Project acronym DUB-DECODE
Project Systematic Decoding of Deubiquitylase-Regulated Signaling Networks
Researcher (PI) Chuna Ram Choudhary
Host Institution (HI) KOBENHAVNS UNIVERSITET
Country Denmark
Call Details Consolidator Grant (CoG), LS2, ERC-2014-CoG
Summary Cellular processes are largely governed by sophisticated protein posttranslational modification (PTM)-dependent signaling networks, and a systematic understanding of regulatory PTM-based networks is a key goal in modern biology. Ubiquitin is a small, evolutionarily conserved signaling protein that acts as a PTM after being covalently conjugated to other proteins. Reversible ubiquitylation forms the most versatile and largest eukaryote-exclusive signaling system, and regulates the stability and function of almost all proteins in cells. Deubiquitylases (DUBs) are ubiquitin-specific proteases that remove substrate-conjugated ubiquitin, and thereby regulate virtually all ubiquitylation-dependent signaling. Because of their central role in ubiquitin signaling, DUBs have essential functions in mammalian physiology and development, and the dysregulated expression and mutation of DUBs is frequently associated with human diseases. Despite their vital functions, very little is known about the proteins and ubiquitylation sites that are regulated by DUBs and this knowledge gap is hampering our understanding of the molecular mechanisms by which DUBs control diverse biological processes. Recently, we developed a mass spectrometry-based proteomics approach that allowed unbiased and site-specific quantification of ubiquitylation on a systems-wide scale. Here we propose to comprehensively investigate DUB-regulated ubiquitin signaling in human cells. We will integrate interdisciplinary approaches to develop next-generation cell models and innovative proteomic technologies to systematically decode DUB function in human cells. This will enable a novel and detailed understanding of DUB-regulated signaling networks, and open up new avenues for further research into the mechanisms and biological functions of ubiquitylation and of ubiquitin-like modifiers.
Summary
Cellular processes are largely governed by sophisticated protein posttranslational modification (PTM)-dependent signaling networks, and a systematic understanding of regulatory PTM-based networks is a key goal in modern biology. Ubiquitin is a small, evolutionarily conserved signaling protein that acts as a PTM after being covalently conjugated to other proteins. Reversible ubiquitylation forms the most versatile and largest eukaryote-exclusive signaling system, and regulates the stability and function of almost all proteins in cells. Deubiquitylases (DUBs) are ubiquitin-specific proteases that remove substrate-conjugated ubiquitin, and thereby regulate virtually all ubiquitylation-dependent signaling. Because of their central role in ubiquitin signaling, DUBs have essential functions in mammalian physiology and development, and the dysregulated expression and mutation of DUBs is frequently associated with human diseases. Despite their vital functions, very little is known about the proteins and ubiquitylation sites that are regulated by DUBs and this knowledge gap is hampering our understanding of the molecular mechanisms by which DUBs control diverse biological processes. Recently, we developed a mass spectrometry-based proteomics approach that allowed unbiased and site-specific quantification of ubiquitylation on a systems-wide scale. Here we propose to comprehensively investigate DUB-regulated ubiquitin signaling in human cells. We will integrate interdisciplinary approaches to develop next-generation cell models and innovative proteomic technologies to systematically decode DUB function in human cells. This will enable a novel and detailed understanding of DUB-regulated signaling networks, and open up new avenues for further research into the mechanisms and biological functions of ubiquitylation and of ubiquitin-like modifiers.
