Project acronym 2SEXES_1GENOME
Project Sex-specific genetic effects on fitness and human disease
Researcher (PI) Edward Hugh Morrow
Host Institution (HI) THE UNIVERSITY OF SUSSEX
Call Details Starting Grant (StG), LS8, ERC-2011-StG_20101109
Summary Darwin’s theory of natural selection rests on the principle that fitness variation in natural populations has a heritable component, on which selection acts, thereby leading to evolutionary change. A fundamental and so far unresolved question for the field of evolutionary biology is to identify the genetic loci responsible for this fitness variation, thereby coming closer to an understanding of how variation is maintained in the face of continual selection. One important complicating factor in the search for fitness related genes however is the existence of separate sexes – theoretical expectations and empirical data both suggest that sexually antagonistic genes are common. The phrase “two sexes, one genome” nicely sums up the problem; selection may favour alleles in one sex, even if they have detrimental effects on the fitness of the opposite sex, since it is their net effect across both sexes that determine the likelihood that alleles persist in a population. This theoretical framework raises an interesting, and so far entirely unexplored issue: that in one sex the functional performance of some alleles is predicted to be compromised and this effect may account for some common human diseases and conditions which show genotype-sex interactions. I propose to explore the genetic basis of sex-specific fitness in a model organism in both laboratory and natural conditions and to test whether those genes identified as having sexually antagonistic effects can help explain the incidence of human diseases that display sexual dimorphism in prevalence, age of onset or severity. This multidisciplinary project directly addresses some fundamental unresolved questions in evolutionary biology: the genetic basis and maintenance of fitness variation; the evolution of sexual dimorphism; and aims to provide novel insights into the genetic basis of some common human diseases.
Summary
Darwin’s theory of natural selection rests on the principle that fitness variation in natural populations has a heritable component, on which selection acts, thereby leading to evolutionary change. A fundamental and so far unresolved question for the field of evolutionary biology is to identify the genetic loci responsible for this fitness variation, thereby coming closer to an understanding of how variation is maintained in the face of continual selection. One important complicating factor in the search for fitness related genes however is the existence of separate sexes – theoretical expectations and empirical data both suggest that sexually antagonistic genes are common. The phrase “two sexes, one genome” nicely sums up the problem; selection may favour alleles in one sex, even if they have detrimental effects on the fitness of the opposite sex, since it is their net effect across both sexes that determine the likelihood that alleles persist in a population. This theoretical framework raises an interesting, and so far entirely unexplored issue: that in one sex the functional performance of some alleles is predicted to be compromised and this effect may account for some common human diseases and conditions which show genotype-sex interactions. I propose to explore the genetic basis of sex-specific fitness in a model organism in both laboratory and natural conditions and to test whether those genes identified as having sexually antagonistic effects can help explain the incidence of human diseases that display sexual dimorphism in prevalence, age of onset or severity. This multidisciplinary project directly addresses some fundamental unresolved questions in evolutionary biology: the genetic basis and maintenance of fitness variation; the evolution of sexual dimorphism; and aims to provide novel insights into the genetic basis of some common human diseases.
Max ERC Funding
1 500 000 €
Duration
Start date: 2012-01-01, End date: 2016-12-31
Project acronym 3Ps
Project 3Ps
Plastic-Antibodies, Plasmonics and Photovoltaic-Cells: on-site screening of cancer biomarkers made possible
Researcher (PI) Maria Goreti Ferreira Sales
Host Institution (HI) INSTITUTO SUPERIOR DE ENGENHARIA DO PORTO
Call Details Starting Grant (StG), LS7, ERC-2012-StG_20111109
Summary This project presents a new concept for the detection, diagnosis and monitoring of cancer biomarker patterns in point-of-care. The device under development will make use of the selectivity of the plastic antibodies as sensing materials and the interference they will play on the normal operation of a photovoltaic cell.
