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
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 DAMONA
Project Mutation and Recombination in the Cattle Germline: Genomic Analysis and Impact on Fertility
Researcher (PI) Michel Alphonse Julien Georges
Host Institution (HI) UNIVERSITE DE LIEGE
Call Details Advanced Grant (AdG), LS2, ERC-2012-ADG_20120314
Summary "Mutation and recombination are fundamental biological processes that determine adaptability of populations. The mutation rate reflects the equilibrium between the need to adapt, the burden of mutation load, the “cost of fidelity”, and random drift that determines a lower limit in achievable fidelity. Recombination fulfills an essential mechanistic role during meiosis, ensuring proper chromosomal segregation. Recombination affects the rate of creation and loss of favorable haplotypes, imposing 2nd-order selection pressure on modifiers of recombination.
It is becoming apparent that recombination and mutation rates vary between individuals, and that these differences are in part inherited. Both processes are therefore “evolvable”, and amenable to genomic analysis. Identifying genetic determinants underlying these differences will provide insights in the regulation of mutation and recombination. The mutational load, and in particular the number of lethal equivalents per individual, remains poorly defined as epidemiological and molecular data yield estimates that differ by one order of magnitude. A relationship between recombination and fertility has been reported in women but awaits confirmation.
Population structure (small effective population size; large harems), phenotypic data collection (systematic recording of > 50 traits on millions of cows), and large-scale SNP genotyping (for genomic selection), make cattle populations uniquely suited for genetic analysis. DAMONA proposes to exploit these unique resources, combined with recent advances in next generation sequencing and genotyping, to:
(i) quantify and characterize inter-individual variation in male and female mutation and recombination rates,
(ii) map, fine-map and identify causative genes underlying QTL for these four phenotypes,
(iii) test the effect of loss-of-function variants on >50 traits including fertility, and
(iv) study the effect of variation in recombination on fertility."
Summary
"Mutation and recombination are fundamental biological processes that determine adaptability of populations. The mutation rate reflects the equilibrium between the need to adapt, the burden of mutation load, the “cost of fidelity”, and random drift that determines a lower limit in achievable fidelity. Recombination fulfills an essential mechanistic role during meiosis, ensuring proper chromosomal segregation. Recombination affects the rate of creation and loss of favorable haplotypes, imposing 2nd-order selection pressure on modifiers of recombination.
It is becoming apparent that recombination and mutation rates vary between individuals, and that these differences are in part inherited. Both processes are therefore “evolvable”, and amenable to genomic analysis. Identifying genetic determinants underlying these differences will provide insights in the regulation of mutation and recombination. The mutational load, and in particular the number of lethal equivalents per individual, remains poorly defined as epidemiological and molecular data yield estimates that differ by one order of magnitude. A relationship between recombination and fertility has been reported in women but awaits confirmation.
Population structure (small effective population size; large harems), phenotypic data collection (systematic recording of > 50 traits on millions of cows), and large-scale SNP genotyping (for genomic selection), make cattle populations uniquely suited for genetic analysis. DAMONA proposes to exploit these unique resources, combined with recent advances in next generation sequencing and genotyping, to:
(i) quantify and characterize inter-individual variation in male and female mutation and recombination rates,
(ii) map, fine-map and identify causative genes underlying QTL for these four phenotypes,
(iii) test the effect of loss-of-function variants on >50 traits including fertility, and
(iv) study the effect of variation in recombination on fertility."
