Project acronym A-BINGOS
Project Accreting binary populations in Nearby Galaxies: Observations and Simulations
Researcher (PI) Andreas Zezas
Host Institution (HI) IDRYMA TECHNOLOGIAS KAI EREVNAS
Call Details Consolidator Grant (CoG), PE9, ERC-2013-CoG
Summary "High-energy observations of our Galaxy offer a good, albeit not complete, picture of the X-ray source populations, in particular the accreting binary sources. Recent ability to study accreting binaries in nearby galaxies has shown that we would be short-sighted if we restricted ourselves to our Galaxy or to a few nearby ones. I propose an ambitious project that involves a comprehensive study of all the galaxies within 10 Mpc for which we can study in detail their X-ray sources and stellar populations. The study will combine data from a unique suite of observatories (Chandra, XMM-Newton, HST, Spitzer) with state-of-the-art theoretical modelling of binary systems. I propose a novel approach that links the accreting binary populations to their parent stellar populations and surpasses any current studies of X-ray binary populations, both in scale and in scope, by: (a) combining methods and results from several different areas of astrophysics (compact objects, binary systems, stellar populations, galaxy evolution); (b) using data from almost the whole electromagnetic spectrum (infrared to X-ray bands); (c) identifying and studying the different sub-populations of accreting binaries; and (d) performing direct comparison between observations and theoretical predictions, over a broad parameter space. The project: (a) will answer the long-standing question of the formation efficiency of accreting binaries in different environments; and (b) will constrain their evolutionary paths. As by-products the project will provide eagerly awaited input to the fields of gravitational-wave sources, γ-ray bursts, and X-ray emitting galaxies at cosmological distances and it will produce a heritage multi-wavelength dataset and library of models for future studies of galaxies and accreting binaries."
Summary
"High-energy observations of our Galaxy offer a good, albeit not complete, picture of the X-ray source populations, in particular the accreting binary sources. Recent ability to study accreting binaries in nearby galaxies has shown that we would be short-sighted if we restricted ourselves to our Galaxy or to a few nearby ones. I propose an ambitious project that involves a comprehensive study of all the galaxies within 10 Mpc for which we can study in detail their X-ray sources and stellar populations. The study will combine data from a unique suite of observatories (Chandra, XMM-Newton, HST, Spitzer) with state-of-the-art theoretical modelling of binary systems. I propose a novel approach that links the accreting binary populations to their parent stellar populations and surpasses any current studies of X-ray binary populations, both in scale and in scope, by: (a) combining methods and results from several different areas of astrophysics (compact objects, binary systems, stellar populations, galaxy evolution); (b) using data from almost the whole electromagnetic spectrum (infrared to X-ray bands); (c) identifying and studying the different sub-populations of accreting binaries; and (d) performing direct comparison between observations and theoretical predictions, over a broad parameter space. The project: (a) will answer the long-standing question of the formation efficiency of accreting binaries in different environments; and (b) will constrain their evolutionary paths. As by-products the project will provide eagerly awaited input to the fields of gravitational-wave sources, γ-ray bursts, and X-ray emitting galaxies at cosmological distances and it will produce a heritage multi-wavelength dataset and library of models for future studies of galaxies and accreting binaries."
Max ERC Funding
1 242 000 €
Duration
Start date: 2014-04-01, End date: 2019-03-31
Project acronym AgeingStemCellFate
Project The Role of Ectopic Adipocyte Progenitors in Age-related Stem Cell Dysfunction, Systemic Inflammation, and Metabolic Disease
Researcher (PI) Tim Julius Schulz
Host Institution (HI) DEUTSCHES INSTITUT FUER ERNAEHRUNGSFORSCHUNG POTSDAM REHBRUECKE
Call Details Starting Grant (StG), LS4, ERC-2012-StG_20111109
Summary Ageing is accompanied by ectopic white adipose tissue depositions in skeletal muscle and other anatomical locations, such as brown adipose tissue and the bone marrow. Ectopic fat accrual contributes to organ dysfunction, systemic insulin resistance, and other perturbations that have been implicated in metabolic diseases.
This research proposal aims to identify the regulatory cues that control the development of ectopic progenitor cells that give rise to this type of fat. It is hypothesized that an age-related dysfunction of the stem cell niche leads to an imbalance between (1) tissue-specific stem cells and (2) fibroblast-like, primarily adipogenic progenitors that reside within many tissues. Novel methodologies that assess stem/progenitor cell characteristics on the single cell level will be combined with animal models of lineage tracing to determine the developmental origin of these adipogenic progenitors and processes that regulate their function.
