncRNA levels correlate with human disease phenotypes and RNA turnover complexes are linked to disease biology. Still, solid models for how ncRNA turnover regulate biological processes in higher eukaryotes are not available. Moreover, which ncRNAs retain function and which are merely transcriptional by-products remain a major challenge to sort out. The circumstances and kinetics of ncRNA turnover are therefore important to delineate as these will ultimately relate to the likelihood of molecular function. A fundamental challenge here is to also discern which protein complements of non-coding ribonucleoprotein particles (ncRNPs) are (in)compatible with function. Balancing single transcript/factor analysis with high-throughput methodology, EURECA will address these questions."
Summary
"Regulation and fidelity of gene expression is fundamental to the differentiation and maintenance of all living organisms. While historically attention has been focused on the process of transcriptional activation, we predict that RNA turnover pathways are equally important for gene expression regulation. This has been implied for selected protein-coding RNAs (mRNAs) but is virtually unexplored for non-protein-coding RNAs (ncRNAs).
The intention of the EURECA proposal is to establish cutting-edge research to characterize mammalian nuclear RNA turnover; its factor utility, substrate specificity and regulatory capacity. We foresee that RNA turnover is at the core of gene expression regulation - forming intricate connection to RNA productive systems – thus, being centrally placed to determine RNA fate. EURECA seeks to dramatically improve our understanding of cellular decision processes impacting RNA levels and to establish models for how regulated RNA turnover helps control key biological processes.
The realization that the number of ncRNA producing genes was previously grossly underestimated foretells that ncRNA regulation will impact on most aspects of cell biology. Consistently, aberrant ncRNA levels correlate with human disease phenotypes and RNA turnover complexes are linked to disease biology. Still, solid models for how ncRNA turnover regulate biological processes in higher eukaryotes are not available. Moreover, which ncRNAs retain function and which are merely transcriptional by-products remain a major challenge to sort out. The circumstances and kinetics of ncRNA turnover are therefore important to delineate as these will ultimately relate to the likelihood of molecular function. A fundamental challenge here is to also discern which protein complements of non-coding ribonucleoprotein particles (ncRNPs) are (in)compatible with function. Balancing single transcript/factor analysis with high-throughput methodology, EURECA will address these questions."
Max ERC Funding
2 497 960 €
Duration
Start date: 2014-04-01, End date: 2019-03-31
Project acronym LYSOSOME
Project Lysosomes as targets for cancer therapy
Researcher (PI) Marja Helena Jaeaettelae
Host Institution (HI) KRAEFTENS BEKAEMPELSE
Country Denmark
Call Details Advanced Grant (AdG), LS7, ERC-2013-ADG
Summary "Knowing that the lysosomes contain a powerful cocktail of hydrolases capable of digesting cells and entire tissues, it is obvious that the maintenance of lysosomal membrane integrity is of utmost importance for all cells, and especially for cancer cells with dramatically increased lysosomal activity. Yet, the mechanisms that regulate lysosomal membrane stability have remained obscure, largely due to the lack of methods sensitive enough to detect partial lysosomal leakage and suitable for screening purposes. We have finally succeeded in developing such a method, which allows me to propose here a project whose major aim is to reveal how cells maintain the integrity of lysosomal membranes. Based on our emerging data that firmly connect heat shock protein 70 and sphingolipid metabolism to lysosomal membrane stability, we will devote a large part of the project to the molecular details of these connections and to the characterization of the effects of new and already approved (cationic amphiphilic drugs) sphingolipid-regulating drugs on lysosomal membrane stability and cell survival. Additionally, we will screen selected siRNA libraries to identify signaling networks and lysosome-associated proteins essential for lysosomal membrane integrity, and small molecule libraries to identify compounds that induce lysosomal cell death. The next step is to identify lysosome-stabilizing mechanisms that are especially important for cancer cell survival. And the ultimate goal is to validate corresponding drug targets and drugs (old and new) for the induction of lysosomal cell death in therapy resistant cancers. As a “by-product” we expect to identify putative drug targets for the treatment of degenerative diseases and lipid storage disorders, where the stabilization of the lysosomal membranes promotes cell survival."
Summary
"Knowing that the lysosomes contain a powerful cocktail of hydrolases capable of digesting cells and entire tissues, it is obvious that the maintenance of lysosomal membrane integrity is of utmost importance for all cells, and especially for cancer cells with dramatically increased lysosomal activity. Yet, the mechanisms that regulate lysosomal membrane stability have remained obscure, largely due to the lack of methods sensitive enough to detect partial lysosomal leakage and suitable for screening purposes. We have finally succeeded in developing such a method, which allows me to propose here a project whose major aim is to reveal how cells maintain the integrity of lysosomal membranes. Based on our emerging data that firmly connect heat shock protein 70 and sphingolipid metabolism to lysosomal membrane stability, we will devote a large part of the project to the molecular details of these connections and to the characterization of the effects of new and already approved (cationic amphiphilic drugs) sphingolipid-regulating drugs on lysosomal membrane stability and cell survival. Additionally, we will screen selected siRNA libraries to identify signaling networks and lysosome-associated proteins essential for lysosomal membrane integrity, and small molecule libraries to identify compounds that induce lysosomal cell death. The next step is to identify lysosome-stabilizing mechanisms that are especially important for cancer cell survival. And the ultimate goal is to validate corresponding drug targets and drugs (old and new) for the induction of lysosomal cell death in therapy resistant cancers. As a “by-product” we expect to identify putative drug targets for the treatment of degenerative diseases and lipid storage disorders, where the stabilization of the lysosomal membranes promotes cell survival."
Max ERC Funding
2 499 960 €
Duration
Start date: 2014-02-01, End date: 2019-01-31
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