Max ERC Funding
2 258 000 €
Duration
Start date: 2013-03-01, End date: 2018-02-28
Project acronym DOUBLE-UP
Project The importance of gene and genome duplications for natural and artificial organism populations
Researcher (PI) Yves Eddy Philomena Van De Peer
Host Institution (HI) VIB
Call Details Advanced Grant (AdG), LS2, ERC-2012-ADG_20120314
Summary The long-term establishment of ancient organisms that have undergone whole genome duplications has been exceedingly rare. On the other hand, tens of thousands of now-living species are polyploid and contain multiple copies of their genome. The paucity of ancient genome duplications and the existence of so many species that are currently polyploid provide an interesting and fascinating enigma. A question that remains is whether these older genome duplications have survived by coincidence or because they did occur at very specific times, for instance during major ecological upheavals and periods of extinction. It has indeed been proposed that chromosome doubling conveys greater stress tolerance by fostering slower development, delayed reproduction and longer life span. Furthermore, polyploids have also been considered to have greater ability to colonize new or disturbed habitats. If polyploidy allowed many plant lineages to survive and adapt during global changes, as suggested, we might wonder whether polyploidy will confer a similar advantage in the current period of global warming and general ecological pressure caused by the human race. Given predictions that species extinction is now occurring at as high rates as during previous mass extinctions, will the presumed extra adaptability of polyploid plants mean they will become the dominant species? In the current proposal, we hope to address these questions at different levels through 1) the analysis of whole plant genome sequence data and 2) the in silico modelling of artificial gene regulatory networks to mimic the genomic consequences of genome doubling and how this may affect network structure and dosage balance. Furthermore, we aim at using simulated robotic models running on artificial gene regulatory networks in complex environments to evaluate how both natural and artificial organism populations can potentially benefit from gene and genome duplications for adaptation, survival, and evolution in general.
Summary
The long-term establishment of ancient organisms that have undergone whole genome duplications has been exceedingly rare. On the other hand, tens of thousands of now-living species are polyploid and contain multiple copies of their genome. The paucity of ancient genome duplications and the existence of so many species that are currently polyploid provide an interesting and fascinating enigma. A question that remains is whether these older genome duplications have survived by coincidence or because they did occur at very specific times, for instance during major ecological upheavals and periods of extinction. It has indeed been proposed that chromosome doubling conveys greater stress tolerance by fostering slower development, delayed reproduction and longer life span. Furthermore, polyploids have also been considered to have greater ability to colonize new or disturbed habitats. If polyploidy allowed many plant lineages to survive and adapt during global changes, as suggested, we might wonder whether polyploidy will confer a similar advantage in the current period of global warming and general ecological pressure caused by the human race. Given predictions that species extinction is now occurring at as high rates as during previous mass extinctions, will the presumed extra adaptability of polyploid plants mean they will become the dominant species? In the current proposal, we hope to address these questions at different levels through 1) the analysis of whole plant genome sequence data and 2) the in silico modelling of artificial gene regulatory networks to mimic the genomic consequences of genome doubling and how this may affect network structure and dosage balance. Furthermore, we aim at using simulated robotic models running on artificial gene regulatory networks in complex environments to evaluate how both natural and artificial organism populations can potentially benefit from gene and genome duplications for adaptation, survival, and evolution in general.
Max ERC Funding
2 217 525 €
Duration
Start date: 2013-10-01, End date: 2018-09-30
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
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 GENEWELL
Project Genetics and epigenetics of animal welfare
Researcher (PI) Per Ole Stokmann Jensen
Host Institution (HI) LINKOPINGS UNIVERSITET
Call Details Advanced Grant (AdG), LS9, ERC-2012-ADG_20120314
Summary Animal welfare is a topic of highest societal and scientific priority. Here, I propose to use genomic and epigenetic tools to provide a new perspective on the biology of animal welfare. This will reveal mechanisms involved in modulating stress responses. Groundbreaking aspects include new insights into how environmental conditions shape the orchestration of the genome by means of epigenetic mechanisms, and how this in turn modulates coping patterns of animals. The flexible epigenome comprises the interface between the environment and the genome. It is involved in both short- and long-term, including transgenerational, adaptations of animals. Hence, populations may adapt to environmental conditions over generations, using epigenetic mechanisms. The project will primarily be based on chickens, but will also be extended to a novel species, the dog. We will generate congenic chicken strains, where interesting alleles and epialleles will be fixed against a common background of either RJF or domestic genotypes. In these, we will apply a broad phenotyping strategy, to characterize the effects on different welfare relevant behaviors. Furthermore, we will characterize how environmental stress affects the epigenome of birds, and tissue samples from more than 500 birds from an intercross between RJF and White Leghorn layers will be used to perform an extensive meth-QTL-analysis. This will reveal environmental and genetic mechanisms affecting gene-specific methylation. The dog is another highly interesting species in the context of behavior genetics, because of its high inter-breed variation in behavior, and its compact and sequenced genome. We will set up a large-scale F2-intercross experiment and phenotype about 400 dogs in standardized behavioral tests. All individuals will be genotyped on about 1000 genetic markers, and this will be used for performing an extensive QTL-analysis in order to find new loci and alleles associated with personalities and coping patterns.
