Project acronym 5D Heart Patch
Project A Functional, Mature In vivo Human Ventricular Muscle Patch for Cardiomyopathy
Researcher (PI) Kenneth Randall Chien
Host Institution (HI) KAROLINSKA INSTITUTET
Country Sweden
Call Details Advanced Grant (AdG), LS7, ERC-2016-ADG
Summary Developing new therapeutic strategies for heart regeneration is a major goal for cardiac biology and medicine. While cardiomyocytes can be generated from human pluripotent stem (hPSC) cells in vitro, it has proven difficult to use these cells to generate a large scale, mature human heart ventricular muscle graft on the injured heart in vivo. The central objective of this proposal is to optimize the generation of a large-scale pure, fully functional human ventricular muscle patch in vivo through the self-assembly of purified human ventricular progenitors and the localized expression of defined paracrine factors that drive their expansion, differentiation, vascularization, matrix formation, and maturation. Recently, we have found that purified hPSC-derived ventricular progenitors (HVPs) can self-assemble in vivo on the epicardial surface into a 3D vascularized, and functional ventricular patch with its own extracellular matrix via a cell autonomous pathway. A two-step protocol and FACS purification of HVP receptors can generate billions of pure HVPs- The current proposal will lead to the identification of defined paracrine pathways to enhance the survival, grafting/implantation, expansion, differentiation, matrix formation, vascularization and maturation of the graft in vivo. We will captalize on our unique HVP system and our novel modRNA technology to deliver therapeutic strategies by using the in vivo human ventricular muscle to model in vivo arrhythmogenic cardiomyopathy, and optimize the ability of the graft to compensate for the massive loss of functional muscle during ischemic cardiomyopathy and post-myocardial infarction. The studies will lead to new in vivo chimeric models of human cardiac disease and an experimental paradigm to optimize organ-on-organ cardiac tissue engineers of an in vivo, functional mature ventricular patch for cardiomyopathy
Summary
Developing new therapeutic strategies for heart regeneration is a major goal for cardiac biology and medicine. While cardiomyocytes can be generated from human pluripotent stem (hPSC) cells in vitro, it has proven difficult to use these cells to generate a large scale, mature human heart ventricular muscle graft on the injured heart in vivo. The central objective of this proposal is to optimize the generation of a large-scale pure, fully functional human ventricular muscle patch in vivo through the self-assembly of purified human ventricular progenitors and the localized expression of defined paracrine factors that drive their expansion, differentiation, vascularization, matrix formation, and maturation. Recently, we have found that purified hPSC-derived ventricular progenitors (HVPs) can self-assemble in vivo on the epicardial surface into a 3D vascularized, and functional ventricular patch with its own extracellular matrix via a cell autonomous pathway. A two-step protocol and FACS purification of HVP receptors can generate billions of pure HVPs- The current proposal will lead to the identification of defined paracrine pathways to enhance the survival, grafting/implantation, expansion, differentiation, matrix formation, vascularization and maturation of the graft in vivo. We will captalize on our unique HVP system and our novel modRNA technology to deliver therapeutic strategies by using the in vivo human ventricular muscle to model in vivo arrhythmogenic cardiomyopathy, and optimize the ability of the graft to compensate for the massive loss of functional muscle during ischemic cardiomyopathy and post-myocardial infarction. The studies will lead to new in vivo chimeric models of human cardiac disease and an experimental paradigm to optimize organ-on-organ cardiac tissue engineers of an in vivo, functional mature ventricular patch for cardiomyopathy
Max ERC Funding
2 149 228 €
Duration
Start date: 2017-12-01, End date: 2022-11-30
Project acronym ANGIOFAT
Project New mechanisms of angiogenesis modulators in switching between white and brown adipose tissues
Researcher (PI) Yihai Cao
Host Institution (HI) KAROLINSKA INSTITUTET
Country Sweden
Call Details Advanced Grant (AdG), LS4, ERC-2009-AdG
Summary Understanding the molecular mechanisms underlying adipose blood vessel growth or regression opens new fundamentally insight into novel therapeutic options for the treatment of obesity and its related metabolic diseases such as type 2 diabetes and cancer. Unlike any other tissues in the body, the adipose tissue constantly experiences expansion and shrinkage throughout the adult life. Adipocytes in the white adipose tissue have the ability to switch into metabolically highly active brown-like adipocytes. Brown adipose tissue (BAT) contains significantly higher numbers of microvessels than white adipose tissue (WAT) in order to adopt the high rates of metabolism. Thus, an angiogenic phenotype has to be switched on during the transition from WAT into BAT. We have found that acclimation of mice in cold could induce transition from inguinal and epidedymal WAT into BAT by upregulation of angiogenic factor expression and down-regulations of angiogenesis inhibitors (Xue et al, Cell Metabolism, 2009). The transition from WAT into BAT is dependent on vascular endothelial growth factor (VEGF) that primarily targets on vascular endothelial cells via a tissue hypoxia-independent mechanism. VEGF blockade significantly alters adipose tissue metabolism. In another genetic model, we show similar findings that angiogenesis is crucial to mediate the transition from WAT into BAT (Xue et al, PNAS, 2008). Here we propose that the vascular tone determines the metabolic switch between WAT and BAT. Characterization of these novel angiogenic pathways may reveal new mechanisms underlying development of obesity- and metabolism-related disease complications and may define novel therapeutic targets. Thus, the benefit of this research proposal is enormous and is aimed to treat the most common and highly risk human health conditions in the modern time.