Notch signalling is a key signalling pathway that relies on direct physical interaction to control stem cell fate. It is proposed that impaired Notch activity contributes to the phenotypical shift of precursor cell distribution in aged tissues.
Lastly, the role of the stem cell niche in ectopic adipocyte progenitor formation will be analyzed. External signals originating from the surrounding niche cells regulate the developmental fate of stem cells. Secreted factors and their role in the formation of ectopic adipocyte precursors during senescence will be identified using a combination of biochemical and systems biology approaches.
Accomplishment of these studies will help to understand the basic processes of stem cell ageing and identify mechanisms of age-related functional decline in tissue regeneration. By targeting the population of tissue-resident adipogenic progenitor cells, therapeutic strategies could be developed to counteract metabolic complications associated with the ageing process.
Summary
Ageing is accompanied by ectopic white adipose tissue depositions in skeletal muscle and other anatomical locations, such as brown adipose tissue and the bone marrow. Ectopic fat accrual contributes to organ dysfunction, systemic insulin resistance, and other perturbations that have been implicated in metabolic diseases.
This research proposal aims to identify the regulatory cues that control the development of ectopic progenitor cells that give rise to this type of fat. It is hypothesized that an age-related dysfunction of the stem cell niche leads to an imbalance between (1) tissue-specific stem cells and (2) fibroblast-like, primarily adipogenic progenitors that reside within many tissues. Novel methodologies that assess stem/progenitor cell characteristics on the single cell level will be combined with animal models of lineage tracing to determine the developmental origin of these adipogenic progenitors and processes that regulate their function.
Notch signalling is a key signalling pathway that relies on direct physical interaction to control stem cell fate. It is proposed that impaired Notch activity contributes to the phenotypical shift of precursor cell distribution in aged tissues.
Lastly, the role of the stem cell niche in ectopic adipocyte progenitor formation will be analyzed. External signals originating from the surrounding niche cells regulate the developmental fate of stem cells. Secreted factors and their role in the formation of ectopic adipocyte precursors during senescence will be identified using a combination of biochemical and systems biology approaches.
Accomplishment of these studies will help to understand the basic processes of stem cell ageing and identify mechanisms of age-related functional decline in tissue regeneration. By targeting the population of tissue-resident adipogenic progenitor cells, therapeutic strategies could be developed to counteract metabolic complications associated with the ageing process.
Max ERC Funding
1 496 444 €
Duration
Start date: 2013-03-01, End date: 2018-02-28
Project acronym Angiolnc
Project Endothelial long non-coding RNAs
Researcher (PI) Stefanie Dimmeler
Host Institution (HI) JOHANN WOLFGANG GOETHE-UNIVERSITATFRANKFURT AM MAIN
Call Details Advanced Grant (AdG), LS4, ERC-2014-ADG
Summary Endothelial cells comprise the inner cellular cover of the vasculature, which delivers metabolites and oxygen to the tissue. Dysfunction of endothelial cells as it occurs during aging or metabolic syndromes can result in atherosclerosis, which can lead to myocardial infarction or stroke, whereas pathological angiogenesis contributes to tumor growth and diabetic retinopathy. Thus, endothelial cells play central roles in pathophysiological processes of many diseases including cardiovascular diseases and cancer. Many studies explored the regulation of endothelial cell functions by growth factors, but the impact of epigenetic mechanisms and particularly the role of novel non-coding RNAs is largely unknown. More than 70 % of the human genome encodes for non-coding RNAs (ncRNAs) and increasing evidence suggests that a significant portion of these ncRNAs are functionally active as RNA molecules. Angiolnc aims to explore the function of long ncRNAs (lncRNAs) and particular circular RNAs (circRNAs) in the endothelium. LncRNAs comprise a heterogenic class of RNAs with a length of > 200 nucleotides and circRNAs are generated by back splicing.
Angiolnc is based on the discovery of novel endothelial hypoxia-regulated lncRNAs and circRNAs by next generation sequencing. To begin to understand the potential functions of lncRNAs in the endothelium, we will study two lncRNAs, named Angiolnc1 und Angiolnc2, as prototypical examples of endothelial cell-enriched lncRNAs that are regulated by oxygen levels. We will further dissect the epigenetic mechanisms, by which these lncRNAs regulate endothelial cell function. In the second part of the application, we will determine the regulation and function of circRNAs, which may act as molecular sponges in the cytoplasm. Finally, we will study the function of identified lncRNAs and circRNAs in mouse models and measure their expression in human specimens in order to determine their role as therapeutic targets or diagnostic tools.