Plastic antibodies will be designed by surface imprinting procedures. Self-assembled monolayer and molecular imprinting techniques will be merged in this process because they allow the self-assembly of nanostructured materials on a “bottom-up” nanofabrication approach. A dye-sensitized solar cell will be used as photovoltaic cell. It includes a liquid interface in the cell circuit, which allows the introduction of the sample (also in liquid phase) without disturbing the normal cell operation. Furthermore, it works well with rather low cost materials and requires mild and easy processing conditions. The cell will be equipped with plasmonic structures to enhance light absorption and cell efficiency.
The device under development will be easily operated by any clinician or patient. It will require ambient light and a regular multimeter. Eye detection will be also tried out.
Summary
This project presents a new concept for the detection, diagnosis and monitoring of cancer biomarker patterns in point-of-care. The device under development will make use of the selectivity of the plastic antibodies as sensing materials and the interference they will play on the normal operation of a photovoltaic cell.
Plastic antibodies will be designed by surface imprinting procedures. Self-assembled monolayer and molecular imprinting techniques will be merged in this process because they allow the self-assembly of nanostructured materials on a “bottom-up” nanofabrication approach. A dye-sensitized solar cell will be used as photovoltaic cell. It includes a liquid interface in the cell circuit, which allows the introduction of the sample (also in liquid phase) without disturbing the normal cell operation. Furthermore, it works well with rather low cost materials and requires mild and easy processing conditions. The cell will be equipped with plasmonic structures to enhance light absorption and cell efficiency.
The device under development will be easily operated by any clinician or patient. It will require ambient light and a regular multimeter. Eye detection will be also tried out.
Max ERC Funding
998 584 €
Duration
Start date: 2013-02-01, End date: 2018-01-31
Project acronym ABYSS
Project ABYSS - Assessment of bacterial life and matter cycling in deep-sea surface sediments
Researcher (PI) Antje Boetius
Host Institution (HI) ALFRED-WEGENER-INSTITUT HELMHOLTZ-ZENTRUM FUR POLAR- UND MEERESFORSCHUNG
Call Details Advanced Grant (AdG), LS8, ERC-2011-ADG_20110310
Summary The deep-sea floor hosts a distinct microbial biome covering 67% of the Earth’s surface, characterized by cold temperatures, permanent darkness, high pressure and food limitation. The surface sediments are dominated by bacteria, with on average a billion cells per ml. Benthic bacteria are highly relevant to the Earth’s element cycles as they remineralize most of the organic matter sinking from the productive surface ocean, and return nutrients, thereby promoting ocean primary production. What passes the bacterial filter is a relevant sink for carbon on geological time scales, influencing global oxygen and carbon budgets, and fueling the deep subsurface biosphere. Despite the relevance of deep-sea sediment bacteria to climate, geochemical cycles and ecology of the seafloor, their genetic and functional diversity, niche differentiation and biological interactions remain unknown. Our preliminary work in a global survey of deep-sea sediments enables us now to target specific genes for the quantification of abyssal bacteria. We can trace isotope-labeled elements into communities and single cells, and analyze the molecular alteration of organic matter during microbial degradation, all in context with environmental dynamics recorded at the only long-term deep-sea ecosystem observatory in the Arctic that we maintain. I propose to bridge biogeochemistry, ecology, microbiology and marine biology to develop a systematic understanding of abyssal sediment bacterial community distribution, diversity, function and interactions, by combining in situ flux studies and different visualization techniques with a wide range of molecular tools. Substantial progress is expected in understanding I) identity and function of the dominant types of indigenous benthic bacteria, II) dynamics in bacterial activity and diversity caused by variations in particle flux, III) interactions with different types and ages of organic matter, and other biological factors.
