Project acronym MCTRinIA
Project Resolution Pharmacology and Physiology of MCTR in Arthritis
Researcher (PI) Jesmond Dalli
Host Institution (HI) QUEEN MARY UNIVERSITY OF LONDON
Country United Kingdom
Call Details Starting Grant (StG), LS4, ERC-2015-STG
Summary Chronic inflammation may result from failure of the host response to engage pro-resolving pathways. The current treatment armamentarium for chronic inflammatory conditions may lead to immune suppression. Thus, identification of novel therapeutics that control inflammation without immune suppression will provide an attractive alternative approach. This is especially important since incidence of these conditions increases with an ageing global population. In planaria, mice, human peripheral blood and milk I recently uncovered a new family of endogenous molecules, named Maresin Conjugates in Tissue Regeneration (MCTR). These potently regulate white blood cell responses, promote the resolution of acute inflammation and accelerate tissue regeneration. The aim of this Starting Grant is to identify pathways that lead to failed resolution in inflammatory arthritis, as a prototypical chronic inflammatory condition. The hypothesis is that MCTR biosynthesis is dysregulated in inflammatory arthritis, leading to an unbridled host response, chronic inflammation and tissue destruction. This proposal will employ a multipronged approach to test this hypothesis by 1) Determining MCTR regulation in self-resolving and delayed-resolving arthritis; 2) Investigating the host protective and tissue regenerative actions of MCTRs in inflammatory arthritis; 3) Establishing the MCTR biosynthetic pathway and 4) Determining the regulation if its components during self-limited and delayed-resolving arthritis. Anticipated results will uncover novel pathways that become dysregulated during failed resolution. Results from this Starting Grant will also identify targets and new therapeutic approaches that will engage pro-resolution programs as well as tissue regeneration in conditions characterised by persistent inflammation and hence failed resolution. This will lay the basis for informed structure-activity based studies and the design of therapeutics for treatment of chronic inflammatory conditions.
Summary
Chronic inflammation may result from failure of the host response to engage pro-resolving pathways. The current treatment armamentarium for chronic inflammatory conditions may lead to immune suppression. Thus, identification of novel therapeutics that control inflammation without immune suppression will provide an attractive alternative approach. This is especially important since incidence of these conditions increases with an ageing global population. In planaria, mice, human peripheral blood and milk I recently uncovered a new family of endogenous molecules, named Maresin Conjugates in Tissue Regeneration (MCTR). These potently regulate white blood cell responses, promote the resolution of acute inflammation and accelerate tissue regeneration. The aim of this Starting Grant is to identify pathways that lead to failed resolution in inflammatory arthritis, as a prototypical chronic inflammatory condition. The hypothesis is that MCTR biosynthesis is dysregulated in inflammatory arthritis, leading to an unbridled host response, chronic inflammation and tissue destruction. This proposal will employ a multipronged approach to test this hypothesis by 1) Determining MCTR regulation in self-resolving and delayed-resolving arthritis; 2) Investigating the host protective and tissue regenerative actions of MCTRs in inflammatory arthritis; 3) Establishing the MCTR biosynthetic pathway and 4) Determining the regulation if its components during self-limited and delayed-resolving arthritis. Anticipated results will uncover novel pathways that become dysregulated during failed resolution. Results from this Starting Grant will also identify targets and new therapeutic approaches that will engage pro-resolution programs as well as tissue regeneration in conditions characterised by persistent inflammation and hence failed resolution. This will lay the basis for informed structure-activity based studies and the design of therapeutics for treatment of chronic inflammatory conditions.
