Project acronym ALTERUMMA
Project Creating an Alternative umma: Clerical Authority and Religio-political Mobilisation in Transnational Shii Islam
Researcher (PI) Oliver Paul SCHARBRODT
Host Institution (HI) THE UNIVERSITY OF BIRMINGHAM
Country United Kingdom
Call Details Consolidator Grant (CoG), SH5, ERC-2016-COG
Summary This interdisciplinary project investigates the transformation of Shii Islam in the Middle East and Europe since the 1950s. The project examines the formation of modern Shii communal identities and the role Shii clerical authorities and their transnational networks have played in their religio-political mobilisation. The volatile situation post-Arab Spring, the rise of militant movements such as ISIS and the sectarianisation of geopolitical conflicts in the Middle East have intensified efforts to forge distinct Shii communal identities and to conceive Shii Muslims as part of an alternative umma (Islamic community). The project focusses on Iran, Iraq and significant but unexplored diasporic links to Syria, Kuwait and Britain. In response to the rise of modern nation-states in the Middle East, Shii clerical authorities resorted to a wide range of activities: (a) articulating intellectual responses to the ideologies underpinning modern Middle Eastern nation-states, (b) forming political parties and other platforms of socio-political activism and (c) using various forms of cultural production by systematising and promoting Shii ritual practices and utilising visual art, poetry and new media.
The project yields a perspectival shift on the factors that led to Shii communal mobilisation by:
- Analysing unacknowledged intellectual responses of Shii clerical authorities to the secular or sectarian ideologies of post-colonial nation-states and to the current sectarianisation of geopolitics in the Middle East.
- Emphasising the central role of diasporic networks in the Middle East and Europe in mobilising Shii communities and in influencing discourses and agendas of clerical authorities based in Iraq and Iran.
- Exploring new modes of cultural production in the form of a modern Shii aesthetics articulated in ritual practices, visual art, poetry and new media and thus creating a more holistic narrative on Shii religio-political mobilisation.
Summary
This interdisciplinary project investigates the transformation of Shii Islam in the Middle East and Europe since the 1950s. The project examines the formation of modern Shii communal identities and the role Shii clerical authorities and their transnational networks have played in their religio-political mobilisation. The volatile situation post-Arab Spring, the rise of militant movements such as ISIS and the sectarianisation of geopolitical conflicts in the Middle East have intensified efforts to forge distinct Shii communal identities and to conceive Shii Muslims as part of an alternative umma (Islamic community). The project focusses on Iran, Iraq and significant but unexplored diasporic links to Syria, Kuwait and Britain. In response to the rise of modern nation-states in the Middle East, Shii clerical authorities resorted to a wide range of activities: (a) articulating intellectual responses to the ideologies underpinning modern Middle Eastern nation-states, (b) forming political parties and other platforms of socio-political activism and (c) using various forms of cultural production by systematising and promoting Shii ritual practices and utilising visual art, poetry and new media.
The project yields a perspectival shift on the factors that led to Shii communal mobilisation by:
- Analysing unacknowledged intellectual responses of Shii clerical authorities to the secular or sectarian ideologies of post-colonial nation-states and to the current sectarianisation of geopolitics in the Middle East.
- Emphasising the central role of diasporic networks in the Middle East and Europe in mobilising Shii communities and in influencing discourses and agendas of clerical authorities based in Iraq and Iran.
- Exploring new modes of cultural production in the form of a modern Shii aesthetics articulated in ritual practices, visual art, poetry and new media and thus creating a more holistic narrative on Shii religio-political mobilisation.
Max ERC Funding
1 952 374 €
Duration
Start date: 2018-01-01, End date: 2022-12-31
Project acronym ARCTIC CULT
Project ARCTIC CULTURES: SITES OF COLLECTION IN THE FORMATION OF THE EUROPEAN AND AMERICAN NORTHLANDS
Researcher (PI) Richard Charles POWELL
Host Institution (HI) THE CHANCELLOR MASTERS AND SCHOLARS OF THE UNIVERSITY OF CAMBRIDGE
Country United Kingdom
Call Details Consolidator Grant (CoG), SH5, ERC-2016-COG
Summary The Arctic has risen to global attention in recent years, as it has been reconfigured through debates about global environmental change, resource extraction and disputes over sovereign rights. Within these discourses, little attention has been paid to the cultures of the Arctic. Indeed, it often seems as if the Circumpolar Arctic in global public understanding remains framed as a 'natural region' - that is, a place where the environment dominates the creation of culture. This framing has consequences for the region, because through this the Arctic becomes constructed as a space where people are absent. This proposal aims to discover how and why this might be so.
