Project acronym AGNOSTIC
Project Actively Enhanced Cognition based Framework for Design of Complex Systems
Researcher (PI) Björn Ottersten
Host Institution (HI) UNIVERSITE DU LUXEMBOURG
Call Details Advanced Grant (AdG), PE7, ERC-2016-ADG
Summary Parameterized mathematical models have been central to the understanding and design of communication, networking, and radar systems. However, they often lack the ability to model intricate interactions innate in complex systems. On the other hand, data-driven approaches do not need explicit mathematical models for data generation and have a wider applicability at the cost of flexibility. These approaches need labelled data, representing all the facets of the system interaction with the environment. With the aforementioned systems becoming increasingly complex with intricate interactions and operating in dynamic environments, the number of system configurations can be rather large leading to paucity of labelled data. Thus there are emerging networks of systems of critical importance whose cognition is not effectively covered by traditional approaches. AGNOSTIC uses the process of exploration through system probing and exploitation of observed data in an iterative manner drawing upon traditional model-based approaches and data-driven discriminative learning to enhance functionality, performance, and robustness through the notion of active cognition. AGNOSTIC clearly departs from a passive assimilation of data and aims to formalize the exploitation/exploration framework in dynamic environments. The development of this framework in three applications areas is central to AGNOSTIC. The project aims to provide active cognition in radar to learn the environment and other active systems to ensure situational awareness and coexistence; to apply active probing in radio access networks to infer network behaviour towards spectrum sharing and self-configuration; and to learn and adapt to user demand for content distribution in caching networks, drastically improving network efficiency. Although these cognitive systems interact with the environment in very different ways, sufficient abstraction allows cross-fertilization of insights and approaches motivating their joint treatment.
Summary
Parameterized mathematical models have been central to the understanding and design of communication, networking, and radar systems. However, they often lack the ability to model intricate interactions innate in complex systems. On the other hand, data-driven approaches do not need explicit mathematical models for data generation and have a wider applicability at the cost of flexibility. These approaches need labelled data, representing all the facets of the system interaction with the environment. With the aforementioned systems becoming increasingly complex with intricate interactions and operating in dynamic environments, the number of system configurations can be rather large leading to paucity of labelled data. Thus there are emerging networks of systems of critical importance whose cognition is not effectively covered by traditional approaches. AGNOSTIC uses the process of exploration through system probing and exploitation of observed data in an iterative manner drawing upon traditional model-based approaches and data-driven discriminative learning to enhance functionality, performance, and robustness through the notion of active cognition. AGNOSTIC clearly departs from a passive assimilation of data and aims to formalize the exploitation/exploration framework in dynamic environments. The development of this framework in three applications areas is central to AGNOSTIC. The project aims to provide active cognition in radar to learn the environment and other active systems to ensure situational awareness and coexistence; to apply active probing in radio access networks to infer network behaviour towards spectrum sharing and self-configuration; and to learn and adapt to user demand for content distribution in caching networks, drastically improving network efficiency. Although these cognitive systems interact with the environment in very different ways, sufficient abstraction allows cross-fertilization of insights and approaches motivating their joint treatment.
Max ERC Funding
2 499 595 €
Duration
Start date: 2017-10-01, End date: 2022-09-30
Project acronym B2C
Project Beasts to Craft: BioCodicology as a new approach to the study of parchment manuscripts
Researcher (PI) Matthew COLLINS
Host Institution (HI) KOBENHAVNS UNIVERSITET
Call Details Advanced Grant (AdG), SH6, ERC-2017-ADG
Summary The intention of Beasts to Craft (B2C) is to document the biological and craft records in parchment in order to reveal the entangled histories of animal improvement and parchment production in Europe from 500-1900 AD.
B2C will lay the foundations for a new approach to the the study of parchment manuscripts —biocodicology— which draws evidence from the overlooked first stages in production, the raising of livestock and the preparation of the skins.
1. Parchment is an extraordinary but overlooked high resolution zooarchaeological record and a molecular archive. Livestock genetics is revealing breed diversity and markers of character traits such as fleece quality. B2C will exploit this new-found knowledge, using progressively older dated archival (sheep) parchments to study the history of improvement 1300 - 1900. Visual examination of the skins will search for direct evidence of disease and fleece quality.
