Project acronym ACUITY
Project Algorithms for coping with uncertainty and intractability
Researcher (PI) Nikhil Bansal
Host Institution (HI) TECHNISCHE UNIVERSITEIT EINDHOVEN
Call Details Consolidator Grant (CoG), PE6, ERC-2013-CoG
Summary The two biggest challenges in solving practical optimization problems are computational intractability, and the presence
of uncertainty: most problems are either NP-hard, or have incomplete input data which
makes an exact computation impossible.
Recently, there has been a huge progress in our understanding of intractability, based on spectacular algorithmic and lower bound techniques. For several problems, especially those with only local constraints, we can design optimum
approximation algorithms that are provably the best possible.
However, typical optimization problems usually involve complex global constraints and are much less understood. The situation is even worse for coping with uncertainty. Most of the algorithms are based on ad-hoc techniques and there is no deeper understanding of what makes various problems easy or hard.
This proposal describes several new directions, together with concrete intermediate goals, that will break important new ground in the theory of approximation and online algorithms. The particular directions we consider are (i) extend the primal dual method to systematically design online algorithms, (ii) build a structural theory of online problems based on work functions, (iii) develop new tools to use the power of strong convex relaxations and (iv) design new algorithmic approaches based on non-constructive proof techniques.
The proposed research is at the
cutting edge of algorithm design, and builds upon the recent success of the PI in resolving several longstanding questions in these areas. Any progress is likely to be a significant contribution to theoretical
computer science and combinatorial optimization.
Summary
The two biggest challenges in solving practical optimization problems are computational intractability, and the presence
of uncertainty: most problems are either NP-hard, or have incomplete input data which
makes an exact computation impossible.
Recently, there has been a huge progress in our understanding of intractability, based on spectacular algorithmic and lower bound techniques. For several problems, especially those with only local constraints, we can design optimum
approximation algorithms that are provably the best possible.
However, typical optimization problems usually involve complex global constraints and are much less understood. The situation is even worse for coping with uncertainty. Most of the algorithms are based on ad-hoc techniques and there is no deeper understanding of what makes various problems easy or hard.
This proposal describes several new directions, together with concrete intermediate goals, that will break important new ground in the theory of approximation and online algorithms. The particular directions we consider are (i) extend the primal dual method to systematically design online algorithms, (ii) build a structural theory of online problems based on work functions, (iii) develop new tools to use the power of strong convex relaxations and (iv) design new algorithmic approaches based on non-constructive proof techniques.
The proposed research is at the
cutting edge of algorithm design, and builds upon the recent success of the PI in resolving several longstanding questions in these areas. Any progress is likely to be a significant contribution to theoretical
computer science and combinatorial optimization.
Max ERC Funding
1 519 285 €
Duration
Start date: 2014-05-01, End date: 2019-04-30
Project acronym ALERT
Project ALERT - The Apertif-LOFAR Exploration of the Radio Transient Sky
Researcher (PI) Albert Van Leeuwen
Host Institution (HI) STICHTING ASTRON, NETHERLANDS INSTITUTE FOR RADIO ASTRONOMY
Call Details Consolidator Grant (CoG), PE9, ERC-2013-CoG
Summary "In our largely unchanging radio Universe, a highly dynamic component was recently discovered: flashes of bright radio emission that last only milliseconds but appear all over the sky. Some of these radio bursts can be traced to intermittently pulsating neutron stars. Other bursts however, apparently originate far outside our Galaxy. Due to great observational challenges, the evolution of the neutron stars is not understood, while more importantly, the nature of the extragalactic bursts remains an outright mystery.
My overall aim is to understand the physics that drives both kinds of brief and luminous bursts.
My primary goal is to identify the highly compact astrophysical explosions powering the extragalactic bursts. My previous surveys are the state of the art in fast-transient detection; I will now increase by a factor of 10 this exploration volume. In real-time I will provide arcsec positions, 10,000-fold more accurate than currently possible, to localize such extragalactic bursts for the first time and understand their origin.
My secondary goal is to unravel the unexplained evolution of intermittently pulsating neutron stars (building on e.g., my recent papers in Science, 2013), by doubling their number and modeling their population.
To achieve these goals, I will carry out a highly innovative survey: the Apertif-LOFAR Exploration of the Radio Transient Sky. ALERT is over an order of magnitude more sensitive than all current state-of-the art fast-transient surveys.