Max ERC Funding
1 964 303 €
Duration
Start date: 2016-03-01, End date: 2021-08-31
Project acronym Niche Fibrosis
Project Identification of regulatory signals from vascular niche in alveolar regeneration and pulmonary fibrosis
Researcher (PI) Joo-Hyeon Lee
Host Institution (HI) THE CHANCELLOR MASTERS AND SCHOLARS OF THE UNIVERSITY OF CAMBRIDGE
Country United Kingdom
Call Details Starting Grant (StG), LS4, ERC-2015-STG
Summary Pulmonary fibrosis is a multifaceted and fatal disease that includes damaged alveolar epithelial cells and disorganization of multiple stromal cells. Dysregulation of multicellular crosstalk between epithelial and stromal cells is likely to contribute to fibrosis. However, the precise way this tissue damage occurs is unknown. I hypothesize that impaired function of lung epithelial stem cell lead to alveolar epithelial damage in pulmonary fibrosis, and which may be caused by altered stromal/niche cells. Epithelial injury repair and regeneration in the adult lung is carried out by numerous epithelial stem/progenitor cells. Recently, I identified a crucial interaction between lung endothelial cells and lung stem cells during alveolar injury response, and demonstrated a new regulatory signalling pathway that operates in endothelial cells to support alveolar injury repair by driving alveolar lineage specification of stem cells. Importantly, introduction of endothelial-derived factors into the lung after fibrotic damage enhances alveolar regeneration and reduces pulmonary fibrosis.
Given these results and unique my background knowledge, I will bring a new concept of stem cell-niche interactions in alveolar injury repair and pulmonary fibrosis. Using both in vivo murine and organoid culture, as well as human lung organoid culture systems, I will define 1) whether and how the fibrotic response affects lung stem cells and 2) how lung stem cells are regulated by endothelial cells that may comprise their respective niches during injury repair. 3) The mechanisms involved in the normal and pathological regulation of lung stem cells will be elucidated by determining secreted factors and regulatory signals endothelial cells confer through paracrine and direct physical interaction with stem cells. Insights gained from these studies will accelerate the development of novel and selective therapeutic approaches that directly target stem cells or their niches in pulmonary fibrosis.
Summary
Pulmonary fibrosis is a multifaceted and fatal disease that includes damaged alveolar epithelial cells and disorganization of multiple stromal cells. Dysregulation of multicellular crosstalk between epithelial and stromal cells is likely to contribute to fibrosis. However, the precise way this tissue damage occurs is unknown. I hypothesize that impaired function of lung epithelial stem cell lead to alveolar epithelial damage in pulmonary fibrosis, and which may be caused by altered stromal/niche cells. Epithelial injury repair and regeneration in the adult lung is carried out by numerous epithelial stem/progenitor cells. Recently, I identified a crucial interaction between lung endothelial cells and lung stem cells during alveolar injury response, and demonstrated a new regulatory signalling pathway that operates in endothelial cells to support alveolar injury repair by driving alveolar lineage specification of stem cells. Importantly, introduction of endothelial-derived factors into the lung after fibrotic damage enhances alveolar regeneration and reduces pulmonary fibrosis.
Given these results and unique my background knowledge, I will bring a new concept of stem cell-niche interactions in alveolar injury repair and pulmonary fibrosis. Using both in vivo murine and organoid culture, as well as human lung organoid culture systems, I will define 1) whether and how the fibrotic response affects lung stem cells and 2) how lung stem cells are regulated by endothelial cells that may comprise their respective niches during injury repair. 3) The mechanisms involved in the normal and pathological regulation of lung stem cells will be elucidated by determining secreted factors and regulatory signals endothelial cells confer through paracrine and direct physical interaction with stem cells. Insights gained from these studies will accelerate the development of novel and selective therapeutic approaches that directly target stem cells or their niches in pulmonary fibrosis.
Max ERC Funding
1 499 272 €
Duration
Start date: 2016-05-01, End date: 2021-04-30
Project acronym SCHISTO_PERSIST
Project New approaches to characterise Schistosoma mansoni infections persisting despite mass drug administration
Researcher (PI) Poppy Lamberton
Host Institution (HI) UNIVERSITY OF GLASGOW
Country United Kingdom
Call Details Starting Grant (StG), LS7, ERC-2015-STG
Summary Neglected tropical diseases affect over 1.4 billion people and cause a greater disease burden than HIV/AIDS. Despite extensive mass drug administration (MDA) schistosomiasis remains a major public health issue, with a socio-economic impact second only to malaria amongst parasites. I will evaluate novel strategies and new technologies to monitor the impact of MDA programmes, to identify threats to MDA effectiveness, and enhance control of schistosomiasis in sub-Saharan Africa.