Summary
Understanding the molecular mechanisms underlying adipose blood vessel growth or regression opens new fundamentally insight into novel therapeutic options for the treatment of obesity and its related metabolic diseases such as type 2 diabetes and cancer. Unlike any other tissues in the body, the adipose tissue constantly experiences expansion and shrinkage throughout the adult life. Adipocytes in the white adipose tissue have the ability to switch into metabolically highly active brown-like adipocytes. Brown adipose tissue (BAT) contains significantly higher numbers of microvessels than white adipose tissue (WAT) in order to adopt the high rates of metabolism. Thus, an angiogenic phenotype has to be switched on during the transition from WAT into BAT. We have found that acclimation of mice in cold could induce transition from inguinal and epidedymal WAT into BAT by upregulation of angiogenic factor expression and down-regulations of angiogenesis inhibitors (Xue et al, Cell Metabolism, 2009). The transition from WAT into BAT is dependent on vascular endothelial growth factor (VEGF) that primarily targets on vascular endothelial cells via a tissue hypoxia-independent mechanism. VEGF blockade significantly alters adipose tissue metabolism. In another genetic model, we show similar findings that angiogenesis is crucial to mediate the transition from WAT into BAT (Xue et al, PNAS, 2008). Here we propose that the vascular tone determines the metabolic switch between WAT and BAT. Characterization of these novel angiogenic pathways may reveal new mechanisms underlying development of obesity- and metabolism-related disease complications and may define novel therapeutic targets. Thus, the benefit of this research proposal is enormous and is aimed to treat the most common and highly risk human health conditions in the modern time.
Max ERC Funding
2 411 547 €
Duration
Start date: 2010-03-01, End date: 2015-02-28
Project acronym BBBARRIER
Project Mechanisms of regulation of the blood-brain barrier; towards opening and closing the barrier on demand
Researcher (PI) Bjoern Christer Betsholtz
Host Institution (HI) UPPSALA UNIVERSITET
Country Sweden
Call Details Advanced Grant (AdG), LS4, ERC-2011-ADG_20110310
Summary In the bone-enclosed CNS, increased vascular permeability may cause life-threatening tissue swelling, and/or ischemia and inflammation which compromise tissue repair after trauma or stroke. The brain vasculature possesses several unique features collectively named the blood-brain barrier (BBB) in which passive permeability is almost completely abolished and replaced by a complex of specific transport mechanisms. The BBB is necessary to uphold the specific milieu necessary for neuronal function. Whereas breakdown of the BBB is part of many CNS diseases, including stroke, neuroinflammation, trauma and neurodegenerative disorders, its molecular mechanisms and consequences are unclear and debated. Conversely, the intact BBB is a huge obstacle for drug delivery to the brain. Research on the BBB therefore has two seemingly opposing aims: 1) to seal a damaged BBB and protect the brain from toxic blood products, and 2) to open the BBB “on demand” for drug delivery. A major problem in the BBB field has been the lack of in vivo animal models for molecular and functional studies. So far, available in vitro models are not recapitulating the in vivo BBB. Our recent work on mouse models lacking pericytes, a BBB-associated cell type, demonstrates a specific role for pericytes in the development and regulation of the mammalian BBB. These animal models are the first ones showing a general and significant BBB impairment in adulthood, and as such they provide a unique opportunity to address molecular mechanisms of BBB disruption in disease and in drug transport across the BBB. Importantly, the new models and tools that we have developed allow us to search for relevant druggable mechanisms and molecular targets in the BBB. The long-term goals of this proposal are to develop molecular strategies and tools to open and close the BBB “on demand” for drug delivery to the CNS, and to explore the importance and mechanisms of BBB dysfunction in neurodegenerative diseases and stroke.
