Project acronym 5D Heart Patch
Project A Functional, Mature In vivo Human Ventricular Muscle Patch for Cardiomyopathy
Researcher (PI) Kenneth Randall Chien
Host Institution (HI) KAROLINSKA INSTITUTET
Country Sweden
Call Details Advanced Grant (AdG), LS7, ERC-2016-ADG
Summary Developing new therapeutic strategies for heart regeneration is a major goal for cardiac biology and medicine. While cardiomyocytes can be generated from human pluripotent stem (hPSC) cells in vitro, it has proven difficult to use these cells to generate a large scale, mature human heart ventricular muscle graft on the injured heart in vivo. The central objective of this proposal is to optimize the generation of a large-scale pure, fully functional human ventricular muscle patch in vivo through the self-assembly of purified human ventricular progenitors and the localized expression of defined paracrine factors that drive their expansion, differentiation, vascularization, matrix formation, and maturation. Recently, we have found that purified hPSC-derived ventricular progenitors (HVPs) can self-assemble in vivo on the epicardial surface into a 3D vascularized, and functional ventricular patch with its own extracellular matrix via a cell autonomous pathway. A two-step protocol and FACS purification of HVP receptors can generate billions of pure HVPs- The current proposal will lead to the identification of defined paracrine pathways to enhance the survival, grafting/implantation, expansion, differentiation, matrix formation, vascularization and maturation of the graft in vivo. We will captalize on our unique HVP system and our novel modRNA technology to deliver therapeutic strategies by using the in vivo human ventricular muscle to model in vivo arrhythmogenic cardiomyopathy, and optimize the ability of the graft to compensate for the massive loss of functional muscle during ischemic cardiomyopathy and post-myocardial infarction. The studies will lead to new in vivo chimeric models of human cardiac disease and an experimental paradigm to optimize organ-on-organ cardiac tissue engineers of an in vivo, functional mature ventricular patch for cardiomyopathy
Summary
Developing new therapeutic strategies for heart regeneration is a major goal for cardiac biology and medicine. While cardiomyocytes can be generated from human pluripotent stem (hPSC) cells in vitro, it has proven difficult to use these cells to generate a large scale, mature human heart ventricular muscle graft on the injured heart in vivo. The central objective of this proposal is to optimize the generation of a large-scale pure, fully functional human ventricular muscle patch in vivo through the self-assembly of purified human ventricular progenitors and the localized expression of defined paracrine factors that drive their expansion, differentiation, vascularization, matrix formation, and maturation. Recently, we have found that purified hPSC-derived ventricular progenitors (HVPs) can self-assemble in vivo on the epicardial surface into a 3D vascularized, and functional ventricular patch with its own extracellular matrix via a cell autonomous pathway. A two-step protocol and FACS purification of HVP receptors can generate billions of pure HVPs- The current proposal will lead to the identification of defined paracrine pathways to enhance the survival, grafting/implantation, expansion, differentiation, matrix formation, vascularization and maturation of the graft in vivo. We will captalize on our unique HVP system and our novel modRNA technology to deliver therapeutic strategies by using the in vivo human ventricular muscle to model in vivo arrhythmogenic cardiomyopathy, and optimize the ability of the graft to compensate for the massive loss of functional muscle during ischemic cardiomyopathy and post-myocardial infarction. The studies will lead to new in vivo chimeric models of human cardiac disease and an experimental paradigm to optimize organ-on-organ cardiac tissue engineers of an in vivo, functional mature ventricular patch for cardiomyopathy
Max ERC Funding
2 149 228 €
Duration
Start date: 2017-12-01, End date: 2022-11-30
Project acronym AAA
Project Adaptive Actin Architectures
Researcher (PI) Laurent Blanchoin
Host Institution (HI) CENTRE NATIONAL DE LA RECHERCHE SCIENTIFIQUE CNRS
Country France
Call Details Advanced Grant (AdG), LS3, ERC-2016-ADG
Summary Although we have extensive knowledge of many important processes in cell biology, including information on many of the molecules involved and the physical interactions among them, we still do not understand most of the dynamical features that are the essence of living systems. This is particularly true for the actin cytoskeleton, a major component of the internal architecture of eukaryotic cells. In living cells, actin networks constantly assemble and disassemble filaments while maintaining an apparent stable structure, suggesting a perfect balance between the two processes. Such behaviors are called “dynamic steady states”. They confer upon actin networks a high degree of plasticity allowing them to adapt in response to external changes and enable cells to adjust to their environments. Despite their fundamental importance in the regulation of cell physiology, the basic mechanisms that control the coordinated dynamics of co-existing actin networks are poorly understood. In the AAA project, first, we will characterize the parameters that allow the coupling among co-existing actin networks at steady state. In vitro reconstituted systems will be used to control the actin nucleation patterns, the closed volume of the reaction chamber and the physical interaction of the networks. We hope to unravel the mechanism allowing the global coherence of a dynamic actin cytoskeleton. Second, we will use our unique capacity to perform dynamic micropatterning, to add or remove actin nucleation sites in real time, in order to investigate the ability of dynamic networks to adapt to changes and the role of coupled network dynamics in this emergent property. In this part, in vitro experiments will be complemented by the analysis of actin network remodeling in living cells. In the end, our project will provide a comprehensive understanding of how the adaptive response of the cytoskeleton derives from the complex interplay between its biochemical, structural and mechanical properties.