2. Craft skills can be read from parchment and, when combined with chemical data and comparison with modern analogues, will produce the first European wide record of the craft from 500-1900. The size and scope of this the parchment archive means it is one of the largest and most highly resolved records of a specialist medieval craft. We will explore how these skills develop and when and where regional patterns appear and decline.
These two remarkable records requires a large interdisciplinary team. However biocodicology draws from and informs upon a wide and diverse spectrum of existing scholarship in conservation, the arts and sciences. A third strand of the project will (i) furnish manuscript scholars with some of the information available to the scribe at time of production (ii) inform and shape attitudes to parchment conservation (iii) provide high resolution biological data on animal management, movement and health and (iv) explore methods to link datasets and promote data reuse.
Summary
The intention of Beasts to Craft (B2C) is to document the biological and craft records in parchment in order to reveal the entangled histories of animal improvement and parchment production in Europe from 500-1900 AD.
B2C will lay the foundations for a new approach to the the study of parchment manuscripts —biocodicology— which draws evidence from the overlooked first stages in production, the raising of livestock and the preparation of the skins.
1. Parchment is an extraordinary but overlooked high resolution zooarchaeological record and a molecular archive. Livestock genetics is revealing breed diversity and markers of character traits such as fleece quality. B2C will exploit this new-found knowledge, using progressively older dated archival (sheep) parchments to study the history of improvement 1300 - 1900. Visual examination of the skins will search for direct evidence of disease and fleece quality.
2. Craft skills can be read from parchment and, when combined with chemical data and comparison with modern analogues, will produce the first European wide record of the craft from 500-1900. The size and scope of this the parchment archive means it is one of the largest and most highly resolved records of a specialist medieval craft. We will explore how these skills develop and when and where regional patterns appear and decline.
These two remarkable records requires a large interdisciplinary team. However biocodicology draws from and informs upon a wide and diverse spectrum of existing scholarship in conservation, the arts and sciences. A third strand of the project will (i) furnish manuscript scholars with some of the information available to the scribe at time of production (ii) inform and shape attitudes to parchment conservation (iii) provide high resolution biological data on animal management, movement and health and (iv) explore methods to link datasets and promote data reuse.
Max ERC Funding
2 499 462 €
Duration
Start date: 2018-12-01, End date: 2023-11-30
Project acronym BIOMEMOS
Project Higher order structure and function of biomembranes
Researcher (PI) Poul Nissen
Host Institution (HI) AARHUS UNIVERSITET
Call Details Advanced Grant (AdG), LS1, ERC-2009-AdG
Summary The biomembrane is a prerequisite of life. It enables the cell to maintain a controlled environment and to establish electrochemical gradients as rapidly accessible energy stores. Biomembranes also provide scaffold for organisation and spatial definition of signal transmission in the cell. Crystal structures of membrane proteins are determined with an increasing pace. Along with functional studies integral studies of individual membrane proteins are now widely implemented. The BIOMEMOS proposal goes a step further and approaches the function of the biomembrane at the higher level of membrane protein complexes. Through a combination of X-ray crystallography, electrophysiology, general biochemistry, biophysics and bioinformatics and including also the application of single-particle cryo-EM and small-angle X-ray scattering, the structure and function of membrane protein complexes of key importance in life will be investigated. The specific targets for investigation in this proposal include: 1) higher-order complexes of P-type ATPase pumps such as signalling complexes of Na+,K+-ATPase, and 2) development of methods for structural studies of membrane protein complexes Based on my unique track record in structural studies of large, difficult structures (ribosomes and membrane proteins) in the setting of a thriving research community in structural biology and biomembrane research in Aarhus provides a critical momentum for a long-term activity. The activity will take advantage of the new possibilities offered by synchrotron sources in Europe. Furthermore, a single-particle cryo-EM research group formed on my initiative in Aarhus, and a well-established small-angle X-ray scattering community provides for an optimal setting through multiple cues in structural biology and functional studies
Summary
