Project acronym 3DBIOLUNG
Project Bioengineering lung tissue using extracellular matrix based 3D bioprinting
Researcher (PI) Darcy WAGNER
Host Institution (HI) LUNDS UNIVERSITET
Country Sweden
Call Details Starting Grant (StG), LS9, ERC-2018-STG
Summary Chronic lung diseases are increasing in prevalence with over 65 million patients worldwide. Lung transplantation remains the only potential option at end-stage disease. Around 4000 patients receive lung transplants annually with more awaiting transplantation, including 1000 patients in Europe. New options to increase available tissue for lung transplantation are desperately needed.
An exciting new research area focuses on generating lung tissue ex vivo using bioengineering approaches. Scaffolds can be generated from synthetic or biologically-derived (acellular) materials, seeded with cells and grown in a bioreactor prior to transplantation. Ideally, scaffolds would be seeded with cells derived from the transplant recipient, thus obviating the need for long-term immunosuppression. However, functional regeneration has yet to be achieved. New advances in 3D printing and 3D bioprinting (when cells are printed) indicate that this once thought of science-fiction concept might finally be mature enough for complex tissues, including lung. 3D bioprinting addresses a number of concerns identified in previous approaches, such as a) patient heterogeneity in acellular human scaffolds, b) anatomical differences in xenogeneic sources, c) lack of biological cues on synthetic materials and d) difficulty in manufacturing the complex lung architecture. 3D bioprinting could be a reproducible, scalable, and controllable approach for generating functional lung tissue.
The aim of this proposal is to use custom 3D bioprinters to generate constructs mimicking lung tissue using an innovative approach combining primary cells, the engineering reproducibility of synthetic materials, and the biologically conductive properties of acellular lung (hybrid). We will 3D bioprint hybrid murine and human lung tissue models and test gas exchange, angiogenesis and in vivo immune responses. This proposal will be a critical first step in demonstrating feasibility of 3D bioprinting lung tissue.
Summary
Chronic lung diseases are increasing in prevalence with over 65 million patients worldwide. Lung transplantation remains the only potential option at end-stage disease. Around 4000 patients receive lung transplants annually with more awaiting transplantation, including 1000 patients in Europe. New options to increase available tissue for lung transplantation are desperately needed.
An exciting new research area focuses on generating lung tissue ex vivo using bioengineering approaches. Scaffolds can be generated from synthetic or biologically-derived (acellular) materials, seeded with cells and grown in a bioreactor prior to transplantation. Ideally, scaffolds would be seeded with cells derived from the transplant recipient, thus obviating the need for long-term immunosuppression. However, functional regeneration has yet to be achieved. New advances in 3D printing and 3D bioprinting (when cells are printed) indicate that this once thought of science-fiction concept might finally be mature enough for complex tissues, including lung. 3D bioprinting addresses a number of concerns identified in previous approaches, such as a) patient heterogeneity in acellular human scaffolds, b) anatomical differences in xenogeneic sources, c) lack of biological cues on synthetic materials and d) difficulty in manufacturing the complex lung architecture. 3D bioprinting could be a reproducible, scalable, and controllable approach for generating functional lung tissue.
The aim of this proposal is to use custom 3D bioprinters to generate constructs mimicking lung tissue using an innovative approach combining primary cells, the engineering reproducibility of synthetic materials, and the biologically conductive properties of acellular lung (hybrid). We will 3D bioprint hybrid murine and human lung tissue models and test gas exchange, angiogenesis and in vivo immune responses. This proposal will be a critical first step in demonstrating feasibility of 3D bioprinting lung tissue.
Max ERC Funding
1 499 975 €
Duration
Start date: 2019-01-01, End date: 2023-12-31
Project acronym AfricanNeo
Project The African Neolithic: A genetic perspective
Researcher (PI) Carina SCHLEBUSCH
Host Institution (HI) UPPSALA UNIVERSITET
Country Sweden
Call Details Starting Grant (StG), SH6, ERC-2017-STG
Summary The spread of farming practices in various parts of the world had a marked influence on how humans live today and how we are distributed around the globe. Around 10,000 years ago, warmer conditions lead to population increases, coinciding with the invention of farming in several places around the world. Archaeological evidence attest to the spread of these practices to neighboring regions. In many cases this lead to whole continents being converted from hunter-gatherer to farming societies. It is however difficult to see from archaeological records if only the farming culture spread to other places or whether the farming people themselves migrated. Investigating patterns of genetic variation for farming populations and for remaining hunter-gatherer groups can help to resolve questions on population movements co-occurring with the spread of farming practices. It can further shed light on the routes of migration and dates when migrants arrived.