Summary
Endothelial cells comprise the inner cellular cover of the vasculature, which delivers metabolites and oxygen to the tissue. Dysfunction of endothelial cells as it occurs during aging or metabolic syndromes can result in atherosclerosis, which can lead to myocardial infarction or stroke, whereas pathological angiogenesis contributes to tumor growth and diabetic retinopathy. Thus, endothelial cells play central roles in pathophysiological processes of many diseases including cardiovascular diseases and cancer. Many studies explored the regulation of endothelial cell functions by growth factors, but the impact of epigenetic mechanisms and particularly the role of novel non-coding RNAs is largely unknown. More than 70 % of the human genome encodes for non-coding RNAs (ncRNAs) and increasing evidence suggests that a significant portion of these ncRNAs are functionally active as RNA molecules. Angiolnc aims to explore the function of long ncRNAs (lncRNAs) and particular circular RNAs (circRNAs) in the endothelium. LncRNAs comprise a heterogenic class of RNAs with a length of > 200 nucleotides and circRNAs are generated by back splicing.
Angiolnc is based on the discovery of novel endothelial hypoxia-regulated lncRNAs and circRNAs by next generation sequencing. To begin to understand the potential functions of lncRNAs in the endothelium, we will study two lncRNAs, named Angiolnc1 und Angiolnc2, as prototypical examples of endothelial cell-enriched lncRNAs that are regulated by oxygen levels. We will further dissect the epigenetic mechanisms, by which these lncRNAs regulate endothelial cell function. In the second part of the application, we will determine the regulation and function of circRNAs, which may act as molecular sponges in the cytoplasm. Finally, we will study the function of identified lncRNAs and circRNAs in mouse models and measure their expression in human specimens in order to determine their role as therapeutic targets or diagnostic tools.
Max ERC Funding
2 497 398 €
Duration
Start date: 2016-01-01, End date: 2020-12-31
Project acronym AngioMature
Project Mechanisms of vascular maturation and quiescence during development, homeostasis and aging
Researcher (PI) Hellmut AUGUSTIN
Host Institution (HI) RUPRECHT-KARLS-UNIVERSITAET HEIDELBERG
Call Details Advanced Grant (AdG), LS4, ERC-2017-ADG
Summary Angiogenesis research has focused on the sprouting of new capillaries. The mechanisms of vessel maturation are much less well understood. Yet, the maintenance of a mature, quiescent, and organotypically-differentiated layer of endothelial cells (ECs) lining the inside of all blood vessels is vital for human health. The goal of ANGIOMATURE is to identify, validate, and implement novel mechanisms of vascular maturation and organotypic EC differentiation that are active during development, maintenance of vascular stability in adults, and undergo changes in aging. We recently identified previously unrecognized gene expression signatures of vascular maturation in a genome-wide screen of ECs isolated from newborn and adult mice. Epigenetic mechanisms were identified that control the EC transcriptome through gain and loss of DNA methylation as well as EC differentiation and signaling specification. These findings pave the way for groundbreaking novel opportunities to study vascular maturation. By characterizing functionally diverse types of blood vessels, including continuous ECs in lung and brain and sinusoidal ECs in liver and bone marrow, the ANGIOMATURE project will (1) determine up to single cell resolution the transcriptional and epigenetic program(s) of vascular maturation and organotypic differentiation during adolescence, (2) analyze the functional consequences of such program(s) in differentiated ECs and their adaptation to challenge, and (3) study changes of maturation and differentiation program(s) and vascular responses during aging. We will towards this end employ an interdisciplinary matrix of approaches involving omics, systems biology, conditional gene targeting, organoid cell culture, and experimental pathology to create a high-resolution structural and functional organotypic angioarchitectural map. The project will thereby yield transformative mechanistic insights into vital biological processes that are most important for human health and healthy aging.
Summary
Angiogenesis research has focused on the sprouting of new capillaries. The mechanisms of vessel maturation are much less well understood. Yet, the maintenance of a mature, quiescent, and organotypically-differentiated layer of endothelial cells (ECs) lining the inside of all blood vessels is vital for human health. The goal of ANGIOMATURE is to identify, validate, and implement novel mechanisms of vascular maturation and organotypic EC differentiation that are active during development, maintenance of vascular stability in adults, and undergo changes in aging. We recently identified previously unrecognized gene expression signatures of vascular maturation in a genome-wide screen of ECs isolated from newborn and adult mice. Epigenetic mechanisms were identified that control the EC transcriptome through gain and loss of DNA methylation as well as EC differentiation and signaling specification. These findings pave the way for groundbreaking novel opportunities to study vascular maturation. By characterizing functionally diverse types of blood vessels, including continuous ECs in lung and brain and sinusoidal ECs in liver and bone marrow, the ANGIOMATURE project will (1) determine up to single cell resolution the transcriptional and epigenetic program(s) of vascular maturation and organotypic differentiation during adolescence, (2) analyze the functional consequences of such program(s) in differentiated ECs and their adaptation to challenge, and (3) study changes of maturation and differentiation program(s) and vascular responses during aging. We will towards this end employ an interdisciplinary matrix of approaches involving omics, systems biology, conditional gene targeting, organoid cell culture, and experimental pathology to create a high-resolution structural and functional organotypic angioarchitectural map. The project will thereby yield transformative mechanistic insights into vital biological processes that are most important for human health and healthy aging.