Through its novel, extremely wide field-of-view, Westerbork/Apertif will detect many tens of extragalactic bursts. Through real-time triggers to LOFAR I will next provide the precise localisation that is essential for radio, optical and high-energy follow-up to, for the first time, shed light on the physics and objects driving these bursts – evaporating primordial black holes; explosions in host galaxies; or, the unknown?"
Summary
"In our largely unchanging radio Universe, a highly dynamic component was recently discovered: flashes of bright radio emission that last only milliseconds but appear all over the sky. Some of these radio bursts can be traced to intermittently pulsating neutron stars. Other bursts however, apparently originate far outside our Galaxy. Due to great observational challenges, the evolution of the neutron stars is not understood, while more importantly, the nature of the extragalactic bursts remains an outright mystery.
My overall aim is to understand the physics that drives both kinds of brief and luminous bursts.
My primary goal is to identify the highly compact astrophysical explosions powering the extragalactic bursts. My previous surveys are the state of the art in fast-transient detection; I will now increase by a factor of 10 this exploration volume. In real-time I will provide arcsec positions, 10,000-fold more accurate than currently possible, to localize such extragalactic bursts for the first time and understand their origin.
My secondary goal is to unravel the unexplained evolution of intermittently pulsating neutron stars (building on e.g., my recent papers in Science, 2013), by doubling their number and modeling their population.
To achieve these goals, I will carry out a highly innovative survey: the Apertif-LOFAR Exploration of the Radio Transient Sky. ALERT is over an order of magnitude more sensitive than all current state-of-the art fast-transient surveys.
Through its novel, extremely wide field-of-view, Westerbork/Apertif will detect many tens of extragalactic bursts. Through real-time triggers to LOFAR I will next provide the precise localisation that is essential for radio, optical and high-energy follow-up to, for the first time, shed light on the physics and objects driving these bursts – evaporating primordial black holes; explosions in host galaxies; or, the unknown?"
Max ERC Funding
1 999 823 €
Duration
Start date: 2014-12-01, End date: 2019-11-30
Project acronym DEEPINSIGHT
Project Preclinical micro-endoscopy in tumors: targeting metastatic intravasation and resistance
Researcher (PI) Peter Friedl
Host Institution (HI) STICHTING KATHOLIEKE UNIVERSITEIT
Call Details Consolidator Grant (CoG), LS4, ERC-2013-CoG
Summary Poor prognosis of cancer results from two central progression events, (i) the intravasation of cancer cells into blood vessels which leads to metastasis to distant organs and ultimately lethal tumor overload and (ii) cancer cell survival and adaptation to metabolic stress which causes resistance to anti-cancer therapy and limits life expectancy. Using a novel multiphoton microendoscope device recently developed by myself and collaborators, I here aim to overcome tissue penetration limits and identify important progression events deeply inside tumors. The hard- and software of the microendoscope will be optimized for automated position control and panoramic rotation to sample large tissue volumes and validated for stability and safety. We then will address the locations and mechanisms inside tumors that: (1) enable tumor-cell migration and penetration into blood vessels for distant metastasis and (2) mediate enhanced tumor-cell survival and resistance to experimental radiation- and chemotherapy. This basic inventory will serve to address (3) whether and how the niches for both intravasation and resistance overlap and connected with microenvironmental triggers, including defective blood vessels, signalling pathways of malnutrition and hypoxia, and tissue damage. The strategies include 3D microscopy of live fluorescent multi-color tumors and molecular reporters to record cancer cell migration, proliferation and death in the context with embedding tissue structures and metabolic signals. Once identified and characterized, (4) the niches and signals inducing intravasation and resistance (i.e. integrin adhesion receptors, cytoskeletal regulators, metabolic signalling) will be exploited as targets to enhance experimental radiation and chemotherapy. Preclinical microendoscopy will deliver new insight into cancer progression further contribute impulses to microendoscopy for disease monitoring in patients (“optical biopsy”).