The proposal argues that this construction of the Arctic emerged from the exploration of the region by Europeans and North Americans and their contacts with indigenous people from the middle of the eighteenth century. Particular texts, cartographic representations and objects were collected and returned to sites like London, Copenhagen, Berlin and Philadelphia. The construction of the Arctic thereby became entwined within the growth of colonial museum cultures and, indeed, western modernity. This project aims to delineate the networks and collecting cultures involved in this creation of Arctic Cultures. It will bring repositories in colonial metropoles into dialogue with sites of collection in the Arctic by tracing the contexts of discovery and memorialisation. In doing so, it aspires to a new understanding of the consequences of certain forms of colonial representation for debates about the Circumpolar Arctic today.
The project involves research by the Principal Investigator and four Post Doctoral Researchers at museums, archives, libraries and repositories across Europe and North America, as well as in Greenland and the Canadian Arctic. A Project Assistant based in Oxford will help facilitate the completion of the research.
Summary
The Arctic has risen to global attention in recent years, as it has been reconfigured through debates about global environmental change, resource extraction and disputes over sovereign rights. Within these discourses, little attention has been paid to the cultures of the Arctic. Indeed, it often seems as if the Circumpolar Arctic in global public understanding remains framed as a 'natural region' - that is, a place where the environment dominates the creation of culture. This framing has consequences for the region, because through this the Arctic becomes constructed as a space where people are absent. This proposal aims to discover how and why this might be so.
The proposal argues that this construction of the Arctic emerged from the exploration of the region by Europeans and North Americans and their contacts with indigenous people from the middle of the eighteenth century. Particular texts, cartographic representations and objects were collected and returned to sites like London, Copenhagen, Berlin and Philadelphia. The construction of the Arctic thereby became entwined within the growth of colonial museum cultures and, indeed, western modernity. This project aims to delineate the networks and collecting cultures involved in this creation of Arctic Cultures. It will bring repositories in colonial metropoles into dialogue with sites of collection in the Arctic by tracing the contexts of discovery and memorialisation. In doing so, it aspires to a new understanding of the consequences of certain forms of colonial representation for debates about the Circumpolar Arctic today.
The project involves research by the Principal Investigator and four Post Doctoral Researchers at museums, archives, libraries and repositories across Europe and North America, as well as in Greenland and the Canadian Arctic. A Project Assistant based in Oxford will help facilitate the completion of the research.
Max ERC Funding
1 996 250 €
Duration
Start date: 2017-10-01, End date: 2022-09-30
Project acronym AUTOCOMPLEMENT
Project The role of complement in the induction of autoimmunity against post-translationally modified proteins
Researcher (PI) Leendert TROUW
Host Institution (HI) ACADEMISCH ZIEKENHUIS LEIDEN
Country Netherlands
Call Details Consolidator Grant (CoG), LS7, ERC-2016-COG
Summary In many prevalent autoimmune diseases such as rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE) autoantibodies are used as diagnostic and prognostic tools. Several of these autoantibodies target proteins that have been post-translationally modified (PTM). Examples of such modifications are citrullination and carbamylation. The success of B cell-targeted therapies in many auto-antibody positive diseases suggests that B cell mediated auto-immunity is playing a direct pathogenic role. Despite the wealth of information on the clinical associations of these anti-PTM protein antibodies as biomarkers we have currently no insight into why these antibodies are formed.