Max ERC Funding
2 338 918 €
Duration
Start date: 2018-08-01, End date: 2023-07-31
Project acronym ANGIOMET
Project Angiogenesis-metabolism crosstalk in vascular homeostasis and disease
Researcher (PI) Michael Potente
Host Institution (HI) MAX-PLANCK-GESELLSCHAFT ZUR FORDERUNG DER WISSENSCHAFTEN EV
Call Details Starting Grant (StG), LS4, ERC-2012-StG_20111109
Summary "Blood vessels pervade all tissues in the body to supply nutrients and oxygen. Aberrant vessel growth and function are hallmarks of cancer and cardiovascular diseases and they contribute to disease pathogenesis. Antiangiogenic therapeutics have reached the clinic, but limited efficacy and resistance raise unresolved challenges. The current limitations of angiogenic medicine call for a more integrated understanding of the angiogenic process that focuses not only on the instigators of vessel branching but also on mechanisms that sustain vessel growth. Recent insights into fundamental aspects of cell growth move metabolism into spotlight and establish how proliferating cells reprogram their metabolism to provide energy and building blocks for cell replication. During angiogenesis, endothelial cells (ECs) also convert between growth states: although mostly quiescent in adult tissues, ECs divide and migrate rapidly upon angiogenic stimulation. To allow growth of new vessel branches, ECs therefore need to adjust their metabolism to increase energy production and biosynthetic activity. However, the molecular mechanisms that coordinate EC metabolism with angiogenic signalling are not known to date. In this proposal, we put forth the hypothesis that metabolic regulation is a key component of the endothelial angiogenic machinery that is required to sustain vessel growth. Thus, this proposal aims (I) to define transcriptional circuits that link EC growth with metabolism, (II) to explore the regulation of these transcriptional networks by lysine acetylation, a nutrient-regulated protein modification with key functions in metabolism, and (III) to assess the role of sirtuin deacetylases for sensing endothelial energetics during vascular growth. Understanding the principles of angiogenesis-metabolism crosstalk will not only yield novel insights into the basic mechanisms of vessel formation but will also provide unprecedented opportunities for future drug development."
Summary
"Blood vessels pervade all tissues in the body to supply nutrients and oxygen. Aberrant vessel growth and function are hallmarks of cancer and cardiovascular diseases and they contribute to disease pathogenesis. Antiangiogenic therapeutics have reached the clinic, but limited efficacy and resistance raise unresolved challenges. The current limitations of angiogenic medicine call for a more integrated understanding of the angiogenic process that focuses not only on the instigators of vessel branching but also on mechanisms that sustain vessel growth. Recent insights into fundamental aspects of cell growth move metabolism into spotlight and establish how proliferating cells reprogram their metabolism to provide energy and building blocks for cell replication. During angiogenesis, endothelial cells (ECs) also convert between growth states: although mostly quiescent in adult tissues, ECs divide and migrate rapidly upon angiogenic stimulation. To allow growth of new vessel branches, ECs therefore need to adjust their metabolism to increase energy production and biosynthetic activity. However, the molecular mechanisms that coordinate EC metabolism with angiogenic signalling are not known to date. In this proposal, we put forth the hypothesis that metabolic regulation is a key component of the endothelial angiogenic machinery that is required to sustain vessel growth. Thus, this proposal aims (I) to define transcriptional circuits that link EC growth with metabolism, (II) to explore the regulation of these transcriptional networks by lysine acetylation, a nutrient-regulated protein modification with key functions in metabolism, and (III) to assess the role of sirtuin deacetylases for sensing endothelial energetics during vascular growth. Understanding the principles of angiogenesis-metabolism crosstalk will not only yield novel insights into the basic mechanisms of vessel formation but will also provide unprecedented opportunities for future drug development."