Summary
The deep-sea floor hosts a distinct microbial biome covering 67% of the Earth’s surface, characterized by cold temperatures, permanent darkness, high pressure and food limitation. The surface sediments are dominated by bacteria, with on average a billion cells per ml. Benthic bacteria are highly relevant to the Earth’s element cycles as they remineralize most of the organic matter sinking from the productive surface ocean, and return nutrients, thereby promoting ocean primary production. What passes the bacterial filter is a relevant sink for carbon on geological time scales, influencing global oxygen and carbon budgets, and fueling the deep subsurface biosphere. Despite the relevance of deep-sea sediment bacteria to climate, geochemical cycles and ecology of the seafloor, their genetic and functional diversity, niche differentiation and biological interactions remain unknown. Our preliminary work in a global survey of deep-sea sediments enables us now to target specific genes for the quantification of abyssal bacteria. We can trace isotope-labeled elements into communities and single cells, and analyze the molecular alteration of organic matter during microbial degradation, all in context with environmental dynamics recorded at the only long-term deep-sea ecosystem observatory in the Arctic that we maintain. I propose to bridge biogeochemistry, ecology, microbiology and marine biology to develop a systematic understanding of abyssal sediment bacterial community distribution, diversity, function and interactions, by combining in situ flux studies and different visualization techniques with a wide range of molecular tools. Substantial progress is expected in understanding I) identity and function of the dominant types of indigenous benthic bacteria, II) dynamics in bacterial activity and diversity caused by variations in particle flux, III) interactions with different types and ages of organic matter, and other biological factors.
Max ERC Funding
3 375 693 €
Duration
Start date: 2012-06-01, End date: 2018-05-31
Project acronym ADaPTIVE
Project Analysing Diversity with a Phenomic approach: Trends in Vertebrate Evolution
Researcher (PI) Anjali Goswami
Host Institution (HI) NATURAL HISTORY MUSEUM
Call Details Starting Grant (StG), LS8, ERC-2014-STG
Summary What processes shape vertebrate diversity through deep time? Approaches to this question can focus on many different factors, from life history and ecology to large-scale environmental change and extinction. To date, the majority of studies on the evolution of vertebrate diversity have focused on relatively simple metrics, specifically taxon counts or univariate measures, such as body size. However, multivariate morphological data provides a more complete picture of evolutionary and palaeoecological change. Morphological data can also bridge deep-time palaeobiological analyses with studies of the genetic and developmental factors that shape variation and must also influence large-scale patterns of evolutionary change. Thus, accurately reconstructing the patterns and processes underlying evolution requires an approach that can fully represent an organism’s phenome, the sum total of their observable traits.
Recent advances in imaging and data analysis allow large-scale study of phenomic evolution. In this project, I propose to quantitatively analyse the deep-time evolutionary diversity of tetrapods (amphibians, reptiles, birds, and mammals). Specifically, I will apply and extend new imaging, morphometric, and analytical tools to construct a multivariate phenomic dataset for living and extinct tetrapods from 3-D scans. I will use these data to rigorously compare extinction selectivity, timing, pace, and shape of adaptive radiations, and ecomorphological response to large-scale climatic shifts across all tetrapod clades. To do so, I will quantify morphological diversity (disparity) and rates of evolution spanning over 300 million years of tetrapod history. I will further analyse the evolution of phenotypic integration by quantifying not just the traits themselves, but changes in the relationships among traits, which reflect the genetic, developmental, and functional interactions that shape variation, the raw material for natural selection.
Summary
What processes shape vertebrate diversity through deep time? Approaches to this question can focus on many different factors, from life history and ecology to large-scale environmental change and extinction. To date, the majority of studies on the evolution of vertebrate diversity have focused on relatively simple metrics, specifically taxon counts or univariate measures, such as body size. However, multivariate morphological data provides a more complete picture of evolutionary and palaeoecological change. Morphological data can also bridge deep-time palaeobiological analyses with studies of the genetic and developmental factors that shape variation and must also influence large-scale patterns of evolutionary change. Thus, accurately reconstructing the patterns and processes underlying evolution requires an approach that can fully represent an organism’s phenome, the sum total of their observable traits.
