Project acronym 3D-OA-HISTO
Project Development of 3D Histopathological Grading of Osteoarthritis
Researcher (PI) Simo Jaakko Saarakkala
Host Institution (HI) OULUN YLIOPISTO
Country Finland
Call Details Starting Grant (StG), LS7, ERC-2013-StG
Summary "Background: Osteoarthritis (OA) is a common musculoskeletal disease occurring worldwide. Despite extensive research, etiology of OA is still poorly understood. Histopathological grading (HPG) of 2D tissue sections is the gold standard reference method for determination of OA stage. However, traditional 2D-HPG is destructive and based only on subjective visual evaluation. These limitations induce bias to clinical in vitro OA diagnostics and basic research that both rely strongly on HPG.
Objectives: 1) To establish and validate the very first 3D-HPG of OA based on cutting-edge nano/micro-CT (Computed Tomography) technologies in vitro; 2) To use the established method to clarify the beginning phases of OA; and 3) To validate 3D-HPG of OA for in vivo use.
Methods: Several hundreds of human osteochondral samples from patients undergoing total knee arthroplasty will be collected. The samples will be imaged in vitro with nano/micro-CT and clinical high-end extremity CT devices using specific contrast-agents to quantify tissue constituents and structure in 3D in large volume. From this information, a novel 3D-HPG is developed with statistical classification algorithms. Finally, the developed novel 3D-HPG of OA will be applied clinically in vivo.
Significance: This is the very first study to establish 3D-HPG of OA pathology in vitro and in vivo. Furthermore, the developed technique hugely improves the understanding of the beginning phases of OA. Ultimately, the study will contribute for improving OA patients’ quality of life by slowing the disease progression, and for providing powerful tools to develop new OA therapies."
Summary
"Background: Osteoarthritis (OA) is a common musculoskeletal disease occurring worldwide. Despite extensive research, etiology of OA is still poorly understood. Histopathological grading (HPG) of 2D tissue sections is the gold standard reference method for determination of OA stage. However, traditional 2D-HPG is destructive and based only on subjective visual evaluation. These limitations induce bias to clinical in vitro OA diagnostics and basic research that both rely strongly on HPG.
Objectives: 1) To establish and validate the very first 3D-HPG of OA based on cutting-edge nano/micro-CT (Computed Tomography) technologies in vitro; 2) To use the established method to clarify the beginning phases of OA; and 3) To validate 3D-HPG of OA for in vivo use.
Methods: Several hundreds of human osteochondral samples from patients undergoing total knee arthroplasty will be collected. The samples will be imaged in vitro with nano/micro-CT and clinical high-end extremity CT devices using specific contrast-agents to quantify tissue constituents and structure in 3D in large volume. From this information, a novel 3D-HPG is developed with statistical classification algorithms. Finally, the developed novel 3D-HPG of OA will be applied clinically in vivo.
Significance: This is the very first study to establish 3D-HPG of OA pathology in vitro and in vivo. Furthermore, the developed technique hugely improves the understanding of the beginning phases of OA. Ultimately, the study will contribute for improving OA patients’ quality of life by slowing the disease progression, and for providing powerful tools to develop new OA therapies."
Max ERC Funding
1 500 000 €
Duration
Start date: 2014-02-01, End date: 2019-01-31
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
Country Portugal
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 ABC
Project Targeting Multidrug Resistant Cancer
Researcher (PI) Gergely Szakacs
Host Institution (HI) TERMESZETTUDOMANYI KUTATOKOZPONT
Country Hungary
Call Details Starting Grant (StG), LS7, ERC-2010-StG_20091118
Summary Despite considerable advances in drug discovery, resistance to anticancer chemotherapy confounds the effective treatment of patients. Cancer cells can acquire broad cross-resistance to mechanistically and structurally unrelated drugs. P-glycoprotein (Pgp) actively extrudes many types of drugs from cancer cells, thereby conferring resistance to those agents. The central tenet of my work is that Pgp, a universally accepted biomarker of drug resistance, should in addition be considered as a molecular target of multidrug-resistant (MDR) cancer cells. Successful targeting of MDR cells would reduce the tumor burden and would also enable the elimination of ABC transporter-overexpressing cancer stem cells that are responsible for the replenishment of tumors. The proposed project is based on the following observations:
- First, by using a pharmacogenomic approach, I have revealed the hidden vulnerability of MDRcells (Szakács et al. 2004, Cancer Cell 6, 129-37);
- Second, I have identified a series of MDR-selective compounds with increased toxicity toPgp-expressing cells
(Turk et al.,Cancer Res, 2009. 69(21));
- Third, I have shown that MDR-selective compounds can be used to prevent theemergence of MDR (Ludwig, Szakács et al. 2006, Cancer Res 66, 4808-15);
- Fourth, we have generated initial pharmacophore models for cytotoxicity and MDR-selectivity (Hall et al. 2009, J Med Chem 52, 3191-3204).