Max ERC Funding
1 487 920 €
Duration
Start date: 2012-09-01, End date: 2017-08-31
Project acronym ANGIOMIRS
Project microRNAs in vascular homeostasis
Researcher (PI) Stefanie Dimmeler
Host Institution (HI) JOHANN WOLFGANG GOETHE-UNIVERSITATFRANKFURT AM MAIN
Call Details Advanced Grant (AdG), LS4, ERC-2008-AdG
Summary Despite improved therapy, cardiovascular diseases remain the most prevalent diseases in the European Union and the incidence is rising due to increased obesity and ageing. The fine-tuned regulation of vascular functions is essential not only for preventing atherosclerotic diseases, but also after tissue injury, where the coordinated growth and maturation of new blood vessels provides oxygen and nutrient supply. On the other hand, excessive vessel growth or the generation of immature, leaky vessels contributes to pathological angiogenesis. Thus, the regulation of the complex processes governing vessel growth and maturation has broad impacts for several diseases ranging from tumor angiogenesis, diabetic retinopathy, to ischemic cardiovascular diseases. MicroRNAs (miRs) are small noncoding RNAs, which play a crucial role in embryonic development and tissue homeostasis. However, only limited information is available regarding the role of miRs in the vasculature. MiRs regulate gene expression by binding to the target mRNA leading either to degradation or to translational repression. Because miRs control patterns of target genes, miRs represent an attractive and promising therapeutic target to interfere with complex processes such as neovascularization and repair of ischemic tissues. Therefore, the present application aims to identify miRs in the vasculature, which regulate vessel growth and vessel remodelling and may, thus, serve as therapeutic targets in ischemic diseases. Since ageing critically impairs endothelial function, neovascularization and vascular repair, we will specifically identify miRs, which are dysregulated during ageing in endothelial cells and pro-angiogenic progenitor cells, in order to develop novel strategies to rescue age-induced impairment of neovascularization. Beyond the specific scope of the present application, the principle findings may have impact for other diseases, where deregulated vessel growth causes or accelerates disease states.
Summary
Despite improved therapy, cardiovascular diseases remain the most prevalent diseases in the European Union and the incidence is rising due to increased obesity and ageing. The fine-tuned regulation of vascular functions is essential not only for preventing atherosclerotic diseases, but also after tissue injury, where the coordinated growth and maturation of new blood vessels provides oxygen and nutrient supply. On the other hand, excessive vessel growth or the generation of immature, leaky vessels contributes to pathological angiogenesis. Thus, the regulation of the complex processes governing vessel growth and maturation has broad impacts for several diseases ranging from tumor angiogenesis, diabetic retinopathy, to ischemic cardiovascular diseases. MicroRNAs (miRs) are small noncoding RNAs, which play a crucial role in embryonic development and tissue homeostasis. However, only limited information is available regarding the role of miRs in the vasculature. MiRs regulate gene expression by binding to the target mRNA leading either to degradation or to translational repression. Because miRs control patterns of target genes, miRs represent an attractive and promising therapeutic target to interfere with complex processes such as neovascularization and repair of ischemic tissues. Therefore, the present application aims to identify miRs in the vasculature, which regulate vessel growth and vessel remodelling and may, thus, serve as therapeutic targets in ischemic diseases. Since ageing critically impairs endothelial function, neovascularization and vascular repair, we will specifically identify miRs, which are dysregulated during ageing in endothelial cells and pro-angiogenic progenitor cells, in order to develop novel strategies to rescue age-induced impairment of neovascularization. Beyond the specific scope of the present application, the principle findings may have impact for other diseases, where deregulated vessel growth causes or accelerates disease states.
Max ERC Funding
2 375 394 €
Duration
Start date: 2009-03-01, End date: 2014-02-28
Project acronym ApoptoMDS
Project Hematopoietic stem cell Apoptosis in bone marrow failure and MyeloDysplastic Syndromes: Friend or foe?