The spread of farming to Europe has been thoroughly investigated in the fields of archaeology, linguistics and genetics, while on other continents these events have been less investigated. In Africa, mainly linguistic and archaeological studies have attempted to elucidate the spread of farming and herding practices. I propose to investigate the movement of farmer and pastoral groups in Africa, by typing densely spaced genome-wide variant positions in a large number of African populations. The data will be used to infer how farming and pastoralism was introduced to various regions, where the incoming people originated from and when these (potential) population movements occurred. Through this study, the Holocene history of Africa will be revealed and placed into a global context of migration, mobility and cultural transitions. Additionally the study will give due credence to one of the largest Neolithic expansion events, the Bantu-expansion, which caused a pronounced change in the demographic landscape of the African continent
Summary
The spread of farming practices in various parts of the world had a marked influence on how humans live today and how we are distributed around the globe. Around 10,000 years ago, warmer conditions lead to population increases, coinciding with the invention of farming in several places around the world. Archaeological evidence attest to the spread of these practices to neighboring regions. In many cases this lead to whole continents being converted from hunter-gatherer to farming societies. It is however difficult to see from archaeological records if only the farming culture spread to other places or whether the farming people themselves migrated. Investigating patterns of genetic variation for farming populations and for remaining hunter-gatherer groups can help to resolve questions on population movements co-occurring with the spread of farming practices. It can further shed light on the routes of migration and dates when migrants arrived.
The spread of farming to Europe has been thoroughly investigated in the fields of archaeology, linguistics and genetics, while on other continents these events have been less investigated. In Africa, mainly linguistic and archaeological studies have attempted to elucidate the spread of farming and herding practices. I propose to investigate the movement of farmer and pastoral groups in Africa, by typing densely spaced genome-wide variant positions in a large number of African populations. The data will be used to infer how farming and pastoralism was introduced to various regions, where the incoming people originated from and when these (potential) population movements occurred. Through this study, the Holocene history of Africa will be revealed and placed into a global context of migration, mobility and cultural transitions. Additionally the study will give due credence to one of the largest Neolithic expansion events, the Bantu-expansion, which caused a pronounced change in the demographic landscape of the African continent
Max ERC Funding
1 500 000 €
Duration
Start date: 2017-11-01, End date: 2022-10-31
Project acronym collectiveQCD
Project Collectivity in small, srongly interacting systems
Researcher (PI) Korinna ZAPP
Host Institution (HI) LUNDS UNIVERSITET
Country Sweden
Call Details Starting Grant (StG), PE2, ERC-2018-STG
Summary In collisions of heavy nuclei at collider energies, for instance at the Large Hadron Collider (LHC) at CERN, the energy density is so high that an equilibrated Quark-Gluon Plasma (QGP), an exotic state of matter consisting of deconfined quarks and gluons, is formed. In proton-proton (p+p) collisions, on the other hand, the density of produced particles is low. The traditional view on such reactions is that final state particles are free and do not rescatter. This picture is challenged by recent LHC data, which found features in p+p collisions that are indicative of collective behaviour and/or the formation of a hot and dense system. These findings have been taken as signs of QGP formation in p+p reactions. Such an interpretation is complicated by the fact that jets, which are the manifestation of very energetic quarks and gluons, are quenched in heavy ion collisions, but appear to be unmodified in p+p reactions. This is puzzling because collectivity and jet quenching are caused by the same processes. So far there is no consensus about the interpretation of these results, which is also due to a lack of suitable tools.
It is the objective of this proposal to address the question whether there are collective effects in p+p collisions. To this end two models capable of describing all relevant aspects of p+p and heavy ion collisions will be developed. They will be obtained by extending a successful description of p+p to heavy ion reactions and vice versa.
The answer to these questions will either clarify the long-standing problem how collectivity emerges from fundamental interactions, or it will necessitate qualitative changes to our interpretation of collective phenomena in p+p and/or heavy ion collisions.