Recent advances in imaging and data analysis allow large-scale study of phenomic evolution. In this project, I propose to quantitatively analyse the deep-time evolutionary diversity of tetrapods (amphibians, reptiles, birds, and mammals). Specifically, I will apply and extend new imaging, morphometric, and analytical tools to construct a multivariate phenomic dataset for living and extinct tetrapods from 3-D scans. I will use these data to rigorously compare extinction selectivity, timing, pace, and shape of adaptive radiations, and ecomorphological response to large-scale climatic shifts across all tetrapod clades. To do so, I will quantify morphological diversity (disparity) and rates of evolution spanning over 300 million years of tetrapod history. I will further analyse the evolution of phenotypic integration by quantifying not just the traits themselves, but changes in the relationships among traits, which reflect the genetic, developmental, and functional interactions that shape variation, the raw material for natural selection.
Max ERC Funding
1 482 818 €
Duration
Start date: 2015-06-01, End date: 2020-05-31
Project acronym AdaptoSCOPE
Project Using cis-regulatory mutations to highlight polygenic adaptation in natural plant systems
Researcher (PI) Juliette de Meaux
Host Institution (HI) UNIVERSITAET ZU KOELN
Call Details Consolidator Grant (CoG), LS8, ERC-2014-CoG
Summary The goal of this project is to demonstrate that novel aspects of the molecular basis of Darwinian adaptation can be discovered if the polygenic basis of adaptation is taken into account. This project will use the genome-wide distribution of cis-regulatory variants to discover the molecular pathways that are optimized during adaptation via accumulation of small effect mutations. Current approaches include scans for outlier genes with strong population genetics signatures of selection, or large effect QTL associating with fitness. They can only reveal a small subset of the molecular changes recruited along adaptive paths. Here, instead, the distribution of small effect mutations will be used to make inferences on the targets of polygenic adaptation across divergent populations in each of the two closely related species, A. thaliana and A. lyrata. These species are both found at diverse latitudes and show sign of local adaptation to climatic differences. Mutations affecting cis-regulation will be identified in leaves of plants exposed to various temperature regimes triggering phenotypic responses of adaptive relevance. Their distribution in clusters of functionally connected genes will be quantified. The phylogeographic differences in the distribution of the mutations will be used to disentangle neutral from adaptive clusters of functionally connected genes in each of the two species. This project will identify the molecular pathways subjected collectively to natural selection and provide a completely novel view on adaptive landscapes. It will further examine whether local adaptation occurs by convergent evolution of molecular systems in plants. This approach has the potential to find broad applications in ecology and agriculture.
Summary
The goal of this project is to demonstrate that novel aspects of the molecular basis of Darwinian adaptation can be discovered if the polygenic basis of adaptation is taken into account. This project will use the genome-wide distribution of cis-regulatory variants to discover the molecular pathways that are optimized during adaptation via accumulation of small effect mutations. Current approaches include scans for outlier genes with strong population genetics signatures of selection, or large effect QTL associating with fitness. They can only reveal a small subset of the molecular changes recruited along adaptive paths. Here, instead, the distribution of small effect mutations will be used to make inferences on the targets of polygenic adaptation across divergent populations in each of the two closely related species, A. thaliana and A. lyrata. These species are both found at diverse latitudes and show sign of local adaptation to climatic differences. Mutations affecting cis-regulation will be identified in leaves of plants exposed to various temperature regimes triggering phenotypic responses of adaptive relevance. Their distribution in clusters of functionally connected genes will be quantified. The phylogeographic differences in the distribution of the mutations will be used to disentangle neutral from adaptive clusters of functionally connected genes in each of the two species. This project will identify the molecular pathways subjected collectively to natural selection and provide a completely novel view on adaptive landscapes. It will further examine whether local adaptation occurs by convergent evolution of molecular systems in plants. This approach has the potential to find broad applications in ecology and agriculture.