Immunization studies reveal that PTM proteins can induce antibody responses even in the absence of exogenous adjuvant. The reason why these PTM proteins have ‘autoadjuvant’ properties that lead to a breach of tolerance is currently unknown. In this proposal, I hypothesise that the breach of tolerance towards PTM proteins is mediated by complement factors that bind directly to these PTM. Our preliminary data indeed reveal that several complement factors bind specifically to PTM proteins. Complement could be involved in the autoadjuvant property of PTM proteins as next to killing pathogens complement can also boost adaptive immune responses. I plan to unravel the importance of the complement–PTM protein interaction by answering these questions:
1) What is the physiological function of complement binding to PTM proteins?
2) Is the breach of tolerance towards PTM proteins influenced by complement?
3) Can the adjuvant function of PTM be used to increase vaccine efficacy and/or decrease autoreactivity?
With AUTOCOMPLEMENT I will elucidate how PTM-reactive B cells receive ‘autoadjuvant’ signals. This insight will impact on patient care as we can now design strategies to either block unwanted ‘autoadjuvant’ signals to inhibit autoimmunity or to utilize ‘autoadjuvant’ signals to potentiate vaccination.
Summary
In many prevalent autoimmune diseases such as rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE) autoantibodies are used as diagnostic and prognostic tools. Several of these autoantibodies target proteins that have been post-translationally modified (PTM). Examples of such modifications are citrullination and carbamylation. The success of B cell-targeted therapies in many auto-antibody positive diseases suggests that B cell mediated auto-immunity is playing a direct pathogenic role. Despite the wealth of information on the clinical associations of these anti-PTM protein antibodies as biomarkers we have currently no insight into why these antibodies are formed.
Immunization studies reveal that PTM proteins can induce antibody responses even in the absence of exogenous adjuvant. The reason why these PTM proteins have ‘autoadjuvant’ properties that lead to a breach of tolerance is currently unknown. In this proposal, I hypothesise that the breach of tolerance towards PTM proteins is mediated by complement factors that bind directly to these PTM. Our preliminary data indeed reveal that several complement factors bind specifically to PTM proteins. Complement could be involved in the autoadjuvant property of PTM proteins as next to killing pathogens complement can also boost adaptive immune responses. I plan to unravel the importance of the complement–PTM protein interaction by answering these questions:
1) What is the physiological function of complement binding to PTM proteins?
2) Is the breach of tolerance towards PTM proteins influenced by complement?
3) Can the adjuvant function of PTM be used to increase vaccine efficacy and/or decrease autoreactivity?
With AUTOCOMPLEMENT I will elucidate how PTM-reactive B cells receive ‘autoadjuvant’ signals. This insight will impact on patient care as we can now design strategies to either block unwanted ‘autoadjuvant’ signals to inhibit autoimmunity or to utilize ‘autoadjuvant’ signals to potentiate vaccination.
Max ERC Funding
1 999 803 €
Duration
Start date: 2017-09-01, End date: 2022-08-31
Project acronym AveTransRisk
Project Average - Transaction Costs and Risk Management during the First Globalization (Sixteenth-Eighteenth Centuries)
Researcher (PI) Maria FUSARO
Host Institution (HI) THE UNIVERSITY OF EXETER
Country United Kingdom
Call Details Consolidator Grant (CoG), SH6, ERC-2016-COG
Summary This project focuses on the historical analysis of institutions and their impact on economic development through the investigation of a legal instrument – general average (GA) – which underpins maritime trade by redistributing damages’ costs across all interested parties. This will be pursued through the comparative investigation of GA in those European countries where substantial data exists: Italy, Spain, England, France and the Low Countries (1500-1800). Average and insurance were both created in the Middle Ages to facilitate trade through the redistribution of risk. Insurance has been widely studied, average – the expenses which can befall ships and cargoes from the time of their loading aboard until their unloading (due to accidents, jettison, and unexpected costs) – has been neglected. GA still plays an essential role in the redistribution of transaction costs, and being a form of strictly mutual self-protection, never evolved into a speculative financial instrument as insurance did; it therefore represents an excellent case of long-term effectiveness of a non-market economic phenomenon. Although the principle behind GA was very similar across Europe, in practice there were substantial differences in declaring and adjudicating claims. GA reports provide unparalleled evidence on maritime trade which, analysed quantitatively and quantitatively through a novel interdisciplinary approach, will contribute to the reassessment of the role played by the maritime sector in fostering economic growth during the early modern first globalization, when GA was the object of fierce debates on state jurisdiction and standardization of practice. Today they are regulated by the York-Antwerp Rules (YAR), currently under revision. This timely conjuncture provides plenty of opportunities for active engagement with practitioners, thereby fostering a creative dialogue on GA historical study and its future development to better face the challenges of mature globalization.