Max ERC Funding
1 972 570 €
Duration
Start date: 2015-10-01, End date: 2021-03-31
Project acronym EyeRegen
Project Engineering a scaffold based therapy for corneal regeneration
Researcher (PI) Mark Joseph Ahearne
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
Country Ireland
Call Details Starting Grant (StG), PE8, ERC-2014-STG
Summary Corneal blindness resulting from disease, physical injury or chemical burns affects millions worldwide and has a considerable economic and social impact on the lives of people across Europe. In many cases corneal transplants can restore vision however the shortage of donor corneas suitable for transplantation has necessitated the development of alternative treatments. The aim of this project is to develop a new approach to corneal tissue regeneration. Previous approaches at engineering corneal tissue have required access to donor cells and lengthy culture periods in an attempt to grow tissue in vitro prior to implantation with only limited success and at great expense. Our approach will differ fundamentally from these in that we will design artificial corneal scaffolds that do not require donated cells or in vitro culture but instead will recruit the patient’s own cells to regenerate the cornea post-implantation. These biomaterial scaffolds will incorporate specific chemical and physical cues with the deliberate aim of attracting cells and inducing tissue formation. Studies will be undertaken to examine how different chemical, biochemical, physical and mechanical cues can be used to control the behaviour of corneal epithelial, stromal and endothelial cells. Once the optimal combination of these cues has been determined, this information will be incorporated into the design of the scaffold. Recent advances in manufacturing and material processing technology will enable us to develop scaffolds with organized nanometric architectures and that incorporate controlled growth factor release mechanisms. Techniques such as 3D bio-printing and nanofiber electrospinning will be used to fabricate scaffolds. The ability of the scaffold to attract cells and promote matrix remodelling will be examined by developing an in vitro bioreactor system capable of mimicking the ocular environment and by performing in vivo tests using a live animal model.
Summary
Corneal blindness resulting from disease, physical injury or chemical burns affects millions worldwide and has a considerable economic and social impact on the lives of people across Europe. In many cases corneal transplants can restore vision however the shortage of donor corneas suitable for transplantation has necessitated the development of alternative treatments. The aim of this project is to develop a new approach to corneal tissue regeneration. Previous approaches at engineering corneal tissue have required access to donor cells and lengthy culture periods in an attempt to grow tissue in vitro prior to implantation with only limited success and at great expense. Our approach will differ fundamentally from these in that we will design artificial corneal scaffolds that do not require donated cells or in vitro culture but instead will recruit the patient’s own cells to regenerate the cornea post-implantation. These biomaterial scaffolds will incorporate specific chemical and physical cues with the deliberate aim of attracting cells and inducing tissue formation. Studies will be undertaken to examine how different chemical, biochemical, physical and mechanical cues can be used to control the behaviour of corneal epithelial, stromal and endothelial cells. Once the optimal combination of these cues has been determined, this information will be incorporated into the design of the scaffold. Recent advances in manufacturing and material processing technology will enable us to develop scaffolds with organized nanometric architectures and that incorporate controlled growth factor release mechanisms. Techniques such as 3D bio-printing and nanofiber electrospinning will be used to fabricate scaffolds. The ability of the scaffold to attract cells and promote matrix remodelling will be examined by developing an in vitro bioreactor system capable of mimicking the ocular environment and by performing in vivo tests using a live animal model.
Max ERC Funding
1 498 734 €
Duration
Start date: 2015-07-01, End date: 2020-12-31
Project acronym JointPrinting
Project 3D Printing of Cell Laden Biomimetic Materials and Biomolecules for Joint Regeneration
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
Country Ireland
Call Details Consolidator Grant (CoG), PE8, ERC-2014-CoG
Summary Osteoarthritis (OA) is a serious disease of the joints affecting nearly 10% of the population worldwide. Realising an efficacious therapeutic solution for treating OA remains one of the greatest challenges in the field of orthopaedic medicine. This proposal envisions a future where 3D bioprinting systems located in hospitals will provide ‘off-the-shelf’, patient-specific biological implants to treat diseases such as OA. To realise this vision, this project will use 3D bioprinting to generate anatomically accurate, biomimetic constructs that can be used to regenerate both the cartilage and bone in a diseased joint. The first aim of this proposal is to print a mesenchymal stem cell laden biomaterial that is both immediately load bearing and can facilitate the regeneration of articular cartilage in vivo, such that the bioprinted construct will not require in vitro maturation prior to implantation. Mechanical function will be realised by integrating an interpenetrating network hydrogel into a 3D printed polymeric scaffold, while chondro-inductivity will be enhanced by the spatially-defined incorporation of cartilage extracellular matrix components and chondrogenic growth factors into the bioprinted construct. The second aim of the proposal is to use 3D bioprinting to create a cell-free, composite construct to facilitate regeneration of the bony region of a large osteochondral defect, where vascularization will be accelerated by immobilizing spatial gradients of vascular endothelial growth factor into the implant. The third aim of the proposal is to scale-up the proposed 3D bioprinted construct to enable whole joint regeneration. Finite element modelling will be used determine the optimal structural characteristics of the scaled-up implant for it to fulfil its required mechanical function. If successful, such an implant would form the basis of a truly transformative therapy for treating degenerative joint disease.