Max ERC Funding
1 683 120 €
Duration
Start date: 2015-09-01, End date: 2020-08-31
Project acronym ALCOHOLLIFECOURSE
Project Alcohol Consumption across the Life-course: Determinants and Consequences
Researcher (PI) Anne Rebecca Britton
Host Institution (HI) UNIVERSITY COLLEGE LONDON
Call Details Starting Grant (StG), LS7, ERC-2012-StG_20111109
Summary The epidemiology of alcohol use and related health consequences plays a vital role by monitoring populations’ alcohol consumption patterns and problems associated with drinking. Such studies seek to explain mechanisms linking consumption to harm and ultimately to reduce the health burden. Research needs to consider changes in drinking behaviour over the life-course. The current evidence base lacks the consideration of the complexity of lifetime consumption patterns, the predictors of change and subsequent health risks.
Aims of the study
1. To describe age-related trajectories of drinking in different settings and to determine the extent to which individual and social contextual factors, including socioeconomic position, social networks and life events influence drinking pattern trajectories.
2. To estimate the impact of drinking trajectories on physical functioning and disease and to disentangle the exposure-outcome associations in terms of a) timing, i.e. health effect of drinking patterns in early, mid and late life; and b) duration, i.e. whether the impact of drinking accumulates over time.
3. To test the bidirectional associations between health and changes in consumption over the life-course in order to estimate the relative importance of these effects and to determine the dominant temporal direction.
4. To explore mechanisms and pathways through which drinking trajectories affect health and functioning in later life and to examine the role played by potential effect modifiers of the association between drinking and poor health.
Several large, longitudinal cohort studies from European countries with repeated measures of alcohol consumption will be combined and analysed to address the aims. A new team will be formed consisting of the PI, a Research Associate and two PhD students. Dissemination will be through journals, conferences, and culminating in a one-day workshop for academics, practitioners and policy makers in the alcohol field.
Summary
The epidemiology of alcohol use and related health consequences plays a vital role by monitoring populations’ alcohol consumption patterns and problems associated with drinking. Such studies seek to explain mechanisms linking consumption to harm and ultimately to reduce the health burden. Research needs to consider changes in drinking behaviour over the life-course. The current evidence base lacks the consideration of the complexity of lifetime consumption patterns, the predictors of change and subsequent health risks.
Aims of the study
1. To describe age-related trajectories of drinking in different settings and to determine the extent to which individual and social contextual factors, including socioeconomic position, social networks and life events influence drinking pattern trajectories.
2. To estimate the impact of drinking trajectories on physical functioning and disease and to disentangle the exposure-outcome associations in terms of a) timing, i.e. health effect of drinking patterns in early, mid and late life; and b) duration, i.e. whether the impact of drinking accumulates over time.
3. To test the bidirectional associations between health and changes in consumption over the life-course in order to estimate the relative importance of these effects and to determine the dominant temporal direction.
4. To explore mechanisms and pathways through which drinking trajectories affect health and functioning in later life and to examine the role played by potential effect modifiers of the association between drinking and poor health.
Several large, longitudinal cohort studies from European countries with repeated measures of alcohol consumption will be combined and analysed to address the aims. A new team will be formed consisting of the PI, a Research Associate and two PhD students. Dissemination will be through journals, conferences, and culminating in a one-day workshop for academics, practitioners and policy makers in the alcohol field.
Max ERC Funding
1 032 815 €
Duration
Start date: 2013-01-01, End date: 2017-12-31
Project acronym APGREID
Project Ancient Pathogen Genomics of Re-Emerging Infectious Disease
Researcher (PI) Johannes Krause
Host Institution (HI) MAX-PLANCK-GESELLSCHAFT ZUR FORDERUNG DER WISSENSCHAFTEN EV
Call Details Starting Grant (StG), LS8, ERC-2012-StG_20111109
Summary Here we propose a first step toward a direct reconstruction of the evolutionary history of human infectious disease agents by obtaining genome wide data of historic pathogens. Through an extensive screening of skeletal collections from well-characterized catastrophe, or emergency, mass burials we plan to detect and sequence pathogen DNA from various historic pandemics spanning at least 2,500 years using a general purpose molecular capture method that will screen for hundreds of pathogens in a single assay. Subsequent experiments will attempt to reconstruct full genomes from all pathogenic species identified. The molecular fossil record of human pathogens will provide insights into host adaptation and evolutionary rates of infectious disease. In addition, human genomic regions relating to disease susceptibility and immunity will be characterized in the skeletal material in order to observe the direct effect that pathogens have made on the genetic makeup of human populations over time. The results of this project will allow a multidisciplinary interpretation of historical pandemics that have influenced the course of human history. It will provide priceless information for the field of history, evolutionary biology, anthropology as well as medicine and will have direct consequences on how we manage emerging and re-emerging infectious disease in the future.