Specifically I will address five ambitious questions:
1. What is the best way to monitor schistosome infections and drug efficacy?
2. Has drug resistance been selected for?
3. What is the potential for drug resistance to spread?
4. What other factors drive transmission?
5. What other factors affect parasite clearance?
These aims are feasible through innovative interdisciplinary methods including a) state-of-the-art DNA-chip diagnostics, b) novel application of genetic analysis to differentiate surviving worms from juveniles, c) use of drug screening technology to measure in vitro drug susceptibility, providing the first quantifiable in vitro phenotype without using mammals, d) combination of molecular techniques with mathematical models to elucidate the potential spread of phenotypes and e) an unparalleled interdisciplinary approach deducing host effects in non-clearers.
These methods and technologies have not previously been used to assess MDA effectiveness for any helminth infection. My pioneering research will enable a comparative assessment of how transmission is affected by untreated adults and pre-school children, individuals with heavy infections, coinfections, and drug coverage. This will elucidate optimal strategies to reduce transmission hotspots.
My results will improve monitoring protocols and inform policy makers on how best to treat schistosomiasis. I will fill a critical global health knowledge gap, with findings transferable across a range of MDA controlled diseases.
Summary
Neglected tropical diseases affect over 1.4 billion people and cause a greater disease burden than HIV/AIDS. Despite extensive mass drug administration (MDA) schistosomiasis remains a major public health issue, with a socio-economic impact second only to malaria amongst parasites. I will evaluate novel strategies and new technologies to monitor the impact of MDA programmes, to identify threats to MDA effectiveness, and enhance control of schistosomiasis in sub-Saharan Africa.
Specifically I will address five ambitious questions:
1. What is the best way to monitor schistosome infections and drug efficacy?
2. Has drug resistance been selected for?
3. What is the potential for drug resistance to spread?
4. What other factors drive transmission?
5. What other factors affect parasite clearance?
These aims are feasible through innovative interdisciplinary methods including a) state-of-the-art DNA-chip diagnostics, b) novel application of genetic analysis to differentiate surviving worms from juveniles, c) use of drug screening technology to measure in vitro drug susceptibility, providing the first quantifiable in vitro phenotype without using mammals, d) combination of molecular techniques with mathematical models to elucidate the potential spread of phenotypes and e) an unparalleled interdisciplinary approach deducing host effects in non-clearers.
These methods and technologies have not previously been used to assess MDA effectiveness for any helminth infection. My pioneering research will enable a comparative assessment of how transmission is affected by untreated adults and pre-school children, individuals with heavy infections, coinfections, and drug coverage. This will elucidate optimal strategies to reduce transmission hotspots.
My results will improve monitoring protocols and inform policy makers on how best to treat schistosomiasis. I will fill a critical global health knowledge gap, with findings transferable across a range of MDA controlled diseases.
Max ERC Funding
1 490 270 €
Duration
Start date: 2016-04-01, End date: 2022-03-31
Project acronym Token Communities
Project Token Communities in the Ancient Mediterranean
Researcher (PI) Clare Phillpa Rowan
Host Institution (HI) THE UNIVERSITY OF WARWICK
Country United Kingdom
Call Details Starting Grant (StG), SH6, ERC-2015-STG
Summary This project will provide the first comprehensive analysis of the role played by tokens in the ancient Mediterranean. Tokens are frequently found on archaeological sites and within museum collections, but are little studied and poorly understood. These objects played a central role in cultural, religious, political and economic life in antiquity; closer study of these objects is thus imperative in gaining a fuller picture of the ancient world and its cultural legacy. An interdisciplinary team will examine tokens and their contexts within the ancient world, focusing on the periods when they are in highest use: the Hellenistic period (postdoctoral researcher) and the Roman world (PI and 2 PhD students).