Summary
Although we have extensive knowledge of many important processes in cell biology, including information on many of the molecules involved and the physical interactions among them, we still do not understand most of the dynamical features that are the essence of living systems. This is particularly true for the actin cytoskeleton, a major component of the internal architecture of eukaryotic cells. In living cells, actin networks constantly assemble and disassemble filaments while maintaining an apparent stable structure, suggesting a perfect balance between the two processes. Such behaviors are called “dynamic steady states”. They confer upon actin networks a high degree of plasticity allowing them to adapt in response to external changes and enable cells to adjust to their environments. Despite their fundamental importance in the regulation of cell physiology, the basic mechanisms that control the coordinated dynamics of co-existing actin networks are poorly understood. In the AAA project, first, we will characterize the parameters that allow the coupling among co-existing actin networks at steady state. In vitro reconstituted systems will be used to control the actin nucleation patterns, the closed volume of the reaction chamber and the physical interaction of the networks. We hope to unravel the mechanism allowing the global coherence of a dynamic actin cytoskeleton. Second, we will use our unique capacity to perform dynamic micropatterning, to add or remove actin nucleation sites in real time, in order to investigate the ability of dynamic networks to adapt to changes and the role of coupled network dynamics in this emergent property. In this part, in vitro experiments will be complemented by the analysis of actin network remodeling in living cells. In the end, our project will provide a comprehensive understanding of how the adaptive response of the cytoskeleton derives from the complex interplay between its biochemical, structural and mechanical properties.
Max ERC Funding
2 349 898 €
Duration
Start date: 2017-09-01, End date: 2022-08-31
Project acronym ARTHUS
Project Advances in Research on Theories of the Dark Universe - Inhomogeneity Effects in Relativistic Cosmology
Researcher (PI) Thomas BUCHERT
Host Institution (HI) UNIVERSITE LYON 1 CLAUDE BERNARD
Country France
Call Details Advanced Grant (AdG), PE9, ERC-2016-ADG
Summary The project ARTHUS aims at determining the physical origin of Dark Energy: in addition to the energy sources of the standard model of cosmology, effective terms arise through spatially averaging inhomogeneous cosmological models in General Relativity. It has been demonstrated that these additional terms can play the role of Dark Energy on large scales (but they can also mimic Dark Matter on scales of mass accumulations). The underlying rationale is that fluctuations in the Universe generically couple to spatially averaged intrinsic properties of space, such as its averaged scalar curvature, thus changing the global evolution of the effective (spatially averaged) cosmological model. At present, we understand these so- called backreaction effects only qualitatively. The project ARTHUS is directed towards a conclusive quantitative evaluation of these effects by developing generic and non-perturbative relativistic models of structure formation, by statistically measuring the key-variables of the models in observations and in simulation data, and by reinterpreting observational results in light of the new models. It is to be emphasized that there is no doubt about the existence of backreaction effects; the question is whether they are even capable of getting rid of the dark sources (as some models discussed in the literature suggest), or whether their impact is substantially smaller. The project thus addresses an essential issue of current cosmological research: to find pertinent answers concerning the quantitative impact of inhomogeneity effects, a necessary, worldwide recognized step toward high-precision cosmology. If the project objectives are attained, the results will have a far-reaching impact on theoretical and observational cosmology, on the interpretation of astronomical experiments such as Planck and Euclid, as well as on a wide spectrum of particle physics theories and experiments.
