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 AGINGSEXDIFF
Project Aging Differently: Understanding Sex Differences in Reproductive, Demographic and Functional Senescence
Researcher (PI) Alexei Maklakov
Host Institution (HI) UPPSALA UNIVERSITET
Country Sweden
Call Details Starting Grant (StG), LS8, ERC-2010-StG_20091118
Summary Sex differences in life span and aging are ubiquitous across the animal kingdom and represent a
long-standing challenge in evolutionary biology. In most species, including humans, sexes differ not
only in how long they live and when they start to senesce, but also in how they react to
environmental interventions aimed at prolonging their life span or decelerating the onset of aging.
Therefore, sex differences in life span and aging have important implications beyond the questions
posed by fundamental science. Both evolutionary reasons and medical implications of sex
differences in demographic, reproductive and physiological senescence are and will be crucial
targets of present and future research in the biology of aging. Here I propose a two-step approach
that can provide a significant breakthrough in our understanding of the biological basis of sex
differences in aging. First, I propose to resolve the age-old conundrum regarding the role of sexspecific
mortality rate in sex differences in aging by developing a series of targeted experimental
evolution studies in a novel model organism – the nematode, Caenorhabditis remanei. Second, I
address the role of intra-locus sexual conflict in the evolution of aging by combining novel
methodology from nutritional ecology – the Geometric Framework – with artificial selection
approach using the cricket Teleogryllus commodus and the fruitfly Drosophila melanogaster. I will
directly test the hypothesis that intra-locus sexual conflict mediates aging by restricting the
adaptive evolution of diet choice. By combining techniques from evolutionary biology and
nutritional ecology, this proposal will raise EU’s profile in integrative research, and contribute to
the training of young scientists in this rapidly developing field.
Summary
Sex differences in life span and aging are ubiquitous across the animal kingdom and represent a
long-standing challenge in evolutionary biology. In most species, including humans, sexes differ not
only in how long they live and when they start to senesce, but also in how they react to
environmental interventions aimed at prolonging their life span or decelerating the onset of aging.
Therefore, sex differences in life span and aging have important implications beyond the questions
posed by fundamental science. Both evolutionary reasons and medical implications of sex
differences in demographic, reproductive and physiological senescence are and will be crucial
targets of present and future research in the biology of aging. Here I propose a two-step approach
that can provide a significant breakthrough in our understanding of the biological basis of sex
differences in aging. First, I propose to resolve the age-old conundrum regarding the role of sexspecific
mortality rate in sex differences in aging by developing a series of targeted experimental
evolution studies in a novel model organism – the nematode, Caenorhabditis remanei. Second, I
address the role of intra-locus sexual conflict in the evolution of aging by combining novel
methodology from nutritional ecology – the Geometric Framework – with artificial selection
approach using the cricket Teleogryllus commodus and the fruitfly Drosophila melanogaster. I will
directly test the hypothesis that intra-locus sexual conflict mediates aging by restricting the
adaptive evolution of diet choice. By combining techniques from evolutionary biology and
nutritional ecology, this proposal will raise EU’s profile in integrative research, and contribute to
the training of young scientists in this rapidly developing field.
Max ERC Funding
1 391 904 €
Duration
Start date: 2010-12-01, End date: 2016-05-31
Project acronym Allelic Regulation
Project Revealing Allele-level Regulation and Dynamics using Single-cell Gene Expression Analyses
Researcher (PI) Thore Rickard Hakan Sandberg
Host Institution (HI) KAROLINSKA INSTITUTET
Country Sweden
Call Details Consolidator Grant (CoG), LS2, ERC-2014-CoG
Summary As diploid organisms inherit one gene copy from each parent, a gene can be expressed from both alleles (biallelic) or from only one allele (monoallelic). Although transcription from both alleles is detected for most genes in cell population experiments, little is known about allele-specific expression in single cells and its phenotypic consequences. To answer fundamental questions about allelic transcription heterogeneity in single cells, this research program will focus on single-cell transcriptome analyses with allelic-origin resolution. To this end, we will investigate both clonally stable and dynamic random monoallelic expression across a large number of cell types, including cells from embryonic and adult stages. This research program will be accomplished with the novel single-cell RNA-seq method developed within my lab to obtain quantitative, genome-wide gene expression measurement. To distinguish between mitotically stable and dynamic patterns of allelic expression, we will analyze large numbers a clonally related cells per cell type, from both primary cultures (in vitro) and using transgenic models to obtain clonally related cells in vivo.
