Project acronym Bits2Cosmology
Project Time-domain Gibbs sampling: From bits to inflationary gravitational waves
Researcher (PI) Hans Kristian ERIKSEN
Host Institution (HI) UNIVERSITETET I OSLO
Call Details Consolidator Grant (CoG), PE9, ERC-2017-COG
Summary The detection of primordial gravity waves created during the Big Bang ranks among the greatest potential intellectual achievements in modern science. During the last few decades, the instrumental progress necessary to achieve this has been nothing short of breathtaking, and we today are able to measure the microwave sky with better than one-in-a-million precision. However, from the latest ultra-sensitive experiments such as BICEP2 and Planck, it is clear that instrumental sensitivity alone will not be sufficient to make a robust detection of gravitational waves. Contamination in the form of astrophysical radiation from the Milky Way, for instance thermal dust and synchrotron radiation, obscures the cosmological signal by orders of magnitude. Even more critically, though, are second-order interactions between this radiation and the instrument characterization itself that lead to a highly non-linear and complicated problem.
I propose a ground-breaking solution to this problem that allows for joint estimation of cosmological parameters, astrophysical components, and instrument specifications. The engine of this method is called Gibbs sampling, which I have already applied extremely successfully to basic CMB component separation. The new and ciritical step is to apply this method to raw time-ordered observations observed directly by the instrument, as opposed to pre-processed frequency maps. While representing a ~100-fold increase in input data volume, this step is unavoidable in order to break through the current foreground-induced systematics floor. I will apply this method to the best currently available and future data sets (WMAP, Planck, SPIDER and LiteBIRD), and thereby derive the world's tightest constraint on the amplitude of inflationary gravitational waves. Additionally, the resulting ancillary science in the form of robust cosmological parameters and astrophysical component maps will represent the state-of-the-art in observational cosmology in years to come.
Summary
The detection of primordial gravity waves created during the Big Bang ranks among the greatest potential intellectual achievements in modern science. During the last few decades, the instrumental progress necessary to achieve this has been nothing short of breathtaking, and we today are able to measure the microwave sky with better than one-in-a-million precision. However, from the latest ultra-sensitive experiments such as BICEP2 and Planck, it is clear that instrumental sensitivity alone will not be sufficient to make a robust detection of gravitational waves. Contamination in the form of astrophysical radiation from the Milky Way, for instance thermal dust and synchrotron radiation, obscures the cosmological signal by orders of magnitude. Even more critically, though, are second-order interactions between this radiation and the instrument characterization itself that lead to a highly non-linear and complicated problem.
I propose a ground-breaking solution to this problem that allows for joint estimation of cosmological parameters, astrophysical components, and instrument specifications. The engine of this method is called Gibbs sampling, which I have already applied extremely successfully to basic CMB component separation. The new and ciritical step is to apply this method to raw time-ordered observations observed directly by the instrument, as opposed to pre-processed frequency maps. While representing a ~100-fold increase in input data volume, this step is unavoidable in order to break through the current foreground-induced systematics floor. I will apply this method to the best currently available and future data sets (WMAP, Planck, SPIDER and LiteBIRD), and thereby derive the world's tightest constraint on the amplitude of inflationary gravitational waves. Additionally, the resulting ancillary science in the form of robust cosmological parameters and astrophysical component maps will represent the state-of-the-art in observational cosmology in years to come.
Max ERC Funding
1 999 205 €
Duration
Start date: 2018-04-01, End date: 2023-03-31
Project acronym CombaTCancer
Project Rational combination therapies for metastatic cancer
Researcher (PI) Anna Obenauf
Host Institution (HI) FORSCHUNGSINSTITUT FUR MOLEKULARE PATHOLOGIE GESELLSCHAFT MBH
Call Details Starting Grant (StG), LS4, ERC-2017-STG
Summary Targeted therapy (TT) is frequently used to treat metastatic cancer. Although TT can achieve effective tumor control for several months, durable treatment responses are rare, due to emergence of aggressive, drug-resistant clones (RCs) with high metastatic competence. Tumor heterogeneity and plasticity result in multifaceted resistance mechanisms and targeting RCs poses a daunting challenge.