Summary
Here we propose a first step toward a direct reconstruction of the evolutionary history of human infectious disease agents by obtaining genome wide data of historic pathogens. Through an extensive screening of skeletal collections from well-characterized catastrophe, or emergency, mass burials we plan to detect and sequence pathogen DNA from various historic pandemics spanning at least 2,500 years using a general purpose molecular capture method that will screen for hundreds of pathogens in a single assay. Subsequent experiments will attempt to reconstruct full genomes from all pathogenic species identified. The molecular fossil record of human pathogens will provide insights into host adaptation and evolutionary rates of infectious disease. In addition, human genomic regions relating to disease susceptibility and immunity will be characterized in the skeletal material in order to observe the direct effect that pathogens have made on the genetic makeup of human populations over time. The results of this project will allow a multidisciplinary interpretation of historical pandemics that have influenced the course of human history. It will provide priceless information for the field of history, evolutionary biology, anthropology as well as medicine and will have direct consequences on how we manage emerging and re-emerging infectious disease in the future.
Max ERC Funding
1 474 560 €
Duration
Start date: 2013-01-01, End date: 2017-12-31
Project acronym APPLAUSE
Project Adolescent Precursors to Psychiatric Disorders – Learing from Analysis of User-Service Engagement
Researcher (PI) Sara Evans
Host Institution (HI) LONDON SCHOOL OF ECONOMICS AND POLITICAL SCIENCE
Call Details Starting Grant (StG), LS7, ERC-2013-StG
Summary APPLAUSE’s aim is to produce a body of evidence that illustrates how young people with mental health problems currently interact with both formal mental health services and informal social and familial support structures. Careful analysis of data gathered in the UK and Brazil will allow formulation of globally relevant insights into mental health care delivery for young people, which will be presented internationally as a resource for future health care service design.
APPLAUSE will allow the collection of an important data set that does not currently exist in this field, and will look to other disciplines for innovative approaches to data analysis. Whist standard analysis may allow for snapshots of health service use, using innovative life course methods will allow us to to characterise patterns of complete service use of each individual participant’s experience of accessing mental health care and social support.
Adolescence is a critical period in mental health development, which has been largely neglected by public health efforts. Psychiatric disorders rank as the primary cause of disability among individuals aged 10-24 years, worldwide. Moreover, many health risk behaviours emerge during adolescence and 70% of adult psychiatric disorders are preceded by mental health problems during adolescent years. However, delays to receiving care for psychiatric disorders, following disorder onset, avreage more than ten years and little is known about factors which impede access to and continuity of care among young people with mental health problems. APPLAUSE will analyse current access models, reports of individual experiences of positive and negative interactions with health care services and the culturally embedded social factors that impact on such access. Addressing this complex problem from a global perspective will advance the development of a more diverse and innovative set of strategies for improving earlier access to care.
Summary
APPLAUSE’s aim is to produce a body of evidence that illustrates how young people with mental health problems currently interact with both formal mental health services and informal social and familial support structures. Careful analysis of data gathered in the UK and Brazil will allow formulation of globally relevant insights into mental health care delivery for young people, which will be presented internationally as a resource for future health care service design.
APPLAUSE will allow the collection of an important data set that does not currently exist in this field, and will look to other disciplines for innovative approaches to data analysis. Whist standard analysis may allow for snapshots of health service use, using innovative life course methods will allow us to to characterise patterns of complete service use of each individual participant’s experience of accessing mental health care and social support.
