Project acronym 15CBOOKTRADE
Project The 15th-century Book Trade: An Evidence-based Assessment and Visualization of the Distribution, Sale, and Reception of Books in the Renaissance
Researcher (PI) Cristina Dondi
Host Institution (HI) THE CHANCELLOR, MASTERS AND SCHOLARS OF THE UNIVERSITY OF OXFORD
Country United Kingdom
Call Details Consolidator Grant (CoG), SH6, ERC-2013-CoG
Summary The idea that underpins this project is to use the material evidence from thousands of surviving 15th-c. books, as well as unique documentary evidence — the unpublished ledger of a Venetian bookseller in the 1480s which records the sale of 25,000 printed books with their prices — to address four fundamental questions relating to the introduction of printing in the West which have so far eluded scholarship, partly because of lack of evidence, partly because of the lack of effective tools to deal with existing evidence. The book trade differs from other trades operating in the medieval and early modern periods in that the goods traded survive in considerable numbers. Not only do they survive, but many of them bear stratified evidence of their history in the form of marks of ownership, prices, manuscript annotations, binding and decoration styles. A British Academy pilot project conceived by the PI produced a now internationally-used database which gathers together this kind of evidence for thousands of surviving 15th-c. printed books. For the first time, this makes it possible to track the circulation of books, their trade routes and later collecting, across Europe and the USA, and throughout the centuries. The objectives of this project are to examine (1) the distribution and trade-routes, national and international, of 15th-c. printed books, along with the identity of the buyers and users (private, institutional, religious, lay, female, male, and by profession) and their reading practices; (2) the books' contemporary market value; (3) the transmission and dissemination of the texts they contain, their survival and their loss (rebalancing potentially skewed scholarship); and (4) the circulation and re-use of the illustrations they contain. Finally, the project will experiment with the application of scientific visualization techniques to represent, geographically and chronologically, the movement of 15th-c. printed books and of the texts they contain.
Summary
The idea that underpins this project is to use the material evidence from thousands of surviving 15th-c. books, as well as unique documentary evidence — the unpublished ledger of a Venetian bookseller in the 1480s which records the sale of 25,000 printed books with their prices — to address four fundamental questions relating to the introduction of printing in the West which have so far eluded scholarship, partly because of lack of evidence, partly because of the lack of effective tools to deal with existing evidence. The book trade differs from other trades operating in the medieval and early modern periods in that the goods traded survive in considerable numbers. Not only do they survive, but many of them bear stratified evidence of their history in the form of marks of ownership, prices, manuscript annotations, binding and decoration styles. A British Academy pilot project conceived by the PI produced a now internationally-used database which gathers together this kind of evidence for thousands of surviving 15th-c. printed books. For the first time, this makes it possible to track the circulation of books, their trade routes and later collecting, across Europe and the USA, and throughout the centuries. The objectives of this project are to examine (1) the distribution and trade-routes, national and international, of 15th-c. printed books, along with the identity of the buyers and users (private, institutional, religious, lay, female, male, and by profession) and their reading practices; (2) the books' contemporary market value; (3) the transmission and dissemination of the texts they contain, their survival and their loss (rebalancing potentially skewed scholarship); and (4) the circulation and re-use of the illustrations they contain. Finally, the project will experiment with the application of scientific visualization techniques to represent, geographically and chronologically, the movement of 15th-c. printed books and of the texts they contain.
Max ERC Funding
1 999 172 €
Duration
Start date: 2014-04-01, End date: 2019-03-31
Project acronym 3D-REPAIR
Project Spatial organization of DNA repair within the nucleus
Researcher (PI) Evanthia Soutoglou
Host Institution (HI) THE UNIVERSITY OF SUSSEX
Country United Kingdom
Call Details Consolidator Grant (CoG), LS2, ERC-2015-CoG
Summary Faithful repair of double stranded DNA breaks (DSBs) is essential, as they are at the origin of genome instability, chromosomal translocations and cancer. Cells repair DSBs through different pathways, which can be faithful or mutagenic, and the balance between them at a given locus must be tightly regulated to preserve genome integrity. Although, much is known about DSB repair factors, how the choice between pathways is controlled within the nuclear environment is not understood. We have shown that nuclear architecture and non-random genome organization determine the frequency of chromosomal translocations and that pathway choice is dictated by the spatial organization of DNA in the nucleus. Nevertheless, what determines which pathway is activated in response to DSBs at specific genomic locations is not understood. Furthermore, the impact of 3D-genome folding on the kinetics and efficiency of DSB repair is completely unknown.
Here we aim to understand how nuclear compartmentalization, chromatin structure and genome organization impact on the efficiency of detection, signaling and repair of DSBs. We will unravel what determines the DNA repair specificity within distinct nuclear compartments using protein tethering, promiscuous biotinylation and quantitative proteomics. We will determine how DNA repair is orchestrated at different heterochromatin structures using a CRISPR/Cas9-based system that allows, for the first time robust induction of DSBs at specific heterochromatin compartments. Finally, we will investigate the role of 3D-genome folding in the kinetics of DNA repair and pathway choice using single nucleotide resolution DSB-mapping coupled to 3D-topological maps.