To better understand the clinical emergence of RCs, my work focuses on the poorly understood events during TT-induced tumor regression. We recently reported that during this phase drug-responsive cancer cells release a therapy-induced secretome, which remodels the tumor microenvironment (TME) and propagates disease relapse by promoting the survival of drug-sensitive cells and stimulating the outgrowth of RCs. Consequently, intervening with combination therapies during the tumor regression period has the potential to prevent the clinical emergence of RCs in the first place.
Here, we outline strategies to (1) understand how RCs emerge and (2) to leverage our findings on the TME remodeling for combination therapies. First, we will develop a novel and innovative parental clone-lookup method, that will allow us to identify and isolate treatment-naïve, parental clones (PCs) that gave rise to RCs. In functional experiments, we will assess (i) whether PCs were already resistant before or developed resistance during TT, (ii) whether PCs have a higher susceptibility to develop resistance than random clones, and (iii) the mechanistic basis for metastatic competence in different clones. Second, we will study the TT-induced TME remodeling, focusing on the effects on tumor vasculature and immune cells. We will utilize our results to target PCs and RCs by combining TT in the phase of tumor regression with other therapies, such as immunotherapies. Our study will provide new mechanistic insights into the biological processes during tumor regression and aims for novel therapeutic strategies.
Summary
Targeted therapy (TT) is frequently used to treat metastatic cancer. Although TT can achieve effective tumor control for several months, durable treatment responses are rare, due to emergence of aggressive, drug-resistant clones (RCs) with high metastatic competence. Tumor heterogeneity and plasticity result in multifaceted resistance mechanisms and targeting RCs poses a daunting challenge.
To better understand the clinical emergence of RCs, my work focuses on the poorly understood events during TT-induced tumor regression. We recently reported that during this phase drug-responsive cancer cells release a therapy-induced secretome, which remodels the tumor microenvironment (TME) and propagates disease relapse by promoting the survival of drug-sensitive cells and stimulating the outgrowth of RCs. Consequently, intervening with combination therapies during the tumor regression period has the potential to prevent the clinical emergence of RCs in the first place.
Here, we outline strategies to (1) understand how RCs emerge and (2) to leverage our findings on the TME remodeling for combination therapies. First, we will develop a novel and innovative parental clone-lookup method, that will allow us to identify and isolate treatment-naïve, parental clones (PCs) that gave rise to RCs. In functional experiments, we will assess (i) whether PCs were already resistant before or developed resistance during TT, (ii) whether PCs have a higher susceptibility to develop resistance than random clones, and (iii) the mechanistic basis for metastatic competence in different clones. Second, we will study the TT-induced TME remodeling, focusing on the effects on tumor vasculature and immune cells. We will utilize our results to target PCs and RCs by combining TT in the phase of tumor regression with other therapies, such as immunotherapies. Our study will provide new mechanistic insights into the biological processes during tumor regression and aims for novel therapeutic strategies.
Max ERC Funding
1 500 000 €
Duration
Start date: 2018-03-01, End date: 2023-02-28
Project acronym Daphne
Project Circuits of Visual Attention
Researcher (PI) Maximilian Jösch
Host Institution (HI) INSTITUTE OF SCIENCE AND TECHNOLOGYAUSTRIA
Call Details Starting Grant (StG), LS5, ERC-2017-STG
Summary The evolutionary arms race has optimized and shaped the way animals attend to relevant sensory stimuli in an ever-changing environment. This is a complex task, because the vast majority of sensory experiences are not relevant. In humans, attentional disorders are a serious public health concern because of its high prevalence, but its causes are mostly unknown. In this proposal, I will explore the neuronal mechanisms used by the nervous system to attend visual cues to enable appropriate behaviors.