The biomembrane is a prerequisite of life. It enables the cell to maintain a controlled environment and to establish electrochemical gradients as rapidly accessible energy stores. Biomembranes also provide scaffold for organisation and spatial definition of signal transmission in the cell. Crystal structures of membrane proteins are determined with an increasing pace. Along with functional studies integral studies of individual membrane proteins are now widely implemented. The BIOMEMOS proposal goes a step further and approaches the function of the biomembrane at the higher level of membrane protein complexes. Through a combination of X-ray crystallography, electrophysiology, general biochemistry, biophysics and bioinformatics and including also the application of single-particle cryo-EM and small-angle X-ray scattering, the structure and function of membrane protein complexes of key importance in life will be investigated. The specific targets for investigation in this proposal include: 1) higher-order complexes of P-type ATPase pumps such as signalling complexes of Na+,K+-ATPase, and 2) development of methods for structural studies of membrane protein complexes Based on my unique track record in structural studies of large, difficult structures (ribosomes and membrane proteins) in the setting of a thriving research community in structural biology and biomembrane research in Aarhus provides a critical momentum for a long-term activity. The activity will take advantage of the new possibilities offered by synchrotron sources in Europe. Furthermore, a single-particle cryo-EM research group formed on my initiative in Aarhus, and a well-established small-angle X-ray scattering community provides for an optimal setting through multiple cues in structural biology and functional studies
Max ERC Funding
2 444 180 €
Duration
Start date: 2010-04-01, End date: 2015-03-31
Project acronym CASTELLANY ACCOUNTS
Project Record-keeping, fiscal reform, and the rise of institutional accountability in late-medieval Savoy: a source-oriented approach
Researcher (PI) Ionut Epurescu-Pascovici
Host Institution (HI) UNIVERSITATEA DIN BUCURESTI
Call Details Starting Grant (StG), SH6, ERC-2014-STG
Summary The present research project focuses on an unjustly neglected corpus of late-medieval sources, the administrative and fiscal accounts (‘computi’) of the castellanies – basic administrative units – of the county of Savoy. I propose a holistic model of analysis that can fully capitalise on the unusual wealth of detail of the Savoyard source material, in order to illuminate some key topics in late-medieval institutional and socio-economic history, from the development of state institutions through administrative and fiscal reform – with particular attention to the transition from personal to institutional accountability – to the question of socio-economic growth, decline, and recovery during the turbulent period of the late-thirteenth to the late-fourteenth century. More broadly, my research into these topics aims to contribute to our understanding of the late-medieval origins of European modernity. The advances of pragmatic literacy, record-keeping, and auditing practices will be analysed with the aid of anthropological and social scientific theories of practice. By comparing the Savoyard ‘computi’ with their sources of inspiration, from the Anglo-Norman pipe rolls to the Catalan fiscal records, the project aims to highlight the creative adaptation of imported administrative models, and thus to contribute to our knowledge of institutional transfers in European history. The project will develop an inclusive frame of analysis in which the ‘computi’ will be read against the evidence from enfeoffment charters, castellany surveys (‘extente’), and the records of direct taxation (‘subsidia’). The serial data will be analysed by building a database; the findings of quantitative analysis will be verified by case studies of the individuals and families (many from the middle social strata) that surface in the fiscal records.
Summary
The present research project focuses on an unjustly neglected corpus of late-medieval sources, the administrative and fiscal accounts (‘computi’) of the castellanies – basic administrative units – of the county of Savoy. I propose a holistic model of analysis that can fully capitalise on the unusual wealth of detail of the Savoyard source material, in order to illuminate some key topics in late-medieval institutional and socio-economic history, from the development of state institutions through administrative and fiscal reform – with particular attention to the transition from personal to institutional accountability – to the question of socio-economic growth, decline, and recovery during the turbulent period of the late-thirteenth to the late-fourteenth century. More broadly, my research into these topics aims to contribute to our understanding of the late-medieval origins of European modernity. The advances of pragmatic literacy, record-keeping, and auditing practices will be analysed with the aid of anthropological and social scientific theories of practice. By comparing the Savoyard ‘computi’ with their sources of inspiration, from the Anglo-Norman pipe rolls to the Catalan fiscal records, the project aims to highlight the creative adaptation of imported administrative models, and thus to contribute to our knowledge of institutional transfers in European history. The project will develop an inclusive frame of analysis in which the ‘computi’ will be read against the evidence from enfeoffment charters, castellany surveys (‘extente’), and the records of direct taxation (‘subsidia’). The serial data will be analysed by building a database; the findings of quantitative analysis will be verified by case studies of the individuals and families (many from the middle social strata) that surface in the fiscal records.
