Project acronym EASY
Project Ejection Accretion Structures in YSOs (EASY)
Researcher (PI) Thomas RAY
Host Institution (HI) DUBLIN INSTITUTE FOR ADVANCED STUDIES
Call Details Advanced Grant (AdG), PE9, ERC-2016-ADG
Summary For a number of reasons, in particular their proximity and the abundant range of diagnostics to determine their characteristics, outflows from young stellar objects (YSOs) offer us the best opportunity of discovering how astrophysical jets are generated and the nature of the link between outflows and their accretion disks. Models predict that the jet is initially launched from within 0.1 to a few au of the star and focused on scales at most ten times larger. Thus, even for the nearest star formation region, we need high spatial resolution to image the “central engine” and test current models.
With these ideas in mind, and the availability of a whole new set of observational and computational resources, it is proposed to investigate the origin of YSO jets, and the jet/accretion zone link, using a number of highly novel approaches to test magneto-hydrodynamic (MHD) models including:
(a) Near-infrared interferometry to determine the spatial distribution and kinematics of the outflow as it is launched as a way of discriminating between competing models.
(b) A multi-epoch study of the strength and configuration of the magnetic field of the parent star to see whether model values and geometries agree with observations and the nature of its variability.
(c) Examining, through high spatial resolution radio observations, how the ionized component of these jets are collimated very close to the source and how shocks in the flow can give rise to low energy cosmic rays.
(d) Use the James Webb Space Telescope (JWST) and, in particular, the Mid-Infrared Instrument (MIRI) and Near-Infrared Spectrograph (NIRSpec) to investigate with high spatial resolution atomic jets from protostars that are still acquiring most of their mass. In addition, we will study how accretion is affected by metallicity by studying young solar-like stars in the low metallicity Magellanic Clouds.
In all cases the required observational campaigns have been approved.
Summary
For a number of reasons, in particular their proximity and the abundant range of diagnostics to determine their characteristics, outflows from young stellar objects (YSOs) offer us the best opportunity of discovering how astrophysical jets are generated and the nature of the link between outflows and their accretion disks. Models predict that the jet is initially launched from within 0.1 to a few au of the star and focused on scales at most ten times larger. Thus, even for the nearest star formation region, we need high spatial resolution to image the “central engine” and test current models.
With these ideas in mind, and the availability of a whole new set of observational and computational resources, it is proposed to investigate the origin of YSO jets, and the jet/accretion zone link, using a number of highly novel approaches to test magneto-hydrodynamic (MHD) models including:
(a) Near-infrared interferometry to determine the spatial distribution and kinematics of the outflow as it is launched as a way of discriminating between competing models.
(b) A multi-epoch study of the strength and configuration of the magnetic field of the parent star to see whether model values and geometries agree with observations and the nature of its variability.
(c) Examining, through high spatial resolution radio observations, how the ionized component of these jets are collimated very close to the source and how shocks in the flow can give rise to low energy cosmic rays.
(d) Use the James Webb Space Telescope (JWST) and, in particular, the Mid-Infrared Instrument (MIRI) and Near-Infrared Spectrograph (NIRSpec) to investigate with high spatial resolution atomic jets from protostars that are still acquiring most of their mass. In addition, we will study how accretion is affected by metallicity by studying young solar-like stars in the low metallicity Magellanic Clouds.
In all cases the required observational campaigns have been approved.