Summary
In the bone-enclosed CNS, increased vascular permeability may cause life-threatening tissue swelling, and/or ischemia and inflammation which compromise tissue repair after trauma or stroke. The brain vasculature possesses several unique features collectively named the blood-brain barrier (BBB) in which passive permeability is almost completely abolished and replaced by a complex of specific transport mechanisms. The BBB is necessary to uphold the specific milieu necessary for neuronal function. Whereas breakdown of the BBB is part of many CNS diseases, including stroke, neuroinflammation, trauma and neurodegenerative disorders, its molecular mechanisms and consequences are unclear and debated. Conversely, the intact BBB is a huge obstacle for drug delivery to the brain. Research on the BBB therefore has two seemingly opposing aims: 1) to seal a damaged BBB and protect the brain from toxic blood products, and 2) to open the BBB “on demand” for drug delivery. A major problem in the BBB field has been the lack of in vivo animal models for molecular and functional studies. So far, available in vitro models are not recapitulating the in vivo BBB. Our recent work on mouse models lacking pericytes, a BBB-associated cell type, demonstrates a specific role for pericytes in the development and regulation of the mammalian BBB. These animal models are the first ones showing a general and significant BBB impairment in adulthood, and as such they provide a unique opportunity to address molecular mechanisms of BBB disruption in disease and in drug transport across the BBB. Importantly, the new models and tools that we have developed allow us to search for relevant druggable mechanisms and molecular targets in the BBB. The long-term goals of this proposal are to develop molecular strategies and tools to open and close the BBB “on demand” for drug delivery to the CNS, and to explore the importance and mechanisms of BBB dysfunction in neurodegenerative diseases and stroke.
Max ERC Funding
2 499 427 €
Duration
Start date: 2012-08-01, End date: 2017-07-31
Project acronym BETAIMAGE
Project An in vivo imaging approach to understand pancreatic beta-cell signal-transduction
Researcher (PI) Per-Olof Berggren
Host Institution (HI) KAROLINSKA INSTITUTET
Country Sweden
Call Details Advanced Grant (AdG), LS4, ERC-2013-ADG
Summary The challenge in cell physiology/pathology today is to translate in vitro findings to the living organism. We have developed a unique approach where signal-transduction can be investigated in vivo non-invasively, longitudinally at single cell resolution, using the anterior chamber of the eye as a natural body window for imaging. We will use this approach to understand how the universally important and highly complex signal Ca2+ is regulated in the pancreatic beta-cell, while localized in the vascularized and innervated islet of Langerhans, and how that affects the insulin secretory machinery in vivo. Engrafted islets in the eye take on identical innervation- and vascularization patterns as those in the pancreas and are proficient in regulating glucose homeostasis in the animal. Since the pancreatic islet constitutes a micro-organ, this imaging approach offers a seminal model system to understand Ca2+ signaling in individual cells at the organ level in real life. We will test the hypothesis that the Ca2+-signal has a key role in pancreatic beta-cell function and survival in vivo and that perturbation in the Ca2+-signal serves as a common denominator for beta-cell pathology associated with impaired glucose homeostasis and diabetes. Of special interest is how innervation impacts on Ca2+-dynamics and the integration of autocrine, paracrine and endocrine signals in fine-tuning the Ca2+-signal with regard to beta-cell function and survival. We aim to define key defects in the machinery regulating Ca2+-dynamics in association with the autoimmune reaction, inflammation and obesity eventually resulting in diabetes. Our imaging platform will be applied to clarify in vivo regulation of Ca2+-dynamics in both healthy and diabetic human beta-cells. To define novel drugable targets for treatment of diabetes, it is crucial to identify similarities and differences in the molecular machinery regulating the in vivo Ca2+-signal in the human and in the rodent beta-cell.