Summary
The project ARTHUS aims at determining the physical origin of Dark Energy: in addition to the energy sources of the standard model of cosmology, effective terms arise through spatially averaging inhomogeneous cosmological models in General Relativity. It has been demonstrated that these additional terms can play the role of Dark Energy on large scales (but they can also mimic Dark Matter on scales of mass accumulations). The underlying rationale is that fluctuations in the Universe generically couple to spatially averaged intrinsic properties of space, such as its averaged scalar curvature, thus changing the global evolution of the effective (spatially averaged) cosmological model. At present, we understand these so- called backreaction effects only qualitatively. The project ARTHUS is directed towards a conclusive quantitative evaluation of these effects by developing generic and non-perturbative relativistic models of structure formation, by statistically measuring the key-variables of the models in observations and in simulation data, and by reinterpreting observational results in light of the new models. It is to be emphasized that there is no doubt about the existence of backreaction effects; the question is whether they are even capable of getting rid of the dark sources (as some models discussed in the literature suggest), or whether their impact is substantially smaller. The project thus addresses an essential issue of current cosmological research: to find pertinent answers concerning the quantitative impact of inhomogeneity effects, a necessary, worldwide recognized step toward high-precision cosmology. If the project objectives are attained, the results will have a far-reaching impact on theoretical and observational cosmology, on the interpretation of astronomical experiments such as Planck and Euclid, as well as on a wide spectrum of particle physics theories and experiments.
Max ERC Funding
2 091 000 €
Duration
Start date: 2017-09-01, End date: 2023-08-31
Project acronym AXION
Project Axions: From Heaven to Earth
Researcher (PI) Frank Wilczek
Host Institution (HI) STOCKHOLMS UNIVERSITET
Country Sweden
Call Details Advanced Grant (AdG), PE2, ERC-2016-ADG
Summary Axions are hypothetical particles whose existence would solve two major problems: the strong P, T problem (a major blemish on the standard model); and the dark matter problem. It is a most important goal to either observe or rule out the existence of a cosmic axion background. It appears that decisive observations may be possible, but only after orchestrating insight from specialities ranging from quantum field theory and astrophysical modeling to ultra-low noise quantum measurement theory. Detailed predictions for the magnitude and structure of the cosmic axion background depend on cosmological and astrophysical modeling, which can be constrained by theoretical insight and numerical simulation. In parallel, we must optimize strategies for extracting accessible signals from that very weakly interacting source.
While the existence of axions as fundamental particles remains hypothetical, the equations governing how axions interact with electromagnetic fields also govern (with different parameters) how certain materials interact with electromagnetic fields. Thus those materials embody “emergent” axions. The equations have remarkable properties, which one can test in these materials, and possibly put to practical use.
Closely related to axions, mathematically, are anyons. Anyons are particle-like excitations that elude the familiar classification into bosons and fermions. Theoretical and numerical studies indicate that they are common emergent features of highly entangled states of matter in two dimensions. Recent work suggests the existence of states of matter, both natural and engineered, in which anyon dynamics is both important and experimentally accessible. Since the equations for anyons and axions are remarkably similar, and both have common, deep roots in symmetry and topology, it will be fruitful to consider them together.
Summary
Axions are hypothetical particles whose existence would solve two major problems: the strong P, T problem (a major blemish on the standard model); and the dark matter problem. It is a most important goal to either observe or rule out the existence of a cosmic axion background. It appears that decisive observations may be possible, but only after orchestrating insight from specialities ranging from quantum field theory and astrophysical modeling to ultra-low noise quantum measurement theory. Detailed predictions for the magnitude and structure of the cosmic axion background depend on cosmological and astrophysical modeling, which can be constrained by theoretical insight and numerical simulation. In parallel, we must optimize strategies for extracting accessible signals from that very weakly interacting source.
While the existence of axions as fundamental particles remains hypothetical, the equations governing how axions interact with electromagnetic fields also govern (with different parameters) how certain materials interact with electromagnetic fields. Thus those materials embody “emergent” axions. The equations have remarkable properties, which one can test in these materials, and possibly put to practical use.
Closely related to axions, mathematically, are anyons. Anyons are particle-like excitations that elude the familiar classification into bosons and fermions. Theoretical and numerical studies indicate that they are common emergent features of highly entangled states of matter in two dimensions. Recent work suggests the existence of states of matter, both natural and engineered, in which anyon dynamics is both important and experimentally accessible. Since the equations for anyons and axions are remarkably similar, and both have common, deep roots in symmetry and topology, it will be fruitful to consider them together.