The biological significance of the research program is first an understanding of allelic transcription, including the nature and extent of random monoallelic expression across in vivo tissues and cell types. These novel insights into allelic transcription will be important for an improved understanding of how variable phenotypes (e.g. incomplete penetrance and variable expressivity) can arise in genetically identical individuals. Additionally, the single-cell transcriptome analyses of clonally related cells in vivo will provide unique insights into the clonality of gene expression per se.
Summary
As diploid organisms inherit one gene copy from each parent, a gene can be expressed from both alleles (biallelic) or from only one allele (monoallelic). Although transcription from both alleles is detected for most genes in cell population experiments, little is known about allele-specific expression in single cells and its phenotypic consequences. To answer fundamental questions about allelic transcription heterogeneity in single cells, this research program will focus on single-cell transcriptome analyses with allelic-origin resolution. To this end, we will investigate both clonally stable and dynamic random monoallelic expression across a large number of cell types, including cells from embryonic and adult stages. This research program will be accomplished with the novel single-cell RNA-seq method developed within my lab to obtain quantitative, genome-wide gene expression measurement. To distinguish between mitotically stable and dynamic patterns of allelic expression, we will analyze large numbers a clonally related cells per cell type, from both primary cultures (in vitro) and using transgenic models to obtain clonally related cells in vivo.
The biological significance of the research program is first an understanding of allelic transcription, including the nature and extent of random monoallelic expression across in vivo tissues and cell types. These novel insights into allelic transcription will be important for an improved understanding of how variable phenotypes (e.g. incomplete penetrance and variable expressivity) can arise in genetically identical individuals. Additionally, the single-cell transcriptome analyses of clonally related cells in vivo will provide unique insights into the clonality of gene expression per se.
Max ERC Funding
1 923 060 €
Duration
Start date: 2015-07-01, End date: 2020-12-31
Project acronym ANALYTICAL SOCIOLOGY
Project Analytical Sociology: Theoretical Developments and Empirical Research
Researcher (PI) Mats Peter Hedstroem
Host Institution (HI) LINKOPINGS UNIVERSITET
Country Sweden
Call Details Advanced Grant (AdG), SH2, ERC-2012-ADG_20120411
Summary This proposal outlines a highly ambitious and path-breaking research program. Through a tightly integrated package of basic theoretical work, strategic empirical research projects, international workshops, and a large number of publications in leading journals, the research program seeks to move sociology in a more analytical direction.
One part of the research program focuses on the epistemological and methodological foundations of analytical sociology, an approach to sociological theory and research that currently receives considerable attention in the international scholarly community. This work will be organized around two core themes: (1) the principles of mechanism-based explanations and (2) the micro-macro link.
The empirical research analyzes in great detail the ethnic, gender, and socio-economic segregation of key interaction domains in Sweden using the approach of analytical sociology. The interaction domains focused upon are schools, workplaces and neighborhoods; domains where people spend a considerable part of their time, where much of the social interaction between people takes place, where identities are formed, and where important resources are distributed.
Large-scale longitudinal micro data on the entire Swedish population, unique longitudinal data on social networks within school classes, and various agent-based simulation techniques, are used to better understand the processes through which schools, workplaces and neighborhoods become segregated along various dimensions, how the domains interact with one another, and how the structure and extent of segregation affects diverse social and economic outcomes.
Summary
This proposal outlines a highly ambitious and path-breaking research program. Through a tightly integrated package of basic theoretical work, strategic empirical research projects, international workshops, and a large number of publications in leading journals, the research program seeks to move sociology in a more analytical direction.
One part of the research program focuses on the epistemological and methodological foundations of analytical sociology, an approach to sociological theory and research that currently receives considerable attention in the international scholarly community. This work will be organized around two core themes: (1) the principles of mechanism-based explanations and (2) the micro-macro link.
The empirical research analyzes in great detail the ethnic, gender, and socio-economic segregation of key interaction domains in Sweden using the approach of analytical sociology. The interaction domains focused upon are schools, workplaces and neighborhoods; domains where people spend a considerable part of their time, where much of the social interaction between people takes place, where identities are formed, and where important resources are distributed.
Large-scale longitudinal micro data on the entire Swedish population, unique longitudinal data on social networks within school classes, and various agent-based simulation techniques, are used to better understand the processes through which schools, workplaces and neighborhoods become segregated along various dimensions, how the domains interact with one another, and how the structure and extent of segregation affects diverse social and economic outcomes.