I propose a comprehensive series of studies that will address thefollowing critical questions:
- First, what is the scope of MDR-selective compounds?
- Second, what is their mechanism of action?
- Third, what is the optimal therapeutic modality?
Extensive biological, pharmacological and bioinformatic analyses will be utilized to address four major specific aims. These aims address basic questions concerning the physiology of MDR ABC transporters in determining the mechanism of action of MDR-selective compounds, setting the stage for a fresh therapeutic approach that may eventually translate into improved patient care.
Summary
Despite considerable advances in drug discovery, resistance to anticancer chemotherapy confounds the effective treatment of patients. Cancer cells can acquire broad cross-resistance to mechanistically and structurally unrelated drugs. P-glycoprotein (Pgp) actively extrudes many types of drugs from cancer cells, thereby conferring resistance to those agents. The central tenet of my work is that Pgp, a universally accepted biomarker of drug resistance, should in addition be considered as a molecular target of multidrug-resistant (MDR) cancer cells. Successful targeting of MDR cells would reduce the tumor burden and would also enable the elimination of ABC transporter-overexpressing cancer stem cells that are responsible for the replenishment of tumors. The proposed project is based on the following observations:
- First, by using a pharmacogenomic approach, I have revealed the hidden vulnerability of MDRcells (Szakács et al. 2004, Cancer Cell 6, 129-37);
- Second, I have identified a series of MDR-selective compounds with increased toxicity toPgp-expressing cells
(Turk et al.,Cancer Res, 2009. 69(21));
- Third, I have shown that MDR-selective compounds can be used to prevent theemergence of MDR (Ludwig, Szakács et al. 2006, Cancer Res 66, 4808-15);
- Fourth, we have generated initial pharmacophore models for cytotoxicity and MDR-selectivity (Hall et al. 2009, J Med Chem 52, 3191-3204).
I propose a comprehensive series of studies that will address thefollowing critical questions:
- First, what is the scope of MDR-selective compounds?
- Second, what is their mechanism of action?
- Third, what is the optimal therapeutic modality?
Extensive biological, pharmacological and bioinformatic analyses will be utilized to address four major specific aims. These aims address basic questions concerning the physiology of MDR ABC transporters in determining the mechanism of action of MDR-selective compounds, setting the stage for a fresh therapeutic approach that may eventually translate into improved patient care.
Max ERC Funding
1 499 640 €
Duration
Start date: 2012-01-01, End date: 2016-12-31
Project acronym AI-PREVENT
Project A nationwide artificial intelligence risk assessment for primary prevention of cardiometabolic diseases
Researcher (PI) Andrea Ganna
Host Institution (HI) HELSINGIN YLIOPISTO
Country Finland
Call Details Starting Grant (StG), LS7, ERC-2020-STG
Summary Diabetes, stroke and coronary artery disease (cardiometabolic diseases) are the leading cause of death in Europe. Given that effective pharmacological and lifestyle interventions are available, it is important to identify high risk individuals at an early stage. Traditionally, this is done using clinical prediction models. However, the established models have substantial limitations: they are often used by doctors only when an underlying disease is already suspected, they are not developed on updated nationally-representative data and they require time-consuming clinical measurements. Thus, a substantial part of the population is not provided with risk assessment. I propose to revolutionize the existing approaches to primary prevention by providing risk assessment of cardiometabolic diseases before an individual even steps into the doctor’s office for a visit. To this end my project has three main objectives:
1) Development of artificial intelligence (AI) approaches to model health trajectories based on nationwide registry data on medications, diagnoses, familial risk and socio-demographic information to obtain accurate risk estimates for cardiometabolic disease. I will integrate high quality data from selected countries that have long traditions of registry data (Finland and Sweden, over 7.5 million individuals).