Max ERC Funding
2 324 391 €
Duration
Start date: 2017-09-01, End date: 2022-08-31
Project acronym BARCODED-CELLTRACING
Project Endogenous barcoding for in vivo fate mapping of lineage development in the blood and immune system
Researcher (PI) Hans-Reimer RODEWALD
Host Institution (HI) DEUTSCHES KREBSFORSCHUNGSZENTRUM HEIDELBERG
Country Germany
Call Details Advanced Grant (AdG), LS6, ERC-2016-ADG
Summary The immune system is a complex ensemble of diverse lineages. Studies on in-vivo-hematopoiesis have until
now largely rested on transplantation. More physiological experiments have been limited by the inability to
analyze hematopoietic stem (HSC) and progenitor cells in situ without cell isolation and other disruptive
manipulations. We have developed mouse mutants in which a fluorescent marker can be switched on in HSC
in situ (inducible fate mapping), and traced HSC lineage output under unperturbed conditions in vivo. These
experiments uncovered marked differences comparing in situ and post-transplantation hematopoiesis. These
new developments raise several important questions, notably on the developmental fates HSC realize in vivo
(as opposed to their experimental potential), and on the structure (routes and nodes) of hematopoiesis from
HSC to peripheral blood and immune lineages. Answers to these questions (and in fact the deconvolution of
any tissue) require the development of non-invasive, high resolution barcoding systems. We have now
designed, built and tested a DNA-based barcoding system, termed Polylox, that is based on an artificial
recombination locus in which Cre recombinase can generate several hundred thousand genetic tags in mice.
We chose the Cre-loxP system to link high resolution barcoding (i.e. the ability to barcode single cells and to
fate map their progeny) to the zoo of tissue- or stage-specific, inducible Cre-driver mice. Here, I will present
the principles of this endogenous barcoding system, demonstrate its experimental and analytical feasibilities
and its power to resolve complex lineages. The work program addresses in a comprehensive manner major
open questions on the structure of the hematopoietic system that builds and maintains the immune system.
This project ultimately aims at an in depth dissection of unique or common lineage pathways emerging from
HSC, and at resolving relationships within cell lineages of the immune system.
Summary
The immune system is a complex ensemble of diverse lineages. Studies on in-vivo-hematopoiesis have until
now largely rested on transplantation. More physiological experiments have been limited by the inability to
analyze hematopoietic stem (HSC) and progenitor cells in situ without cell isolation and other disruptive
manipulations. We have developed mouse mutants in which a fluorescent marker can be switched on in HSC
in situ (inducible fate mapping), and traced HSC lineage output under unperturbed conditions in vivo. These
experiments uncovered marked differences comparing in situ and post-transplantation hematopoiesis. These
new developments raise several important questions, notably on the developmental fates HSC realize in vivo
(as opposed to their experimental potential), and on the structure (routes and nodes) of hematopoiesis from
HSC to peripheral blood and immune lineages. Answers to these questions (and in fact the deconvolution of
any tissue) require the development of non-invasive, high resolution barcoding systems. We have now
designed, built and tested a DNA-based barcoding system, termed Polylox, that is based on an artificial
recombination locus in which Cre recombinase can generate several hundred thousand genetic tags in mice.
We chose the Cre-loxP system to link high resolution barcoding (i.e. the ability to barcode single cells and to
fate map their progeny) to the zoo of tissue- or stage-specific, inducible Cre-driver mice. Here, I will present
the principles of this endogenous barcoding system, demonstrate its experimental and analytical feasibilities
and its power to resolve complex lineages. The work program addresses in a comprehensive manner major
open questions on the structure of the hematopoietic system that builds and maintains the immune system.
This project ultimately aims at an in depth dissection of unique or common lineage pathways emerging from
HSC, and at resolving relationships within cell lineages of the immune system.