Summary
Animal welfare is a topic of highest societal and scientific priority. Here, I propose to use genomic and epigenetic tools to provide a new perspective on the biology of animal welfare. This will reveal mechanisms involved in modulating stress responses. Groundbreaking aspects include new insights into how environmental conditions shape the orchestration of the genome by means of epigenetic mechanisms, and how this in turn modulates coping patterns of animals. The flexible epigenome comprises the interface between the environment and the genome. It is involved in both short- and long-term, including transgenerational, adaptations of animals. Hence, populations may adapt to environmental conditions over generations, using epigenetic mechanisms. The project will primarily be based on chickens, but will also be extended to a novel species, the dog. We will generate congenic chicken strains, where interesting alleles and epialleles will be fixed against a common background of either RJF or domestic genotypes. In these, we will apply a broad phenotyping strategy, to characterize the effects on different welfare relevant behaviors. Furthermore, we will characterize how environmental stress affects the epigenome of birds, and tissue samples from more than 500 birds from an intercross between RJF and White Leghorn layers will be used to perform an extensive meth-QTL-analysis. This will reveal environmental and genetic mechanisms affecting gene-specific methylation. The dog is another highly interesting species in the context of behavior genetics, because of its high inter-breed variation in behavior, and its compact and sequenced genome. We will set up a large-scale F2-intercross experiment and phenotype about 400 dogs in standardized behavioral tests. All individuals will be genotyped on about 1000 genetic markers, and this will be used for performing an extensive QTL-analysis in order to find new loci and alleles associated with personalities and coping patterns.
Max ERC Funding
2 499 828 €
Duration
Start date: 2013-03-01, End date: 2018-02-28
Project acronym HEPASPHER
Project Mimicking liver disease and regeneration in vitro for drug development and liver transplantation
Researcher (PI) Magnus INGELMAN-SUNDBERG
Host Institution (HI) KAROLINSKA INSTITUTET
Call Details Advanced Grant (AdG), LS7, ERC-2016-ADG
Summary The liver is a vital organ for synthesis and detoxification. The most significant liver diseases are hepatitis, non alcoholic fatty liver disease (NAFLD), non-alcoholic fatty liver steatohepatitis (NASH), carcinoma and cirrhosis. An additional and important cause of liver injury is adverse drug reactions (ADRs). In particular NAFLD is the most common liver disease affecting between 20% and 44% of European adults and 43-70% of patients with type 2 diabetes, and is one prime cause for chronic and end-stage liver disease, such as cirrhosis and primary hepatocellular carcinoma.
This proposal is based on recent findings in the laboratory: The development of novel 3D spheroid system with chemically defined media allowing studies of chronic drug toxicity, relevant liver disease and liver function for 5 weeks in vitro, the finding of the role of miRNA in hepatocyte dedifferentiation and that hepatocytes during spheroid formation first de-differentiate but later in spheroids re-differentiate to an in vivo relevant phenotype. This forms the basis for the main objectives: i) to study diseased liver in vitro with identification of mechanisms, biomarkers and novel drug candidates for treatment of NAFLD and fibrosis, ii) evaluate drug toxicity sensitivity and mechanisms in diseased liver systems and iii) further develop methods for hepatocyte proliferation and regeneration in vitro for transplantation purposes, including genetic editing in cases of hepatocytes obtained from patients with genetically inherited liver diseases.
This work is carried out in close contact with the Hepatology unit at the Karolinska Hospital partly using resources at the Science for Life Laboratory at Karolinska. It is anticipated that the project can provide with novel mechanisms, biomarkers and new targets for treatment of liver disease as well as novel methods for clinically applicable liver regeneration without the use of stem cells or transformed cells.