The project will combine an analysis of museum material with the known archaeological contexts of these objects. It will be the first project to approach these items in a cross regional and fully contextualised manner. This approach will enable researchers to better define what tokens were in antiquity, and what roles they played. Moreover, through a careful consideration of type, context, and distribution, the project will also explore how these objects actively contributed to the generation of different types of community. The envisaged outcomes will provide a basis for the study of tokens more broadly, generating insights that will inform the display, scholarly use and understanding of these objects within museums and other spaces. The exploration of how tokens and token-communities within antiquity existed alongside official currencies and groups will also provide an important historical parallel for the contemporary development of alternative currencies, their associated values, and communities.
Summary
This project will provide the first comprehensive analysis of the role played by tokens in the ancient Mediterranean. Tokens are frequently found on archaeological sites and within museum collections, but are little studied and poorly understood. These objects played a central role in cultural, religious, political and economic life in antiquity; closer study of these objects is thus imperative in gaining a fuller picture of the ancient world and its cultural legacy. An interdisciplinary team will examine tokens and their contexts within the ancient world, focusing on the periods when they are in highest use: the Hellenistic period (postdoctoral researcher) and the Roman world (PI and 2 PhD students).
The project will combine an analysis of museum material with the known archaeological contexts of these objects. It will be the first project to approach these items in a cross regional and fully contextualised manner. This approach will enable researchers to better define what tokens were in antiquity, and what roles they played. Moreover, through a careful consideration of type, context, and distribution, the project will also explore how these objects actively contributed to the generation of different types of community. The envisaged outcomes will provide a basis for the study of tokens more broadly, generating insights that will inform the display, scholarly use and understanding of these objects within museums and other spaces. The exploration of how tokens and token-communities within antiquity existed alongside official currencies and groups will also provide an important historical parallel for the contemporary development of alternative currencies, their associated values, and communities.
Max ERC Funding
1 033 723 €
Duration
Start date: 2016-06-01, End date: 2021-08-31
Project acronym TransposonsReprogram
Project How retrotransposons remodel the genome during early development and reprogramming
Researcher (PI) HELEN MARY Rowe
Host Institution (HI) QUEEN MARY UNIVERSITY OF LONDON
Country United Kingdom
Call Details Starting Grant (StG), LS2, ERC-2015-STG
Summary Retrotransposons (RTNs) are ancient viruses that have stably integrated themselves into mammalian genomes and they now occupy around half of the human or mouse genome. These mobile genetic elements that have coevolved with us drive evolution by creating new genes and plasticity of genomes. Exciting data including ours has shown that even RTNs that are no longer active retain enhancer, promoter or repressor sequences that regulate developmental genes, through largely uncharacterized transcription factors. We have employed CRISPR/Cas9 gene disruption to determine that Zfp37 and Zfp819 bind to and regulate RTNs in mouse embryonic stem cells (ESCs). Identification of these zinc finger proteins (ZFPs) now allows us to ask new questions about how RTNs have been co-opted to orchestrate gene circuits in vitro and in vivo. Both these factors have already been implicated to play a role in reprogramming or genome integrity.
We hypothesize that RTNs have been co-opted to remodel the genome by acting as structural platforms that recruit transcription factors like Zfp37 and Zfp819. We will test this hypothesis assessing the role of RTNs and these two ZFPs in three dynamic contexts where the genome is remodelled. These are in ESC differentiation to neurons, in reprogramming and in early mouse development, three scenarios where RTNs have been documented to become expressed and serve an unknown function.
This work will exploit mouse development to unravel the mechanism of how RTNs remodel the genome. It will help us to understand how ZFPs can be engaged to reprogram cells and in stem-cell therapies, and will explain more broadly how RTNs, which dominate our genomes, control cell fate.