The PI is in a unique position to accomplish this goal, as she has spent her entire career working on different aspects of p+p and heavy ion collisions. The group in Lund is the ideal host, as it is very active in developing alternative interpretations of the data.
Summary
In collisions of heavy nuclei at collider energies, for instance at the Large Hadron Collider (LHC) at CERN, the energy density is so high that an equilibrated Quark-Gluon Plasma (QGP), an exotic state of matter consisting of deconfined quarks and gluons, is formed. In proton-proton (p+p) collisions, on the other hand, the density of produced particles is low. The traditional view on such reactions is that final state particles are free and do not rescatter. This picture is challenged by recent LHC data, which found features in p+p collisions that are indicative of collective behaviour and/or the formation of a hot and dense system. These findings have been taken as signs of QGP formation in p+p reactions. Such an interpretation is complicated by the fact that jets, which are the manifestation of very energetic quarks and gluons, are quenched in heavy ion collisions, but appear to be unmodified in p+p reactions. This is puzzling because collectivity and jet quenching are caused by the same processes. So far there is no consensus about the interpretation of these results, which is also due to a lack of suitable tools.
It is the objective of this proposal to address the question whether there are collective effects in p+p collisions. To this end two models capable of describing all relevant aspects of p+p and heavy ion collisions will be developed. They will be obtained by extending a successful description of p+p to heavy ion reactions and vice versa.
The answer to these questions will either clarify the long-standing problem how collectivity emerges from fundamental interactions, or it will necessitate qualitative changes to our interpretation of collective phenomena in p+p and/or heavy ion collisions.
The PI is in a unique position to accomplish this goal, as she has spent her entire career working on different aspects of p+p and heavy ion collisions. The group in Lund is the ideal host, as it is very active in developing alternative interpretations of the data.
Max ERC Funding
1 500 000 €
Duration
Start date: 2019-02-01, End date: 2024-01-31
Project acronym GRASP
Project Overcoming plant graft incompatibility by modifying signalling and perception
Researcher (PI) Charles MELNYK
Host Institution (HI) SVERIGES LANTBRUKSUNIVERSITET
Country Sweden
Call Details Starting Grant (StG), LS9, ERC-2018-STG
Summary For millennia, people have cut and joined together different plants through a process known as grafting. Plants tissues from different genotypes fuse, vasculature connects and a chimeric organism forms that combines desirable characteristics from different plants such as high yields or disease resistance. However, plants can only be grafted to closely related species and in some instances, they cannot be grafted to themselves. This phenomenon is referred to as graft incompatibility and the mechanistic basis is completely unknown. Our previous work on graft formation in Arabidopsis thaliana has uncovered genes that rapidly activate in grafted tissues to signal the presence of adjoining tissue and initiate a vascular reconnection process. These genes activate around the cut only during graft formation and present a powerful tool to screen large numbers of chemicals and genes that could promote tissue perception and vascular formation. With these sensors and our previously established grafting tools in the model plant Arabidopsis, we can address fundamental questions about grafting biology that have direct relevance to improving graft formation through:
1. Identifying genes required for the recognition response using forward and reverse genetic screens.
2. Determining and characterising signals that activate vascular induction using a chemical genetics screen.
3. Characterising the transcriptional basis for compatibility and incompatibility by analysing
tissues and species that graft and comparing these to tissues and species that do not graft.
4. Overcoming graft incompatibility and improving graft formation by applying the knowledge obtained from the three previous objectives.
We thus aim to broaden our fundamental understanding of the processes associated with grafting including wound healing, vascular formation and tissue regeneration, while at the same time, use this information to improve graft formation and expand the range of grafted species.
Summary
For millennia, people have cut and joined together different plants through a process known as grafting. Plants tissues from different genotypes fuse, vasculature connects and a chimeric organism forms that combines desirable characteristics from different plants such as high yields or disease resistance. However, plants can only be grafted to closely related species and in some instances, they cannot be grafted to themselves. This phenomenon is referred to as graft incompatibility and the mechanistic basis is completely unknown. Our previous work on graft formation in Arabidopsis thaliana has uncovered genes that rapidly activate in grafted tissues to signal the presence of adjoining tissue and initiate a vascular reconnection process. These genes activate around the cut only during graft formation and present a powerful tool to screen large numbers of chemicals and genes that could promote tissue perception and vascular formation. With these sensors and our previously established grafting tools in the model plant Arabidopsis, we can address fundamental questions about grafting biology that have direct relevance to improving graft formation through:
1. Identifying genes required for the recognition response using forward and reverse genetic screens.
2. Determining and characterising signals that activate vascular induction using a chemical genetics screen.
3. Characterising the transcriptional basis for compatibility and incompatibility by analysing
tissues and species that graft and comparing these to tissues and species that do not graft.