This proposal has significant implications for understanding the mechanisms controlling DNA repair within the nuclear environment and will reveal the regions of the genome that are susceptible to genomic instability and help us understand why certain mutations and translocations are recurrent in cancer
Summary
Faithful repair of double stranded DNA breaks (DSBs) is essential, as they are at the origin of genome instability, chromosomal translocations and cancer. Cells repair DSBs through different pathways, which can be faithful or mutagenic, and the balance between them at a given locus must be tightly regulated to preserve genome integrity. Although, much is known about DSB repair factors, how the choice between pathways is controlled within the nuclear environment is not understood. We have shown that nuclear architecture and non-random genome organization determine the frequency of chromosomal translocations and that pathway choice is dictated by the spatial organization of DNA in the nucleus. Nevertheless, what determines which pathway is activated in response to DSBs at specific genomic locations is not understood. Furthermore, the impact of 3D-genome folding on the kinetics and efficiency of DSB repair is completely unknown.
Here we aim to understand how nuclear compartmentalization, chromatin structure and genome organization impact on the efficiency of detection, signaling and repair of DSBs. We will unravel what determines the DNA repair specificity within distinct nuclear compartments using protein tethering, promiscuous biotinylation and quantitative proteomics. We will determine how DNA repair is orchestrated at different heterochromatin structures using a CRISPR/Cas9-based system that allows, for the first time robust induction of DSBs at specific heterochromatin compartments. Finally, we will investigate the role of 3D-genome folding in the kinetics of DNA repair and pathway choice using single nucleotide resolution DSB-mapping coupled to 3D-topological maps.
This proposal has significant implications for understanding the mechanisms controlling DNA repair within the nuclear environment and will reveal the regions of the genome that are susceptible to genomic instability and help us understand why certain mutations and translocations are recurrent in cancer
Max ERC Funding
1 999 750 €
Duration
Start date: 2017-03-01, End date: 2022-02-28
Project acronym 3DIMAGE
Project 3D Imaging Across Lengthscales: From Atoms to Grains
Researcher (PI) Paul Anthony Midgley
Host Institution (HI) THE CHANCELLOR MASTERS AND SCHOLARS OF THE UNIVERSITY OF CAMBRIDGE
Country United Kingdom
Call Details Advanced Grant (AdG), PE4, ERC-2011-ADG_20110209
Summary "Understanding structure-property relationships across lengthscales is key to the design of functional and structural materials and devices. Moreover, the complexity of modern devices extends to three dimensions and as such 3D characterization is required across those lengthscales to provide a complete understanding and enable improvement in the material’s physical and chemical behaviour. 3D imaging and analysis from the atomic scale through to granular microstructure is proposed through the development of electron tomography using (S)TEM, and ‘dual beam’ SEM-FIB, techniques offering complementary approaches to 3D imaging across lengthscales stretching over 5 orders of magnitude.
We propose to extend tomography to include novel methods to determine atom positions in 3D with approaches incorporating new reconstruction algorithms, image processing and complementary nano-diffraction techniques. At the nanoscale, true 3D nano-metrology of morphology and composition is a key objective of the project, minimizing reconstruction and visualization artefacts. Mapping strain and optical properties in 3D are ambitious and exciting challenges that will yield new information at the nanoscale. Using the SEM-FIB, 3D ‘mesoscale’ structures will be revealed: morphology, crystallography and composition can be mapped simultaneously, with ~5nm resolution and over volumes too large to tackle by (S)TEM and too small for most x-ray techniques. In parallel, we will apply 3D imaging to a wide variety of key materials including heterogeneous catalysts, aerospace alloys, biomaterials, photovoltaic materials, and novel semiconductors.
We will collaborate with many departments in Cambridge and institutes worldwide. The personnel on the proposal will cover all aspects of the tomography proposed using high-end TEMs, including an aberration-corrected Titan, and a Helios dual beam. Importantly, a postdoc is dedicated to developing new algorithms for reconstruction, image and spectral processing."
Summary
"Understanding structure-property relationships across lengthscales is key to the design of functional and structural materials and devices. Moreover, the complexity of modern devices extends to three dimensions and as such 3D characterization is required across those lengthscales to provide a complete understanding and enable improvement in the material’s physical and chemical behaviour. 3D imaging and analysis from the atomic scale through to granular microstructure is proposed through the development of electron tomography using (S)TEM, and ‘dual beam’ SEM-FIB, techniques offering complementary approaches to 3D imaging across lengthscales stretching over 5 orders of magnitude.
We propose to extend tomography to include novel methods to determine atom positions in 3D with approaches incorporating new reconstruction algorithms, image processing and complementary nano-diffraction techniques. At the nanoscale, true 3D nano-metrology of morphology and composition is a key objective of the project, minimizing reconstruction and visualization artefacts. Mapping strain and optical properties in 3D are ambitious and exciting challenges that will yield new information at the nanoscale. Using the SEM-FIB, 3D ‘mesoscale’ structures will be revealed: morphology, crystallography and composition can be mapped simultaneously, with ~5nm resolution and over volumes too large to tackle by (S)TEM and too small for most x-ray techniques. In parallel, we will apply 3D imaging to a wide variety of key materials including heterogeneous catalysts, aerospace alloys, biomaterials, photovoltaic materials, and novel semiconductors.