Summary
The challenge in cell physiology/pathology today is to translate in vitro findings to the living organism. We have developed a unique approach where signal-transduction can be investigated in vivo non-invasively, longitudinally at single cell resolution, using the anterior chamber of the eye as a natural body window for imaging. We will use this approach to understand how the universally important and highly complex signal Ca2+ is regulated in the pancreatic beta-cell, while localized in the vascularized and innervated islet of Langerhans, and how that affects the insulin secretory machinery in vivo. Engrafted islets in the eye take on identical innervation- and vascularization patterns as those in the pancreas and are proficient in regulating glucose homeostasis in the animal. Since the pancreatic islet constitutes a micro-organ, this imaging approach offers a seminal model system to understand Ca2+ signaling in individual cells at the organ level in real life. We will test the hypothesis that the Ca2+-signal has a key role in pancreatic beta-cell function and survival in vivo and that perturbation in the Ca2+-signal serves as a common denominator for beta-cell pathology associated with impaired glucose homeostasis and diabetes. Of special interest is how innervation impacts on Ca2+-dynamics and the integration of autocrine, paracrine and endocrine signals in fine-tuning the Ca2+-signal with regard to beta-cell function and survival. We aim to define key defects in the machinery regulating Ca2+-dynamics in association with the autoimmune reaction, inflammation and obesity eventually resulting in diabetes. Our imaging platform will be applied to clarify in vivo regulation of Ca2+-dynamics in both healthy and diabetic human beta-cells. To define novel drugable targets for treatment of diabetes, it is crucial to identify similarities and differences in the molecular machinery regulating the in vivo Ca2+-signal in the human and in the rodent beta-cell.
Max ERC Funding
2 499 590 €
Duration
Start date: 2014-03-01, End date: 2019-02-28
Project acronym CUSTOMER
Project Customizable Embedded Real-Time Systems: Challenges and Key Techniques
Researcher (PI) Yi WANG
Host Institution (HI) UPPSALA UNIVERSITET
Country Sweden
Call Details Advanced Grant (AdG), PE6, ERC-2018-ADG
Summary Today, many industrial products are defined by software and therefore customizable: their functionalities implemented by software can be modified and extended by dynamic software updates on demand. This trend towards customizable products is rapidly expanding into all domains of IT, including Embedded Real-Time Systems (ERTS) deployed in Cyber-Physical Systems such as cars, medical devices etc. However, the current state-of-practice in safety-critical systems allows hardly any modifications once they are put in operation. The lack of techniques to preserve crucial safety conditions for customizable systems severely restricts the benefits of advances in software-defined systems engineering.
CUSTOMER is to provide the missing paradigm and technology for building and updating ERTS after deployment – subject to stringent timing constraints, dynamic workloads, and limited resources on complex platforms. CUSTOMER explores research areas crossing two fields: Real-Time Computing and Formal Verification to develop the key techniques enabling (1) dynamic updates of ERTS in the field, (2) incremental updates over the products life time and (3) safe updates by verification to avoid updates that may compromise system safety.
CUSTOMER will develop a unified model-based framework supported with tools for the design, modelling, verification, deployment and update of ERTS, aiming at advancing the research fields by establishing the missing scientific foundation for multiprocessor real-time computing and providing the next generation of design tools with significantly enhanced capability and scalability increased by orders of magnitude compared with state-of-the-art tools e.g. UPPAAL.
Summary
Today, many industrial products are defined by software and therefore customizable: their functionalities implemented by software can be modified and extended by dynamic software updates on demand. This trend towards customizable products is rapidly expanding into all domains of IT, including Embedded Real-Time Systems (ERTS) deployed in Cyber-Physical Systems such as cars, medical devices etc. However, the current state-of-practice in safety-critical systems allows hardly any modifications once they are put in operation. The lack of techniques to preserve crucial safety conditions for customizable systems severely restricts the benefits of advances in software-defined systems engineering.