Adolescence is a critical period in mental health development, which has been largely neglected by public health efforts. Psychiatric disorders rank as the primary cause of disability among individuals aged 10-24 years, worldwide. Moreover, many health risk behaviours emerge during adolescence and 70% of adult psychiatric disorders are preceded by mental health problems during adolescent years. However, delays to receiving care for psychiatric disorders, following disorder onset, avreage more than ten years and little is known about factors which impede access to and continuity of care among young people with mental health problems. APPLAUSE will analyse current access models, reports of individual experiences of positive and negative interactions with health care services and the culturally embedded social factors that impact on such access. Addressing this complex problem from a global perspective will advance the development of a more diverse and innovative set of strategies for improving earlier access to care.
Max ERC Funding
1 499 948 €
Duration
Start date: 2014-01-01, End date: 2018-12-31
Project acronym ARMOR-T
Project Armoring multifunctional T cells for cancer therapy
Researcher (PI) Sebastian Kobold
Host Institution (HI) LUDWIG-MAXIMILIANS-UNIVERSITAET MUENCHEN
Call Details Starting Grant (StG), LS7, ERC-2017-STG
Summary Adoptive T cell therapy (ACT) is a powerful approach to treat even advanced cancer diseases where poor prognosis calls for innovative treatments. However ACT is critically limited by insufficient T cell infiltration into the tumor, T cell activation at the tumor site and local T cell suppression. Few advances have been made in the field to tackle these limitations besides increasing T cell activation. My group has focussed on these unaddressed issues but came to realise that tackling these one by one will not be sufficient. I have developed a panel of unpublished chemokine receptors and innovative modular antibody-activated receptors which have the potential to overcome the limitations of ACT against solid tumors. This ground-breaking portfolio places my group in the unique position to address combination of synergistic receptors and enable cellular therapies in previously unsuccessful indications. My project will provide the rationale for provision of an effective cancer treatment. The goal is to develop the next generation of ACT through T cell engineering both by forced expression of migratory and activating receptors and simultaneous deletion of immune suppressive molecules by gene editing. ARMOR-T will provide the basis for further preclinical and clinical development of a pioneering cellular product devoid of the limitations of available products to date. I will prove 1) synergy between migratory and modular activating receptors, 2) feasibility to integrate gene editing into a T cell expansion protocol, 3) synergy between gene editing, migratory and modular receptors and 4) efficacy, safety and mode of action. The main work of the project will be carried out in models of pancreatic cancer. The ARMOR-T platform will subsequently be translated to other cancer entities where response to ACT is likely such as melanoma, breast or colon cancer, providing less toxic and more effective therapies to otherwise untreatable disease.
Summary
Adoptive T cell therapy (ACT) is a powerful approach to treat even advanced cancer diseases where poor prognosis calls for innovative treatments. However ACT is critically limited by insufficient T cell infiltration into the tumor, T cell activation at the tumor site and local T cell suppression. Few advances have been made in the field to tackle these limitations besides increasing T cell activation. My group has focussed on these unaddressed issues but came to realise that tackling these one by one will not be sufficient. I have developed a panel of unpublished chemokine receptors and innovative modular antibody-activated receptors which have the potential to overcome the limitations of ACT against solid tumors. This ground-breaking portfolio places my group in the unique position to address combination of synergistic receptors and enable cellular therapies in previously unsuccessful indications. My project will provide the rationale for provision of an effective cancer treatment. The goal is to develop the next generation of ACT through T cell engineering both by forced expression of migratory and activating receptors and simultaneous deletion of immune suppressive molecules by gene editing. ARMOR-T will provide the basis for further preclinical and clinical development of a pioneering cellular product devoid of the limitations of available products to date. I will prove 1) synergy between migratory and modular activating receptors, 2) feasibility to integrate gene editing into a T cell expansion protocol, 3) synergy between gene editing, migratory and modular receptors and 4) efficacy, safety and mode of action. The main work of the project will be carried out in models of pancreatic cancer. The ARMOR-T platform will subsequently be translated to other cancer entities where response to ACT is likely such as melanoma, breast or colon cancer, providing less toxic and more effective therapies to otherwise untreatable disease.