Summary
Poor prognosis of cancer results from two central progression events, (i) the intravasation of cancer cells into blood vessels which leads to metastasis to distant organs and ultimately lethal tumor overload and (ii) cancer cell survival and adaptation to metabolic stress which causes resistance to anti-cancer therapy and limits life expectancy. Using a novel multiphoton microendoscope device recently developed by myself and collaborators, I here aim to overcome tissue penetration limits and identify important progression events deeply inside tumors. The hard- and software of the microendoscope will be optimized for automated position control and panoramic rotation to sample large tissue volumes and validated for stability and safety. We then will address the locations and mechanisms inside tumors that: (1) enable tumor-cell migration and penetration into blood vessels for distant metastasis and (2) mediate enhanced tumor-cell survival and resistance to experimental radiation- and chemotherapy. This basic inventory will serve to address (3) whether and how the niches for both intravasation and resistance overlap and connected with microenvironmental triggers, including defective blood vessels, signalling pathways of malnutrition and hypoxia, and tissue damage. The strategies include 3D microscopy of live fluorescent multi-color tumors and molecular reporters to record cancer cell migration, proliferation and death in the context with embedding tissue structures and metabolic signals. Once identified and characterized, (4) the niches and signals inducing intravasation and resistance (i.e. integrin adhesion receptors, cytoskeletal regulators, metabolic signalling) will be exploited as targets to enhance experimental radiation and chemotherapy. Preclinical microendoscopy will deliver new insight into cancer progression further contribute impulses to microendoscopy for disease monitoring in patients (“optical biopsy”).
Max ERC Funding
2 000 000 €
Duration
Start date: 2014-12-01, End date: 2019-11-30
Project acronym DRAGNET
Project "DRAGNET: A high-speed, wide-angle camera for catching extreme astrophysical events"
Researcher (PI) Jason William Thomas Hessels
Host Institution (HI) STICHTING ASTRON, NETHERLANDS INSTITUTE FOR RADIO ASTRONOMY
Call Details Starting Grant (StG), PE9, ERC-2013-StG
Summary "Looking up on a starry night, it’s easy to imagine that the Universe is unchanging. In reality, however, the Universe is teeming with activity: there are massive explosions from accreting black holes, bright radio flashes from ultra-magnetic pulsars, and likely other spectacles that have so far escaped our prying eyes. These fleeting events can happen faster than the blink of an eye and, importantly, they trace the most extreme astrophysical phenomena. Catching these rare performances poses a major challenge for observational astronomers, but the scientific payoff is well worth the effort.
With this proposal, I will mould the Low-Frequency Array (LOFAR) telescope into DRAGNET, the world's premier high-speed, wide-angle camera for radio astronomy. Radio waves are a unique and powerful way of investigating the most extreme astrophysical processes. With DRAGNET I will characterize the rate of fast radio transients, i.e. astrophysical bursts lasting less than a second, and search for new astrophysical phenomena in this largely unexplored domain. This has the potential to give us transformative insight into the extremes of gravity and dense matter. Alongside this, I will simultaneously monitor hundreds of radio-emitting neutron stars (pulsars) on a regular basis. This will allow me to understand why some neutron stars pulse regularly, while others show rapid switches in their emission properties. This will address the physics behind the strongest magnetic fields in the Universe.
I have led the construction of LOFAR's high-time-resolution observing capabilities; in this project I will capitalize on that investment and do cutting-edge science that is beyond the reach of any other existing telescope. Simply put, this project will establish a world-leading research group in the emerging field of fast radio transients and will crystallize the wide-field radio telescope as an essential tool for unveiling the bustling activity that makes our Universe so interesting to study."
Summary
"Looking up on a starry night, it’s easy to imagine that the Universe is unchanging. In reality, however, the Universe is teeming with activity: there are massive explosions from accreting black holes, bright radio flashes from ultra-magnetic pulsars, and likely other spectacles that have so far escaped our prying eyes. These fleeting events can happen faster than the blink of an eye and, importantly, they trace the most extreme astrophysical phenomena. Catching these rare performances poses a major challenge for observational astronomers, but the scientific payoff is well worth the effort.
With this proposal, I will mould the Low-Frequency Array (LOFAR) telescope into DRAGNET, the world's premier high-speed, wide-angle camera for radio astronomy. Radio waves are a unique and powerful way of investigating the most extreme astrophysical processes. With DRAGNET I will characterize the rate of fast radio transients, i.e. astrophysical bursts lasting less than a second, and search for new astrophysical phenomena in this largely unexplored domain. This has the potential to give us transformative insight into the extremes of gravity and dense matter. Alongside this, I will simultaneously monitor hundreds of radio-emitting neutron stars (pulsars) on a regular basis. This will allow me to understand why some neutron stars pulse regularly, while others show rapid switches in their emission properties. This will address the physics behind the strongest magnetic fields in the Universe.
