Project acronym CEAD
Project Contextualizing Evidence for Action on Diabetes in low-resource Settings: A mixed-methods case study in Quito and Esmeraldas, Ecuador.
Researcher (PI) Lucy Anne Parker
Host Institution (HI) UNIVERSIDAD MIGUEL HERNANDEZ DE ELCHE
Country Spain
Call Details Starting Grant (StG), SH3, ERC-2018-STG
Summary The relentless rise in diabetes is one of the greatest global health emergencies of the 21st century. The increase is most pronounced in low and middle income countries where today three quarters of people with diabetes live and over 80% of the deaths attributed to non-communicable diseases occur. In light of the wealth of knowledge already available about how to tackle the problem, most major international organizations call for the adoption healthy public policies and initiatives to strengthening health systems. However, implementation of recommended action remains limited in many settings. Most evidence comes from high-income settings and may generate recommendations that cannot be successfully implemented in other settings without careful consideration and contextualization. I propose here that this “know-do” gap can be reduced by revealing the barriers to implementing evidence-based recommendations, engaging local stakeholders in developing context-led innovations and developing a tool-kit for contextualizing and implementing diabetes recommendations in low-resource settings. I plan the research in two carefully selected settings in Ecuador, with mixed-methods combining quantitative epidemiological research and qualitative methodology to generate the rich and varied knowledge that is required to trigger policy action and/or changes in care models. Furthermore, I will engage patients, community members, health workers and decision makers in the process of knowledge generation, interpretation and use. The overarching objective is hence, to explore the process by which global recommendations can be translated into context-specific, evidence-informed action for diabetes prevention in low-resource settings. The findings will support the global endeavour to bridge the global “know-do” gap, one of the most important public health challenges this century and a great opportunity for strengthening health systems and achieving health equity.
Summary
The relentless rise in diabetes is one of the greatest global health emergencies of the 21st century. The increase is most pronounced in low and middle income countries where today three quarters of people with diabetes live and over 80% of the deaths attributed to non-communicable diseases occur. In light of the wealth of knowledge already available about how to tackle the problem, most major international organizations call for the adoption healthy public policies and initiatives to strengthening health systems. However, implementation of recommended action remains limited in many settings. Most evidence comes from high-income settings and may generate recommendations that cannot be successfully implemented in other settings without careful consideration and contextualization. I propose here that this “know-do” gap can be reduced by revealing the barriers to implementing evidence-based recommendations, engaging local stakeholders in developing context-led innovations and developing a tool-kit for contextualizing and implementing diabetes recommendations in low-resource settings. I plan the research in two carefully selected settings in Ecuador, with mixed-methods combining quantitative epidemiological research and qualitative methodology to generate the rich and varied knowledge that is required to trigger policy action and/or changes in care models. Furthermore, I will engage patients, community members, health workers and decision makers in the process of knowledge generation, interpretation and use. The overarching objective is hence, to explore the process by which global recommendations can be translated into context-specific, evidence-informed action for diabetes prevention in low-resource settings. The findings will support the global endeavour to bridge the global “know-do” gap, one of the most important public health challenges this century and a great opportunity for strengthening health systems and achieving health equity.
Max ERC Funding
1 475 334 €
Duration
Start date: 2019-01-01, End date: 2023-12-31
Project acronym EllipticPDE
Project Regularity and singularities in elliptic PDE's: beyond monotonicity formulas
Researcher (PI) Xavier ROS-OTON
Host Institution (HI) UNIVERSITAT DE BARCELONA
Country Spain
Call Details Starting Grant (StG), PE1, ERC-2018-STG
Summary One of the oldest and most important questions in PDE theory is that of regularity. A classical example is Hilbert's XIXth problem (1900), solved by De Giorgi and Nash in 1956. During the second half of the XXth century, the regularity theory for elliptic and parabolic PDE's experienced a huge development, and many fundamental questions were answered by Caffarelli, Nirenberg, Krylov, Evans, Nadirashvili, Friedman, and many others. Still, there are problems of crucial importance that remain open.