Max ERC Funding
1 745 098 €
Duration
Start date: 2013-03-01, End date: 2018-02-28
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 ANSR
Project Ab initio approach to nuclear structure and reactions (++)
Researcher (PI) Christian Erik Forssen
Host Institution (HI) CHALMERS TEKNISKA HOEGSKOLA AB
Country Sweden
Call Details Starting Grant (StG), PE2, ERC-2009-StG
Summary Today, much interest in several fields of physics is devoted to the study of small, open quantum systems, whose properties are profoundly affected by the environment; i.e., the continuum of decay channels. In nuclear physics, these problems were originally studied in the context of nuclear reactions but their importance has been reestablished with the advent of radioactive-beam physics and the resulting interest in exotic nuclei. In particular, strong theory initiatives in this area of research will be instrumental for the success of the experimental program at the Facility for Antiproton and Ion Research (FAIR) in Germany. In addition, many of the aspects of open quantum systems are also being explored in the rapidly evolving research on ultracold atomic gases, quantum dots, and other nanodevices. A first-principles description of open quantum systems presents a substantial theoretical and computational challenge. However, the current availability of enormous computing power has allowed theorists to make spectacular progress on problems that were previously thought intractable. The importance of computational methods to study quantum many-body systems is stressed in this proposal. Our approach is based on the ab initio no-core shell model (NCSM), which is a well-established theoretical framework aimed originally at an exact description of nuclear structure starting from realistic inter-nucleon forces. A successful completion of this project requires extensions of the NCSM mathematical framework and the development of highly advanced computer codes. The '++' in the project title indicates the interdisciplinary aspects of the present research proposal and the ambition to make a significant impact on connected fields of many-body physics.
Summary
Today, much interest in several fields of physics is devoted to the study of small, open quantum systems, whose properties are profoundly affected by the environment; i.e., the continuum of decay channels. In nuclear physics, these problems were originally studied in the context of nuclear reactions but their importance has been reestablished with the advent of radioactive-beam physics and the resulting interest in exotic nuclei. In particular, strong theory initiatives in this area of research will be instrumental for the success of the experimental program at the Facility for Antiproton and Ion Research (FAIR) in Germany. In addition, many of the aspects of open quantum systems are also being explored in the rapidly evolving research on ultracold atomic gases, quantum dots, and other nanodevices. A first-principles description of open quantum systems presents a substantial theoretical and computational challenge. However, the current availability of enormous computing power has allowed theorists to make spectacular progress on problems that were previously thought intractable. The importance of computational methods to study quantum many-body systems is stressed in this proposal. Our approach is based on the ab initio no-core shell model (NCSM), which is a well-established theoretical framework aimed originally at an exact description of nuclear structure starting from realistic inter-nucleon forces. A successful completion of this project requires extensions of the NCSM mathematical framework and the development of highly advanced computer codes. The '++' in the project title indicates the interdisciplinary aspects of the present research proposal and the ambition to make a significant impact on connected fields of many-body physics.
Max ERC Funding
1 304 800 €
Duration
Start date: 2009-12-01, End date: 2014-11-30
Project acronym AXION
Project Axions: From Heaven to Earth
Researcher (PI) Frank Wilczek
Host Institution (HI) STOCKHOLMS UNIVERSITET
Country Sweden
Call Details Advanced Grant (AdG), PE2, ERC-2016-ADG
Summary Axions are hypothetical particles whose existence would solve two major problems: the strong P, T problem (a major blemish on the standard model); and the dark matter problem. It is a most important goal to either observe or rule out the existence of a cosmic axion background. It appears that decisive observations may be possible, but only after orchestrating insight from specialities ranging from quantum field theory and astrophysical modeling to ultra-low noise quantum measurement theory. Detailed predictions for the magnitude and structure of the cosmic axion background depend on cosmological and astrophysical modeling, which can be constrained by theoretical insight and numerical simulation. In parallel, we must optimize strategies for extracting accessible signals from that very weakly interacting source.
While the existence of axions as fundamental particles remains hypothetical, the equations governing how axions interact with electromagnetic fields also govern (with different parameters) how certain materials interact with electromagnetic fields. Thus those materials embody “emergent” axions. The equations have remarkable properties, which one can test in these materials, and possibly put to practical use.