Summary
This project focuses on the historical analysis of institutions and their impact on economic development through the investigation of a legal instrument – general average (GA) – which underpins maritime trade by redistributing damages’ costs across all interested parties. This will be pursued through the comparative investigation of GA in those European countries where substantial data exists: Italy, Spain, England, France and the Low Countries (1500-1800). Average and insurance were both created in the Middle Ages to facilitate trade through the redistribution of risk. Insurance has been widely studied, average – the expenses which can befall ships and cargoes from the time of their loading aboard until their unloading (due to accidents, jettison, and unexpected costs) – has been neglected. GA still plays an essential role in the redistribution of transaction costs, and being a form of strictly mutual self-protection, never evolved into a speculative financial instrument as insurance did; it therefore represents an excellent case of long-term effectiveness of a non-market economic phenomenon. Although the principle behind GA was very similar across Europe, in practice there were substantial differences in declaring and adjudicating claims. GA reports provide unparalleled evidence on maritime trade which, analysed quantitatively and quantitatively through a novel interdisciplinary approach, will contribute to the reassessment of the role played by the maritime sector in fostering economic growth during the early modern first globalization, when GA was the object of fierce debates on state jurisdiction and standardization of practice. Today they are regulated by the York-Antwerp Rules (YAR), currently under revision. This timely conjuncture provides plenty of opportunities for active engagement with practitioners, thereby fostering a creative dialogue on GA historical study and its future development to better face the challenges of mature globalization.
Max ERC Funding
1 854 256 €
Duration
Start date: 2017-07-01, End date: 2022-12-31
Project acronym BENDER
Project BiogENesis and Degradation of Endoplasmic Reticulum proteins
Researcher (PI) Friedrich Foerster
Host Institution (HI) UNIVERSITEIT UTRECHT
Country Netherlands
Call Details Consolidator Grant (CoG), LS1, ERC-2016-COG
Summary The Endoplasmic Reticulum (ER) membrane in all eukaryotic cells has an intricate protein network that facilitates protein biogene-sis and homeostasis. The molecular complexity and sophisticated regulation of this machinery favours study-ing it in its native microenvironment by novel approaches. Cryo-electron tomography (CET) allows 3D im-aging of membrane-associated complexes in their native surrounding. Computational analysis of many sub-tomograms depicting the same type of macromolecule, a technology I pioneered, provides subnanometer resolution insights into different conformations of native complexes.
I propose to leverage CET of cellular and cell-free systems to reveal the molecular details of ER protein bio-genesis and homeostasis. In detail, I will study: (a) The structure of the ER translocon, the dynamic gateway for import of nascent proteins into the ER and their maturation. The largest component is the oligosaccharyl transferase complex. (b) Cotranslational ER import, N-glycosylation, chaperone-mediated stabilization and folding as well as oligomerization of established model substrate such a major histocompatibility complex (MHC) class I and II complexes. (c) The degradation of misfolded ER-residing proteins by the cytosolic 26S proteasome using cytomegalovirus-induced depletion of MHC class I as a model system. (d) The structural changes of the ER-bound translation machinery upon ER stress through IRE1-mediated degradation of mRNA that is specific for ER-targeted proteins. (e) The improved ‘in silico purification’ of different states of native macromolecules by maximum likelihood subtomogram classification and its application to a-d.
This project will be the blueprint for a new approach to structural biology of membrane-associated processes. It will contribute to our mechanistic understanding of viral immune evasion and glycosylation disorders as well as numerous diseases involving chronic ER stress including diabetes and neurodegenerative diseases.
Summary
The Endoplasmic Reticulum (ER) membrane in all eukaryotic cells has an intricate protein network that facilitates protein biogene-sis and homeostasis. The molecular complexity and sophisticated regulation of this machinery favours study-ing it in its native microenvironment by novel approaches. Cryo-electron tomography (CET) allows 3D im-aging of membrane-associated complexes in their native surrounding. Computational analysis of many sub-tomograms depicting the same type of macromolecule, a technology I pioneered, provides subnanometer resolution insights into different conformations of native complexes.