The aim of this project is to go significantly beyond the state of the art in some of the most important open questions in this context. In particular, three key objectives of the project are the following. First, to introduce new techniques to obtain fine description of singularities in nonlinear elliptic PDE's. Aside from its intrinsic interest, a good regularity theory for singular points is likely to provide insightful applications in other contexts. A second aim of the project is to establish generic regularity results for free boundaries and other PDE problems. The development of methods which would allow one to prove generic regularity results may be viewed as one of the greatest challenges not only for free boundary problems, but for PDE problems in general. Finally, the third main objective is to achieve a complete regularity theory for nonlinear elliptic PDE's that does not rely on monotonicity formulas. These three objectives, while seemingly different, are in fact deeply interrelated.
Summary
One of the oldest and most important questions in PDE theory is that of regularity. A classical example is Hilbert's XIXth problem (1900), solved by De Giorgi and Nash in 1956. During the second half of the XXth century, the regularity theory for elliptic and parabolic PDE's experienced a huge development, and many fundamental questions were answered by Caffarelli, Nirenberg, Krylov, Evans, Nadirashvili, Friedman, and many others. Still, there are problems of crucial importance that remain open.
The aim of this project is to go significantly beyond the state of the art in some of the most important open questions in this context. In particular, three key objectives of the project are the following. First, to introduce new techniques to obtain fine description of singularities in nonlinear elliptic PDE's. Aside from its intrinsic interest, a good regularity theory for singular points is likely to provide insightful applications in other contexts. A second aim of the project is to establish generic regularity results for free boundaries and other PDE problems. The development of methods which would allow one to prove generic regularity results may be viewed as one of the greatest challenges not only for free boundary problems, but for PDE problems in general. Finally, the third main objective is to achieve a complete regularity theory for nonlinear elliptic PDE's that does not rely on monotonicity formulas. These three objectives, while seemingly different, are in fact deeply interrelated.
Max ERC Funding
1 335 250 €
Duration
Start date: 2019-01-01, End date: 2023-12-31
Project acronym KryptonInt
Project Erasing the superintegron to understand the role of chromosomal integrons in bacterial evolution
Researcher (PI) Jose Antonio ESCUDERO
Host Institution (HI) UNIVERSIDAD COMPLUTENSE DE MADRID
Country Spain
Call Details Starting Grant (StG), LS2, ERC-2018-STG
Summary Integrons are genetic platforms that enhance bacterial evolvability through the acquisition and stockpiling of new genes encoded in mobile elements named cassettes. They are found in the chromosomes of environmental bacteria but some have acquired mobility through their association to transposons and conjugative plasmids. These mobile integrons (MI) caused the unexpected rise of multidrug resistance that is now a major threat to modern medicine, and are good proof of the adaptive power of integrons. Class 1 integrons are the most relevant MI and the major experimental model. Yet little is known about the hundreds of sedentary chromosomal integrons (SCI) that have driven bacterial evolution for eons. The paradigm of SCI is the superintegron (SI), an extremely large integron located in the chromosome of Vibrio cholerae, the causative agent of Cholera disease. Despite its role in the adaptability of one of the deadliest pathogens in history, the SI is poorly characterized because it is only functional in its native genetic background, yet its presence interferes with, and precludes all studies performed in V. cholerae. I propose to solve this paradoxical situation by deleting the SI, an ambitious project not only for its size (126 Kb) but because it is highly stabilized by 17 toxin-antitoxin systems. To do so, I have developed SeqDelTA, a novel method that is already giving excellent preliminary results. I will then use V. cholerae∆SI to study fundamental aspects of SCIs, yet out of reach. I will elucidate the functions encoded in SI cassettes to understand the role and adaptive value of integrons in nature; I will also unravel the genesis of cassettes: how a gene is exapted from its genetic context to become a mobile module; and I will explore the circulation of antibiotic resistance cassettes among humans, animals, food, and the environment with a novel biosynthetic tool (the I3C). KryptonInt will open and explore the historically inaccessible field of study of SCIs.