Summary
Retrotransposons (RTNs) are ancient viruses that have stably integrated themselves into mammalian genomes and they now occupy around half of the human or mouse genome. These mobile genetic elements that have coevolved with us drive evolution by creating new genes and plasticity of genomes. Exciting data including ours has shown that even RTNs that are no longer active retain enhancer, promoter or repressor sequences that regulate developmental genes, through largely uncharacterized transcription factors. We have employed CRISPR/Cas9 gene disruption to determine that Zfp37 and Zfp819 bind to and regulate RTNs in mouse embryonic stem cells (ESCs). Identification of these zinc finger proteins (ZFPs) now allows us to ask new questions about how RTNs have been co-opted to orchestrate gene circuits in vitro and in vivo. Both these factors have already been implicated to play a role in reprogramming or genome integrity.
We hypothesize that RTNs have been co-opted to remodel the genome by acting as structural platforms that recruit transcription factors like Zfp37 and Zfp819. We will test this hypothesis assessing the role of RTNs and these two ZFPs in three dynamic contexts where the genome is remodelled. These are in ESC differentiation to neurons, in reprogramming and in early mouse development, three scenarios where RTNs have been documented to become expressed and serve an unknown function.
This work will exploit mouse development to unravel the mechanism of how RTNs remodel the genome. It will help us to understand how ZFPs can be engaged to reprogram cells and in stem-cell therapies, and will explain more broadly how RTNs, which dominate our genomes, control cell fate.
Max ERC Funding
1 499 055 €
Duration
Start date: 2016-05-01, End date: 2022-12-31
Project acronym War and Supernature
Project War and the Supernatural in Early Modern Europe
Researcher (PI) Ian Campbell
Host Institution (HI) THE QUEEN'S UNIVERSITY OF BELFAST
Country United Kingdom
Call Details Starting Grant (StG), SH6, ERC-2015-STG
Summary The debates of intellectuals both Catholic and Protestant have much to tell us about the nature of religious warfare in early modern Europe. In the seventeenth century, the small numbers of radical Catholics and Protestants who favoured imposing their own version of Christianity on others by force were accused by moderates (no less religiously sincere) within their own communities of promoting wars incompatible with Christian orthodoxy. Religious faith, the moderates insisted, was a supernatural thing, a gift of God, rather than a natural thing, a creation of rational humans, and thus could not be imposed by force. Arguments for religious war in the sense of evangelisation by force were thus resisted by most of the educated European elite. These debates among university-based Catholic and Protestant intellectuals took place in the Latin language and are insufficiently known to political historians of early modern Europe. Political historians examining the phenomenon of early modern religious war impose the modern categories of sacred (which they associate with the irrational) and secular (which they posit must be drained of the divine) on the past, mistakenly assuming that those who opposed evangelisation by force were somehow more secular than their opponents and composing a false history of secularisation.
This project will analyse, translate, edit, and publish these scholastic debates between religious militants and religious moderates on the role of force in religious life in order to inform and re-shape arguments among political historians on the nature of religious warfare. One focus of the project will be the Franciscan intellectual tradition which favoured evangelisation by force. But some Protestants and especially Calvinists also brought the supernatural very far into human life, and the project will insist on the utility of that distinction between natural and supernatural in composing a trans-confessional history of religious militancy.
Summary
The debates of intellectuals both Catholic and Protestant have much to tell us about the nature of religious warfare in early modern Europe. In the seventeenth century, the small numbers of radical Catholics and Protestants who favoured imposing their own version of Christianity on others by force were accused by moderates (no less religiously sincere) within their own communities of promoting wars incompatible with Christian orthodoxy. Religious faith, the moderates insisted, was a supernatural thing, a gift of God, rather than a natural thing, a creation of rational humans, and thus could not be imposed by force. Arguments for religious war in the sense of evangelisation by force were thus resisted by most of the educated European elite. These debates among university-based Catholic and Protestant intellectuals took place in the Latin language and are insufficiently known to political historians of early modern Europe. Political historians examining the phenomenon of early modern religious war impose the modern categories of sacred (which they associate with the irrational) and secular (which they posit must be drained of the divine) on the past, mistakenly assuming that those who opposed evangelisation by force were somehow more secular than their opponents and composing a false history of secularisation.