I have led the construction of LOFAR's high-time-resolution observing capabilities; in this project I will capitalize on that investment and do cutting-edge science that is beyond the reach of any other existing telescope. Simply put, this project will establish a world-leading research group in the emerging field of fast radio transients and will crystallize the wide-field radio telescope as an essential tool for unveiling the bustling activity that makes our Universe so interesting to study."
Max ERC Funding
1 964 587 €
Duration
Start date: 2014-01-01, End date: 2018-12-31
Project acronym FEALORA
Project "Feasibility, logic and randomness in computational complexity"
Researcher (PI) Pavel Pudlák
Host Institution (HI) MATEMATICKY USTAV AV CR V.V.I.
Call Details Advanced Grant (AdG), PE6, ERC-2013-ADG
Summary "We will study fundamental problems in complexity theory using means developed in logic, specifically, in the filed of proof complexity. Since these problems seem extremely difficult and little progress has been achieved in solving them, we will prove results that will explain why they are so difficult and in which direction theory should be developed.
Our aim is to develop a system of conjectures based on the concepts of feasible incompleteness and pseudorandomness. Feasible incompleteness refers to conjectures about unprovability of statements concerning low complexity computations and about lengths of proofs of finite consistency statements. Essentially, they say that incompleteness in the finite domain behaves in a similar way as in the infinite. Several conjectures of this kind have been already stated. They have strong consequences concerning separation of complexity classes, but only a few special cases have been proved. We want to develop a unified system which will also include conjectures connecting feasible incompleteness with pseudorandomness. A major part of our work will concern proving special cases and relativized versions of these conjectures in order to provide evidence for their truth. We believe that the essence of the fundamental problems in complexity theory is logical, and thus developing theory in the way described above will eventually lead to their solution."
Summary
"We will study fundamental problems in complexity theory using means developed in logic, specifically, in the filed of proof complexity. Since these problems seem extremely difficult and little progress has been achieved in solving them, we will prove results that will explain why they are so difficult and in which direction theory should be developed.
Our aim is to develop a system of conjectures based on the concepts of feasible incompleteness and pseudorandomness. Feasible incompleteness refers to conjectures about unprovability of statements concerning low complexity computations and about lengths of proofs of finite consistency statements. Essentially, they say that incompleteness in the finite domain behaves in a similar way as in the infinite. Several conjectures of this kind have been already stated. They have strong consequences concerning separation of complexity classes, but only a few special cases have been proved. We want to develop a unified system which will also include conjectures connecting feasible incompleteness with pseudorandomness. A major part of our work will concern proving special cases and relativized versions of these conjectures in order to provide evidence for their truth. We believe that the essence of the fundamental problems in complexity theory is logical, and thus developing theory in the way described above will eventually lead to their solution."
Max ERC Funding
1 259 596 €
Duration
Start date: 2014-01-01, End date: 2018-12-31
Project acronym GLITTER
Project Glioblastoma Inhibition: Targeting Tumour-derived Extracellular-Vesicle Driven Cell-Recruitment
Researcher (PI) Thomas Wurdinger
Host Institution (HI) STICHTING VUMC
Call Details Starting Grant (StG), LS4, ERC-2013-StG
Summary Glioblastomas (GBMs) are malignant brain tumours and among the most aggressive human cancers. GBMs patients have an extremely poor survival rate due to a complete absence of adequate therapies capable of efficiently targeting GBM cells inside the brain. Recently, we demonstrated that GBM cells release pro-tumoural extracellular vesicles (EVs) into the bloodstream, which emerged as important intermediates in communication with distant peripheral cells in the body. Of note, the distribution of GBM-derived EVs can now be monitored in vivo by employing a novel Cre/LoxP mouse reporter model. This sophisticated imaging model enables the visualisation of normal peripheral cells that have taken up circulating GBM-derived EVs and allows for subsequent tracking of the recruitment of these cells to the tumour. Recent studies have shown that GBM-derived EVs have the capability to manipulate non-neoplastic cells, exploiting them for tumour expansion. Moreover, we have preliminary evidence that GBM-derived EV receptor pathways can be identified and blocked, possibly causing stagnation of GBM tumour growth by preventing recruitment of essential support cells. We aim at identifying these pathways using unbiased RNAi screening, followed by interference with pro-tumoural cell recruitment, using small molecule drugs in our GBM in vivo models. Finally, circulating GBM-derived EVs and their RNA content are also efficiently captured and internalised by blood platelets (PLTs) that can act as efficient EV carriers. Hence, tumour-derived RNA in circulating EVs and PLTs, isolated from the blood of GBM mouse models and patients, may serve as non-invasive biomarkers and companion diagnostics platform. GLITTER aims to; 1) Analyse in detail the EV-driven recruitment and signalling of essential GBM support cells; 2) Halt GBM tumour growth by interference with EV-mediated recruitment of pro-tumoural non-neoplastic cells; 3) Validate the EV/PLT-based diagnostic platform.