CUSTOMER is to provide the missing paradigm and technology for building and updating ERTS after deployment – subject to stringent timing constraints, dynamic workloads, and limited resources on complex platforms. CUSTOMER explores research areas crossing two fields: Real-Time Computing and Formal Verification to develop the key techniques enabling (1) dynamic updates of ERTS in the field, (2) incremental updates over the products life time and (3) safe updates by verification to avoid updates that may compromise system safety.
CUSTOMER will develop a unified model-based framework supported with tools for the design, modelling, verification, deployment and update of ERTS, aiming at advancing the research fields by establishing the missing scientific foundation for multiprocessor real-time computing and providing the next generation of design tools with significantly enhanced capability and scalability increased by orders of magnitude compared with state-of-the-art tools e.g. UPPAAL.
Max ERC Funding
2 499 894 €
Duration
Start date: 2019-10-01, End date: 2024-09-30
Project acronym EcoImmuneCosts
Project Immunity in Ecology and Evolution: 'Hidden' costs of disease, immune function and their consequences for Darwinian fitness
Researcher (PI) Dennis Lennart HASSELQUIST
Host Institution (HI) LUNDS UNIVERSITET
Country Sweden
Call Details Advanced Grant (AdG), LS8, ERC-2016-ADG
Summary Eco-immunology targets one of the great challenges in biology and medicine - how the immune system has evolved to optimize protection and minimize immunopathology (incl. autoimmune) costs. A primary target of my proposal is to study low-virulent pathogens causing mild infections, which for long have been considered harmless. Recent research suggests that this notion is false and that seemingly harmless pathogens entail delayed (‘hidden’) fitness costs. However, the mechanisms mediating these costs are still unknown. I will experimentally test if accelerated telomere degradation is a causative mechanism through which small immune costs can accumulate and be translated into senescence and reduced Darwinian fitness. Another key target is immune costs, which may be ‘hidden’ because of sexually antagonistic effects, and I will study how this may affect immune gene variation, immune costs and Darwinian fitness. These aspects are central for advancing our understanding of the evolution of disease resistance and immune function, incl. immune over-reactions (autoimmunity).
My project exploits a comprehensive 32-year study of great reed warblers to analyze selection patterns in the wild (Fig. 1a), and uses established captive songbird set-ups to conduct carefully designed experiments. The exceptional quality of the long-term data set, together with cutting-edge techniques to measure and manipulate parasite infection, telomere length, oxidative stress and immune gene diversity, provides exciting opportunities to conduct research that previously was unfeasible, pushing the rapidly growing field of eco-immunology (Fig. 1b) to new frontiers. The work integrates theory and methods of evolutionary ecology, immunology and molecular biology, and has broad significance including for e.g. epidemiology and ageing research. I envision my research to change how we look upon causes, consequences (and precautions) of mild infectious, autoimmune and degenerative diseases.
Summary
Eco-immunology targets one of the great challenges in biology and medicine - how the immune system has evolved to optimize protection and minimize immunopathology (incl. autoimmune) costs. A primary target of my proposal is to study low-virulent pathogens causing mild infections, which for long have been considered harmless. Recent research suggests that this notion is false and that seemingly harmless pathogens entail delayed (‘hidden’) fitness costs. However, the mechanisms mediating these costs are still unknown. I will experimentally test if accelerated telomere degradation is a causative mechanism through which small immune costs can accumulate and be translated into senescence and reduced Darwinian fitness. Another key target is immune costs, which may be ‘hidden’ because of sexually antagonistic effects, and I will study how this may affect immune gene variation, immune costs and Darwinian fitness. These aspects are central for advancing our understanding of the evolution of disease resistance and immune function, incl. immune over-reactions (autoimmunity).
My project exploits a comprehensive 32-year study of great reed warblers to analyze selection patterns in the wild (Fig. 1a), and uses established captive songbird set-ups to conduct carefully designed experiments. The exceptional quality of the long-term data set, together with cutting-edge techniques to measure and manipulate parasite infection, telomere length, oxidative stress and immune gene diversity, provides exciting opportunities to conduct research that previously was unfeasible, pushing the rapidly growing field of eco-immunology (Fig. 1b) to new frontiers. The work integrates theory and methods of evolutionary ecology, immunology and molecular biology, and has broad significance including for e.g. epidemiology and ageing research. I envision my research to change how we look upon causes, consequences (and precautions) of mild infectious, autoimmune and degenerative diseases.