Summary
Integrons are genetic platforms that enhance bacterial evolvability through the acquisition and stockpiling of new genes encoded in mobile elements named cassettes. They are found in the chromosomes of environmental bacteria but some have acquired mobility through their association to transposons and conjugative plasmids. These mobile integrons (MI) caused the unexpected rise of multidrug resistance that is now a major threat to modern medicine, and are good proof of the adaptive power of integrons. Class 1 integrons are the most relevant MI and the major experimental model. Yet little is known about the hundreds of sedentary chromosomal integrons (SCI) that have driven bacterial evolution for eons. The paradigm of SCI is the superintegron (SI), an extremely large integron located in the chromosome of Vibrio cholerae, the causative agent of Cholera disease. Despite its role in the adaptability of one of the deadliest pathogens in history, the SI is poorly characterized because it is only functional in its native genetic background, yet its presence interferes with, and precludes all studies performed in V. cholerae. I propose to solve this paradoxical situation by deleting the SI, an ambitious project not only for its size (126 Kb) but because it is highly stabilized by 17 toxin-antitoxin systems. To do so, I have developed SeqDelTA, a novel method that is already giving excellent preliminary results. I will then use V. cholerae∆SI to study fundamental aspects of SCIs, yet out of reach. I will elucidate the functions encoded in SI cassettes to understand the role and adaptive value of integrons in nature; I will also unravel the genesis of cassettes: how a gene is exapted from its genetic context to become a mobile module; and I will explore the circulation of antibiotic resistance cassettes among humans, animals, food, and the environment with a novel biosynthetic tool (the I3C). KryptonInt will open and explore the historically inaccessible field of study of SCIs.
Max ERC Funding
1 499 516 €
Duration
Start date: 2019-01-01, End date: 2023-12-31
Project acronym MULTIPALEOIBERIA
Project Population dynamics and cultural adaptations of the last Neandertals and first Modern humans in inland Iberia: a multi-proxy investigation
Researcher (PI) Manuel ALCARAZ-CASTAnO
Host Institution (HI) UNIVERSIDAD DE ALCALA
Country Spain
Call Details Starting Grant (StG), SH6, ERC-2018-STG
Summary The relations between cultural developments and environmental change among hunter-gatherers are crucial for studying population dynamics during the last glaciation (110,000–11,700 years ago). However, proposing solid interpretations on how climate and environment variability affected the social and techno-economic organisation of hominins, requires robust geoarchaeological, chronological, and palaeoecological evidence. In the Iberian Peninsula, a key area for this period due to its geographic position and ecological variability, models on these topics are biased by the poor quality of available evidence for its interior lands. The Iberian interior has been traditionally depicted as a marginal and few populated region due to its harsh ecological conditions compared to the coastal areas. Based on preliminary data suggesting that this picture could be wrong, I hypothesize (1) that the human settlement of interior Iberia during this period was more stable than previously thought and (2) that his has relevant implications at the European scale for problems such as the replacement of Neandertals by modern humans, the first modern human peopling of Europe, and the patterns of land use and mobility during the coldest stages of the last glacial. To test these hypotheses, this project will investigate population dynamics and human-environment interactions of the last Neandertals and first modern humans in interior Iberia based on completely unprecedented evidence gathered by means of a macro-regional and interdisciplinary research project. This involves the participation of a wide team of scholars coordinated by the PI, and a network of methods including field surveys, geoarchaeological excavations and chronometric, paleoecological, zooarchaeological, techno-economic and symbolic studies. The results will significantly change our views on key biocultural and ecological processes of the European prehistory, and the way human societies have dealt with challenging environments.
Summary
The relations between cultural developments and environmental change among hunter-gatherers are crucial for studying population dynamics during the last glaciation (110,000–11,700 years ago). However, proposing solid interpretations on how climate and environment variability affected the social and techno-economic organisation of hominins, requires robust geoarchaeological, chronological, and palaeoecological evidence. In the Iberian Peninsula, a key area for this period due to its geographic position and ecological variability, models on these topics are biased by the poor quality of available evidence for its interior lands. The Iberian interior has been traditionally depicted as a marginal and few populated region due to its harsh ecological conditions compared to the coastal areas. Based on preliminary data suggesting that this picture could be wrong, I hypothesize (1) that the human settlement of interior Iberia during this period was more stable than previously thought and (2) that his has relevant implications at the European scale for problems such as the replacement of Neandertals by modern humans, the first modern human peopling of Europe, and the patterns of land use and mobility during the coldest stages of the last glacial. To test these hypotheses, this project will investigate population dynamics and human-environment interactions of the last Neandertals and first modern humans in interior Iberia based on completely unprecedented evidence gathered by means of a macro-regional and interdisciplinary research project. This involves the participation of a wide team of scholars coordinated by the PI, and a network of methods including field surveys, geoarchaeological excavations and chronometric, paleoecological, zooarchaeological, techno-economic and symbolic studies. The results will significantly change our views on key biocultural and ecological processes of the European prehistory, and the way human societies have dealt with challenging environments.