Researcher (PI) Miriam Erlacher
Host Institution (HI) UNIVERSITAETSKLINIKUM FREIBURG
Call Details Starting Grant (StG), LS4, ERC-2014-STG
Summary Deregulated apoptotic signaling in hematopoietic stem and progenitor cells (HSPCs) strongly contributes to the pathogenesis and phenotypes of congenital bone marrow failure and myelodysplastic syndromes (MDS) and their progression to acute myeloid leukemia (AML). HSPCs are highly susceptible to apoptosis during bone marrow failure and early MDS, but AML evolution selects for apoptosis resistance. Little is known about the main apoptotic players and their regulators. ApoptoMDS will investigate the impact of apoptotic deregulation for pathogenesis, correlate apoptotic susceptibility with the kinetics of disease progression and characterize the mechanism by which apoptotic susceptibility turns into resistance. ApoptoMDS will draw on a large collection of patient-derived samples and genetically engineered mouse models to investigate disease progression in serially transplanted and xenotransplanted mice. How activated DNA damage checkpoint signaling contributes to syndrome phenotypes and HSPC hypersusceptibility to apoptosis will be assessed. Checkpoint activation confers a competitive disadvantage, and HSPCs undergoing malignant transformation are under high selective pressure to inactivate it. Checkpoint abrogation mitigates the hematological phenotype, but increases the risk of AML evolution. ApoptoMDS aims to analyze if inhibiting apoptosis in HSPCs from bone marrow failure and early-stage MDS can overcome the dilemma of checkpoint abrogation. Whether inhibiting apoptosis is sufficient to improve HSPC function will be tested on several levels and validated in patient-derived samples. How inhibiting apoptosis in the presence of functional checkpoint signaling influences malignant transformation kinetics will be assessed. If, as hypothesized, inhibiting apoptosis both mitigates hematological symptoms and delays AML evolution, ApoptoMDS will pave the way for novel therapeutic approaches to expand the less severe symptomatic period for patients with these syndromes.
Summary
Deregulated apoptotic signaling in hematopoietic stem and progenitor cells (HSPCs) strongly contributes to the pathogenesis and phenotypes of congenital bone marrow failure and myelodysplastic syndromes (MDS) and their progression to acute myeloid leukemia (AML). HSPCs are highly susceptible to apoptosis during bone marrow failure and early MDS, but AML evolution selects for apoptosis resistance. Little is known about the main apoptotic players and their regulators. ApoptoMDS will investigate the impact of apoptotic deregulation for pathogenesis, correlate apoptotic susceptibility with the kinetics of disease progression and characterize the mechanism by which apoptotic susceptibility turns into resistance. ApoptoMDS will draw on a large collection of patient-derived samples and genetically engineered mouse models to investigate disease progression in serially transplanted and xenotransplanted mice. How activated DNA damage checkpoint signaling contributes to syndrome phenotypes and HSPC hypersusceptibility to apoptosis will be assessed. Checkpoint activation confers a competitive disadvantage, and HSPCs undergoing malignant transformation are under high selective pressure to inactivate it. Checkpoint abrogation mitigates the hematological phenotype, but increases the risk of AML evolution. ApoptoMDS aims to analyze if inhibiting apoptosis in HSPCs from bone marrow failure and early-stage MDS can overcome the dilemma of checkpoint abrogation. Whether inhibiting apoptosis is sufficient to improve HSPC function will be tested on several levels and validated in patient-derived samples. How inhibiting apoptosis in the presence of functional checkpoint signaling influences malignant transformation kinetics will be assessed. If, as hypothesized, inhibiting apoptosis both mitigates hematological symptoms and delays AML evolution, ApoptoMDS will pave the way for novel therapeutic approaches to expand the less severe symptomatic period for patients with these syndromes.
Max ERC Funding
1 372 525 €
Duration
Start date: 2015-06-01, End date: 2020-05-31
Project acronym ASSESS
Project Episodic Mass Loss in the Most Massive Stars: Key to Understanding the Explosive Early Universe
Researcher (PI) Alceste BONANOS
Host Institution (HI) NATIONAL OBSERVATORY OF ATHENS
Call Details Consolidator Grant (CoG), PE9, ERC-2017-COG
Summary Massive stars dominate their surroundings during their short lifetimes, while their explosive deaths impact the chemical evolution and spatial cohesion of their hosts. After birth, their evolution is largely dictated by their ability to remove layers of hydrogen from their envelopes. Multiple lines of evidence are pointing to violent, episodic mass-loss events being responsible for removing a large part of the massive stellar envelope, especially in low-metallicity galaxies. Episodic mass loss, however, is not understood theoretically, neither accounted for in state-of-the-art models of stellar evolution, which has far-reaching consequences for many areas of astronomy. We aim to determine whether episodic mass loss is a dominant process in the evolution of the most massive stars by conducting the first extensive, multi-wavelength survey of evolved massive stars in the nearby Universe. The project hinges on the fact that mass-losing stars form dust and are bright in the mid-infrared. We plan to (i) derive physical parameters of a large sample of dusty, evolved targets and estimate the amount of ejected mass, (ii) constrain evolutionary models, (iii) quantify the duration and frequency of episodic mass loss as a function of metallicity. The approach involves applying machine-learning algorithms to existing multi-band and time-series photometry of luminous sources in ~25 nearby galaxies. Dusty, luminous evolved massive stars will thus be automatically classified and follow-up spectroscopy will be obtained for selected targets. Atmospheric and SED modeling will yield parameters and estimates of time-dependent mass loss for ~1000 luminous stars. The emerging trend for the ubiquity of episodic mass loss, if confirmed, will be key to understanding the explosive early Universe and will have profound consequences for low-metallicity stars, reionization, and the chemical evolution of galaxies.