Summary
Osteoarthritis (OA) is a serious disease of the joints affecting nearly 10% of the population worldwide. Realising an efficacious therapeutic solution for treating OA remains one of the greatest challenges in the field of orthopaedic medicine. This proposal envisions a future where 3D bioprinting systems located in hospitals will provide ‘off-the-shelf’, patient-specific biological implants to treat diseases such as OA. To realise this vision, this project will use 3D bioprinting to generate anatomically accurate, biomimetic constructs that can be used to regenerate both the cartilage and bone in a diseased joint. The first aim of this proposal is to print a mesenchymal stem cell laden biomaterial that is both immediately load bearing and can facilitate the regeneration of articular cartilage in vivo, such that the bioprinted construct will not require in vitro maturation prior to implantation. Mechanical function will be realised by integrating an interpenetrating network hydrogel into a 3D printed polymeric scaffold, while chondro-inductivity will be enhanced by the spatially-defined incorporation of cartilage extracellular matrix components and chondrogenic growth factors into the bioprinted construct. The second aim of the proposal is to use 3D bioprinting to create a cell-free, composite construct to facilitate regeneration of the bony region of a large osteochondral defect, where vascularization will be accelerated by immobilizing spatial gradients of vascular endothelial growth factor into the implant. The third aim of the proposal is to scale-up the proposed 3D bioprinted construct to enable whole joint regeneration. Finite element modelling will be used determine the optimal structural characteristics of the scaled-up implant for it to fulfil its required mechanical function. If successful, such an implant would form the basis of a truly transformative therapy for treating degenerative joint disease.
Max ERC Funding
1 999 700 €
Duration
Start date: 2015-09-01, End date: 2020-08-31
Project acronym LimitMDR
Project Utilizing evolutionary interactions to limit multidrug resistance
Researcher (PI) Morten Otto Alexander Sommer
Host Institution (HI) DANMARKS TEKNISKE UNIVERSITET
Country Denmark
Call Details Starting Grant (StG), LS2, ERC-2014-STG
Summary Drug resistance is limiting our ability to treat most infectious diseases and forms of cancer. Indeed this relentless evolution is the major driver of treatment failure for diseases that are responsible for over half of the global disease related mortality. Yet, the underlying principles that guide this evolutionary response are poorly understood, in particular with regards to understanding the impact of multidrug treatment.
LimitMDR will characterize evolutionary trajectories leading to multidrug resistance in response to individual and combination drug treatment through the execution of large-scale adaptive evolution experiment with two bacterial pathogens followed by genome sequencing and phenotyping. This effort will enable testing of contrasting hypotheses regarding the evolution of multidrug resistance in response to combination treatment.
We will characterize the cause-and-effect of resistance and sensitivity mutations identified in our global data set and map comprehensive fitness landscapes of mutations accumulated during drug resistance evolution to understand the evolutionary dynamics underlying resistance evolution. To accomplish these bold goals we shall develop novel multiplexed methodologies enabling unprecedented scale of construction and phenotypic testing of identified mutations. While genetic epistasis is considered of key importance to resistance evolution most studies focus on mutations within an individual gene. Through the development of a novel experimental approach we shall elucidate complex epistatic interaction networks between mutations accumulated during resistance evolution.