This project will analyse, translate, edit, and publish these scholastic debates between religious militants and religious moderates on the role of force in religious life in order to inform and re-shape arguments among political historians on the nature of religious warfare. One focus of the project will be the Franciscan intellectual tradition which favoured evangelisation by force. But some Protestants and especially Calvinists also brought the supernatural very far into human life, and the project will insist on the utility of that distinction between natural and supernatural in composing a trans-confessional history of religious militancy.
Max ERC Funding
1 324 885 €
Duration
Start date: 2016-03-01, End date: 2021-02-28
Project acronym ZF_Blood
Project Less is more: Single Cell Analysis of Zebrafish Blood Development
Researcher (PI) Ana Cvejic
Host Institution (HI) THE CHANCELLOR MASTERS AND SCHOLARS OF THE UNIVERSITY OF CAMBRIDGE
Country United Kingdom
Call Details Starting Grant (StG), LS3, ERC-2015-STG
Summary Blood stem cells need to both perpetuate themselves (self-renew) and differentiate into all mature blood cells to maintain blood formation throughout life. However, it is unclear how the underlying gene regulatory network maintains this population of self-renewing and differentiating stem cells, and how it accommodates the transition from a stem cell to a mature blood cell. Our current knowledge of transcriptomes of various blood cell types has mainly been advanced by population-level analysis. However, the population of seemingly homogenous blood cells may include many distinct cell types with substantially different transcriptomes and abilities to make diverse fate decisions. To overcome these limitations, I will use single-cell transcriptome sequencing of zebrafish blood cells. I will apply an integrative strategy, combining genetic perturbation with computational sequence and network analysis methods, to reconstruct the regulatory networks that maintain the dynamic balance between different blood cell types. This will be achieved by pursuing two main aims:
1) I will create a comprehensive atlas of single cell gene expression in adult zebrafish blood cells and computationally reconstruct the blood lineage tree. I will order cells according to their most likely developmental chronology and identify genes and gene regulatory networks that define distinct cell types. The completion of the first aim will be followed by a more ambitious long-term one that is based on:
2) The in-depth functional characterisation of a subset of novel key regulators of blood formation and identified cell types in vivo. To achieve this I will generate a number of loss-of-function and transgenic zebrafish lines.
By sequencing thousands of single cells, this study is poised to go beyond traditional approaches in examining the complex relationships between the continuous spectra of blood cells, and will provide unprecedented insight into the regulation of blood cell formation.
Summary
Blood stem cells need to both perpetuate themselves (self-renew) and differentiate into all mature blood cells to maintain blood formation throughout life. However, it is unclear how the underlying gene regulatory network maintains this population of self-renewing and differentiating stem cells, and how it accommodates the transition from a stem cell to a mature blood cell. Our current knowledge of transcriptomes of various blood cell types has mainly been advanced by population-level analysis. However, the population of seemingly homogenous blood cells may include many distinct cell types with substantially different transcriptomes and abilities to make diverse fate decisions. To overcome these limitations, I will use single-cell transcriptome sequencing of zebrafish blood cells. I will apply an integrative strategy, combining genetic perturbation with computational sequence and network analysis methods, to reconstruct the regulatory networks that maintain the dynamic balance between different blood cell types. This will be achieved by pursuing two main aims:
1) I will create a comprehensive atlas of single cell gene expression in adult zebrafish blood cells and computationally reconstruct the blood lineage tree. I will order cells according to their most likely developmental chronology and identify genes and gene regulatory networks that define distinct cell types. The completion of the first aim will be followed by a more ambitious long-term one that is based on:
2) The in-depth functional characterisation of a subset of novel key regulators of blood formation and identified cell types in vivo. To achieve this I will generate a number of loss-of-function and transgenic zebrafish lines.
By sequencing thousands of single cells, this study is poised to go beyond traditional approaches in examining the complex relationships between the continuous spectra of blood cells, and will provide unprecedented insight into the regulation of blood cell formation.
Max ERC Funding
1 500 000 €
Duration
Start date: 2016-05-01, End date: 2022-04-30