Summary
Massive stars dominate their surroundings during their short lifetimes, while their explosive deaths impact the chemical evolution and spatial cohesion of their hosts. After birth, their evolution is largely dictated by their ability to remove layers of hydrogen from their envelopes. Multiple lines of evidence are pointing to violent, episodic mass-loss events being responsible for removing a large part of the massive stellar envelope, especially in low-metallicity galaxies. Episodic mass loss, however, is not understood theoretically, neither accounted for in state-of-the-art models of stellar evolution, which has far-reaching consequences for many areas of astronomy. We aim to determine whether episodic mass loss is a dominant process in the evolution of the most massive stars by conducting the first extensive, multi-wavelength survey of evolved massive stars in the nearby Universe. The project hinges on the fact that mass-losing stars form dust and are bright in the mid-infrared. We plan to (i) derive physical parameters of a large sample of dusty, evolved targets and estimate the amount of ejected mass, (ii) constrain evolutionary models, (iii) quantify the duration and frequency of episodic mass loss as a function of metallicity. The approach involves applying machine-learning algorithms to existing multi-band and time-series photometry of luminous sources in ~25 nearby galaxies. Dusty, luminous evolved massive stars will thus be automatically classified and follow-up spectroscopy will be obtained for selected targets. Atmospheric and SED modeling will yield parameters and estimates of time-dependent mass loss for ~1000 luminous stars. The emerging trend for the ubiquity of episodic mass loss, if confirmed, will be key to understanding the explosive early Universe and will have profound consequences for low-metallicity stars, reionization, and the chemical evolution of galaxies.
Max ERC Funding
1 128 750 €
Duration
Start date: 2018-09-01, End date: 2023-08-31
Project acronym ASTROLAB
Project Cold Collisions and the Pathways Toward Life in Interstellar Space
Researcher (PI) Holger Kreckel
Host Institution (HI) MAX-PLANCK-GESELLSCHAFT ZUR FORDERUNG DER WISSENSCHAFTEN EV
Call Details Starting Grant (StG), PE9, ERC-2012-StG_20111012
Summary Modern telescopes like Herschel and ALMA open up a new window into molecular astrophysics to investigate a surprisingly rich chemistry that operates even at low densities and low temperatures. Observations with these instruments have the potential of unraveling key questions of astrobiology, like the accumulation of water and pre-biotic organic molecules on (exo)planets from asteroids and comets. Hand-in-hand with the heightened observational activities comes a strong demand for a thorough understanding of the molecular formation mechanisms. The vast majority of interstellar molecules are formed in ion-neutral reactions that remain efficient even at low temperatures. Unfortunately, the unusual nature of these processes under terrestrial conditions makes their laboratory study extremely difficult.
To address these issues, I propose to build a versatile merged beams setup for laboratory studies of ion-neutral collisions at the Cryogenic Storage Ring (CSR), the most ambitious of the next-generation storage devices under development worldwide. With this experimental setup, I will make use of a low-temperature and low-density environment that is ideal to simulate the conditions prevailing in interstellar space. The cryogenic surrounding, in combination with laser-generated ground state atom beams, will allow me to perform precise energy-resolved rate coefficient measurements for reactions between cold molecular ions (like, e.g., H2+, H3+, HCO+, CH2+, CH3+, etc.) and neutral atoms (H, D, C or O) in order to shed light on long-standing problems of astrochemistry and the formation of organic molecules in space.
With the large variability of the collision energy (corresponding to 40-40000 K), I will be able to provide data that are crucial for the interpretation of molecular observations in a variety of objects, ranging from cold molecular clouds to warm layers in protoplanetary disks.
Summary
Modern telescopes like Herschel and ALMA open up a new window into molecular astrophysics to investigate a surprisingly rich chemistry that operates even at low densities and low temperatures. Observations with these instruments have the potential of unraveling key questions of astrobiology, like the accumulation of water and pre-biotic organic molecules on (exo)planets from asteroids and comets. Hand-in-hand with the heightened observational activities comes a strong demand for a thorough understanding of the molecular formation mechanisms. The vast majority of interstellar molecules are formed in ion-neutral reactions that remain efficient even at low temperatures. Unfortunately, the unusual nature of these processes under terrestrial conditions makes their laboratory study extremely difficult.