I propose to leverage CET of cellular and cell-free systems to reveal the molecular details of ER protein bio-genesis and homeostasis. In detail, I will study: (a) The structure of the ER translocon, the dynamic gateway for import of nascent proteins into the ER and their maturation. The largest component is the oligosaccharyl transferase complex. (b) Cotranslational ER import, N-glycosylation, chaperone-mediated stabilization and folding as well as oligomerization of established model substrate such a major histocompatibility complex (MHC) class I and II complexes. (c) The degradation of misfolded ER-residing proteins by the cytosolic 26S proteasome using cytomegalovirus-induced depletion of MHC class I as a model system. (d) The structural changes of the ER-bound translation machinery upon ER stress through IRE1-mediated degradation of mRNA that is specific for ER-targeted proteins. (e) The improved ‘in silico purification’ of different states of native macromolecules by maximum likelihood subtomogram classification and its application to a-d.
This project will be the blueprint for a new approach to structural biology of membrane-associated processes. It will contribute to our mechanistic understanding of viral immune evasion and glycosylation disorders as well as numerous diseases involving chronic ER stress including diabetes and neurodegenerative diseases.
Max ERC Funding
2 496 611 €
Duration
Start date: 2017-04-01, End date: 2022-06-30
Project acronym BRASILIAE
Project Indigenous Knowledge in the Making of Science: Historia Naturalis Brasiliae (1648)
Researcher (PI) Mariana DE CAMPOS FRANCOZO
Host Institution (HI) UNIVERSITEIT LEIDEN
Country Netherlands
Call Details Starting Grant (StG), SH6, ERC-2016-STG
Summary This project is an interdisciplinary study of the role of indigenous knowledge in the making of science. Situated at the intersection of history and anthropology, its main research objective is to understand the transformation of information and practices of South American indigenous peoples into a body of knowledge that became part of the Western scholarly canon. It aims to explore, by means of a distinctive case-study, how European science is constructed in intercultural settings.
This project takes the book Historia Naturalis Brasiliae (HNB), published in 1648 by Piso and Marcgraf, as its central focus. The HNB is the first product of the encounter between early modern European scholarship and South American indigenous knowledge. In an encyclopedic format, it brings together information about the natural world, linguistics, and geography of South America as understood and experienced by indigenous peoples as well as enslaved Africans. Its method of construction embodies the intercultural connections that shaped practices of knowledge production in colonial settings across the globe, and is the earliest example of such in South America. With my research team, I will investigate how indigenous knowledge was appropriated and transformed into European science by focusing on ethnobotanics, ethnozoology, and indigenous material culture.
Since the HNB and its associated materials are kept in European museums and archives, this project is timely and relevant in light of the growing concern for the democratization of heritage. The current debate about the societal role of publicly-funded cultural institutions across Europe argues for the importance of multi-vocality in cultural and political processes. This project proposes a more inclusive interpretation and use of the materials in these institutions and thereby sets an example of how European heritage institutions can use their historical collections to reconnect the past with present-day societal concerns.
Summary
This project is an interdisciplinary study of the role of indigenous knowledge in the making of science. Situated at the intersection of history and anthropology, its main research objective is to understand the transformation of information and practices of South American indigenous peoples into a body of knowledge that became part of the Western scholarly canon. It aims to explore, by means of a distinctive case-study, how European science is constructed in intercultural settings.
This project takes the book Historia Naturalis Brasiliae (HNB), published in 1648 by Piso and Marcgraf, as its central focus. The HNB is the first product of the encounter between early modern European scholarship and South American indigenous knowledge. In an encyclopedic format, it brings together information about the natural world, linguistics, and geography of South America as understood and experienced by indigenous peoples as well as enslaved Africans. Its method of construction embodies the intercultural connections that shaped practices of knowledge production in colonial settings across the globe, and is the earliest example of such in South America. With my research team, I will investigate how indigenous knowledge was appropriated and transformed into European science by focusing on ethnobotanics, ethnozoology, and indigenous material culture.