2) To identify health trajectories that maximize the clinical utility of genetic scores by integrating genetic and registry-based data on > 1 million people to identify subgroups of individuals for whom genetic information might improve risk prediction.
3) Validation of AI and genetic-based risk assessment as first-stage screening via a clinical study in 2800 individuals.
My project leverages the latest developments in AI and high-quality data of unprecedented scale to deliver a paradigm shift with important public health consequences by potentially changing the way cardiometabolic disease risk is assessed.
Summary
Diabetes, stroke and coronary artery disease (cardiometabolic diseases) are the leading cause of death in Europe. Given that effective pharmacological and lifestyle interventions are available, it is important to identify high risk individuals at an early stage. Traditionally, this is done using clinical prediction models. However, the established models have substantial limitations: they are often used by doctors only when an underlying disease is already suspected, they are not developed on updated nationally-representative data and they require time-consuming clinical measurements. Thus, a substantial part of the population is not provided with risk assessment. I propose to revolutionize the existing approaches to primary prevention by providing risk assessment of cardiometabolic diseases before an individual even steps into the doctor’s office for a visit. To this end my project has three main objectives:
1) Development of artificial intelligence (AI) approaches to model health trajectories based on nationwide registry data on medications, diagnoses, familial risk and socio-demographic information to obtain accurate risk estimates for cardiometabolic disease. I will integrate high quality data from selected countries that have long traditions of registry data (Finland and Sweden, over 7.5 million individuals).
2) To identify health trajectories that maximize the clinical utility of genetic scores by integrating genetic and registry-based data on > 1 million people to identify subgroups of individuals for whom genetic information might improve risk prediction.
3) Validation of AI and genetic-based risk assessment as first-stage screening via a clinical study in 2800 individuals.
My project leverages the latest developments in AI and high-quality data of unprecedented scale to deliver a paradigm shift with important public health consequences by potentially changing the way cardiometabolic disease risk is assessed.
Max ERC Funding
1 550 057 €
Duration
Start date: 2021-01-01, End date: 2025-12-31
Project acronym ALCOHOLLIFECOURSE
Project Alcohol Consumption across the Life-course: Determinants and Consequences
Researcher (PI) Anne Rebecca Britton
Host Institution (HI) University College London
Country United Kingdom
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 ALLELECHOKER
Project DNA binding proteins for treatment of gain of function mutations
Researcher (PI) Enrico Maria Surace
Host Institution (HI) FONDAZIONE TELETHON
Country Italy
Call Details Starting Grant (StG), LS7, ERC-2012-StG_20111109
Summary Zinc finger (ZF) and transcription activator-like effector (TALE) based technologies are been allowing the tailored design of “artificial” DNA-binding proteins targeted to specific and unique DNA genomic sequences. Coupling DNA binding proteins to effectors domains enables the constitution of DNA binding factors for genomic directed transcriptional modulation or targeted genomic editing. We have demonstrated that pairing a ZF DNA binding protein to the transcriptional repressor Kruppel-associated box enables in vivo, the transcriptional repression of one of the most abundantly expressed gene in mammals, the human rhodopsin gene (RHO). We propose to generate RHO DNA binding silencers (“AlleleChoker”), which inactivate RHO either by transcriptional repression or targeted genome modification, irrespectively to wild-type or mutated alleles (mutational-independent approach), and combine RHO endogenous silencing to RHO replacement (silencing-replacement strategy). With this strategy in principle a single bimodal bio-therapeutic will enable the correction of any photoreceptor disease associated with RHO mutation. Adeno-associated viral (AAV) vector-based delivery will be used for photoreceptors gene transfer. Specifically our objectives are: 1) Construction of transcriptional repressors and nucleases for RHO silencing. Characterization and comparison of RHO silencing mediated by transcriptional repressors (ZFR/ TALER) or nucleases (ZFN/ TALEN) to generate genomic directed inactivation by non-homologous end-joining (NHEJ), and refer these results to RNA interference (RNAi) targeted to RHO; 2) RHO silencing in photoreceptors. to determine genome-wide DNA binding specificity of silencers, chromatin modifications and expression profile on human retinal explants; 3) Tuning silencing and replacement. To determine the impact of gene silencing-replacement strategy on disease progression in animal models of autosomal dominant retinitis pigmentosa (adRP) associated to RHO mutations