4. Overcoming graft incompatibility and improving graft formation by applying the knowledge obtained from the three previous objectives.
We thus aim to broaden our fundamental understanding of the processes associated with grafting including wound healing, vascular formation and tissue regeneration, while at the same time, use this information to improve graft formation and expand the range of grafted species.
Max ERC Funding
1 499 902 €
Duration
Start date: 2019-08-01, End date: 2024-07-31
Project acronym Growth regulation
Project The wide-spread bacterial toxin delivery systems and their role in multicellularity
Researcher (PI) Sanna KOSKINIEMI
Host Institution (HI) UPPSALA UNIVERSITET
Country Sweden
Call Details Starting Grant (StG), LS8, ERC-2018-STG
Summary Bacteria live in environments where resources for growth are scarce and shared with other bacteria. The ability to inhibit the growth of other bacteria is thus favourable and most bacteria use multiple systems for such antagonistic interactions, including delivery of protein toxins to other bacteria (e.g. bacteriocins, type 6 secretion and contact-dependent growth inhibition systems). In addition to their role in competition, all these toxin delivery systems frequently deliver toxins to cells of the same genotype, i.e. cells immune to the toxic activity, but a function for self-delivery of toxins has never been identified. Recent evidence from our lab suggests that self-delivery of toxins generates population heterogeneity in terms of growth at high cell densities, i.e. upon cell-cell contacts. But if this is a common feature of all toxin delivery systems is not known. Here we will investigate if toxin delivery to cells immune to the toxin creates population heterogeneity in terms of growth, mutation rates and gene expression, and if this is important for bacterial evolution and multicellularity. As homologs for many of the toxins can also be found in eukaryotes, including multicellular organisms, we will investigate if the functions of these systems are also conserved across kingdoms.
We will particular characterize the role of bacterial toxin delivery systems for multicellular behaviour and adaptation to new growth environments. This research have important consequences for understanding cell-to-cell contacts and the organization of multicellular tissues in general; from how to control biofilm formation to the understanding of uncontrolled cell growth in higher eukaryotes.
Summary
Bacteria live in environments where resources for growth are scarce and shared with other bacteria. The ability to inhibit the growth of other bacteria is thus favourable and most bacteria use multiple systems for such antagonistic interactions, including delivery of protein toxins to other bacteria (e.g. bacteriocins, type 6 secretion and contact-dependent growth inhibition systems). In addition to their role in competition, all these toxin delivery systems frequently deliver toxins to cells of the same genotype, i.e. cells immune to the toxic activity, but a function for self-delivery of toxins has never been identified. Recent evidence from our lab suggests that self-delivery of toxins generates population heterogeneity in terms of growth at high cell densities, i.e. upon cell-cell contacts. But if this is a common feature of all toxin delivery systems is not known. Here we will investigate if toxin delivery to cells immune to the toxin creates population heterogeneity in terms of growth, mutation rates and gene expression, and if this is important for bacterial evolution and multicellularity. As homologs for many of the toxins can also be found in eukaryotes, including multicellular organisms, we will investigate if the functions of these systems are also conserved across kingdoms.
We will particular characterize the role of bacterial toxin delivery systems for multicellular behaviour and adaptation to new growth environments. This research have important consequences for understanding cell-to-cell contacts and the organization of multicellular tissues in general; from how to control biofilm formation to the understanding of uncontrolled cell growth in higher eukaryotes.