Summary
Glioblastomas (GBMs) are malignant brain tumours and among the most aggressive human cancers. GBMs patients have an extremely poor survival rate due to a complete absence of adequate therapies capable of efficiently targeting GBM cells inside the brain. Recently, we demonstrated that GBM cells release pro-tumoural extracellular vesicles (EVs) into the bloodstream, which emerged as important intermediates in communication with distant peripheral cells in the body. Of note, the distribution of GBM-derived EVs can now be monitored in vivo by employing a novel Cre/LoxP mouse reporter model. This sophisticated imaging model enables the visualisation of normal peripheral cells that have taken up circulating GBM-derived EVs and allows for subsequent tracking of the recruitment of these cells to the tumour. Recent studies have shown that GBM-derived EVs have the capability to manipulate non-neoplastic cells, exploiting them for tumour expansion. Moreover, we have preliminary evidence that GBM-derived EV receptor pathways can be identified and blocked, possibly causing stagnation of GBM tumour growth by preventing recruitment of essential support cells. We aim at identifying these pathways using unbiased RNAi screening, followed by interference with pro-tumoural cell recruitment, using small molecule drugs in our GBM in vivo models. Finally, circulating GBM-derived EVs and their RNA content are also efficiently captured and internalised by blood platelets (PLTs) that can act as efficient EV carriers. Hence, tumour-derived RNA in circulating EVs and PLTs, isolated from the blood of GBM mouse models and patients, may serve as non-invasive biomarkers and companion diagnostics platform. GLITTER aims to; 1) Analyse in detail the EV-driven recruitment and signalling of essential GBM support cells; 2) Halt GBM tumour growth by interference with EV-mediated recruitment of pro-tumoural non-neoplastic cells; 3) Validate the EV/PLT-based diagnostic platform.
Max ERC Funding
1 299 292 €
Duration
Start date: 2014-02-01, End date: 2019-01-31
Project acronym LBCAD
Project Lower bounds for combinatorial algorithms and dynamic problems
Researcher (PI) Michal Koucky
Host Institution (HI) UNIVERZITA KARLOVA
Call Details Consolidator Grant (CoG), PE6, ERC-2013-CoG
Summary This project aims to establish the time complexity of algorithms for two classes of problems. The first class consists of problems related to Boolean matrix multiplication and matrix multiplication over various semirings. This class contains problems such as computing transitive closure of a graph and determining the minimum distance between all-pairs of nodes in a graph. Known combinatorial algorithms for these problems run in slightly sub-cubic time. By combinatorial algorithms we mean algorithms that do not rely on the fast matrix multiplication over rings. Our goal is to show that the known combinatorial algorithms for these problems are essentially optimal. This requires designing a model of combinatorial algorithms and proving almost cubic lower bounds in it.
The other class of problems that we will focus on contains dynamic data structure problems such as dynamic graph reachability and related problems. Known algorithms for these problems exhibit trade-off between the query time and the update time, where at least one of them is always polynomial. Our goal is to show that indeed any algorithm for these problems must have update time or query time at least polynomial.
The two classes of problems are closely associated with so called 3SUM problem which serves as a benchmark for uncomputability in sub-quadratic time. Our goal is to deepen and extend the known connections between 3SUM, the other two classes and problems like formula satisfiability (SAT).