Finally, we will conduct mechanistic studies to uncover the mechanisms of collateral sensitivity. These studies will shed light on this underappreciated phenomenon, which is of critical relevance to drug discovery and the evolution of drug resistance. In conclusion LimitMDR will develop groundbreaking novel methodologies and scientific insights that will c
Summary
Drug resistance is limiting our ability to treat most infectious diseases and forms of cancer. Indeed this relentless evolution is the major driver of treatment failure for diseases that are responsible for over half of the global disease related mortality. Yet, the underlying principles that guide this evolutionary response are poorly understood, in particular with regards to understanding the impact of multidrug treatment.
LimitMDR will characterize evolutionary trajectories leading to multidrug resistance in response to individual and combination drug treatment through the execution of large-scale adaptive evolution experiment with two bacterial pathogens followed by genome sequencing and phenotyping. This effort will enable testing of contrasting hypotheses regarding the evolution of multidrug resistance in response to combination treatment.
We will characterize the cause-and-effect of resistance and sensitivity mutations identified in our global data set and map comprehensive fitness landscapes of mutations accumulated during drug resistance evolution to understand the evolutionary dynamics underlying resistance evolution. To accomplish these bold goals we shall develop novel multiplexed methodologies enabling unprecedented scale of construction and phenotypic testing of identified mutations. While genetic epistasis is considered of key importance to resistance evolution most studies focus on mutations within an individual gene. Through the development of a novel experimental approach we shall elucidate complex epistatic interaction networks between mutations accumulated during resistance evolution.
Finally, we will conduct mechanistic studies to uncover the mechanisms of collateral sensitivity. These studies will shed light on this underappreciated phenomenon, which is of critical relevance to drug discovery and the evolution of drug resistance. In conclusion LimitMDR will develop groundbreaking novel methodologies and scientific insights that will c
Max ERC Funding
1 492 453 €
Duration
Start date: 2015-05-01, End date: 2020-04-30
Project acronym RDRECON
Project Risky Decisions: Revealing Economic Behaviour
Researcher (PI) Steffen Andersen
Host Institution (HI) COPENHAGEN BUSINESS SCHOOL
Country Denmark
Call Details Starting Grant (StG), SH1, ERC-2014-STG
Summary Households are exposed to a wide array of monetary and non-monetary risks: employment risk, financial risk, interest rate risk, and health and mortality risk, to name a few. Society and policymakers can certainly help households manage risk, but to be effective, they need to understand the ways households cope with risk and how vulnerable they are to market and policy changes. For instance, how do households react to bank defaults and market failures? How personal do these experiences have to be for households to change behavior? And how permanent are the changes in behavior?
The goal of the proposed research program is to understand how personal and market experiences affect financial decisions made by households, such as savings behavior, portfolio allocation, borrowing decisions, mortgage choices, and pension savings. RDRECON combines theory and evidence with an empirical research strategy that is comprised of both natural and field experiments. The theoretical component models how households make decisions. The empirical component uses both econometric and experimental methodologies to study actual household behavior across a range of economic and financial margins, as well as the influence of personal and market experiences on a household’s financial choices.
RDRECON’s strength and path-breaking innovation is its combination of administrative register data and controlled field experiments to form treatment and control groups of interest which allow empirical identification of theoretical predictions. This approach puts theory to work and overcomes the limits of identification in natural experiments. To this end, RDRECON will further our understanding of how households respond to personal and market experiences, and provide helpful insights for policy makers.
Summary
Households are exposed to a wide array of monetary and non-monetary risks: employment risk, financial risk, interest rate risk, and health and mortality risk, to name a few. Society and policymakers can certainly help households manage risk, but to be effective, they need to understand the ways households cope with risk and how vulnerable they are to market and policy changes. For instance, how do households react to bank defaults and market failures? How personal do these experiences have to be for households to change behavior? And how permanent are the changes in behavior?