Max ERC Funding
2 500 000 €
Duration
Start date: 2017-07-01, End date: 2022-06-30
Project acronym BaSaR
Project Beyond the Silk Road: Economic Development, Frontier Zones and Inter-Imperiality in the Afro-Eurasian World Region, 300 BCE to 300 CE
Researcher (PI) Sitta Valerie Ilse Alberta VON REDEN
Host Institution (HI) ALBERT-LUDWIGS-UNIVERSITAET FREIBURG
Country Germany
Call Details Advanced Grant (AdG), SH6, ERC-2016-ADG
Summary This interdisciplinary project will show that inter-imperial zones and small to mid-size regional networks of exchange were crucial for ancient Transeurasian exchange connections. It will demonstrate the significance of exchange in imperial frontier zones emerging from political, economic, infrastructural, institutional and technological development within empires. This will lead to a new conceptual frame for analyzing inter-imperiality and the morphology of exchange networks within and across imperial zones.
The centuries from 300 BCE to 300 CE were a period of accelerated empire transformation involving also new regions of the Afro-Eurasian world. Consumption centres shifted, affecting production, settlement, and regional exchange networks. They changed the dynamics of exchange, created new geographies, and greater cultural convergence between imperial spheres of influence. The development of imperial frontier zones of intense exchange and mobility (e.g. Northern China, Bactria, Gandhara, Syria, and the Red Sea/Gulf/Indian Ocean coasts) was related to imperial hinterlands, their fiscal-military-administrative regimes, the development of media of exchange and infrastructures, settlement, urban growth, and so on. It was also related to new forms and levels of consumption in imperial centres. In order to understand Transeurasian connectivity, the interdependence of frontier zone and inner-imperial development is crucial. We will reveal that competitions for social power within empires mobilized and concentrated resources reclaimed from natural landscapes and subsistence economies. Greater mobility of resources, both human and material, endowed competitions for power with economic force, feeding into inter-imperial prestige economies and trade. This new model of Afro-Eurasian connectivity will abandon some problematic assumptions of Silk Road trade, while maintaining the Afro-Eurasian macro-region as a meaningful unit for cultural and economic analysis.
Summary
This interdisciplinary project will show that inter-imperial zones and small to mid-size regional networks of exchange were crucial for ancient Transeurasian exchange connections. It will demonstrate the significance of exchange in imperial frontier zones emerging from political, economic, infrastructural, institutional and technological development within empires. This will lead to a new conceptual frame for analyzing inter-imperiality and the morphology of exchange networks within and across imperial zones.
The centuries from 300 BCE to 300 CE were a period of accelerated empire transformation involving also new regions of the Afro-Eurasian world. Consumption centres shifted, affecting production, settlement, and regional exchange networks. They changed the dynamics of exchange, created new geographies, and greater cultural convergence between imperial spheres of influence. The development of imperial frontier zones of intense exchange and mobility (e.g. Northern China, Bactria, Gandhara, Syria, and the Red Sea/Gulf/Indian Ocean coasts) was related to imperial hinterlands, their fiscal-military-administrative regimes, the development of media of exchange and infrastructures, settlement, urban growth, and so on. It was also related to new forms and levels of consumption in imperial centres. In order to understand Transeurasian connectivity, the interdependence of frontier zone and inner-imperial development is crucial. We will reveal that competitions for social power within empires mobilized and concentrated resources reclaimed from natural landscapes and subsistence economies. Greater mobility of resources, both human and material, endowed competitions for power with economic force, feeding into inter-imperial prestige economies and trade. This new model of Afro-Eurasian connectivity will abandon some problematic assumptions of Silk Road trade, while maintaining the Afro-Eurasian macro-region as a meaningful unit for cultural and economic analysis.
Max ERC Funding
2 498 750 €
Duration
Start date: 2017-09-01, End date: 2022-08-31
Project acronym BrainDrain
Project Translational implications of the discovery of brain-draining lymphatics
Researcher (PI) Kari ALITALO
Host Institution (HI) HELSINGIN YLIOPISTO
Country Finland
Call Details Advanced Grant (AdG), LS7, ERC-2016-ADG
Summary In 2010, 800 billion Euros was spent on brain diseases in Europe and the cost is expected to increase due to the aging population. – Here I propose to exploit our new discovery for research to alleviate this disease burden. In work selected by Nature Medicine among the top 10 ”Notable Advances” and by Science as one of the 10 ”Breakthroughs of the year” 2015, we discovered a meningeal lymphatic vascular system that serves brain homeostasis. We want to reassess current concepts about cerebrovascular dynamics, fluid drainage and cellular trafficking in physiological conditions, in Alzheimer’s disease mouse models and in human postmortem tissues. First, we will study the development and properties of meningeal lymphatics and how they are sustained during aging. We then want to analyse the clearance of macromolecules and protein aggregates in Alzheimer’s disease in mice that lack the newly discovered meningeal lymphatic drainage system. We will study if growth factor-mediated expansion of lymphatic vessels alleviates the parenchymal accumulation of neurotoxic amyloid beta and pathogenesis of Alzheimer’s disease and brain damage after traumatic brain injury. We will further analyse the role of lymphangiogenic growth factors and lymphatic vessels in brain solute clearance, immune cell trafficking and in a mouse model of multiple sclerosis. The meningeal lymphatics could be involved in a number of neurodegenerative and neuroinflammatory diseases of considerable human and socioeconomic burden. Several of our previous concepts have already been translated to clinical development and we aim to develop proof-of-principle therapeutic concepts in this project. I feel that we are just now in a unique position to advance frontline European translational biomedical research in this suddenly emerging field, which has received great attention worldwide.