Summary
Zinc finger (ZF) and transcription activator-like effector (TALE) based technologies are been allowing the tailored design of “artificial” DNA-binding proteins targeted to specific and unique DNA genomic sequences. Coupling DNA binding proteins to effectors domains enables the constitution of DNA binding factors for genomic directed transcriptional modulation or targeted genomic editing. We have demonstrated that pairing a ZF DNA binding protein to the transcriptional repressor Kruppel-associated box enables in vivo, the transcriptional repression of one of the most abundantly expressed gene in mammals, the human rhodopsin gene (RHO). We propose to generate RHO DNA binding silencers (“AlleleChoker”), which inactivate RHO either by transcriptional repression or targeted genome modification, irrespectively to wild-type or mutated alleles (mutational-independent approach), and combine RHO endogenous silencing to RHO replacement (silencing-replacement strategy). With this strategy in principle a single bimodal bio-therapeutic will enable the correction of any photoreceptor disease associated with RHO mutation. Adeno-associated viral (AAV) vector-based delivery will be used for photoreceptors gene transfer. Specifically our objectives are: 1) Construction of transcriptional repressors and nucleases for RHO silencing. Characterization and comparison of RHO silencing mediated by transcriptional repressors (ZFR/ TALER) or nucleases (ZFN/ TALEN) to generate genomic directed inactivation by non-homologous end-joining (NHEJ), and refer these results to RNA interference (RNAi) targeted to RHO; 2) RHO silencing in photoreceptors. to determine genome-wide DNA binding specificity of silencers, chromatin modifications and expression profile on human retinal explants; 3) Tuning silencing and replacement. To determine the impact of gene silencing-replacement strategy on disease progression in animal models of autosomal dominant retinitis pigmentosa (adRP) associated to RHO mutations
Max ERC Funding
1 354 840 €
Duration
Start date: 2013-02-01, End date: 2018-01-31
Project acronym ALLERGENE
Project Allergic multimorbidity from birth to young adulthood: determinants, epigenetic regulation and inflammatory processes
Researcher (PI) Marie Standl
Host Institution (HI) HELMHOLTZ ZENTRUM MUENCHEN DEUTSCHES FORSCHUNGSZENTRUM FUER GESUNDHEIT UND UMWELT GMBH
Country Germany
Call Details Starting Grant (StG), LS7, ERC-2020-STG
Summary The prevalence of allergic diseases, such as atopic eczema, asthma and rhinitis, has increased over the past decades and is currently estimated to be up to 40%. Prevention strategies play a pivotal role, as there are no curative treatments available. Therefore, the aim of ALLERGENE is to understand the complex interplay of genetic, environmental and lifestyle factors and to identify involved mechanisms that distinguish between young adults free of allergic diseases and those suffering from allergic multimorbidity. Therefore, the aims of the present project are to: 1. Define allergic disease trajectories from birth to young adulthood, describe their determinants and identify risk and protective early-life environmental and lifestyle factors contributing to progression towards allergic multimorbidity or remission of allergic diseases. 2. Investigate molecular mechanisms of epigenetic regulation of allergic disease trajectories and test effect modification by inclusion of selected environmental and lifestyle factors. 3. Characterise the underlying inflammation profile of allergic disease trajectories and determine interactions with environmental and lifestyle factors The project makes use of two long-standing, prospective German birth cohort studies, GINIplus and LISA, with available data from birth to young adulthood, and an extensive examination planned at age 25. Within this project, a comprehensive characterisation of allergic disease trajectories, their determinants, comorbidities, risk and protective factors across the life-course will be obtained. ALLERGENE will enhance the understanding of how modifiable factors contribute to allergic disease aetiology. This will be an essential prerequisite to develop effective early intervention strategies for susceptible populations and to identify disease-specific biomarkers for the development and progression of allergic diseases in the future.