Max ERC Funding
1 636 710 €
Duration
Start date: 2018-03-01, End date: 2023-02-28
Project acronym AsthmaPhenotypes
Project Understanding asthma phenotypes: going beyond the atopic/non-atopic paradigm
Researcher (PI) Neil Pearce
Host Institution (HI) LONDON SCHOOL OF HYGIENE AND TROPICAL MEDICINE ROYAL CHARTER
Call Details Advanced Grant (AdG), LS7, ERC-2014-ADG
Summary Fifteen years ago it was widely believed that asthma was an allergic/atopic disease caused by allergen exposure in infancy; this produced atopic sensitization and continued exposure resulted in eosinophilic airways inflammation, bronchial hyper-responsiveness and reversible airflow obstruction. It is now clear that this model is at best incomplete. Less than one-half of asthma cases involve allergic (atopic) mechanisms, and most asthma in low-and-middle income countries is non-atopic. Westernization may be contributing to the global increases in asthma prevalence, but this process appears to involve changes in asthma susceptibility rather than increased exposure to “established” asthma risk factors. Understanding why these changes are occurring is essential in order to halt the growing global asthma epidemic.This will require a combination of epidemiological, clinical and basic science studies in a variety of environments.
A key task is to reclassify asthma phenotypes. These are important to: (i) better understand the aetiological mechanisms of asthma; (ii) identify new causes; and (iii) identify new therapeutic measures. There are major opportunities to address these issues using new techniques for sample collection from the airways (sputum induction, nasal lavage), new methods of analysis (microbiome, epigenetics), and new bioinformatics methods for integrating data from multiple sources and levels. There is an unprecedented potential to go beyond the old atopic/non-atopic categorization of phenotypes.
I will therefore conduct analyses to re-examine and reclassify asthma phenotypes. The key features are the inclusion of: (i) both high and low prevalence centres from both high income countries and low-and-middle income countries; (ii) much more detailed biomarker information than has been used for previous studies of asthma phenotypes; and (iii) new bioinformatics methods for integrating data from multiple sources and levels.
Summary
Fifteen years ago it was widely believed that asthma was an allergic/atopic disease caused by allergen exposure in infancy; this produced atopic sensitization and continued exposure resulted in eosinophilic airways inflammation, bronchial hyper-responsiveness and reversible airflow obstruction. It is now clear that this model is at best incomplete. Less than one-half of asthma cases involve allergic (atopic) mechanisms, and most asthma in low-and-middle income countries is non-atopic. Westernization may be contributing to the global increases in asthma prevalence, but this process appears to involve changes in asthma susceptibility rather than increased exposure to “established” asthma risk factors. Understanding why these changes are occurring is essential in order to halt the growing global asthma epidemic.This will require a combination of epidemiological, clinical and basic science studies in a variety of environments.
A key task is to reclassify asthma phenotypes. These are important to: (i) better understand the aetiological mechanisms of asthma; (ii) identify new causes; and (iii) identify new therapeutic measures. There are major opportunities to address these issues using new techniques for sample collection from the airways (sputum induction, nasal lavage), new methods of analysis (microbiome, epigenetics), and new bioinformatics methods for integrating data from multiple sources and levels. There is an unprecedented potential to go beyond the old atopic/non-atopic categorization of phenotypes.
I will therefore conduct analyses to re-examine and reclassify asthma phenotypes. The key features are the inclusion of: (i) both high and low prevalence centres from both high income countries and low-and-middle income countries; (ii) much more detailed biomarker information than has been used for previous studies of asthma phenotypes; and (iii) new bioinformatics methods for integrating data from multiple sources and levels.
Max ERC Funding
2 348 803 €
Duration
Start date: 2016-01-01, End date: 2020-12-31