Max ERC Funding
2 500 000 €
Duration
Start date: 2017-08-01, End date: 2022-07-31
Project acronym ECOSOCPOL
Project Social and Political Economics: Theory and Evidence
Researcher (PI) Torsten Persson
Host Institution (HI) STOCKHOLMS UNIVERSITET
Country Sweden
Call Details Advanced Grant (AdG), SH1, ERC-2015-AdG
Summary In this project, I will study how individual and social motives interact to drive individual decisions, a question that has fallen between the cracks of different social-science approaches. I will use a common theoretical framework to approach an important, but badly understood, general question: do social motives reinforce or weaken the effect of changes in individual motives? By modifying this common framework to different applications, I will consider its predictions empirically in different large data sets with individual-level information. The planned applications include four subprojects in the social, political, and economic spheres: (i) decisions in China on the ethnicity of children in interethnic marriages and matching into such marriages, (ii) decisions on tax evasion in the U.K. and Sweden, (iii) decisions to give political campaign contributions in the U.S., and (iv) decisions about fertility in Sweden. I may also spell out the common lessons from the results on the interaction between individual and social motives in monograph format intended for a broader audience.
Summary
In this project, I will study how individual and social motives interact to drive individual decisions, a question that has fallen between the cracks of different social-science approaches. I will use a common theoretical framework to approach an important, but badly understood, general question: do social motives reinforce or weaken the effect of changes in individual motives? By modifying this common framework to different applications, I will consider its predictions empirically in different large data sets with individual-level information. The planned applications include four subprojects in the social, political, and economic spheres: (i) decisions in China on the ethnicity of children in interethnic marriages and matching into such marriages, (ii) decisions on tax evasion in the U.K. and Sweden, (iii) decisions to give political campaign contributions in the U.S., and (iv) decisions about fertility in Sweden. I may also spell out the common lessons from the results on the interaction between individual and social motives in monograph format intended for a broader audience.
Max ERC Funding
1 104 812 €
Duration
Start date: 2016-11-01, End date: 2021-10-31
Project acronym ERA
Project Earth Resilience in the Anthropocene (ERA)Integrating non-linear biophysical and social determinantsof Earth-system stability for global sustainabilitythrough a novel community modelling platform
Researcher (PI) johan ROCKSTRoeM
Host Institution (HI) STOCKHOLMS UNIVERSITET
Country Sweden
Call Details Advanced Grant (AdG), SH2, ERC-2016-ADG
Summary In 2015, the UN Sustainable Development Goals (SDGs) and the Paris Agreement on climate recognised the deteriorating resilience of the Earth system in the Anthropocene. Maintaining Earth in the interglacial state that enabled the world’s societies to evolve over the past 12,000 years will require industrialised societies to embark on global-scale social transformations. Otherwise, there is a real risk of crossing tipping points in the Earth system triggering abrupt and irreversible changes.
A critical gap is that although nonlinear social and biophysical dynamics are recognized, we remain trapped in linear thinking. Global modelling and analyses – despite much progress – do not adequately represent nonlinear processes and abrupt changes, and social responses to sustainable development are incremental.
The goal of this project is to fill this gap, by exploring the biophysical and social determinants of the Earth’s long-term stability, building up a novel community modelling platform for analysis of nonlinearity and abrupt shifts, and informing global sustainability policy processes. The project will investigate two hypotheses: 1) Interactions, feedbacks and tipping points in the biosphere could, even in the absence of continued high emissions from fossil-fuel burning, tip Earth into a new state, committing to global warming over 2C and possibly beyond 4C; and 2) Only nonlinear societal transformations that aggregate to the global scale can assure long-term stability of the Earth and keep it in a manageable interglacial state.
The five research tasks are Task 1: analysis of nonlinear biosphere dynamics governing Earth resilience. Task 2: integrating nonlinear dynamics in World-Earth models. Task 3: exploring tipping points in social systems for large-scale transformation. Task 4: backcasting pathways for achieving the SDGs. Task 5: integrating World-Earth dynamics into online learning and virtual-reality games, e.g. Planet3 and Minecraft.