Summary
The liver is a vital organ for synthesis and detoxification. The most significant liver diseases are hepatitis, non alcoholic fatty liver disease (NAFLD), non-alcoholic fatty liver steatohepatitis (NASH), carcinoma and cirrhosis. An additional and important cause of liver injury is adverse drug reactions (ADRs). In particular NAFLD is the most common liver disease affecting between 20% and 44% of European adults and 43-70% of patients with type 2 diabetes, and is one prime cause for chronic and end-stage liver disease, such as cirrhosis and primary hepatocellular carcinoma.
This proposal is based on recent findings in the laboratory: The development of novel 3D spheroid system with chemically defined media allowing studies of chronic drug toxicity, relevant liver disease and liver function for 5 weeks in vitro, the finding of the role of miRNA in hepatocyte dedifferentiation and that hepatocytes during spheroid formation first de-differentiate but later in spheroids re-differentiate to an in vivo relevant phenotype. This forms the basis for the main objectives: i) to study diseased liver in vitro with identification of mechanisms, biomarkers and novel drug candidates for treatment of NAFLD and fibrosis, ii) evaluate drug toxicity sensitivity and mechanisms in diseased liver systems and iii) further develop methods for hepatocyte proliferation and regeneration in vitro for transplantation purposes, including genetic editing in cases of hepatocytes obtained from patients with genetically inherited liver diseases.
This work is carried out in close contact with the Hepatology unit at the Karolinska Hospital partly using resources at the Science for Life Laboratory at Karolinska. It is anticipated that the project can provide with novel mechanisms, biomarkers and new targets for treatment of liver disease as well as novel methods for clinically applicable liver regeneration without the use of stem cells or transformed cells.
Max ERC Funding
2 413 449 €
Duration
Start date: 2017-09-01, End date: 2022-08-31
Project acronym MagneticMoth
Project Hunting for the elusive “sixth” sense: navigation and magnetic sensation in a nocturnal migratory moth
Researcher (PI) Eric James WARRANT
Host Institution (HI) LUNDS UNIVERSITET
Call Details Advanced Grant (AdG), LS8, ERC-2016-ADG
Summary Many animals – including birds, sea turtles and insects – perform spectacular long-distance migrations across the surface of the Earth. Remarkably some, like birds, can accurately migrate between highly specific locations thousands of kilometres apart, a navigational feat that requires an external compass cue and a robust sensory system to detect it. The Earth’s magnetic field is one such compass cue. But exactly how the magnetic field is sensed, and which receptor cells are involved, remains a mystery and its discovery is one of the greatest “holy grails” in modern sensory physiology, and also the main aim of this proposal. Fortuitously, I have made a pioneering discovery that a migratory insect – the Australian Bogong moth – relies on the Earth’s magnetic field to navigate at night. Due to its tractable nervous system, this insect may thus hold the key to uncovering the identity of the enigmatic magnetosensor. By tethering flying migrating moths in a flight simulator, I will dissect for the first time how insects use magnetic cues to navigate, isolating which of the two current (contentious) hypotheses for magnetic sensation apply. The most likely of these involves the action of photoreceptor-based cryptochrome (Cry) molecules in the eyes. Having cloned genes for 4 visual opsins and 2 Cry in Bogong moths, I will use in situ hybridisation to localise putative magnetoreceptors in the eyes, targeting them with intracellular electrophysiology and magnetic stimulation in an attempt to describe the physiology of these elusive sensors for the first time. The project is ground breaking since it will elucidate how a migratory insect, despite its small eyes and brain, detects and uses the Earth’s magnetic field for navigation. The discovery of the enigmatic magnetoreceptor would be a sensation, opening the floodgates for international research on this little understood sense.