Max ERC Funding
1 499 765 €
Duration
Start date: 2019-01-01, End date: 2023-12-31
Project acronym GUTSY
Project The gut microbiota and its systemic effects on metabolism and atherosclerotic disease
Researcher (PI) Tove Elisabet FALL
Host Institution (HI) UPPSALA UNIVERSITET
Country Sweden
Call Details Starting Grant (StG), LS7, ERC-2018-STG
Summary Atherosclerosis is the main pathological mechanism causing myocardial infarction and ischemic stroke. Evidence has mounted about the association between the gut microbiota and cardiovascular disease, but whether the associations are causal is largely unknown. For optimal prevention and treatment of cardiovascular disease, there is an urgent need to determine whether there are any true effects that might be targeted by interventions. The overall goal of this project is to assess causality between gut microbiota and atherosclerotic disease and to provide easily accessible biomarkers for an atherosclerosis-enhancing gut microbiota. To this end, the research program has three main objectives:
1.) Identification of gut microbiota characteristics associated with atherosclerosis measured by coronary computed tomography angiography and high-resolution carotid ultrasound in a population-based sample of 10,000 individuals and through prospective follow-up for myocardial infarction and ischemic stroke. The microbiota will be characterized by next-generation sequencing techniques in faecal samples.
2.) Identification of plasma biomarkers associated with an atherosclerosis- enhancing microbiota using comprehensive metabolomics profiling of 800 named metabolites in plasma from 800 individuals with replication in additional 800 individuals
3.) Clarification of the causal effects of gut microbiota characteristics on atherosclerosis, myocardial infarction and stroke by development of novel genetic instruments and applying Mendelian Randomization analysis
I have access to unique study materials and documented experience of successful projects using large scale -omics data and state-of-the-art epidemiological methodologies. My project is expected to lead to the identification of characteristics of an atherosclerosis-enhancing gut microbiota and associated plasma biomarkers that may open up new avenues for effective prevention of atherosclerotic disease.
Summary
Atherosclerosis is the main pathological mechanism causing myocardial infarction and ischemic stroke. Evidence has mounted about the association between the gut microbiota and cardiovascular disease, but whether the associations are causal is largely unknown. For optimal prevention and treatment of cardiovascular disease, there is an urgent need to determine whether there are any true effects that might be targeted by interventions. The overall goal of this project is to assess causality between gut microbiota and atherosclerotic disease and to provide easily accessible biomarkers for an atherosclerosis-enhancing gut microbiota. To this end, the research program has three main objectives:
1.) Identification of gut microbiota characteristics associated with atherosclerosis measured by coronary computed tomography angiography and high-resolution carotid ultrasound in a population-based sample of 10,000 individuals and through prospective follow-up for myocardial infarction and ischemic stroke. The microbiota will be characterized by next-generation sequencing techniques in faecal samples.
2.) Identification of plasma biomarkers associated with an atherosclerosis- enhancing microbiota using comprehensive metabolomics profiling of 800 named metabolites in plasma from 800 individuals with replication in additional 800 individuals
3.) Clarification of the causal effects of gut microbiota characteristics on atherosclerosis, myocardial infarction and stroke by development of novel genetic instruments and applying Mendelian Randomization analysis
I have access to unique study materials and documented experience of successful projects using large scale -omics data and state-of-the-art epidemiological methodologies. My project is expected to lead to the identification of characteristics of an atherosclerosis-enhancing gut microbiota and associated plasma biomarkers that may open up new avenues for effective prevention of atherosclerotic disease.
Max ERC Funding
1 500 000 €
Duration
Start date: 2019-01-01, End date: 2023-12-31
Project acronym MegaALS
Project Unravelling the Interplay between Metabolism, Gut Microbiome and Adaptive Immunity in Amyotrophic Lateral Sclerosis
Researcher (PI) Fang FANG
Host Institution (HI) KAROLINSKA INSTITUTET
Country Sweden
Call Details Starting Grant (StG), LS7, ERC-2018-STG
Summary Amyotrophic lateral sclerosis (ALS) is a rare but devastating neurodegenerative disorder that in lack of effective treatments leads to death within a few years of diagnosis. ALS is increasingly being recognized as a systemic disease affecting not only the central nervous system but also other physiological aspects. We hypothesize that there is a disease-specific interplay between metabolism, gut microbiome and adaptive immunity, which substantially contributes to the etiopathogenesis of ALS. The overarching aim of this project is therefore to explore such interplay, and to assess the effectiveness of a treatment regimen that specifically targets it. Using a population-based case-control study of ALS in Stockholm, I will first characterize the complex interactions between metabolism, microbiome, and immunity in ALS, through comprehensive proteomic, metagenomic and immune-response profiling. The specificity of these interactions will be tested in contrast to healthy individuals at high risk for ALS (siblings), individuals with similar environmental and lifestyle factors (spouses), and unrelated population-controls. I will then use an established ALS mouse model (SOD1G93A) to understand the usefulness of combining a high-caloric diet with a fecal microbiota transplant from healthy human donors in disease prevention and treatment. To better understand the underlying mechanisms, I will compare microbiome and immune-response profiles before and after the intervention. The proposed research is unique as it 1) combines innovative molecular platforms with a high-quality epidemiological study design, 2) uses a novel strategy of investigating multiple aspects of human physiology, and 3) offers a possibility to directly translate findings between human observational and animal experimental studies. The ultimate goal is to significantly advance our knowledge about ALS as a disease, and more importantly to identify novel and highly warranted preventive and therapeutic targets.