Closely related to axions, mathematically, are anyons. Anyons are particle-like excitations that elude the familiar classification into bosons and fermions. Theoretical and numerical studies indicate that they are common emergent features of highly entangled states of matter in two dimensions. Recent work suggests the existence of states of matter, both natural and engineered, in which anyon dynamics is both important and experimentally accessible. Since the equations for anyons and axions are remarkably similar, and both have common, deep roots in symmetry and topology, it will be fruitful to consider them together.
Summary
Axions are hypothetical particles whose existence would solve two major problems: the strong P, T problem (a major blemish on the standard model); and the dark matter problem. It is a most important goal to either observe or rule out the existence of a cosmic axion background. It appears that decisive observations may be possible, but only after orchestrating insight from specialities ranging from quantum field theory and astrophysical modeling to ultra-low noise quantum measurement theory. Detailed predictions for the magnitude and structure of the cosmic axion background depend on cosmological and astrophysical modeling, which can be constrained by theoretical insight and numerical simulation. In parallel, we must optimize strategies for extracting accessible signals from that very weakly interacting source.
While the existence of axions as fundamental particles remains hypothetical, the equations governing how axions interact with electromagnetic fields also govern (with different parameters) how certain materials interact with electromagnetic fields. Thus those materials embody “emergent” axions. The equations have remarkable properties, which one can test in these materials, and possibly put to practical use.
Closely related to axions, mathematically, are anyons. Anyons are particle-like excitations that elude the familiar classification into bosons and fermions. Theoretical and numerical studies indicate that they are common emergent features of highly entangled states of matter in two dimensions. Recent work suggests the existence of states of matter, both natural and engineered, in which anyon dynamics is both important and experimentally accessible. Since the equations for anyons and axions are remarkably similar, and both have common, deep roots in symmetry and topology, it will be fruitful to consider them together.
Max ERC Funding
2 324 391 €
Duration
Start date: 2017-09-01, End date: 2022-08-31
Project acronym BATESON
Project Dissecting genotype-phenotype relationships using high-throughput genomics and carefully selected study populations
Researcher (PI) Leif Andersson
Host Institution (HI) UPPSALA UNIVERSITET
Country Sweden
Call Details Advanced Grant (AdG), LS2, ERC-2011-ADG_20110310
Summary A major aim in genome research is to reveal how genetic variation affects phenotypic variation. Here I propose to use high-throughput genomics (whole genome sequencing, transcriptome and epigenome analysis) to screen carefully selected study populations where the chances are particularly favourable to obtain novel insight into genotype-phenotype relationships. The ambition is to take discoveries all the way from phenotypic characterization to the identification of the genes and the actual genetic variant causing a phenotypic effect and to understanding the underlying functional mechanisms. The program will involve a fish (the Atlantic herring), a bird (the domestic chicken) and a mammal (the European rabbit). The Atlantic herring will be studied because it provides unique opportunities to study the genetics of adaptation in a natural population and because of the possibilities to revolutionize the fishery management of this economically important marine fish. We will generate a draft assembly of the herring genome and then perform whole genome resequencing of different populations to reveal the population structure and the loci underlying genetic adaptation. The European rabbit is an excellent model for studying the genetics of speciation due to the presence of two distinct subspecies on the Iberian Peninsula. The domestication of the rabbit is also particularly interesting because it is a recent event (about 1500 years ago) and it is well established that domestication happened from the wild rabbit population in southern France. Finally, the domestic chicken provides excellent opportunities for in depth functional studies since it is both a domestic animal harbouring a rich genetic diversity and an experimental organism.
(BATESON is the acronym for this proposal because Bateson (1902) pioneered the study of genotype-phenotype relationships in animals and used the chicken for this work.)
Summary
A major aim in genome research is to reveal how genetic variation affects phenotypic variation. Here I propose to use high-throughput genomics (whole genome sequencing, transcriptome and epigenome analysis) to screen carefully selected study populations where the chances are particularly favourable to obtain novel insight into genotype-phenotype relationships. The ambition is to take discoveries all the way from phenotypic characterization to the identification of the genes and the actual genetic variant causing a phenotypic effect and to understanding the underlying functional mechanisms. The program will involve a fish (the Atlantic herring), a bird (the domestic chicken) and a mammal (the European rabbit). The Atlantic herring will be studied because it provides unique opportunities to study the genetics of adaptation in a natural population and because of the possibilities to revolutionize the fishery management of this economically important marine fish. We will generate a draft assembly of the herring genome and then perform whole genome resequencing of different populations to reveal the population structure and the loci underlying genetic adaptation. The European rabbit is an excellent model for studying the genetics of speciation due to the presence of two distinct subspecies on the Iberian Peninsula. The domestication of the rabbit is also particularly interesting because it is a recent event (about 1500 years ago) and it is well established that domestication happened from the wild rabbit population in southern France. Finally, the domestic chicken provides excellent opportunities for in depth functional studies since it is both a domestic animal harbouring a rich genetic diversity and an experimental organism.