Max ERC Funding
1 853 090 €
Duration
Start date: 2017-10-01, End date: 2022-09-30
Project acronym Metabinnate
Project Metabolic crosstalk in the regulation of inflammation
Researcher (PI) Luke O'NEILL
Host Institution (HI) THE PROVOST, FELLOWS, FOUNDATION SCHOLARS & THE OTHER MEMBERS OF BOARD OF THE COLLEGE OF THE HOLY & UNDIVIDED TRINITY OF QUEEN ELIZABETH NEAR DUBLIN
Call Details Advanced Grant (AdG), LS6, ERC-2018-ADG
Summary The study of the molecular basis to the immune response has for decades concerned receptors and the signalling pathways they activate which lead to immune cell activation. Recently metabolic changes have also been shown to couple to immune effector responses. A shift in appreciation of the role of metabolites beyond energy metabolism and biosynthetic processes has emerged. We have been examining the role of three metabolites in macrophages. We have evidence that two of these, malonyl-CoA and 2-hydroxyglutarate (2-HG) are pro-inflammatory, whilst the third, itaconate, has profound anti-inflammatory effects. In many ways, they mirror cytokines, with malonyl-CoA and 2-HG being akin to pro-inflammatory cytokines, whilst itaconate resembles anti-inflammatory cytokines. The specificity and breadth of the role of these metabolites in macrophages will be mapped in this proposal. For malonyl-CoA we have evidence that it regulates GAPDH, IRG1/CAD (which synthesises itaconate) and the key cytokine IL-1beta. For 2-HG, we will examine the production and actions of its 2 enantiomers, D-2-HG and L-2-HG, focusing on their effect on HIF1alpha and epigenetic regulation. For itaconate we have evidence for a role in Type I interferon modulation, antigen presentation, inflammasome regulation and GAPDH and LDHA (which can produce 2-HG) activities. We also have evidence that OXGR1 is the receptor for itaconate. All of these aspects will be explored in detail. Critically we will also determine the relationship between these metabolites since we have evidence for cross-talk. Their dynamic regulation is likely to be a key aspect of how metabolic reprogramming controls macrophage function. Our studies point to a major shift in our understanding of how intracellular metabolic changes lead to inflammation. The overall aim is therefore to elucidate how metabolic reprogramming controls inflammatory macrophage activation, which may lead to new therapeutic targets for inflammatory diseases.
Summary
The study of the molecular basis to the immune response has for decades concerned receptors and the signalling pathways they activate which lead to immune cell activation. Recently metabolic changes have also been shown to couple to immune effector responses. A shift in appreciation of the role of metabolites beyond energy metabolism and biosynthetic processes has emerged. We have been examining the role of three metabolites in macrophages. We have evidence that two of these, malonyl-CoA and 2-hydroxyglutarate (2-HG) are pro-inflammatory, whilst the third, itaconate, has profound anti-inflammatory effects. In many ways, they mirror cytokines, with malonyl-CoA and 2-HG being akin to pro-inflammatory cytokines, whilst itaconate resembles anti-inflammatory cytokines. The specificity and breadth of the role of these metabolites in macrophages will be mapped in this proposal. For malonyl-CoA we have evidence that it regulates GAPDH, IRG1/CAD (which synthesises itaconate) and the key cytokine IL-1beta. For 2-HG, we will examine the production and actions of its 2 enantiomers, D-2-HG and L-2-HG, focusing on their effect on HIF1alpha and epigenetic regulation. For itaconate we have evidence for a role in Type I interferon modulation, antigen presentation, inflammasome regulation and GAPDH and LDHA (which can produce 2-HG) activities. We also have evidence that OXGR1 is the receptor for itaconate. All of these aspects will be explored in detail. Critically we will also determine the relationship between these metabolites since we have evidence for cross-talk. Their dynamic regulation is likely to be a key aspect of how metabolic reprogramming controls macrophage function. Our studies point to a major shift in our understanding of how intracellular metabolic changes lead to inflammation. The overall aim is therefore to elucidate how metabolic reprogramming controls inflammatory macrophage activation, which may lead to new therapeutic targets for inflammatory diseases.