Max ERC Funding
671 875 €
Duration
Start date: 2015-05-01, End date: 2020-04-30
Project acronym CHROMATINREPLICATION
Project How to Replicate Chromatin - Maturation, Timing Control and Stress-Induced Aberrations
Researcher (PI) Anja Groth
Host Institution (HI) KOBENHAVNS UNIVERSITET
Call Details Starting Grant (StG), LS1, ERC-2011-StG_20101109
Summary Inheritance of DNA sequence and its proper organization into chromatin is fundamental for eukaryotic life. The challenge of propagating genetic and epigenetic information is met in S phase and entails genome-wide disruption and restoration of chromatin coupled to faithful copying of DNA. How specific chromatin structures are restored on new DNA and transmitted through mitotic cell division remains a fundamental question in biology central to understand cell fate and identity.
Chromatin restoration on new DNA involves a complex set of events including nucleosome assembly and remodelling, restoration of marks on DNA and histones, deposition of histone variants and establishment of higher order chromosomal structures including sister-chromatid cohesion. To dissect these fundamental processes and their coordination in time and space with DNA replication, we have developed a novel technology termed nascent chromatin capture (NCC) that provides unique possibility for biochemical and proteomic analysis of chromatin replication in human cells. I propose to apply this innovative cutting-edge technique for a comprehensive characterization of chromatin restoration during DNA replication and to reveal how replication timing and genotoxic stress impact on final chromatin state. This highly topical project brings together the fields of chromatin biology, DNA replication, epigenetics and genome stability and we expect to make groundbreaking discoveries that will improve our understanding of human development, somatic cell reprogramming and complex diseases like cancer.
The proposed research will 1) identify and characterize novel mechanisms in chromatin restoration and 2) address molecularly how replication timing and genotoxic insults influence chromatin maturation and final chromatin state.
Summary
Inheritance of DNA sequence and its proper organization into chromatin is fundamental for eukaryotic life. The challenge of propagating genetic and epigenetic information is met in S phase and entails genome-wide disruption and restoration of chromatin coupled to faithful copying of DNA. How specific chromatin structures are restored on new DNA and transmitted through mitotic cell division remains a fundamental question in biology central to understand cell fate and identity.
Chromatin restoration on new DNA involves a complex set of events including nucleosome assembly and remodelling, restoration of marks on DNA and histones, deposition of histone variants and establishment of higher order chromosomal structures including sister-chromatid cohesion. To dissect these fundamental processes and their coordination in time and space with DNA replication, we have developed a novel technology termed nascent chromatin capture (NCC) that provides unique possibility for biochemical and proteomic analysis of chromatin replication in human cells. I propose to apply this innovative cutting-edge technique for a comprehensive characterization of chromatin restoration during DNA replication and to reveal how replication timing and genotoxic stress impact on final chromatin state. This highly topical project brings together the fields of chromatin biology, DNA replication, epigenetics and genome stability and we expect to make groundbreaking discoveries that will improve our understanding of human development, somatic cell reprogramming and complex diseases like cancer.
The proposed research will 1) identify and characterize novel mechanisms in chromatin restoration and 2) address molecularly how replication timing and genotoxic insults influence chromatin maturation and final chromatin state.