We will combine cutting edge imaging techniques, optogenetic interventions, behavioral read outs and targeted connectomics to study the neuronal transformations of the mouse Superior Colliculus (SC), an evolutionary conserved midbrain area known to process sensorimotor transformations and to be involved in the allocation of attention. First, this work will reveal a detailed description of visual representation in the SC, focusing on understanding how defined retinal information-streams, like motion and color, contribute to these properties. Second, we will characterize sensorimotor transformations instructed by the SC. The combination of the previous two objectives will determine mechanisms of visual saliency and sensory driven attention (“bottom-up” attention). Finally, we will explore the neuronal mechanisms of attention by studying the modulatory effect of higher brain areas (“top-down” attention) on sensory transformation and multisensory integration in the SC.
Taken together, this proposal aims to understand principles underlying sensorimotor transformation and build a framework to study attention in health and disease.
Summary
The evolutionary arms race has optimized and shaped the way animals attend to relevant sensory stimuli in an ever-changing environment. This is a complex task, because the vast majority of sensory experiences are not relevant. In humans, attentional disorders are a serious public health concern because of its high prevalence, but its causes are mostly unknown. In this proposal, I will explore the neuronal mechanisms used by the nervous system to attend visual cues to enable appropriate behaviors.
We will combine cutting edge imaging techniques, optogenetic interventions, behavioral read outs and targeted connectomics to study the neuronal transformations of the mouse Superior Colliculus (SC), an evolutionary conserved midbrain area known to process sensorimotor transformations and to be involved in the allocation of attention. First, this work will reveal a detailed description of visual representation in the SC, focusing on understanding how defined retinal information-streams, like motion and color, contribute to these properties. Second, we will characterize sensorimotor transformations instructed by the SC. The combination of the previous two objectives will determine mechanisms of visual saliency and sensory driven attention (“bottom-up” attention). Finally, we will explore the neuronal mechanisms of attention by studying the modulatory effect of higher brain areas (“top-down” attention) on sensory transformation and multisensory integration in the SC.
Taken together, this proposal aims to understand principles underlying sensorimotor transformation and build a framework to study attention in health and disease.
Max ERC Funding
1 446 542 €
Duration
Start date: 2017-12-01, End date: 2022-11-30
Project acronym NPC-BUILD
Project The Nuclear Pore Basket – Functional Architecture of a Membrane Remodeling Machine
Researcher (PI) Alwin KÖHLER
Host Institution (HI) MEDIZINISCHE UNIVERSITAET WIEN
Call Details Consolidator Grant (CoG), LS1, ERC-2017-COG
Summary Nuclear pore complexes (NPCs) are gatekeepers at the nuclear envelope, mediating traffic between the nucleus and cytoplasm. Unlike simpler protein channels that insert into a single lipid bilayer, NPCs can remodel the outer and inner nuclear membranes to form a specialized pore in the nuclear envelope. High-resolution models of the symmetric NPC core have transformed our understanding of NPC architecture. In contrast, we know little about the NPC basket, a prominent structure on the nucleoplasmic side of NPCs. This lack of knowledge is salient, because the basket impacts on transport, DNA repair, and chromatin activity. Notably, the basket was recently found to play a key role in shaping the nuclear membrane, which is critical for NPC biogenesis. Studying the NPC basket is challenging because of its size, intricate architecture, structural flexibility and embedding in a membrane. Yet, knowledge of the architecture of the NPC basket is central to understanding how it influences gene expression, and operates in membrane remodeling in synergy with the NPC core. I propose to develop new experimental tools that will enable a structural analysis of the basket in its membrane environment. This will provide unprecedented insight into the function of this enigmatic part of the NPC.