The goal of the proposed research program is to understand how personal and market experiences affect financial decisions made by households, such as savings behavior, portfolio allocation, borrowing decisions, mortgage choices, and pension savings. RDRECON combines theory and evidence with an empirical research strategy that is comprised of both natural and field experiments. The theoretical component models how households make decisions. The empirical component uses both econometric and experimental methodologies to study actual household behavior across a range of economic and financial margins, as well as the influence of personal and market experiences on a household’s financial choices.
RDRECON’s strength and path-breaking innovation is its combination of administrative register data and controlled field experiments to form treatment and control groups of interest which allow empirical identification of theoretical predictions. This approach puts theory to work and overcomes the limits of identification in natural experiments. To this end, RDRECON will further our understanding of how households respond to personal and market experiences, and provide helpful insights for policy makers.
Max ERC Funding
1 461 881 €
Duration
Start date: 2015-05-01, End date: 2020-12-31
Project acronym SHARECITY
Project SHARECITY: Assessing the practice and sustainability potential of city-based food sharing economies
Researcher (PI) Anna Ray Davies
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
Country Ireland
Call Details Consolidator Grant (CoG), SH3, ERC-2014-CoG
Summary With planetary urbanization fast approaching there is growing clarity regarding the unsustainability of cities, not least with respect to food consumption. Sharing, including food sharing, is increasingly being identified as one transformative mechanism for sustainable cities: reducing consumption; conserving resources, preventing waste and providing new forms of socio-economic relations. However, such claims currently rest on thin conceptual and empirical foundations. SHARECITY will identify and examine diverse practices of city-based food sharing economies, first determining their form, function and governance and then identifying their impact and potential to reorient eating practices. The research has four objectives: to advance theoretical understanding of contemporary food sharing economies in cities; to generate a significant body of comparative and novel international empirical knowledge about food sharing economies and their governance within global cities; to design and test an assessment framework for establishing the impact of city-based food sharing economies on societal relations, economic vitality and the environment; and to develop and implement a novel variant of backcasting to explore how food sharing economies within cities might evolve in the future. Providing conceptual insights that bridge sharing, social practice and urban transitions theories, SHARECITY will generate a typology of food sharing economies; a database of food sharing activities in 100 global cities; in-depth food sharing profiles of 7 cities from the contrasting contexts of USA, Brazil and Germany, Greece, Portugal, Ireland and Australia; a sustainability impact toolkit to enable examination of city-based food sharing initiatives; and scenarios for future food sharing in cities. Conducting such frontier science SHARECITY will open new research horizons to substantively improve understanding of how, why and to what end people share food within cities in the 21st Century.
Summary
With planetary urbanization fast approaching there is growing clarity regarding the unsustainability of cities, not least with respect to food consumption. Sharing, including food sharing, is increasingly being identified as one transformative mechanism for sustainable cities: reducing consumption; conserving resources, preventing waste and providing new forms of socio-economic relations. However, such claims currently rest on thin conceptual and empirical foundations. SHARECITY will identify and examine diverse practices of city-based food sharing economies, first determining their form, function and governance and then identifying their impact and potential to reorient eating practices. The research has four objectives: to advance theoretical understanding of contemporary food sharing economies in cities; to generate a significant body of comparative and novel international empirical knowledge about food sharing economies and their governance within global cities; to design and test an assessment framework for establishing the impact of city-based food sharing economies on societal relations, economic vitality and the environment; and to develop and implement a novel variant of backcasting to explore how food sharing economies within cities might evolve in the future. Providing conceptual insights that bridge sharing, social practice and urban transitions theories, SHARECITY will generate a typology of food sharing economies; a database of food sharing activities in 100 global cities; in-depth food sharing profiles of 7 cities from the contrasting contexts of USA, Brazil and Germany, Greece, Portugal, Ireland and Australia; a sustainability impact toolkit to enable examination of city-based food sharing initiatives; and scenarios for future food sharing in cities. Conducting such frontier science SHARECITY will open new research horizons to substantively improve understanding of how, why and to what end people share food within cities in the 21st Century.
Max ERC Funding
1 860 009 €
Duration
Start date: 2015-10-01, End date: 2021-07-31