Max ERC Funding
1 692 737 €
Duration
Start date: 2011-11-01, End date: 2017-04-30
Project acronym CLIOARCH
Project Cliodynamic archaeology: Computational approaches to Final Palaeolithic/earliest Mesolithic archaeology and climate change
Researcher (PI) Felix RIEDE
Host Institution (HI) AARHUS UNIVERSITET
Call Details Consolidator Grant (CoG), SH6, ERC-2018-COG
Summary Late Pleistocene/early Holocene Europe is said to be the ideal laboratory for the investigation of human responses to rapidly changing climates and environments, migration and adaptation. Yet, pinpointing precisely how and why contemporaneous Final Palaeolithic/earliest Mesolithic (15,000-11,000 years BP) foragers migrated, and which environmental or other factors they adapted to – or failed to – has remained remarkably elusive. At the core of ClioArch is the radical but, in light of research-historical insights, necessary hypothesis that the current archaeological cultural taxonomy for this iconic period of European prehistory is epistemologically flawed and that operationalisations and interpretations based on this traditional taxonomy – especially those that seek to relate observed changes in material culture and land-use to contemporaneous climatic and environmental changes – are therefore problematic. Hence, novel approaches to crafting the taxonomic building blocks are required, as are novel analyses of human|environment relations in this period. ClioArch’s premier ambition is to provide operational cultural taxonomies for the Final Palaeolithic/earliest Mesolithic of Europe and to couple these with interdisciplinary cultural evolutionary, quantitative ecological methods and field archaeological investigations beyond the state-of-the-art, so as to better capture such adaptations – almost certainly with major implications for the standard culture-historical narrative relating to this period. In so doing, the project will pioneer a fully transparent and replicable – and eminently transferable – methodology for the study of the impacts of climate change and extreme environmental events in deep history. In turn, such a quantitative understanding of past adaptive dynamics will position archaeology more centrally in contemporary debates about climate change, environmental catastrophe and their cultural dimensions.
Summary
Late Pleistocene/early Holocene Europe is said to be the ideal laboratory for the investigation of human responses to rapidly changing climates and environments, migration and adaptation. Yet, pinpointing precisely how and why contemporaneous Final Palaeolithic/earliest Mesolithic (15,000-11,000 years BP) foragers migrated, and which environmental or other factors they adapted to – or failed to – has remained remarkably elusive. At the core of ClioArch is the radical but, in light of research-historical insights, necessary hypothesis that the current archaeological cultural taxonomy for this iconic period of European prehistory is epistemologically flawed and that operationalisations and interpretations based on this traditional taxonomy – especially those that seek to relate observed changes in material culture and land-use to contemporaneous climatic and environmental changes – are therefore problematic. Hence, novel approaches to crafting the taxonomic building blocks are required, as are novel analyses of human|environment relations in this period. ClioArch’s premier ambition is to provide operational cultural taxonomies for the Final Palaeolithic/earliest Mesolithic of Europe and to couple these with interdisciplinary cultural evolutionary, quantitative ecological methods and field archaeological investigations beyond the state-of-the-art, so as to better capture such adaptations – almost certainly with major implications for the standard culture-historical narrative relating to this period. In so doing, the project will pioneer a fully transparent and replicable – and eminently transferable – methodology for the study of the impacts of climate change and extreme environmental events in deep history. In turn, such a quantitative understanding of past adaptive dynamics will position archaeology more centrally in contemporary debates about climate change, environmental catastrophe and their cultural dimensions.
Max ERC Funding
1 907 638 €
Duration
Start date: 2019-09-01, End date: 2024-08-31
Project acronym CosNeD
Project Radio wave propagation in heterogeneous media: implications on the electronics of Cosmic Neutrino Detectors
Researcher (PI) Alina Mihaela BADESCU
Host Institution (HI) UNIVERSITATEA POLITEHNICA DIN BUCURESTI
Call Details Starting Grant (StG), PE7, ERC-2016-STG
Summary Detection of cosmic neutrinos can answer very important questions related to some extremely energetic yet unexplained astrophysical sources such as: compact binary stars, accreting black holes, supernovae etc., key elements in understanding the evolution and fate of the Universe. Moreover, these particles carry the highest
energies per particle known to man, impossible to achieve in any present or foreseen man made accelerator devices thus their detection can test and probe extreme high energy physics.