Summary
This project aims to establish the time complexity of algorithms for two classes of problems. The first class consists of problems related to Boolean matrix multiplication and matrix multiplication over various semirings. This class contains problems such as computing transitive closure of a graph and determining the minimum distance between all-pairs of nodes in a graph. Known combinatorial algorithms for these problems run in slightly sub-cubic time. By combinatorial algorithms we mean algorithms that do not rely on the fast matrix multiplication over rings. Our goal is to show that the known combinatorial algorithms for these problems are essentially optimal. This requires designing a model of combinatorial algorithms and proving almost cubic lower bounds in it.
The other class of problems that we will focus on contains dynamic data structure problems such as dynamic graph reachability and related problems. Known algorithms for these problems exhibit trade-off between the query time and the update time, where at least one of them is always polynomial. Our goal is to show that indeed any algorithm for these problems must have update time or query time at least polynomial.
The two classes of problems are closely associated with so called 3SUM problem which serves as a benchmark for uncomputability in sub-quadratic time. Our goal is to deepen and extend the known connections between 3SUM, the other two classes and problems like formula satisfiability (SAT).
Max ERC Funding
900 200 €
Duration
Start date: 2014-02-01, End date: 2019-01-31
Project acronym LOFARCORE
Project Unravelling the Cosmic Reionization History
Researcher (PI) Antonius Gerardus De Bruyn
Host Institution (HI) STICHTING ASTRON, NETHERLANDS INSTITUTE FOR RADIO ASTRONOMY
Call Details Advanced Grant (AdG), PE9, ERC-2013-ADG
Summary "One of the frontier cosmological research themes of the past decade has been the Epoch of Reionization (EoR). This era marked the start of the formation of visible baryonic structures: stars, (dwarf-)galaxies, clusters and the cosmic web. Some top level questions surrounding COsmic REionization are: ""When did it start ?”, “How long did it take ?”, “What were the main ionizing sources ?”, and “What did the Universe look like during this crucial evolutionary phase ?"" Simulations of reionization suggest how it may have proceeded, but hard observational facts on the EoR are few and far between.
At the start of the EoR all hydrogen was cold and neutral. At redshift z=6 the transition to an ionized Universe was completed. The 21cm line, redshifted to much longer wavelength, is a key diagnostic during this phase. LOFAR, the European LOw Frequency Array, will be the premier instrument to explore this epoch, simultaneously over the full redshift range from z=6.5-11.5 ! The required angular resolution is also well matched to the 2.5 km CORE of LOFAR. Detecting redshifted HI from the EoR is generally acknowledged as the most difficult radio astronomical project ever attempted. As PI of the LOFAR EoR Key Science Project and as LOFAR Calibration Project scientist, I have worked hard for 10 years to prepare LOFAR and myself for this endeavour.
In November 2012 LOFAR commenced a long (> 3-5 years) observing campaign, generating several PB of data per year. A new phase, with extraordinary challenges, still lies ahead. ERC funding for the LOFARCORE team will permit me to ramp up the execution of this program, and in a timely manner (we have competition from US, Australian and Indian groups), solve problems along the way, and analyze and publish what will be ground-breaking results on the COsmic REionization history. The LOFAR EoR project will be the pathfinder for even more daunting future explorations, using SKA, of the phases preceeding the EoR, i.e. Cosmic Dawn."
Summary
"One of the frontier cosmological research themes of the past decade has been the Epoch of Reionization (EoR). This era marked the start of the formation of visible baryonic structures: stars, (dwarf-)galaxies, clusters and the cosmic web. Some top level questions surrounding COsmic REionization are: ""When did it start ?”, “How long did it take ?”, “What were the main ionizing sources ?”, and “What did the Universe look like during this crucial evolutionary phase ?"" Simulations of reionization suggest how it may have proceeded, but hard observational facts on the EoR are few and far between.
At the start of the EoR all hydrogen was cold and neutral. At redshift z=6 the transition to an ionized Universe was completed. The 21cm line, redshifted to much longer wavelength, is a key diagnostic during this phase. LOFAR, the European LOw Frequency Array, will be the premier instrument to explore this epoch, simultaneously over the full redshift range from z=6.5-11.5 ! The required angular resolution is also well matched to the 2.5 km CORE of LOFAR. Detecting redshifted HI from the EoR is generally acknowledged as the most difficult radio astronomical project ever attempted. As PI of the LOFAR EoR Key Science Project and as LOFAR Calibration Project scientist, I have worked hard for 10 years to prepare LOFAR and myself for this endeavour.