Summary
Many animals – including birds, sea turtles and insects – perform spectacular long-distance migrations across the surface of the Earth. Remarkably some, like birds, can accurately migrate between highly specific locations thousands of kilometres apart, a navigational feat that requires an external compass cue and a robust sensory system to detect it. The Earth’s magnetic field is one such compass cue. But exactly how the magnetic field is sensed, and which receptor cells are involved, remains a mystery and its discovery is one of the greatest “holy grails” in modern sensory physiology, and also the main aim of this proposal. Fortuitously, I have made a pioneering discovery that a migratory insect – the Australian Bogong moth – relies on the Earth’s magnetic field to navigate at night. Due to its tractable nervous system, this insect may thus hold the key to uncovering the identity of the enigmatic magnetosensor. By tethering flying migrating moths in a flight simulator, I will dissect for the first time how insects use magnetic cues to navigate, isolating which of the two current (contentious) hypotheses for magnetic sensation apply. The most likely of these involves the action of photoreceptor-based cryptochrome (Cry) molecules in the eyes. Having cloned genes for 4 visual opsins and 2 Cry in Bogong moths, I will use in situ hybridisation to localise putative magnetoreceptors in the eyes, targeting them with intracellular electrophysiology and magnetic stimulation in an attempt to describe the physiology of these elusive sensors for the first time. The project is ground breaking since it will elucidate how a migratory insect, despite its small eyes and brain, detects and uses the Earth’s magnetic field for navigation. The discovery of the enigmatic magnetoreceptor would be a sensation, opening the floodgates for international research on this little understood sense.
Max ERC Funding
2 498 625 €
Duration
Start date: 2017-09-01, End date: 2022-08-31
Project acronym MEMORYSTICK
Project Plasticity and formation of lasting memories in health and disease. Genetic modeling of key regulators in adult and aging mammals and in neurodegenerative disease
Researcher (PI) Lars Olson
Host Institution (HI) KAROLINSKA INSTITUTET
Call Details Advanced Grant (AdG), LS5, ERC-2012-ADG_20120314
Summary When an adult mammal acquires new skills and new knowledge, the degree to which transition will occur from temporary to permanent memories of such events is governed by factors such as emotional weight and importance of the experiences for survival. To execute the necessary structural synaptic reorganisations needed to permanently embed novel memories in the brain, a complex and precisely orchestrated molecular machinery is activated. We have found that rapid down-regulation of Nogo receptor 1 (NgR1) is one key element needed to allow permanent memories to form. Thus, our MemoFlex mice, with inducible overexpression of NgR1 in forebrain neurons, are severely impaired with respect to the ability to form lasting memories. When transgenic NgR1 is turned off in these mice, the ability to form lasting memories is restored. Several other genes are also involved in the process of consolidation of memories, including prompt activity-driven upregulation of BDNF. Very recently, we have discovered that Lotus, a newly identified negative regulator of NgR1, is also upregulated by activity, thus providing additional efficacy to the process of causing nerve endings to become temporarily insensitive to Nogo when plasticity is needed. Based on our experience with neurotrophic factors and the Nogo signaling system, and using additional transgenic mouse models, including the mtDNA Mutator mouse with premature, yet typical aging, NgR1 KO mice and mice modeling neurodegenerative diseases (such as APPSwePSEN mice and our MitoPark mice to model aspects of Alzheimer’s and Parkinson’s disease, respectively) we will examine the formation of lasting normal and pathological (addiction, posttraumatic stress disorder) memories in adult and aging individuals with and without additional neurodegenerative genotypes known to include cognitive impariment. This research will further the understanding of mechanisms behind memory dysfunction and help the design of memory-improving stratetegies.