One of the newest techniques for measuring high energy cosmic neutrinos regards their radio detection in natural salt mines. A first and essential step is to determine experimentally the radio wave attenuation length in salt mines, and this will represent the main goal of this project. The results shall be used to estimate the implications on the construction of the detector. The outcome of this project may rejuvenate the radio detection in salt technique and be a compelling case for Romanian involvement. The same measurements can be used: to validate and improve previous work on theoretical simulation models of propagation in heterogeneous media –a regime not very well understood (which represents another goal of the project), and to study the behavior of classical antennas in non-conventional media (the third major goal).
The results to be obtained would be immediately relevant in determination of the key parameters that describe a cosmic neutrino detector, its performances and limitations. The events detected by such a telescope will allow identification of individual sources indicating a step forward in “neutrino astronomy”. The extensive propagation and antenna behavior studies in heterogeneous media will be in the direct interest for the scientific community and have a prompt impact in telecommunications theory and industry.
Summary
Detection of cosmic neutrinos can answer very important questions related to some extremely energetic yet unexplained astrophysical sources such as: compact binary stars, accreting black holes, supernovae etc., key elements in understanding the evolution and fate of the Universe. Moreover, these particles carry the highest
energies per particle known to man, impossible to achieve in any present or foreseen man made accelerator devices thus their detection can test and probe extreme high energy physics.
One of the newest techniques for measuring high energy cosmic neutrinos regards their radio detection in natural salt mines. A first and essential step is to determine experimentally the radio wave attenuation length in salt mines, and this will represent the main goal of this project. The results shall be used to estimate the implications on the construction of the detector. The outcome of this project may rejuvenate the radio detection in salt technique and be a compelling case for Romanian involvement. The same measurements can be used: to validate and improve previous work on theoretical simulation models of propagation in heterogeneous media –a regime not very well understood (which represents another goal of the project), and to study the behavior of classical antennas in non-conventional media (the third major goal).
The results to be obtained would be immediately relevant in determination of the key parameters that describe a cosmic neutrino detector, its performances and limitations. The events detected by such a telescope will allow identification of individual sources indicating a step forward in “neutrino astronomy”. The extensive propagation and antenna behavior studies in heterogeneous media will be in the direct interest for the scientific community and have a prompt impact in telecommunications theory and industry.
Max ERC Funding
185 925 €
Duration
Start date: 2016-11-01, End date: 2018-10-31
Project acronym CSUMECH
Project Cholesterol and Sugar Uptake Mechanisms
Researcher (PI) Bjørn Pedersen
Host Institution (HI) AARHUS UNIVERSITET
Call Details Starting Grant (StG), LS1, ERC-2014-STG
Summary Cardiovascular disease, diabetes and cancer have a dramatic impact on modern society, and in great part are related to uptake of cholesterol and sugar. We still know surprisingly little about the molecular details of the processes that goes on in this essential part of human basic metabolism. This application addresses cholesterol and sugar transport and aim to elucidate the molecular mechanism of cholesterol and sugar uptake in humans. It moves the frontiers of the field by shifting the focus to in vitro work allowing hitherto untried structural and biochemical experiments to be performed.
Cholesterol uptake from the intestine is mediated by the membrane protein NPC1L1. Despite extensive research, the molecular mechanism of NPC1L1-dependent cholesterol uptake still remains largely unknown.
Facilitated sugar transport in humans is made possible by sugar transporters called GLUTs and SWEETs, and every cell possesses these sugar transport systems. For all these uptake systems structural information is sorely lacking to address important mechanistic questions to help elucidate their molecular mechanism.
I will address this using a complementary set of methods founded in macromolecular crystallography and electron microscopy to determine the 3-dimensional structures of key players in these uptake systems. My unpublished preliminary results have established the feasibility of this approach. This will be followed up by biochemical characterization of the molecular mechanism in vitro and in silico.
This high risk/high reward membrane protein proposal could lead to a breakthrough in how we approach human biochemical pathways that are linked to trans-membrane transport. An improved understanding of cholesterol and sugar homeostasis has tremendous potential for improving general public health, and furthermore this proposal will help to uncover general principles of endocytotic uptake and facilitated diffusion systems at the molecular level.