Since the HNB and its associated materials are kept in European museums and archives, this project is timely and relevant in light of the growing concern for the democratization of heritage. The current debate about the societal role of publicly-funded cultural institutions across Europe argues for the importance of multi-vocality in cultural and political processes. This project proposes a more inclusive interpretation and use of the materials in these institutions and thereby sets an example of how European heritage institutions can use their historical collections to reconnect the past with present-day societal concerns.
Max ERC Funding
1 475 565 €
Duration
Start date: 2018-01-01, End date: 2023-06-30
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 CAVEHEART
Project Heart regeneration in the Mexican cavefish: The difference between healing and scarring
Researcher (PI) Mathilda MOMMERSTEEG
Host Institution (HI) THE CHANCELLOR, MASTERS AND SCHOLARS OF THE UNIVERSITY OF OXFORD
Country United Kingdom
Call Details Starting Grant (StG), LS4, ERC-2016-STG
Summary Whereas the human heart cannot regenerate cardiac muscle after myocardial infarction, certain fish efficiently repair their hearts. Astyanax mexicanus, a close relative of the zebrafish, is a single fish species comprising cave-dwelling and surface river populations. Remarkably, while surface fish regenerate their heart after injury, cavefish cannot and form a permanent fibrotic scar, similar to the human heart. Using transcriptomics analysis and immunohistochemistry, we have identified key differences in the scarring and inflammatory response between the surface and cavefish heart after injury. These differences include extracellular matrix (ECM) proteins, growth factors and macrophage populations present in one, but not the other population, suggesting properties unique to the surface fish scar that promote heart regeneration. The objective of the proposed project is to characterise and utilise these findings to identify therapeutic targets to heal the human heart after myocardial infarction. First, we will analyse the identified differences in scarring and immune response between the fish in detail, before testing the role of the most interesting proteins and macrophage populations during regeneration using CRISPR mutagenesis and clodronate liposomes. Next, we will link the key scarring and inflammatory differences directly to both the genome and the ability for heart regeneration using new and prior Quantitative Trait Loci analyses. This will allow to find the most fundamental molecular mechanisms directing the wound healing process towards regeneration versus scarring. Together with an in vitro and in vivo small molecule screen directed specifically at influencing scarring towards a more ‘fish-like’ regenerative phenotype in the cavefish and mouse heart after injury, this will provide targets for therapeutic strategies to maximise the endogenous regenerative potential of the mammalian heart, with the aim to find a cure for myocardial infarction.
Summary
Whereas the human heart cannot regenerate cardiac muscle after myocardial infarction, certain fish efficiently repair their hearts. Astyanax mexicanus, a close relative of the zebrafish, is a single fish species comprising cave-dwelling and surface river populations. Remarkably, while surface fish regenerate their heart after injury, cavefish cannot and form a permanent fibrotic scar, similar to the human heart. Using transcriptomics analysis and immunohistochemistry, we have identified key differences in the scarring and inflammatory response between the surface and cavefish heart after injury. These differences include extracellular matrix (ECM) proteins, growth factors and macrophage populations present in one, but not the other population, suggesting properties unique to the surface fish scar that promote heart regeneration. The objective of the proposed project is to characterise and utilise these findings to identify therapeutic targets to heal the human heart after myocardial infarction. First, we will analyse the identified differences in scarring and immune response between the fish in detail, before testing the role of the most interesting proteins and macrophage populations during regeneration using CRISPR mutagenesis and clodronate liposomes. Next, we will link the key scarring and inflammatory differences directly to both the genome and the ability for heart regeneration using new and prior Quantitative Trait Loci analyses. This will allow to find the most fundamental molecular mechanisms directing the wound healing process towards regeneration versus scarring. Together with an in vitro and in vivo small molecule screen directed specifically at influencing scarring towards a more ‘fish-like’ regenerative phenotype in the cavefish and mouse heart after injury, this will provide targets for therapeutic strategies to maximise the endogenous regenerative potential of the mammalian heart, with the aim to find a cure for myocardial infarction.
Max ERC Funding
1 499 429 €
Duration
Start date: 2017-03-01, End date: 2022-02-28
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