Summary
Amyotrophic lateral sclerosis (ALS) is a rare but devastating neurodegenerative disorder that in lack of effective treatments leads to death within a few years of diagnosis. ALS is increasingly being recognized as a systemic disease affecting not only the central nervous system but also other physiological aspects. We hypothesize that there is a disease-specific interplay between metabolism, gut microbiome and adaptive immunity, which substantially contributes to the etiopathogenesis of ALS. The overarching aim of this project is therefore to explore such interplay, and to assess the effectiveness of a treatment regimen that specifically targets it. Using a population-based case-control study of ALS in Stockholm, I will first characterize the complex interactions between metabolism, microbiome, and immunity in ALS, through comprehensive proteomic, metagenomic and immune-response profiling. The specificity of these interactions will be tested in contrast to healthy individuals at high risk for ALS (siblings), individuals with similar environmental and lifestyle factors (spouses), and unrelated population-controls. I will then use an established ALS mouse model (SOD1G93A) to understand the usefulness of combining a high-caloric diet with a fecal microbiota transplant from healthy human donors in disease prevention and treatment. To better understand the underlying mechanisms, I will compare microbiome and immune-response profiles before and after the intervention. The proposed research is unique as it 1) combines innovative molecular platforms with a high-quality epidemiological study design, 2) uses a novel strategy of investigating multiple aspects of human physiology, and 3) offers a possibility to directly translate findings between human observational and animal experimental studies. The ultimate goal is to significantly advance our knowledge about ALS as a disease, and more importantly to identify novel and highly warranted preventive and therapeutic targets.
Max ERC Funding
1 499 196 €
Duration
Start date: 2018-11-01, End date: 2023-10-31
Project acronym Meiotic telomere
Project Study of telomere function in germ cells, relevant to the regulations of homologous recombination and telomere length maintenance across generations
Researcher (PI) Hiroki Shibuya
Host Institution (HI) GOETEBORGS UNIVERSITET
Country Sweden
Call Details Starting Grant (StG), LS1, ERC-2018-STG
Summary The length of telomeric DNA is a critical determinant factor for aging and cancer development. In germ cells, the activation of a telomerase-dependent telomere-lengthening pathway is thought to be important in order to maintain telomeric DNA across generations, but the molecular mechanisms involved in this pathway, i.e: how and when telomerase is activated in germ cells, are largely unknown.
A DNA-binding protein complex called shelterin constitutively binds telomeric DNA. However, my recent studies have suggested that a multi-subunit DNA-binding complex, TERB1-TERB2-MAJIN, takes over telomeric DNA from shelterin in mammalian germ cells in order to facilitate homologous recombination. These findings represent a hitherto unknown molecular mechanism at work on the telomeres in germ cells.
In this project, I hypothesize that the drastic reformation of telomere-binding complexes in germ cells contributes also to the telomere-lengthening pathway. The aim of this project is to test this hypothesis in order to reveal the mechanism underlying the transgenerational inheritance of telomeric DNA throughout meiosis. This work is divided into three work packages.
WP1: to determine the molecular rearrangements that take place at telomeres during meiosis.
WP2: to determine how and when telomeres are lengthened during germ cell production.
WP3: to determine how meiotic recombination is achieved.
The proposed project will reveal molecular mechanisms underlying the transgenerational inheritance of genetic information after meiosis, and this will increase our understanding of the etiology of numerous human diseases caused by meiotic errors, such as congenital birth defects and aneuploidy. Further, because the misregulation of telomerase is a leading cause of cancer development, the identification of telomerase-activating mechanisms in germ cells will have multidiscipline impacts in both cancer and reproductive biology fields and will be useful for developing novel cancer therapies.