Max ERC Funding
1 387 515 €
Duration
Start date: 2019-01-01, End date: 2023-12-31
Project acronym NextGen IO
Project Exploiting the hypoxia response in T cells for Next-Generation Immuno-Oncology
Researcher (PI) Francisco de Asis PALAZON GARCIA
Host Institution (HI) ASOCIACION CENTRO DE INVESTIGACION COOPERATIVA EN BIOCIENCIAS
Country Spain
Call Details Starting Grant (StG), LS7, ERC-2018-STG
Summary NextGen_IO has a core focus on immuno-oncology, specifically on target discovery and drug development, to exploit several opportunities that the hypoxia pathway in T cells offers for the treatment of cancer. It is well recognised that the clinical response of immunotherapies depends on the ability of T-cells to mount an effective effector response, persist in treated patients and avoid exhaustion and toxicities. Several approaches to immunotherapy have shown promise in clinical trials, especially the use of immune checkpoint inhibitors and, more recently, autologous adoptive T-cell therapies. However, current state-of-the-art immunotherapies are only effective in a small fraction of patients, offering a medical need to be addressed in several cancer types. Importantly, the tumor microenvironment has specific features that impact the immune response, including decreased oxygenation, aberrant vascularization and altered nutrient availability; all these influence the success of immunotherapies. During the last 10 years, my research has been focused on elucidating the role of the oxygen sensing machinery in T cell function, and the link of hypoxia-driven metabolism and epigenetic modifications with T cell differentiation into effector and memory T cells within the context of cancer immunotherapy. The current proposal aims to exploit these previous findings with a multi-disciplinary strategy, to deliver several early-stage drug discovery outputs.
The main objectives are:
1. Development of a novel small molecule inhibitor to modulate the hypoxic response in T cells.
2. Therapeutic target discovery in T cells, focused on hypoxia-driven epigenetic modifications.
3. Development of hypoxia-inducible molecular switches for adoptive T cell therapy.
Successful completion of the project will allow me to further innovate and consolidate my position as a leader in this field, harness this pathway for therapeutic potential and explore potential combinatorial approaches.
Summary
NextGen_IO has a core focus on immuno-oncology, specifically on target discovery and drug development, to exploit several opportunities that the hypoxia pathway in T cells offers for the treatment of cancer. It is well recognised that the clinical response of immunotherapies depends on the ability of T-cells to mount an effective effector response, persist in treated patients and avoid exhaustion and toxicities. Several approaches to immunotherapy have shown promise in clinical trials, especially the use of immune checkpoint inhibitors and, more recently, autologous adoptive T-cell therapies. However, current state-of-the-art immunotherapies are only effective in a small fraction of patients, offering a medical need to be addressed in several cancer types. Importantly, the tumor microenvironment has specific features that impact the immune response, including decreased oxygenation, aberrant vascularization and altered nutrient availability; all these influence the success of immunotherapies. During the last 10 years, my research has been focused on elucidating the role of the oxygen sensing machinery in T cell function, and the link of hypoxia-driven metabolism and epigenetic modifications with T cell differentiation into effector and memory T cells within the context of cancer immunotherapy. The current proposal aims to exploit these previous findings with a multi-disciplinary strategy, to deliver several early-stage drug discovery outputs.
The main objectives are:
1. Development of a novel small molecule inhibitor to modulate the hypoxic response in T cells.
2. Therapeutic target discovery in T cells, focused on hypoxia-driven epigenetic modifications.
3. Development of hypoxia-inducible molecular switches for adoptive T cell therapy.
Successful completion of the project will allow me to further innovate and consolidate my position as a leader in this field, harness this pathway for therapeutic potential and explore potential combinatorial approaches.
Max ERC Funding
1 993 575 €
Duration
Start date: 2019-02-01, End date: 2024-01-31