(BATESON is the acronym for this proposal because Bateson (1902) pioneered the study of genotype-phenotype relationships in animals and used the chicken for this work.)
Max ERC Funding
2 300 000 €
Duration
Start date: 2012-05-01, End date: 2017-04-30
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 BIOFINDER
Project New biomarkers for Alzheimer’s & Parkinson’s diseases - key tools for early diagnosis and drug development
Researcher (PI) Oskar Hansson
Host Institution (HI) MAX IV Laboratory, Lund University
Country Sweden
Call Details Starting Grant (StG), LS7, ERC-2012-StG_20111109
Summary Alzheimer’s disease (AD) and Parkinson’s disease (PD) are common in elderly and the prevalence of these is increasing. AD and PD have distinct pathogenesis, which precede the overt clinical symptoms by 10-15 years, opening a window for early diagnosis and treatment. New disease-modifying therapies are likely to be most efficient if initiated before the patients exhibit overt symptoms, making biomarkers for early diagnosis crucial for future clinical trials. Validated biomarkers would speed up initiation of treatment, avoid unnecessary investigations, and reduce patient insecurity.
AIMS: (1) identify and validate accurate and cost-effective blood-based biomarkers for early identification of those at high risk to develop AD and PD, (2) develop algorithms using advanced imaging and cerebrospinal fluid biomarkers for earlier more accurate diagnoses, and (3) better understand the underlying pathology and early progression of AD and PD, aiming at finding new relevant drug targets.
We will assess well-characterized and clinically relevant populations of patients and healthy elderly. We will use population- and clinic-based cohorts and follow them prospectively for 4 year. Participants will undergo neurocognitive evaluation, provide blood and cerebrospinal fluid, and have brain imaging using advanced MRI protocols and a newly developed PET-tracer visualizing brain amyloid. Sample will be analyzed with quantitative mass spectrometry and high sensitivity immunoassays.
New biomarkers and brain imaging techniques will aid early diagnosis and facilitate the development of disease-modifying therapies, since treatment can start earlier in the disease process. New methods to quantify relevant drug targets, such as oligomers of β-amyloid and α-synuclein, will be vital when selecting drug candidates for large-scale clinical trials. By improving both diagnosis and therapies the social and economic burden of dementia might be reduced by expanding the period of healthy and active aging
Summary
Alzheimer’s disease (AD) and Parkinson’s disease (PD) are common in elderly and the prevalence of these is increasing. AD and PD have distinct pathogenesis, which precede the overt clinical symptoms by 10-15 years, opening a window for early diagnosis and treatment. New disease-modifying therapies are likely to be most efficient if initiated before the patients exhibit overt symptoms, making biomarkers for early diagnosis crucial for future clinical trials. Validated biomarkers would speed up initiation of treatment, avoid unnecessary investigations, and reduce patient insecurity.
AIMS: (1) identify and validate accurate and cost-effective blood-based biomarkers for early identification of those at high risk to develop AD and PD, (2) develop algorithms using advanced imaging and cerebrospinal fluid biomarkers for earlier more accurate diagnoses, and (3) better understand the underlying pathology and early progression of AD and PD, aiming at finding new relevant drug targets.
We will assess well-characterized and clinically relevant populations of patients and healthy elderly. We will use population- and clinic-based cohorts and follow them prospectively for 4 year. Participants will undergo neurocognitive evaluation, provide blood and cerebrospinal fluid, and have brain imaging using advanced MRI protocols and a newly developed PET-tracer visualizing brain amyloid. Sample will be analyzed with quantitative mass spectrometry and high sensitivity immunoassays.
New biomarkers and brain imaging techniques will aid early diagnosis and facilitate the development of disease-modifying therapies, since treatment can start earlier in the disease process. New methods to quantify relevant drug targets, such as oligomers of β-amyloid and α-synuclein, will be vital when selecting drug candidates for large-scale clinical trials. By improving both diagnosis and therapies the social and economic burden of dementia might be reduced by expanding the period of healthy and active aging
Max ERC Funding
1 500 000 €
Duration
Start date: 2013-06-01, End date: 2018-05-31