Summary
Nuclear pore complexes (NPCs) are gatekeepers at the nuclear envelope, mediating traffic between the nucleus and cytoplasm. Unlike simpler protein channels that insert into a single lipid bilayer, NPCs can remodel the outer and inner nuclear membranes to form a specialized pore in the nuclear envelope. High-resolution models of the symmetric NPC core have transformed our understanding of NPC architecture. In contrast, we know little about the NPC basket, a prominent structure on the nucleoplasmic side of NPCs. This lack of knowledge is salient, because the basket impacts on transport, DNA repair, and chromatin activity. Notably, the basket was recently found to play a key role in shaping the nuclear membrane, which is critical for NPC biogenesis. Studying the NPC basket is challenging because of its size, intricate architecture, structural flexibility and embedding in a membrane. Yet, knowledge of the architecture of the NPC basket is central to understanding how it influences gene expression, and operates in membrane remodeling in synergy with the NPC core. I propose to develop new experimental tools that will enable a structural analysis of the basket in its membrane environment. This will provide unprecedented insight into the function of this enigmatic part of the NPC.
Max ERC Funding
2 178 488 €
Duration
Start date: 2018-02-01, End date: 2023-01-31
Project acronym NterAct
Project Discovery and functional significance of post-translational N-terminal acetylation
Researcher (PI) Thomas ARNESEN
Host Institution (HI) UNIVERSITETET I BERGEN
Call Details Consolidator Grant (CoG), LS1, ERC-2017-COG
Summary In mammalian cells, N-terminal (Nt) acetylation is one of the most abundant protein modifications. It is catalysed by N-terminal acetyltransferases (NATs) and mostly occurs co-translationally. However, in contrast to the defined co-translational NATs, post-translational NATs which have crucial regulatory roles are mostly unexplored. Distinct peptide hormones regulate appetite, metabolism, sexual behaviour and pain, and their biological activity is critically modulated by post-translational Nt-acetylation. However, the identity of the NAT responsible for this modification, ‘HormNat’, is unknown, thus the molecular and physiological ramifications of this regulatory circuit remain elusive. Another example is actin, a key regulator of cell motility and cell division. The actin N-terminus is crucial for actin function and in mammals actin is modified by an unknown post-translational NAT, ‘ActNat’. Hence, the objectives of this project are to identify these human NATs acting post-translationally, and to investigate their molecular mechanisms, regulation and impact.
We will identify the novel NATs by a combination of classical and newly developed in-house tools like in vitro acetylation assays, unique bisubstrate analogues, Nt-acetylation specific antibodies, and targeted mass spectrometry. Interestingly, Nt-acetylation is considered irreversible, but there is reason to believe that specific substrates are Nt-deacetylated. Elucidation of post-translational NATs and the reversible nature of Nt-acetylation would represent a new era in the field of protein and peptide regulation and identify key cellular and organismal switches.
Summary
In mammalian cells, N-terminal (Nt) acetylation is one of the most abundant protein modifications. It is catalysed by N-terminal acetyltransferases (NATs) and mostly occurs co-translationally. However, in contrast to the defined co-translational NATs, post-translational NATs which have crucial regulatory roles are mostly unexplored. Distinct peptide hormones regulate appetite, metabolism, sexual behaviour and pain, and their biological activity is critically modulated by post-translational Nt-acetylation. However, the identity of the NAT responsible for this modification, ‘HormNat’, is unknown, thus the molecular and physiological ramifications of this regulatory circuit remain elusive. Another example is actin, a key regulator of cell motility and cell division. The actin N-terminus is crucial for actin function and in mammals actin is modified by an unknown post-translational NAT, ‘ActNat’. Hence, the objectives of this project are to identify these human NATs acting post-translationally, and to investigate their molecular mechanisms, regulation and impact.
We will identify the novel NATs by a combination of classical and newly developed in-house tools like in vitro acetylation assays, unique bisubstrate analogues, Nt-acetylation specific antibodies, and targeted mass spectrometry. Interestingly, Nt-acetylation is considered irreversible, but there is reason to believe that specific substrates are Nt-deacetylated. Elucidation of post-translational NATs and the reversible nature of Nt-acetylation would represent a new era in the field of protein and peptide regulation and identify key cellular and organismal switches.