Summary
The length of telomeric DNA is a critical determinant factor for aging and cancer development. In germ cells, the activation of a telomerase-dependent telomere-lengthening pathway is thought to be important in order to maintain telomeric DNA across generations, but the molecular mechanisms involved in this pathway, i.e: how and when telomerase is activated in germ cells, are largely unknown.
A DNA-binding protein complex called shelterin constitutively binds telomeric DNA. However, my recent studies have suggested that a multi-subunit DNA-binding complex, TERB1-TERB2-MAJIN, takes over telomeric DNA from shelterin in mammalian germ cells in order to facilitate homologous recombination. These findings represent a hitherto unknown molecular mechanism at work on the telomeres in germ cells.
In this project, I hypothesize that the drastic reformation of telomere-binding complexes in germ cells contributes also to the telomere-lengthening pathway. The aim of this project is to test this hypothesis in order to reveal the mechanism underlying the transgenerational inheritance of telomeric DNA throughout meiosis. This work is divided into three work packages.
WP1: to determine the molecular rearrangements that take place at telomeres during meiosis.
WP2: to determine how and when telomeres are lengthened during germ cell production.
WP3: to determine how meiotic recombination is achieved.
The proposed project will reveal molecular mechanisms underlying the transgenerational inheritance of genetic information after meiosis, and this will increase our understanding of the etiology of numerous human diseases caused by meiotic errors, such as congenital birth defects and aneuploidy. Further, because the misregulation of telomerase is a leading cause of cancer development, the identification of telomerase-activating mechanisms in germ cells will have multidiscipline impacts in both cancer and reproductive biology fields and will be useful for developing novel cancer therapies.
Max ERC Funding
1 500 000 €
Duration
Start date: 2019-01-01, End date: 2023-12-31
Project acronym MICROTOMACROANDBACK
Project Micro Heterogeneity and Macroeconomic Policy
Researcher (PI) Kurt Elliott MITMAN
Host Institution (HI) STOCKHOLMS UNIVERSITET
Country Sweden
Call Details Starting Grant (StG), SH1, ERC-2017-STG
Summary This project will develop macroeconomic models with household heterogeneity and partially demand-determined output to study how the economy is affected by monetary and fiscal policy, and to investigate the importance of housing in macroeconomic fluctuations and the transmission and efficacy of policy. The objective is to provide a modelling framework that simultaneously is consistent with both empirical micro evidence on household consumption and savings behaviour, and macro evidence on the response of the aggregate economy to a variety of economic shocks. The ultimate goal is to help make these models the new standard for the study of fluctuations and policy evaluation in macro.
Inequality and incomplete markets will be a central theme. The first objective of the project is to establish the importance of incomplete financial markets for the response of the economy to changes in monetary policy. The framework will then be used to evaluate the size of the fiscal multiplier and quantitatively evaluate the stimulative effect of extensions to unemployment benefits.
The second theme of the project will focus on housing and mortgage debt as an amplification and propagation mechanism. The recent Great Recession–preceded by an unparalleled boom and bust in house prices – has brought to light the importance of housing for the economy. The project will develop a rich benchmark model of housing and the aggregate economy for policy evaluation. First, the project will investigate how heterogeneity in housing and debt affects the transmission of monetary policy. Next, a cross-country analysis will be performed to quantify the importance of different arrangements in the mortgage market for the response of the economy to shocks. Finally, I will introduce imperfect information above the driving forces of the economy to study booms and busts in the housing market and real economic activity, with the goal of evaluating macroprudential policies geared at the housing market.
Summary
This project will develop macroeconomic models with household heterogeneity and partially demand-determined output to study how the economy is affected by monetary and fiscal policy, and to investigate the importance of housing in macroeconomic fluctuations and the transmission and efficacy of policy. The objective is to provide a modelling framework that simultaneously is consistent with both empirical micro evidence on household consumption and savings behaviour, and macro evidence on the response of the aggregate economy to a variety of economic shocks. The ultimate goal is to help make these models the new standard for the study of fluctuations and policy evaluation in macro.
Inequality and incomplete markets will be a central theme. The first objective of the project is to establish the importance of incomplete financial markets for the response of the economy to changes in monetary policy. The framework will then be used to evaluate the size of the fiscal multiplier and quantitatively evaluate the stimulative effect of extensions to unemployment benefits.