Summary
In 2010, 800 billion Euros was spent on brain diseases in Europe and the cost is expected to increase due to the aging population. – Here I propose to exploit our new discovery for research to alleviate this disease burden. In work selected by Nature Medicine among the top 10 ”Notable Advances” and by Science as one of the 10 ”Breakthroughs of the year” 2015, we discovered a meningeal lymphatic vascular system that serves brain homeostasis. We want to reassess current concepts about cerebrovascular dynamics, fluid drainage and cellular trafficking in physiological conditions, in Alzheimer’s disease mouse models and in human postmortem tissues. First, we will study the development and properties of meningeal lymphatics and how they are sustained during aging. We then want to analyse the clearance of macromolecules and protein aggregates in Alzheimer’s disease in mice that lack the newly discovered meningeal lymphatic drainage system. We will study if growth factor-mediated expansion of lymphatic vessels alleviates the parenchymal accumulation of neurotoxic amyloid beta and pathogenesis of Alzheimer’s disease and brain damage after traumatic brain injury. We will further analyse the role of lymphangiogenic growth factors and lymphatic vessels in brain solute clearance, immune cell trafficking and in a mouse model of multiple sclerosis. The meningeal lymphatics could be involved in a number of neurodegenerative and neuroinflammatory diseases of considerable human and socioeconomic burden. Several of our previous concepts have already been translated to clinical development and we aim to develop proof-of-principle therapeutic concepts in this project. I feel that we are just now in a unique position to advance frontline European translational biomedical research in this suddenly emerging field, which has received great attention worldwide.
Max ERC Funding
2 420 429 €
Duration
Start date: 2017-08-01, End date: 2022-07-31
Project acronym BRCA-ERC
Project Understanding cancer development in BRCA 1/2 mutation carriers for improved Early detection and Risk Control
Researcher (PI) Martin WIDSCHWENDTER
Host Institution (HI) UNIVERSITY COLLEGE LONDON
Country United Kingdom
Call Details Advanced Grant (AdG), LS7, ERC-2016-ADG
Summary Recent evidence demonstrates that cancer is overtaking cardiovascular disease as the number one cause of mortality in Europe. This is largely due to the lack of preventative measures for common (e.g. breast) or highly fatal (e.g. ovarian) human cancers. Most cancers are multifactorial in origin. The core hypothesis of this research programme is that the extremely high risk of BRCA1/2 germline mutation carriers to develop breast and ovarian cancer is a net consequence of cell-autonomous (direct effect of BRCA mutation in cells at risk) and cell non-autonomous (produced in distant organs and affecting organs at risk) factors which both trigger epigenetic, cancer-initiating effects.
The project’s aims are centered around the principles of systems medicine and built on a large cohort of BRCA mutation carriers and controls who will be offered newly established cancer screening programmes. We will uncover how ‘cell non-autonomous’ factors work, provide detail on the epigenetic changes in at-risk tissues and investigate whether these changes are mechanistically linked to cancer, study whether we can neutralise this process and measure success in the organs at risk, and ideally in easy to access samples such as blood, buccal and cervical cells.
In my Department for Women’s Cancer we have assembled a powerful interdisciplinary team including computational biologists, functionalists, immunologists and clinician scientists linked to leading patient advocacy groups which is extremely well placed to lead this pioneering project to develop the fundamental understanding of cancer development in women with BRCA mutations. To reset the epigenome, re-establishing normal cell identity and consequently reducing cancer risk without the need for surgery and being able to monitor the efficacy using multicellular epigenetic outcome predictors will be a major scientific and medical breakthrough and possibly applicable to other chronic diseases.