Max ERC Funding
2 484 858 €
Duration
Start date: 2019-06-01, End date: 2024-05-31
Project acronym MICROINNATE
Project An exploration into the role of microRNAs in innate immune signaling
Researcher (PI) Luke O'neill
Host Institution (HI) THE PROVOST, FELLOWS, FOUNDATION SCHOLARS & THE OTHER MEMBERS OF BOARD OF THE COLLEGE OF THE HOLY & UNDIVIDED TRINITY OF QUEEN ELIZABETH NEAR DUBLIN
Call Details Advanced Grant (AdG), LS6, ERC-2010-AdG_20100317
Summary MicroRNAs (miRNAs) are important regulators of both innate and adaptive immunity. This is very much a frontier area since little is known about miRNA function in vivo, and there is still much discovery to be done. Their emerging functions indicate that they are as potent as cytokines in immunoregulation.
We have found that Toll-like receptor (TLR) signaling is potently modulated by 2 particular miRNAs, miR-21 and miR-107. The programme will have 4 aspects which will build on this initial observation.
1. Extension of our observations on miR-21 and TLR signaling. We found that the translational repressor PDCD4 is a key target. We will study miR-21-deficient mice, construct a mouse model where the miR-21 seed sequence in the 3'UTR of PDCD4 is altered, and target miR-21 in vivo using antagomirs. We will also determine the mRNAs regulated by PDCD4 and examine the role of mTOR in PDCD4 control since PDCD4 is a possible substrate.
2. Examination of the role of miR-107 in TLR signaling. TLRs dramatically decrease it¿s expression. We have found that miR-107 has an inhibitory role in TNF secretion via the targeting of CDK6. Activation of PPAR-alpha increases expression of miR107, which could be part of the anti-inflammatory effect of PPAR-alpha ligands. We will explore miR-107-deficient mice and in vitro models of miR-107 function.
3. Exploring the targeting of miR-155 by IL10, which we have recently found. The miR-155 target SHIP1 may be important in this system. We will analyze this process in detail and determine other targets for miR-155 in IL10 action.
4. Perform a screen for novel regulators of the aforementioned miRNAs and screen for miRNAs as regulators of other innate immune pathways, including Nalp3 and RIG-I, about which little is known. These experiments will yield new insights and components
The focus is the complex role miRNAs are playing in innate immunity and inflammation.
Summary
MicroRNAs (miRNAs) are important regulators of both innate and adaptive immunity. This is very much a frontier area since little is known about miRNA function in vivo, and there is still much discovery to be done. Their emerging functions indicate that they are as potent as cytokines in immunoregulation.
We have found that Toll-like receptor (TLR) signaling is potently modulated by 2 particular miRNAs, miR-21 and miR-107. The programme will have 4 aspects which will build on this initial observation.
1. Extension of our observations on miR-21 and TLR signaling. We found that the translational repressor PDCD4 is a key target. We will study miR-21-deficient mice, construct a mouse model where the miR-21 seed sequence in the 3'UTR of PDCD4 is altered, and target miR-21 in vivo using antagomirs. We will also determine the mRNAs regulated by PDCD4 and examine the role of mTOR in PDCD4 control since PDCD4 is a possible substrate.
2. Examination of the role of miR-107 in TLR signaling. TLRs dramatically decrease it¿s expression. We have found that miR-107 has an inhibitory role in TNF secretion via the targeting of CDK6. Activation of PPAR-alpha increases expression of miR107, which could be part of the anti-inflammatory effect of PPAR-alpha ligands. We will explore miR-107-deficient mice and in vitro models of miR-107 function.
3. Exploring the targeting of miR-155 by IL10, which we have recently found. The miR-155 target SHIP1 may be important in this system. We will analyze this process in detail and determine other targets for miR-155 in IL10 action.
4. Perform a screen for novel regulators of the aforementioned miRNAs and screen for miRNAs as regulators of other innate immune pathways, including Nalp3 and RIG-I, about which little is known. These experiments will yield new insights and components
The focus is the complex role miRNAs are playing in innate immunity and inflammation.
Max ERC Funding
2 480 587 €
Duration
Start date: 2011-06-01, End date: 2016-05-31