In November 2012 LOFAR commenced a long (> 3-5 years) observing campaign, generating several PB of data per year. A new phase, with extraordinary challenges, still lies ahead. ERC funding for the LOFARCORE team will permit me to ramp up the execution of this program, and in a timely manner (we have competition from US, Australian and Indian groups), solve problems along the way, and analyze and publish what will be ground-breaking results on the COsmic REionization history. The LOFAR EoR project will be the pathfinder for even more daunting future explorations, using SKA, of the phases preceeding the EoR, i.e. Cosmic Dawn."
Max ERC Funding
2 952 628 €
Duration
Start date: 2014-04-01, End date: 2018-06-30
Project acronym MICARUS
Project MicroRNA function in cardiac and metabolic disease
Researcher (PI) Eva Van Rooij
Host Institution (HI) KONINKLIJKE NEDERLANDSE AKADEMIE VAN WETENSCHAPPEN - KNAW
Call Details Consolidator Grant (CoG), LS4, ERC-2013-CoG
Summary Cardiovascular disease is the primary cause of morbidity and mortality worldwide. Despite numerous treatment options the prevalence of cardiovascular indications continues to increase, underscoring the need for new therapeutic strategies.
In recent years, prominent roles of microRNAs (miRNAs) have been uncovered in a variety of cardiovascular disorders. miRNAs are short, single stranded RNAs that regulate gene expression by suppressing multiple, often related, mRNAs.
Our studies have focussed on the cardiac specific miRNA, miR-208. We showed that, in the setting of heart failure, genetic deletion as well as therapeutic inhibition of miR-208 resulted in reduced cardiac remodeling (less hypertrophy and fibrosis), the inability to upregulate beta-MHC (a sensitive marker of pathological cardiac stress) and improved survival.
Unexpectedly, mice treated with antimiR-208 displayed resistance to obesity and enhanced glucose metabolism in a mouse model of type II diabetes. These effects suggest that the heart plays a previously unrecognized role in systemic metabolic control via a miR-208 dependent mechanism.
Although these studies indicate a crucial role for miR-208 in cardiac remodeling and systemic metabolism, the mechanism of action still remains to be defined. Our preliminary gene expression data indicate a cohort of miR-208 targets to be regulated in our stress models, many of which so far have unknown or ill-studied cardiac functions.
The aim of the present proposal is to use genetics, gene expression analyses, stress models and antimiR approaches to study the relevance of downstream miR-208 targets for cardiac remodeling and total body metabolism and explore whether additional miRNAs besides miR-208 are relevant for cardiometabolic disease. Together these projects will increase our mechanistic understanding of miRNA function in cardiac and metabolic disease which will advance the clinical application of miRNA therapeutics.
Summary
Cardiovascular disease is the primary cause of morbidity and mortality worldwide. Despite numerous treatment options the prevalence of cardiovascular indications continues to increase, underscoring the need for new therapeutic strategies.
In recent years, prominent roles of microRNAs (miRNAs) have been uncovered in a variety of cardiovascular disorders. miRNAs are short, single stranded RNAs that regulate gene expression by suppressing multiple, often related, mRNAs.
Our studies have focussed on the cardiac specific miRNA, miR-208. We showed that, in the setting of heart failure, genetic deletion as well as therapeutic inhibition of miR-208 resulted in reduced cardiac remodeling (less hypertrophy and fibrosis), the inability to upregulate beta-MHC (a sensitive marker of pathological cardiac stress) and improved survival.
Unexpectedly, mice treated with antimiR-208 displayed resistance to obesity and enhanced glucose metabolism in a mouse model of type II diabetes. These effects suggest that the heart plays a previously unrecognized role in systemic metabolic control via a miR-208 dependent mechanism.
Although these studies indicate a crucial role for miR-208 in cardiac remodeling and systemic metabolism, the mechanism of action still remains to be defined. Our preliminary gene expression data indicate a cohort of miR-208 targets to be regulated in our stress models, many of which so far have unknown or ill-studied cardiac functions.