Summary
The prevalence of allergic diseases, such as atopic eczema, asthma and rhinitis, has increased over the past decades and is currently estimated to be up to 40%. Prevention strategies play a pivotal role, as there are no curative treatments available. Therefore, the aim of ALLERGENE is to understand the complex interplay of genetic, environmental and lifestyle factors and to identify involved mechanisms that distinguish between young adults free of allergic diseases and those suffering from allergic multimorbidity. Therefore, the aims of the present project are to: 1. Define allergic disease trajectories from birth to young adulthood, describe their determinants and identify risk and protective early-life environmental and lifestyle factors contributing to progression towards allergic multimorbidity or remission of allergic diseases. 2. Investigate molecular mechanisms of epigenetic regulation of allergic disease trajectories and test effect modification by inclusion of selected environmental and lifestyle factors. 3. Characterise the underlying inflammation profile of allergic disease trajectories and determine interactions with environmental and lifestyle factors The project makes use of two long-standing, prospective German birth cohort studies, GINIplus and LISA, with available data from birth to young adulthood, and an extensive examination planned at age 25. Within this project, a comprehensive characterisation of allergic disease trajectories, their determinants, comorbidities, risk and protective factors across the life-course will be obtained. ALLERGENE will enhance the understanding of how modifiable factors contribute to allergic disease aetiology. This will be an essential prerequisite to develop effective early intervention strategies for susceptible populations and to identify disease-specific biomarkers for the development and progression of allergic diseases in the future.
Max ERC Funding
1 493 330 €
Duration
Start date: 2021-03-01, End date: 2026-02-28
Project acronym ANGIOPLACE
Project Expression and Methylation Status of Genes Regulating Placental Angiogenesis in Normal, Cloned, IVF and Monoparental Sheep Foetuses
Researcher (PI) Grazyna Ewa Ptak
Host Institution (HI) UNIVERSITA DEGLI STUDI DI TERAMO
Country Italy
Call Details Starting Grant (StG), LS7, ERC-2007-StG
Summary Normal placental angiogenesis is critical for embryonic survival and development. Epigenetic modifications, such as methylation of CpG islands, regulate the expression and imprinting of genes. Epigenetic abnormalities have been observed in embryos from assisted reproductive technologies (ART), which could explain the poor placental vascularisation, embryonic/fetal death, and altered fetal growth in these pregnancies. Both cloned (somatic cell nuclear transfer, or SNCT) and monoparental (parthogenotes, only maternal genes; androgenotes, only paternal genes) embryos provide important models for studying defects in expression and methylation status/imprinting of genes regulating placental function. Our hypothesis is that placental vascular development is compromised during early pregnancy in embryos from ART, in part due to altered expression or imprinting/methylation status of specific genes regulating placental angiogenesis. We will evaluate fetal growth, placental vascular growth, and expression and epigenetic status of genes regulating placental angiogenesis during early pregnancy in 3 Specific Aims: (1) after natural mating; (2) after transfer of biparental embryos from in vitro fertilization, and SCNT; and (3) after transfer of parthenogenetic or androgenetic embryos. These studies will therefore contribute substantially to our understanding of the regulation of placental development and vascularisation during early pregnancy, and could pinpoint the mechanism contributing to embryonic loss and developmental abnormalities in foetuses from ART. Any or all of these observations will contribute to our understanding of and also our ability to successfully employ ART, which are becoming very wide spread and important in human medicine as well as in animal production.
Summary
Normal placental angiogenesis is critical for embryonic survival and development. Epigenetic modifications, such as methylation of CpG islands, regulate the expression and imprinting of genes. Epigenetic abnormalities have been observed in embryos from assisted reproductive technologies (ART), which could explain the poor placental vascularisation, embryonic/fetal death, and altered fetal growth in these pregnancies. Both cloned (somatic cell nuclear transfer, or SNCT) and monoparental (parthogenotes, only maternal genes; androgenotes, only paternal genes) embryos provide important models for studying defects in expression and methylation status/imprinting of genes regulating placental function. Our hypothesis is that placental vascular development is compromised during early pregnancy in embryos from ART, in part due to altered expression or imprinting/methylation status of specific genes regulating placental angiogenesis. We will evaluate fetal growth, placental vascular growth, and expression and epigenetic status of genes regulating placental angiogenesis during early pregnancy in 3 Specific Aims: (1) after natural mating; (2) after transfer of biparental embryos from in vitro fertilization, and SCNT; and (3) after transfer of parthenogenetic or androgenetic embryos. These studies will therefore contribute substantially to our understanding of the regulation of placental development and vascularisation during early pregnancy, and could pinpoint the mechanism contributing to embryonic loss and developmental abnormalities in foetuses from ART. Any or all of these observations will contribute to our understanding of and also our ability to successfully employ ART, which are becoming very wide spread and important in human medicine as well as in animal production.