To address these issues, I propose to build a versatile merged beams setup for laboratory studies of ion-neutral collisions at the Cryogenic Storage Ring (CSR), the most ambitious of the next-generation storage devices under development worldwide. With this experimental setup, I will make use of a low-temperature and low-density environment that is ideal to simulate the conditions prevailing in interstellar space. The cryogenic surrounding, in combination with laser-generated ground state atom beams, will allow me to perform precise energy-resolved rate coefficient measurements for reactions between cold molecular ions (like, e.g., H2+, H3+, HCO+, CH2+, CH3+, etc.) and neutral atoms (H, D, C or O) in order to shed light on long-standing problems of astrochemistry and the formation of organic molecules in space.
With the large variability of the collision energy (corresponding to 40-40000 K), I will be able to provide data that are crucial for the interpretation of molecular observations in a variety of objects, ranging from cold molecular clouds to warm layers in protoplanetary disks.
Max ERC Funding
1 486 800 €
Duration
Start date: 2012-09-01, End date: 2017-11-30
Project acronym ATHEROPROTECT
Project Structure-Function Analysis of the Chemokine Interactome for Therapeutic Targeting and Imaging in Atherosclerosis
Researcher (PI) Christian Weber
Host Institution (HI) LUDWIG-MAXIMILIANS-UNIVERSITAET MUENCHEN
Call Details Advanced Grant (AdG), LS4, ERC-2009-AdG
Summary Atherosclerosis is characterized by chronic inflammation of the arterial wall. Mononuclear cell recruitment is driven by chemokines that can be deposited e.g. by activated platelets on inflamed endothelium. Chemokines require oligomerization and immobilization for efficient function, and recent evidence supports the notion that heterodimer formation between chemokines constitutes a new regulatory principle amplifying specific chemokine activities while suppressing others. Although crucial to inflammatory disease, this has been difficult to prove in vivo, primarily as chemokine heterodimers exist in equilibrium with their homodimer counterparts. We introduce the paradigm that heteromerization of chemokines provides the combinatorial diversity for functional plasticity and fine-tuning, coining this interactome. Given the relevance of chemokine heteromers in vivo, we aim to exploit this in an anti-inflammatory approach to selectively target vascular disease. In a multidisciplinary project, we plan to generate covalently-linked heterodimers to establish their biological significance. Obligate heterodimers of CC and CXC chemokines will be designed using computer-assisted modeling, chemically synthesized and cross-linked, structurally assessed using NMR spectroscopy and crystallography, and subjected to functional characterization in vitro and reconstitution in vivo. Conversely, we will develop cyclic beta-sheet-based peptides binding chemokines to specifically disrupt heteromers and we will generate mice with conditional deletion or knock-in of chemokine mutants with defects in heteromerization or proteoglycan binding to be analyzed in models of atherosclerosis. Peptides will be used for molecular imaging and chemokine heteromers will be quantified in cardiovascular patients.
Summary
Atherosclerosis is characterized by chronic inflammation of the arterial wall. Mononuclear cell recruitment is driven by chemokines that can be deposited e.g. by activated platelets on inflamed endothelium. Chemokines require oligomerization and immobilization for efficient function, and recent evidence supports the notion that heterodimer formation between chemokines constitutes a new regulatory principle amplifying specific chemokine activities while suppressing others. Although crucial to inflammatory disease, this has been difficult to prove in vivo, primarily as chemokine heterodimers exist in equilibrium with their homodimer counterparts. We introduce the paradigm that heteromerization of chemokines provides the combinatorial diversity for functional plasticity and fine-tuning, coining this interactome. Given the relevance of chemokine heteromers in vivo, we aim to exploit this in an anti-inflammatory approach to selectively target vascular disease. In a multidisciplinary project, we plan to generate covalently-linked heterodimers to establish their biological significance. Obligate heterodimers of CC and CXC chemokines will be designed using computer-assisted modeling, chemically synthesized and cross-linked, structurally assessed using NMR spectroscopy and crystallography, and subjected to functional characterization in vitro and reconstitution in vivo. Conversely, we will develop cyclic beta-sheet-based peptides binding chemokines to specifically disrupt heteromers and we will generate mice with conditional deletion or knock-in of chemokine mutants with defects in heteromerization or proteoglycan binding to be analyzed in models of atherosclerosis. Peptides will be used for molecular imaging and chemokine heteromers will be quantified in cardiovascular patients.
Max ERC Funding
2 500 000 €
Duration
Start date: 2010-04-01, End date: 2016-03-31