The aim of the present proposal is to use genetics, gene expression analyses, stress models and antimiR approaches to study the relevance of downstream miR-208 targets for cardiac remodeling and total body metabolism and explore whether additional miRNAs besides miR-208 are relevant for cardiometabolic disease. Together these projects will increase our mechanistic understanding of miRNA function in cardiac and metabolic disease which will advance the clinical application of miRNA therapeutics.
Max ERC Funding
2 000 000 €
Duration
Start date: 2014-04-01, End date: 2019-03-31
Project acronym PROLONGBILESIGNALING
Project Improving Metabolism via Prolonged Bile Acid Signalling
targeting hepatic bile acid uptake to fight metabolic diseases
Researcher (PI) Konstantijn Van De Graaf
Host Institution (HI) ACADEMISCH MEDISCH CENTRUM BIJ DE UNIVERSITEIT VAN AMSTERDAM
Call Details Starting Grant (StG), LS4, ERC-2013-StG
Summary Bile acids play a pivotal role in energy supply as they facilitate the solubilization and absorption of fat in the intestine. Furthermore, bile acids are recently identified as important signalling molecules regulating glucose metabolism, inflammation and energy expenditure. Targeting bile acid signalling is, therefore, appealing to treat metabolic diseases such as diabetes and atherosclerosis. These disorders are potentially affecting >1 billion individuals worldwide and current options to treat them remain insufficient. I postulate that the hepatic bile acid uptake transporter NTCP (gene name SLC10A1) provides an excellent novel target to improve human health as it determines the duration of bile acid signalling by controlling how fast bile acids are removed from serum after a meal. In this proposal I will elucidate the contribution of bile acid dynamics to energy homeostasis and metabolism and identify the molecular mechanisms that regulate NTCP. My aim is to generate novel strategies to reduce hepatic bile acid uptake to prolong bile-acid signalling and increase energy expenditure, improve glucose handling and reduce atherosclerosis.
My key objectives are:
1. to determine the consequence of NTCP modulation on systemic bile acid dynamics, glucose and energy metabolism in animal models. To this end, I will perform careful metabolic analysis of a unique Slc10a1 knockout model in combination with diet-induced and genetic models for atherosclerosis and diabetes.
2. to identify novel means to inhibit NTCP-mediated bile acid uptake. To this end, I will make use of a FRET-based bile acid sensor that I recently developed to characterize the molecular regulation of hepatic bile acid uptake and to identify FDA-approved drugs that inhibit NTCP-mediated bile acid uptake.
This will establish my new research line on serum bile acid dynamics and ultimately provide new ways to treat metabolic diseases related to disturbed bile acid, lipid, glucose and energy homeostasis.
Summary
Bile acids play a pivotal role in energy supply as they facilitate the solubilization and absorption of fat in the intestine. Furthermore, bile acids are recently identified as important signalling molecules regulating glucose metabolism, inflammation and energy expenditure. Targeting bile acid signalling is, therefore, appealing to treat metabolic diseases such as diabetes and atherosclerosis. These disorders are potentially affecting >1 billion individuals worldwide and current options to treat them remain insufficient. I postulate that the hepatic bile acid uptake transporter NTCP (gene name SLC10A1) provides an excellent novel target to improve human health as it determines the duration of bile acid signalling by controlling how fast bile acids are removed from serum after a meal. In this proposal I will elucidate the contribution of bile acid dynamics to energy homeostasis and metabolism and identify the molecular mechanisms that regulate NTCP. My aim is to generate novel strategies to reduce hepatic bile acid uptake to prolong bile-acid signalling and increase energy expenditure, improve glucose handling and reduce atherosclerosis.
My key objectives are:
1. to determine the consequence of NTCP modulation on systemic bile acid dynamics, glucose and energy metabolism in animal models. To this end, I will perform careful metabolic analysis of a unique Slc10a1 knockout model in combination with diet-induced and genetic models for atherosclerosis and diabetes.
2. to identify novel means to inhibit NTCP-mediated bile acid uptake. To this end, I will make use of a FRET-based bile acid sensor that I recently developed to characterize the molecular regulation of hepatic bile acid uptake and to identify FDA-approved drugs that inhibit NTCP-mediated bile acid uptake.
This will establish my new research line on serum bile acid dynamics and ultimately provide new ways to treat metabolic diseases related to disturbed bile acid, lipid, glucose and energy homeostasis.
Max ERC Funding
1 489 320 €
Duration
Start date: 2013-12-01, End date: 2018-11-30