Summary
In 2015, the UN Sustainable Development Goals (SDGs) and the Paris Agreement on climate recognised the deteriorating resilience of the Earth system in the Anthropocene. Maintaining Earth in the interglacial state that enabled the world’s societies to evolve over the past 12,000 years will require industrialised societies to embark on global-scale social transformations. Otherwise, there is a real risk of crossing tipping points in the Earth system triggering abrupt and irreversible changes.
A critical gap is that although nonlinear social and biophysical dynamics are recognized, we remain trapped in linear thinking. Global modelling and analyses – despite much progress – do not adequately represent nonlinear processes and abrupt changes, and social responses to sustainable development are incremental.
The goal of this project is to fill this gap, by exploring the biophysical and social determinants of the Earth’s long-term stability, building up a novel community modelling platform for analysis of nonlinearity and abrupt shifts, and informing global sustainability policy processes. The project will investigate two hypotheses: 1) Interactions, feedbacks and tipping points in the biosphere could, even in the absence of continued high emissions from fossil-fuel burning, tip Earth into a new state, committing to global warming over 2C and possibly beyond 4C; and 2) Only nonlinear societal transformations that aggregate to the global scale can assure long-term stability of the Earth and keep it in a manageable interglacial state.
The five research tasks are Task 1: analysis of nonlinear biosphere dynamics governing Earth resilience. Task 2: integrating nonlinear dynamics in World-Earth models. Task 3: exploring tipping points in social systems for large-scale transformation. Task 4: backcasting pathways for achieving the SDGs. Task 5: integrating World-Earth dynamics into online learning and virtual-reality games, e.g. Planet3 and Minecraft.
Max ERC Funding
2 492 834 €
Duration
Start date: 2017-10-01, End date: 2022-09-30
Project acronym EYELETS
Project A regenerative medicine approach in diabetes.
Researcher (PI) Per-Olof BERGGREN
Host Institution (HI) KAROLINSKA INSTITUTET
Country Sweden
Call Details Advanced Grant (AdG), LS7, ERC-2018-ADG
Summary Pancreatic islet transplantation is essential for diabetes treatment. Outcome varies due to transplantation site, quality of islets and the fact that transplanted islets are affected by the same challenges as in situ islets. Tailor-making islets for transplantation by tissue engineering combined with a more favorable transplantation site that allows for both monitoring and local modulation of islet cells is thus instrumental. We have established the anterior chamber of the eye (ACE) as a favorable environment for long term survival of islet grafts and the cornea as a natural body window for non-invasive, longitudinal optical monitoring of islet function. ACE engrafted islets are able to maintain blood glucose homeostasis in diabetic animals. In addition to studies in non-human primates we are performing human clinical trials, the first patient already being transplanted. Tissue engineering of native islets is technically difficult. We will therefore apply genetically engineered islet organoids. This allows us to generate i) standardized material optimized for transplantation, function and survival, as well as ii) islet organoids suitable for monitoring (sensor islet organoids) and treating (metabolic islet organoids) insulin-dependent diabetes. We hypothesize that genetically engineered islet organoids transplanted to the ACE are superior to native pancreatic islets to monitor and treat insulin-dependent diabetes. Our overall aim is to create a platform allowing monitoring and treatment of insulin-dependent diabetes in mice that can be transferred to large animals for validation. The objective is to combine tissue engineering of islet cell organoids, transplantation to the ACE, synthetic biology, local pharmacological treatment strategies and the development of novel micro electronic/micro optical readout systems for islet cells. This regenerative medicine approach will follow our clinical trial programs and be transferred into the clinic to combat diabetes.
Summary
Pancreatic islet transplantation is essential for diabetes treatment. Outcome varies due to transplantation site, quality of islets and the fact that transplanted islets are affected by the same challenges as in situ islets. Tailor-making islets for transplantation by tissue engineering combined with a more favorable transplantation site that allows for both monitoring and local modulation of islet cells is thus instrumental. We have established the anterior chamber of the eye (ACE) as a favorable environment for long term survival of islet grafts and the cornea as a natural body window for non-invasive, longitudinal optical monitoring of islet function. ACE engrafted islets are able to maintain blood glucose homeostasis in diabetic animals. In addition to studies in non-human primates we are performing human clinical trials, the first patient already being transplanted. Tissue engineering of native islets is technically difficult. We will therefore apply genetically engineered islet organoids. This allows us to generate i) standardized material optimized for transplantation, function and survival, as well as ii) islet organoids suitable for monitoring (sensor islet organoids) and treating (metabolic islet organoids) insulin-dependent diabetes. We hypothesize that genetically engineered islet organoids transplanted to the ACE are superior to native pancreatic islets to monitor and treat insulin-dependent diabetes. Our overall aim is to create a platform allowing monitoring and treatment of insulin-dependent diabetes in mice that can be transferred to large animals for validation. The objective is to combine tissue engineering of islet cell organoids, transplantation to the ACE, synthetic biology, local pharmacological treatment strategies and the development of novel micro electronic/micro optical readout systems for islet cells. This regenerative medicine approach will follow our clinical trial programs and be transferred into the clinic to combat diabetes.