The second theme of the project will focus on housing and mortgage debt as an amplification and propagation mechanism. The recent Great Recession–preceded by an unparalleled boom and bust in house prices – has brought to light the importance of housing for the economy. The project will develop a rich benchmark model of housing and the aggregate economy for policy evaluation. First, the project will investigate how heterogeneity in housing and debt affects the transmission of monetary policy. Next, a cross-country analysis will be performed to quantify the importance of different arrangements in the mortgage market for the response of the economy to shocks. Finally, I will introduce imperfect information above the driving forces of the economy to study booms and busts in the housing market and real economic activity, with the goal of evaluating macroprudential policies geared at the housing market.
Max ERC Funding
1 299 165 €
Duration
Start date: 2017-11-01, End date: 2022-10-31
Project acronym miRCell
Project MicroRNA functions in single cells
Researcher (PI) Marc FRIEDLaeNDER
Host Institution (HI) STOCKHOLMS UNIVERSITET
Country Sweden
Call Details Starting Grant (StG), LS2, ERC-2017-STG
Summary It is now becoming apparent that genes are regulated not only by transcription, but also by thousands of post-transcriptional regulators that can stabilize or degrade mRNAs. Some of the most important regulators are miRNAs, short RNA molecules that are deeply conserved in sequence and are involved in numerous biological processes, including human disease. Surprisingly, transcriptomic and proteomic studies show that most miRNAs only have subtle silencing effects on their targets, suggesting additional important, but yet undiscovered functions. Thus the question is raised: if the main function of miRNAs is not to silence targets, what is it?
I will test two novel hypotheses about miRNA function. The first hypothesis proposes that miRNAs can buffer gene expression noise. The second hypothesis is inspired by my preliminary results and proposes that miRNAs can synchronize expression of genes. If I validate either hypothesis, it would mean that miRNA functions can be investigated in entirely new ways, yielding important new biological insights relevant to both basic research and human health. However, these hypotheses can only be tested in individual cells, and the necessary single-cell technologies and computational tools are only maturing now.
I will apply my expertise in miRNA biology and in combined wet-lab and computational methods to design, develop and apply miRCell-seq to test these two hypotheses in cell cultures and in animals. This new method will for the first time measure miRNAs, their targets, and the interactions between them in single cells and transcriptome-wide. We will use mutant cells devoid of miRNAs and time course experiments to generate sufficient data to develop detailed models of the miRNA impact on their targets. We will then validate our findings with single cell proteomics. This project thus has the potential to reveal novel functions of miRNAs and substantially improve our general understanding of gene regulation.
Summary
It is now becoming apparent that genes are regulated not only by transcription, but also by thousands of post-transcriptional regulators that can stabilize or degrade mRNAs. Some of the most important regulators are miRNAs, short RNA molecules that are deeply conserved in sequence and are involved in numerous biological processes, including human disease. Surprisingly, transcriptomic and proteomic studies show that most miRNAs only have subtle silencing effects on their targets, suggesting additional important, but yet undiscovered functions. Thus the question is raised: if the main function of miRNAs is not to silence targets, what is it?
I will test two novel hypotheses about miRNA function. The first hypothesis proposes that miRNAs can buffer gene expression noise. The second hypothesis is inspired by my preliminary results and proposes that miRNAs can synchronize expression of genes. If I validate either hypothesis, it would mean that miRNA functions can be investigated in entirely new ways, yielding important new biological insights relevant to both basic research and human health. However, these hypotheses can only be tested in individual cells, and the necessary single-cell technologies and computational tools are only maturing now.
I will apply my expertise in miRNA biology and in combined wet-lab and computational methods to design, develop and apply miRCell-seq to test these two hypotheses in cell cultures and in animals. This new method will for the first time measure miRNAs, their targets, and the interactions between them in single cells and transcriptome-wide. We will use mutant cells devoid of miRNAs and time course experiments to generate sufficient data to develop detailed models of the miRNA impact on their targets. We will then validate our findings with single cell proteomics. This project thus has the potential to reveal novel functions of miRNAs and substantially improve our general understanding of gene regulation.
Max ERC Funding
1 497 650 €
Duration
Start date: 2018-03-01, End date: 2023-02-28