Summary
Cardiovascular disease, diabetes and cancer have a dramatic impact on modern society, and in great part are related to uptake of cholesterol and sugar. We still know surprisingly little about the molecular details of the processes that goes on in this essential part of human basic metabolism. This application addresses cholesterol and sugar transport and aim to elucidate the molecular mechanism of cholesterol and sugar uptake in humans. It moves the frontiers of the field by shifting the focus to in vitro work allowing hitherto untried structural and biochemical experiments to be performed.
Cholesterol uptake from the intestine is mediated by the membrane protein NPC1L1. Despite extensive research, the molecular mechanism of NPC1L1-dependent cholesterol uptake still remains largely unknown.
Facilitated sugar transport in humans is made possible by sugar transporters called GLUTs and SWEETs, and every cell possesses these sugar transport systems. For all these uptake systems structural information is sorely lacking to address important mechanistic questions to help elucidate their molecular mechanism.
I will address this using a complementary set of methods founded in macromolecular crystallography and electron microscopy to determine the 3-dimensional structures of key players in these uptake systems. My unpublished preliminary results have established the feasibility of this approach. This will be followed up by biochemical characterization of the molecular mechanism in vitro and in silico.
This high risk/high reward membrane protein proposal could lead to a breakthrough in how we approach human biochemical pathways that are linked to trans-membrane transport. An improved understanding of cholesterol and sugar homeostasis has tremendous potential for improving general public health, and furthermore this proposal will help to uncover general principles of endocytotic uptake and facilitated diffusion systems at the molecular level.
Max ERC Funding
1 499 848 €
Duration
Start date: 2015-07-01, End date: 2020-06-30
Project acronym DDRegulation
Project Regulation of DNA damage responses at the replication fork
Researcher (PI) Niels Mailand
Host Institution (HI) KOBENHAVNS UNIVERSITET
Call Details Consolidator Grant (CoG), LS1, ERC-2013-CoG
Summary This project aims at delineating the regulatory signaling processes that enable cells to overcome DNA damage during DNA replication, a major challenge to the integrity of the genome as the normal replication machinery is unable to replicate past DNA lesions. This may result in collapse of the replication fork, potentially giving rise to gross genomic alterations. To mitigate this threat, all cells have evolved DNA damage bypass strategies such as translesion DNA synthesis (TLS), involving low fidelity DNA polymerases that can replicate damaged DNA, albeit in an error-prone manner, offering a trade-off between limited mutagenesis and gross chromosomal instability. How DNA damage bypass pathways are regulated and integrated with DNA replication and repair remain poorly resolved questions fundamental to understanding genome stability maintenance and disease onset. Regulatory signaling mediated by the small modifier protein ubiquitin has a prominent role in orchestrating the reorganization of the replication fork necessary for overcoming DNA lesions, but this involvement has not been systematically explored. To remedy these gaps in our knowledge, I propose to implement a series of innovative complementary strategies to isolate and identify the regulatory factors and ubiquitin-dependent processes that promote DNA damage responses at the replication fork, allowing for subsequent in-depth characterization of their roles in protecting genome integrity by targeted functional studies. This project will enable an advanced level of mechanistic insight into key regulatory processes underlying replication-associated DNA damage responses that has not been feasible to achieve with exisiting methodologies, providing a realistic outlook for groundbreaking discoveries that will open up many new avenues for further research into mechanisms and biological functions of regulatory signaling processes in the DNA damage response and beyond.
Summary
This project aims at delineating the regulatory signaling processes that enable cells to overcome DNA damage during DNA replication, a major challenge to the integrity of the genome as the normal replication machinery is unable to replicate past DNA lesions. This may result in collapse of the replication fork, potentially giving rise to gross genomic alterations. To mitigate this threat, all cells have evolved DNA damage bypass strategies such as translesion DNA synthesis (TLS), involving low fidelity DNA polymerases that can replicate damaged DNA, albeit in an error-prone manner, offering a trade-off between limited mutagenesis and gross chromosomal instability. How DNA damage bypass pathways are regulated and integrated with DNA replication and repair remain poorly resolved questions fundamental to understanding genome stability maintenance and disease onset. Regulatory signaling mediated by the small modifier protein ubiquitin has a prominent role in orchestrating the reorganization of the replication fork necessary for overcoming DNA lesions, but this involvement has not been systematically explored. To remedy these gaps in our knowledge, I propose to implement a series of innovative complementary strategies to isolate and identify the regulatory factors and ubiquitin-dependent processes that promote DNA damage responses at the replication fork, allowing for subsequent in-depth characterization of their roles in protecting genome integrity by targeted functional studies. This project will enable an advanced level of mechanistic insight into key regulatory processes underlying replication-associated DNA damage responses that has not been feasible to achieve with exisiting methodologies, providing a realistic outlook for groundbreaking discoveries that will open up many new avenues for further research into mechanisms and biological functions of regulatory signaling processes in the DNA damage response and beyond.