Summary
When an adult mammal acquires new skills and new knowledge, the degree to which transition will occur from temporary to permanent memories of such events is governed by factors such as emotional weight and importance of the experiences for survival. To execute the necessary structural synaptic reorganisations needed to permanently embed novel memories in the brain, a complex and precisely orchestrated molecular machinery is activated. We have found that rapid down-regulation of Nogo receptor 1 (NgR1) is one key element needed to allow permanent memories to form. Thus, our MemoFlex mice, with inducible overexpression of NgR1 in forebrain neurons, are severely impaired with respect to the ability to form lasting memories. When transgenic NgR1 is turned off in these mice, the ability to form lasting memories is restored. Several other genes are also involved in the process of consolidation of memories, including prompt activity-driven upregulation of BDNF. Very recently, we have discovered that Lotus, a newly identified negative regulator of NgR1, is also upregulated by activity, thus providing additional efficacy to the process of causing nerve endings to become temporarily insensitive to Nogo when plasticity is needed. Based on our experience with neurotrophic factors and the Nogo signaling system, and using additional transgenic mouse models, including the mtDNA Mutator mouse with premature, yet typical aging, NgR1 KO mice and mice modeling neurodegenerative diseases (such as APPSwePSEN mice and our MitoPark mice to model aspects of Alzheimer’s and Parkinson’s disease, respectively) we will examine the formation of lasting normal and pathological (addiction, posttraumatic stress disorder) memories in adult and aging individuals with and without additional neurodegenerative genotypes known to include cognitive impariment. This research will further the understanding of mechanisms behind memory dysfunction and help the design of memory-improving stratetegies.
Max ERC Funding
2 330 974 €
Duration
Start date: 2013-03-01, End date: 2018-02-28
Project acronym mtDNA-CURE
Project Treating mitochondrial disease caused by pathogenic mtDNA mutations
Researcher (PI) Nils-Göran LARSSON
Host Institution (HI) KAROLINSKA INSTITUTET
Call Details Advanced Grant (AdG), LS4, ERC-2016-ADG
Summary This proposal describes a series of powerful experimental strategies to develop a completely novel treatment for mtDNA mutation disease based on identifying unknown mechanisms controlling mtDNA replication. Several hundred different mtDNA mutations affect tRNA genes and impair mitochondrial translation leading to human disease. There is typically heteroplasmy with a mixture of wild-type and mutated mtDNA, and the mutations are acting in a “recessive” (loss of function) way. Very high levels of mutated mtDNA are needed to cause disease in affected patients whereas maternal relatives with high, but sub-threshold levels of mutated mtDNA are completely healthy. The corollary of these observations is that even a small increase of wild-type mtDNA may efficiently counteract disease in affected patients. This hypothesis will be validated by a series of genetic experiments with mice harbouring single pathogenic mtDNA mutations. Furthermore, novel factors controlling mtDNA replication will be identified. In particular, we will elucidate the formation and function of the mammalian displacement (D) loop, which provides a switch between abortive and genome length mtDNA replication. This very fundamental problem in mammalian mitochondrial biology has remained unsolved for decades, but I feel that the innovative experimental strategies I present in this proposal are very powerful and should have a fair chance of being successful. In any circumstance, the project will provide important molecular insights into novel mechanisms relevant for mammalian mtDNA replication. Over the years I have been strongly convinced that congruent results from in vivo and in vitro studies are needed to obtain reliable mechanistic insights and this project is therefore based on the close integration of biochemistry, advanced proteomics and state-of-the-art mouse and fly genetics. Finally, I describe a powerful large-scale screening approach to develop small molecular stimulators of mtDNA replication.
Summary
This proposal describes a series of powerful experimental strategies to develop a completely novel treatment for mtDNA mutation disease based on identifying unknown mechanisms controlling mtDNA replication. Several hundred different mtDNA mutations affect tRNA genes and impair mitochondrial translation leading to human disease. There is typically heteroplasmy with a mixture of wild-type and mutated mtDNA, and the mutations are acting in a “recessive” (loss of function) way. Very high levels of mutated mtDNA are needed to cause disease in affected patients whereas maternal relatives with high, but sub-threshold levels of mutated mtDNA are completely healthy. The corollary of these observations is that even a small increase of wild-type mtDNA may efficiently counteract disease in affected patients. This hypothesis will be validated by a series of genetic experiments with mice harbouring single pathogenic mtDNA mutations. Furthermore, novel factors controlling mtDNA replication will be identified. In particular, we will elucidate the formation and function of the mammalian displacement (D) loop, which provides a switch between abortive and genome length mtDNA replication. This very fundamental problem in mammalian mitochondrial biology has remained unsolved for decades, but I feel that the innovative experimental strategies I present in this proposal are very powerful and should have a fair chance of being successful. In any circumstance, the project will provide important molecular insights into novel mechanisms relevant for mammalian mtDNA replication. Over the years I have been strongly convinced that congruent results from in vivo and in vitro studies are needed to obtain reliable mechanistic insights and this project is therefore based on the close integration of biochemistry, advanced proteomics and state-of-the-art mouse and fly genetics. Finally, I describe a powerful large-scale screening approach to develop small molecular stimulators of mtDNA replication.