Summary
Recent evidence demonstrates that cancer is overtaking cardiovascular disease as the number one cause of mortality in Europe. This is largely due to the lack of preventative measures for common (e.g. breast) or highly fatal (e.g. ovarian) human cancers. Most cancers are multifactorial in origin. The core hypothesis of this research programme is that the extremely high risk of BRCA1/2 germline mutation carriers to develop breast and ovarian cancer is a net consequence of cell-autonomous (direct effect of BRCA mutation in cells at risk) and cell non-autonomous (produced in distant organs and affecting organs at risk) factors which both trigger epigenetic, cancer-initiating effects.
The project’s aims are centered around the principles of systems medicine and built on a large cohort of BRCA mutation carriers and controls who will be offered newly established cancer screening programmes. We will uncover how ‘cell non-autonomous’ factors work, provide detail on the epigenetic changes in at-risk tissues and investigate whether these changes are mechanistically linked to cancer, study whether we can neutralise this process and measure success in the organs at risk, and ideally in easy to access samples such as blood, buccal and cervical cells.
In my Department for Women’s Cancer we have assembled a powerful interdisciplinary team including computational biologists, functionalists, immunologists and clinician scientists linked to leading patient advocacy groups which is extremely well placed to lead this pioneering project to develop the fundamental understanding of cancer development in women with BRCA mutations. To reset the epigenome, re-establishing normal cell identity and consequently reducing cancer risk without the need for surgery and being able to monitor the efficacy using multicellular epigenetic outcome predictors will be a major scientific and medical breakthrough and possibly applicable to other chronic diseases.
Max ERC Funding
2 497 841 €
Duration
Start date: 2017-09-01, End date: 2022-08-31
Project acronym ChAMPioN
Project Game-changing Precision Medicine for Curing All Myeloproliferative Neoplasms
Researcher (PI) Tessa Holyoake
Host Institution (HI) UNIVERSITY OF GLASGOW
Country United Kingdom
Call Details Advanced Grant (AdG), LS7, ERC-2016-ADG
Summary Despite decades of research, developing ways to overcome drug resistance in cancer is the most challenging bottleneck for curative therapies. This is because, in some forms of cancer, the cancer stem cells from which the diseases arise are constantly evolving, particularly under the selective pressures of drug therapies, in order to survive. The events leading to drug resistance can occur within one or more individual cancer stem cell(s) – and the features of each of these cells need to be studied in detail in order to develop drugs or drug combinations that can eradicate all of them. The BCR-ABL+ and BCR-ABL- myeloproliferative neoplasms (MPN) are a group of proliferative blood diseases that can be considered both exemplars of precision medicine and of the drug resistance bottleneck. While significant advances in the management of MPN have been made using life-long and expensive tyrosine kinase inhibitors (TKI), patients are rarely cured of their disease. This is because TKI fail to eradicate the leukaemia stem cells (LSC) from which MPN arise and which persist in patients on treatment, often leading to pervasive drug resistance, loss of response to therapy and progression to fatal forms of acute leukaemia. My goal is to change the way we study the LSC that persist in MPN patients as a means of delivering more effective precision medicine in MPN that is a “game-changer” leading to therapy-free remission (TFR) and cure. Here, I will apply an innovative strategy, ChAMPioN, to study the response of the MPN LSC to TKI in innovative pre-clinical laboratory models and directly in patients with MPN - up to the resolution of individual LSC. This work will reveal, for the first time, the molecular and clonal evolution of LSC during TKI therapies, thus enabling the development of more accurate predictions of TKI efficacy and resistance and rational approaches for curative drug therapies.