Max ERC Funding
1 999 273 €
Duration
Start date: 2018-06-01, End date: 2023-05-31
Project acronym POLICE
Project The PIDDosome in Centrosome and Ploidy-Surveillance
Researcher (PI) Andreas VILLUNGER
Host Institution (HI) MEDIZINISCHE UNIVERSITAT INNSBRUCK
Call Details Advanced Grant (AdG), LS4, ERC-2017-ADG
Summary Tight control of the number of chromosome sets in a cell (ploidy) is fundamental for normal development and organismal health. Most cells in our body are diploid, yet, some cells, including cardiomyocytes or hepatocytes require a balanced increase in ploidy for proper function. Polyploidization is accompanied by an accumulation of centrosomes, structures needed for nucleating the mitotic spindle and ciliogenesis. Extra centrosomes, however, promote aneuploidy in proliferating cells by causing errors in chromosome segregation, underlying a series of human pathologies, most notably cancer and premature ageing. How polyploidization is controlled in organogenesis and how errors in ploidy control contribute to disease is poorly understood.
We recently demonstrated that the “PIDDosome” complex polices centrosome numbers in mammalian cells, alerting the tumor suppressor p53 in response to extra centrosomes. This is achieved by inactivating MDM2, the key-inhibitor of p53, by targeted proteolysis. MDM2-processing is mediated by caspase-2, a neglected member in a protease family that controls cell death and inflammation, activated in the PIDDosome.
This exciting finding allows examining the consequences of deregulated ploidy and centrosome number in development and disease without interfering with p53, nor the cell fusion or cytokinesis machineries. This puts us in pole position to carry out an integrative study that aims to develop the PIDDosome as a new therapeutic target in cancer, related inflammation and in regenerative medicine. To meet this aim, we will define
(i) the relevance of the PIDDosome in aneuploidy tolerance of cancer
(ii) the role of the PIDDosome in controlling sterile inflammation and immunity
(iii) the PIDDosome as a key-regulator of organ development and regeneration
POLICE will open new lines of research at the interface of cell cycle, cell death & inflammation control and promote the PIDDosome as new target in our efforts to improve human health.
Summary
Tight control of the number of chromosome sets in a cell (ploidy) is fundamental for normal development and organismal health. Most cells in our body are diploid, yet, some cells, including cardiomyocytes or hepatocytes require a balanced increase in ploidy for proper function. Polyploidization is accompanied by an accumulation of centrosomes, structures needed for nucleating the mitotic spindle and ciliogenesis. Extra centrosomes, however, promote aneuploidy in proliferating cells by causing errors in chromosome segregation, underlying a series of human pathologies, most notably cancer and premature ageing. How polyploidization is controlled in organogenesis and how errors in ploidy control contribute to disease is poorly understood.
We recently demonstrated that the “PIDDosome” complex polices centrosome numbers in mammalian cells, alerting the tumor suppressor p53 in response to extra centrosomes. This is achieved by inactivating MDM2, the key-inhibitor of p53, by targeted proteolysis. MDM2-processing is mediated by caspase-2, a neglected member in a protease family that controls cell death and inflammation, activated in the PIDDosome.
This exciting finding allows examining the consequences of deregulated ploidy and centrosome number in development and disease without interfering with p53, nor the cell fusion or cytokinesis machineries. This puts us in pole position to carry out an integrative study that aims to develop the PIDDosome as a new therapeutic target in cancer, related inflammation and in regenerative medicine. To meet this aim, we will define
(i) the relevance of the PIDDosome in aneuploidy tolerance of cancer
(ii) the role of the PIDDosome in controlling sterile inflammation and immunity
(iii) the PIDDosome as a key-regulator of organ development and regeneration
POLICE will open new lines of research at the interface of cell cycle, cell death & inflammation control and promote the PIDDosome as new target in our efforts to improve human health.
Max ERC Funding
2 355 000 €
Duration
Start date: 2018-10-01, End date: 2023-09-30