Max ERC Funding
2 500 000 €
Duration
Start date: 2018-01-01, End date: 2022-12-31
Project acronym Nutri-CARE
Project Nutri-CARE: Nutrient restriction during Critical illness: from induction of Autophagy to Repression of aberrant Epigenetic alterations
Researcher (PI) Greta Herman A Van Den Berghe
Host Institution (HI) KATHOLIEKE UNIVERSITEIT LEUVEN
Call Details Advanced Grant (AdG), LS7, ERC-2012-ADG_20120314
Summary Modern intensive care medicine enables survival from previously lethal conditions. Risk of death is mostly attributable to lack of recovery from organ failure. Although intensive care has been practiced for over 6 decades, the understanding of why certain patients recover and others don’t remains very limited. Furthermore, organs and tissues from patients who do not swiftly recover, do not show overt signs of cell death but instead accumulate damaged organelles and protein aggregates and reprogram towards other cell lineages. Accumulation of cell damage can be compared with what occurs during ageing, but much more pronounced and within a much shorter time. Even when patients survive, many continue to suffer from severe morbidity, referred to as the legacy of critical illness. This indicates that acute life-threatening illnesses, and/or the intensive care management, induce “carry-over” effects with long-term consequences with important humane and financial implications. We recently showed that nutrient restriction early during critical illness is an intervention that affects these processes. Nutrient restriction unexpectedly accelerated recovery from organ failure and enhanced rehabilitation far beyond the time window of the intervention. These data radically contradict the traditional dogma that early anabolism is required for recovery from critical illnesses. Also, they raise the hypothesis that pathways which are activated by fasting play a key role. This project is designed to understand the underlying molecular and cellular mechanisms of the damage-induced “reprogramming” and the benefit of nutrient restriction, which is essential in order to develop novel preventive and therapeutic interventions. We hypothesize that activated autophagy and repressed deleterious epigenetic alterations play a major role. The results of these studies are expected to pave the way towards novel effective interventions to prevent/treat the debilitating legacy of critical illness.
Summary
Modern intensive care medicine enables survival from previously lethal conditions. Risk of death is mostly attributable to lack of recovery from organ failure. Although intensive care has been practiced for over 6 decades, the understanding of why certain patients recover and others don’t remains very limited. Furthermore, organs and tissues from patients who do not swiftly recover, do not show overt signs of cell death but instead accumulate damaged organelles and protein aggregates and reprogram towards other cell lineages. Accumulation of cell damage can be compared with what occurs during ageing, but much more pronounced and within a much shorter time. Even when patients survive, many continue to suffer from severe morbidity, referred to as the legacy of critical illness. This indicates that acute life-threatening illnesses, and/or the intensive care management, induce “carry-over” effects with long-term consequences with important humane and financial implications. We recently showed that nutrient restriction early during critical illness is an intervention that affects these processes. Nutrient restriction unexpectedly accelerated recovery from organ failure and enhanced rehabilitation far beyond the time window of the intervention. These data radically contradict the traditional dogma that early anabolism is required for recovery from critical illnesses. Also, they raise the hypothesis that pathways which are activated by fasting play a key role. This project is designed to understand the underlying molecular and cellular mechanisms of the damage-induced “reprogramming” and the benefit of nutrient restriction, which is essential in order to develop novel preventive and therapeutic interventions. We hypothesize that activated autophagy and repressed deleterious epigenetic alterations play a major role. The results of these studies are expected to pave the way towards novel effective interventions to prevent/treat the debilitating legacy of critical illness.
Max ERC Funding
2 500 000 €
Duration
Start date: 2013-04-01, End date: 2018-03-31