Max ERC Funding
2 500 000 €
Duration
Start date: 2020-01-01, End date: 2024-12-31
Project acronym GENCON
Project The evolutionary implications of genetic conflict
Researcher (PI) Goeran Arnqvist
Host Institution (HI) UPPSALA UNIVERSITET
Country Sweden
Call Details Advanced Grant (AdG), LS8, ERC-2011-ADG_20110310
Summary The study of genetic conflict is developing at an almost explosive rate. The recognition that genes or alleles residing in individuals of the two sexes may have conflicting interests is transforming evolutionary biology and, likewise, conflict between genes showing different modes of transmission may fundamentally affect adaptive evolution. The research proposed here will push the frontiers of genetic conflict research and establish new domains. It is aimed at exploring the novel possibility that conflict between mitochondrial and nuclear genes have far-reaching implications for adaptive evolution and at advancing our understanding of the biological consequences of sexual conflict. The project consists of several interrelated parts and will employ insects as model systems. First, I will assess to what extent genetic variation in fitness is sexually antagonistic and what life history traits contribute to sexually antagonistic variation. Second, I will elucidate the genomics of metabolic rate and measure selection on metabolic phenotypes. Third, I will test whether sexually antagonistic epistatic interactions between mitochondrial and nuclear genes generate conflict over metabolic rate. Fourth, I will test the hypothesis that sexual conflict contribute to the evolution of primary and secondary sexual traits. Fifth, I will shed light on the complicated evolutionary interplay between sexual conflict and mating system evolution. I will employ an innovative research strategy, ‘experimental genomics’, in which genomic data is used to guide experimental evolutionary work with distinct genotypes. The research outlined here will collectively provide an unprecedented wealth of information into the role of genetic conflict in several horizons of adaptive evolution, ranging from DNA sequence evolution over life history evolution to speciation, and will set the standard for a new generation of insightful studies aimed at bridging the gap between phenotypic selection and genomics.
Summary
The study of genetic conflict is developing at an almost explosive rate. The recognition that genes or alleles residing in individuals of the two sexes may have conflicting interests is transforming evolutionary biology and, likewise, conflict between genes showing different modes of transmission may fundamentally affect adaptive evolution. The research proposed here will push the frontiers of genetic conflict research and establish new domains. It is aimed at exploring the novel possibility that conflict between mitochondrial and nuclear genes have far-reaching implications for adaptive evolution and at advancing our understanding of the biological consequences of sexual conflict. The project consists of several interrelated parts and will employ insects as model systems. First, I will assess to what extent genetic variation in fitness is sexually antagonistic and what life history traits contribute to sexually antagonistic variation. Second, I will elucidate the genomics of metabolic rate and measure selection on metabolic phenotypes. Third, I will test whether sexually antagonistic epistatic interactions between mitochondrial and nuclear genes generate conflict over metabolic rate. Fourth, I will test the hypothesis that sexual conflict contribute to the evolution of primary and secondary sexual traits. Fifth, I will shed light on the complicated evolutionary interplay between sexual conflict and mating system evolution. I will employ an innovative research strategy, ‘experimental genomics’, in which genomic data is used to guide experimental evolutionary work with distinct genotypes. The research outlined here will collectively provide an unprecedented wealth of information into the role of genetic conflict in several horizons of adaptive evolution, ranging from DNA sequence evolution over life history evolution to speciation, and will set the standard for a new generation of insightful studies aimed at bridging the gap between phenotypic selection and genomics.
Max ERC Funding
2 497 442 €
Duration
Start date: 2012-05-01, End date: 2017-04-30