Max ERC Funding
363 600 €
Duration
Start date: 2008-10-01, End date: 2012-06-30
Project acronym Antibodyomics
Project Vaccine profiling and immunodiagnostic discovery by high-throughput antibody repertoire analysis
Researcher (PI) Sai Tota Reddy
Host Institution (HI) EIDGENOESSISCHE TECHNISCHE HOCHSCHULE ZUERICH
Country Switzerland
Call Details Starting Grant (StG), LS7, ERC-2015-STG
Summary Vaccines and immunodiagnostics have been vital for public health and medicine, however a quantitative molecular understanding of vaccine-induced antibody responses is lacking. Antibody research is currently going through a big-data driven revolution, largely due to progress in next-generation sequencing (NGS) and bioinformatic analysis of antibody repertoires. A main advantage of high-throughput antibody repertoire analysis is that it provides a wealth of quantitative information not possible with other classical methods of antibody analysis (i.e., serum titers); this information includes: clonal distribution and diversity, somatic hypermutation patterns, and lineage tracing. In preliminary work my group has established standardized methods for antibody repertoire NGS, including an experimental-bioinformatic pipeline for error and bias correction that enables highly accurate repertoire sequencing and analysis. The overall goal of this proposal will be to apply high-throughput antibody repertoire analysis for quantitative vaccine profiling and discovery of next-generation immunodiagnostics. Using mouse subunit vaccination as our model system, we will answer for the first time, a fundamental biological question within the context of antibody responses - what is the link between genotype (antibody repertoire) and phenotype (serum antibodies)? We will expand upon this approach for improved rational vaccine design by quantitatively determining the impact of a comprehensive set of subunit vaccination parameters on complete antibody landscapes. Finally, we will develop advanced bioinformatic methods to discover immunodiagnostics based on antibody repertoire sequences. In summary, this proposal lays the foundation for fundamentally new approaches in the quantitative analysis of antibody responses, which long-term will promote the development of next-generation vaccines and immunodiagnostics.
Summary
Vaccines and immunodiagnostics have been vital for public health and medicine, however a quantitative molecular understanding of vaccine-induced antibody responses is lacking. Antibody research is currently going through a big-data driven revolution, largely due to progress in next-generation sequencing (NGS) and bioinformatic analysis of antibody repertoires. A main advantage of high-throughput antibody repertoire analysis is that it provides a wealth of quantitative information not possible with other classical methods of antibody analysis (i.e., serum titers); this information includes: clonal distribution and diversity, somatic hypermutation patterns, and lineage tracing. In preliminary work my group has established standardized methods for antibody repertoire NGS, including an experimental-bioinformatic pipeline for error and bias correction that enables highly accurate repertoire sequencing and analysis. The overall goal of this proposal will be to apply high-throughput antibody repertoire analysis for quantitative vaccine profiling and discovery of next-generation immunodiagnostics. Using mouse subunit vaccination as our model system, we will answer for the first time, a fundamental biological question within the context of antibody responses - what is the link between genotype (antibody repertoire) and phenotype (serum antibodies)? We will expand upon this approach for improved rational vaccine design by quantitatively determining the impact of a comprehensive set of subunit vaccination parameters on complete antibody landscapes. Finally, we will develop advanced bioinformatic methods to discover immunodiagnostics based on antibody repertoire sequences. In summary, this proposal lays the foundation for fundamentally new approaches in the quantitative analysis of antibody responses, which long-term will promote the development of next-generation vaccines and immunodiagnostics.
Max ERC Funding
1 492 586 €
Duration
Start date: 2016-06-01, End date: 2021-05-31
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
Country United Kingdom
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