Max ERC Funding
1 996 356 €
Duration
Start date: 2014-07-01, End date: 2019-06-30
Project acronym DECOR
Project Dynamic assembly and exchange of RNA polymerase II CTD factors
Researcher (PI) Richard Stefl
Host Institution (HI) Masarykova univerzita
Call Details Consolidator Grant (CoG), LS1, ERC-2014-CoG
Summary The C-terminal domain (CTD) of the RNA polymerase II (RNAPII) largest subunit coordinates co-transcriptional processing and it is decorated by many processing factors throughout the transcription cycle. The composition of this supramolecular assembly is diverse and highly dynamic. Many of the factors associate with RNAPII weakly and transiently, and the association is dictated by different post-translational modification patterns and conformational changes of the CTD. To determine how these accessory factors assemble and exchange on the CTD of RNAPII has remained a major challenge. Here, we aim to unravel the structural and mechanistic bases for the dynamic assembly of RNAPII CTD with its processing factors.
Using NMR, we will determine high-resolution structures of several protein factors bound to the CTD carrying specific modifications. This will enable to decode how CTD modification patterns stimulate or prevent binding of a given processing factor. We will also establish the structural and mechanistic bases of proline isomerisation in the CTD that control the timing of isomer-specific protein-protein interactions. Next, we will combine NMR and SAXS approaches to unravel how the overall CTD structure is remodelled by binding of multiple copies of processing factors and how these factors cross-talk with each other. Finally, we will elucidate a mechanistic basis for the exchange of processing factors on the CTD.
Our study will answer the long-standing questions of how the overall CTD structure is modulated on binding to processing factors, and whether these factors cross-talk and compete with each other. The level of detail that we aim to achieve is currently not available for any transient molecular assemblies of such complexity. In this respect, the project will also provide knowledge and methodology for further studies of large and highly flexible molecular assemblies that still remain poorly understood.
Summary
The C-terminal domain (CTD) of the RNA polymerase II (RNAPII) largest subunit coordinates co-transcriptional processing and it is decorated by many processing factors throughout the transcription cycle. The composition of this supramolecular assembly is diverse and highly dynamic. Many of the factors associate with RNAPII weakly and transiently, and the association is dictated by different post-translational modification patterns and conformational changes of the CTD. To determine how these accessory factors assemble and exchange on the CTD of RNAPII has remained a major challenge. Here, we aim to unravel the structural and mechanistic bases for the dynamic assembly of RNAPII CTD with its processing factors.
Using NMR, we will determine high-resolution structures of several protein factors bound to the CTD carrying specific modifications. This will enable to decode how CTD modification patterns stimulate or prevent binding of a given processing factor. We will also establish the structural and mechanistic bases of proline isomerisation in the CTD that control the timing of isomer-specific protein-protein interactions. Next, we will combine NMR and SAXS approaches to unravel how the overall CTD structure is remodelled by binding of multiple copies of processing factors and how these factors cross-talk with each other. Finally, we will elucidate a mechanistic basis for the exchange of processing factors on the CTD.
Our study will answer the long-standing questions of how the overall CTD structure is modulated on binding to processing factors, and whether these factors cross-talk and compete with each other. The level of detail that we aim to achieve is currently not available for any transient molecular assemblies of such complexity. In this respect, the project will also provide knowledge and methodology for further studies of large and highly flexible molecular assemblies that still remain poorly understood.
Max ERC Funding
1 844 604 €
Duration
Start date: 2015-08-01, End date: 2020-07-31