Summary
Despite decades of research, developing ways to overcome drug resistance in cancer is the most challenging bottleneck for curative therapies. This is because, in some forms of cancer, the cancer stem cells from which the diseases arise are constantly evolving, particularly under the selective pressures of drug therapies, in order to survive. The events leading to drug resistance can occur within one or more individual cancer stem cell(s) – and the features of each of these cells need to be studied in detail in order to develop drugs or drug combinations that can eradicate all of them. The BCR-ABL+ and BCR-ABL- myeloproliferative neoplasms (MPN) are a group of proliferative blood diseases that can be considered both exemplars of precision medicine and of the drug resistance bottleneck. While significant advances in the management of MPN have been made using life-long and expensive tyrosine kinase inhibitors (TKI), patients are rarely cured of their disease. This is because TKI fail to eradicate the leukaemia stem cells (LSC) from which MPN arise and which persist in patients on treatment, often leading to pervasive drug resistance, loss of response to therapy and progression to fatal forms of acute leukaemia. My goal is to change the way we study the LSC that persist in MPN patients as a means of delivering more effective precision medicine in MPN that is a “game-changer” leading to therapy-free remission (TFR) and cure. Here, I will apply an innovative strategy, ChAMPioN, to study the response of the MPN LSC to TKI in innovative pre-clinical laboratory models and directly in patients with MPN - up to the resolution of individual LSC. This work will reveal, for the first time, the molecular and clonal evolution of LSC during TKI therapies, thus enabling the development of more accurate predictions of TKI efficacy and resistance and rational approaches for curative drug therapies.
Max ERC Funding
3 005 818 €
Duration
Start date: 2018-01-01, End date: 2022-12-31
Project acronym CLCLCL
Project Civil Law, Common Law, Customary Law: Consonance, Divergence and Transformation in Western Europe from the late eleventh to the thirteenth centuries
Researcher (PI) John HUDSON
Host Institution (HI) THE UNIVERSITY COURT OF THE UNIVERSITY OF ST ANDREWS
Country United Kingdom
Call Details Advanced Grant (AdG), SH6, ERC-2016-ADG
Summary A highly significant division in present-day Europe is between two types of legal system: the Continental with foundations in Civil Law (law with an ultimately Roman law basis), and English Common Law. Both trace their continuous history back to the twelfth century. The present project re-evaluates this vital period in legal history, by comparing not just English Common Law and Continental Civil Law (or “Ius commune”), but also the customary laws crucially important in Continental Europe even beyond the twelfth century. Such laws shared many features with English law, and the comparison thus disrupts the simplistic English:Continental distinction. The project first analyses the form, functioning and development of local, national, and supra-national laws. Similarities, differences, and influences will then be examined from perspectives of longer-term European legal development. Proper historical re-examination of the subject is very timely because of current invocation of supposed legal histories, be it Eurosceptic celebration of English Common Law or rhetorical use of Ius commune as precedent for a common European Law.
F. W. Maitland wrote that ‘there is not much “comparative jurisprudence” for those who do not know thoroughly well the things to be compared’. A comparative project requires collaboration – PI, senior researcher, post-doctoral and doctoral researchers, and Advisory Board. It also needs an integrated approach, through carefully selected areas, themes, and sources. The purpose is not just to provide geographical and thematic coverage but to assemble scholars who overcome divisions of approach in legal historiography: between lawyers and historians, between national traditions, between Common Law and Civil Law. The project is thus very significant in developing methods for writing comparative legal history - and legal history and comparative law more widely - in terms of uncovering patterns, constructing narratives, and testing theories of causation.
Summary
A highly significant division in present-day Europe is between two types of legal system: the Continental with foundations in Civil Law (law with an ultimately Roman law basis), and English Common Law. Both trace their continuous history back to the twelfth century. The present project re-evaluates this vital period in legal history, by comparing not just English Common Law and Continental Civil Law (or “Ius commune”), but also the customary laws crucially important in Continental Europe even beyond the twelfth century. Such laws shared many features with English law, and the comparison thus disrupts the simplistic English:Continental distinction. The project first analyses the form, functioning and development of local, national, and supra-national laws. Similarities, differences, and influences will then be examined from perspectives of longer-term European legal development. Proper historical re-examination of the subject is very timely because of current invocation of supposed legal histories, be it Eurosceptic celebration of English Common Law or rhetorical use of Ius commune as precedent for a common European Law.
F. W. Maitland wrote that ‘there is not much “comparative jurisprudence” for those who do not know thoroughly well the things to be compared’. A comparative project requires collaboration – PI, senior researcher, post-doctoral and doctoral researchers, and Advisory Board. It also needs an integrated approach, through carefully selected areas, themes, and sources. The purpose is not just to provide geographical and thematic coverage but to assemble scholars who overcome divisions of approach in legal historiography: between lawyers and historians, between national traditions, between Common Law and Civil Law. The project is thus very significant in developing methods for writing comparative legal history - and legal history and comparative law more widely - in terms of uncovering patterns, constructing narratives, and testing theories of causation.
Max ERC Funding
2 161 502 €
Duration
Start date: 2017-05-01, End date: 2022-09-30