We will collaborate with many departments in Cambridge and institutes worldwide. The personnel on the proposal will cover all aspects of the tomography proposed using high-end TEMs, including an aberration-corrected Titan, and a Helios dual beam. Importantly, a postdoc is dedicated to developing new algorithms for reconstruction, image and spectral processing."
Max ERC Funding
2 337 330 €
Duration
Start date: 2012-01-01, End date: 2017-12-31
Project acronym AAMDDR
Project DNA damage response and genome stability: The role of ATM, ATR and the Mre11 complex
Researcher (PI) Vincenzo Costanzo
Host Institution (HI) CANCER RESEARCH UK LBG
Country United Kingdom
Call Details Starting Grant (StG), LS1, ERC-2007-StG
Summary Chromosomal DNA is continuously subjected to exogenous and endogenous damaging insults. In the presence of DNA damage cells activate a multi-faceted checkpoint response that delays cell cycle progression and promotes DNA repair. Failures in this response lead to genomic instability, the main feature of cancer cells. Several cancer-prone human syndromes including the Ataxia teleangiectasia (A-T), the A-T Like Disorder (ATLD) and the Seckel Syndrome reflect defects in the specific genes of the DNA damage response such as ATM, MRE11 and ATR. DNA damage response pathways are poorly understood at biochemical level in vertebrate organisms. We have established a cell-free system based on Xenopus laevis egg extract to study molecular events underlying DNA damage response. This is the first in vitro system that recapitulates different aspects of the DNA damage response in vertebrates. Using this system we propose to study the biochemistry of the ATM, ATR and the Mre11 complex dependent DNA damage response. In particular we will: 1) Dissect the signal transduction pathway that senses DNA damage and promotes cell cycle arrest and DNA damage repair; 2) Analyze at molecular level the role of ATM, ATR, Mre11 in chromosomal DNA replication and mitosis during normal and stressful conditions; 3) Identify substrates of the ATM and ATR dependent DNA damage response using an innovative screening procedure.
Summary
Chromosomal DNA is continuously subjected to exogenous and endogenous damaging insults. In the presence of DNA damage cells activate a multi-faceted checkpoint response that delays cell cycle progression and promotes DNA repair. Failures in this response lead to genomic instability, the main feature of cancer cells. Several cancer-prone human syndromes including the Ataxia teleangiectasia (A-T), the A-T Like Disorder (ATLD) and the Seckel Syndrome reflect defects in the specific genes of the DNA damage response such as ATM, MRE11 and ATR. DNA damage response pathways are poorly understood at biochemical level in vertebrate organisms. We have established a cell-free system based on Xenopus laevis egg extract to study molecular events underlying DNA damage response. This is the first in vitro system that recapitulates different aspects of the DNA damage response in vertebrates. Using this system we propose to study the biochemistry of the ATM, ATR and the Mre11 complex dependent DNA damage response. In particular we will: 1) Dissect the signal transduction pathway that senses DNA damage and promotes cell cycle arrest and DNA damage repair; 2) Analyze at molecular level the role of ATM, ATR, Mre11 in chromosomal DNA replication and mitosis during normal and stressful conditions; 3) Identify substrates of the ATM and ATR dependent DNA damage response using an innovative screening procedure.
Max ERC Funding
1 000 000 €
Duration
Start date: 2008-07-01, End date: 2013-06-30
Project acronym AAREA
Project The Archaeology of Agricultural Resilience in Eastern Africa
Researcher (PI) Daryl Stump
Host Institution (HI) UNIVERSITY OF YORK
Country United Kingdom
Call Details Starting Grant (StG), SH6, ERC-2013-StG
Summary "The twin concepts of sustainability and conservation that are so pivotal within current debates regarding economic development and biodiversity protection both contain an inherent temporal dimension, since both refer to the need to balance short-term gains with long-term resource maintenance. Proponents of resilience theory and of development based on ‘indigenous knowledge’ have thus argued for the necessity of including archaeological, historical and palaeoenvironmental components within development project design. Indeed, some have argued that archaeology should lead these interdisciplinary projects on the grounds that it provides the necessary time depth and bridges the social and natural sciences. The project proposed here accepts this logic and endorses this renewed contemporary relevance of archaeological research. However, it also needs to be admitted that moving beyond critiques of the misuse of historical data presents significant hurdles. When presenting results outside the discipline, for example, archaeological projects tend to downplay the poor archaeological visibility of certain agricultural practices, and computer models designed to test sustainability struggle to adequately account for local cultural preferences. This field will therefore not progress unless there is a frank appraisal of archaeology’s strengths and weaknesses. This project will provide this assessment by employing a range of established and groundbreaking archaeological and modelling techniques to examine the development of two east Africa agricultural systems: one at the abandoned site of Engaruka in Tanzania, commonly seen as an example of resource mismanagement and ecological collapse; and another at the current agricultural landscape in Konso, Ethiopia, described by the UN FAO as one of a select few African “lessons from the past”. The project thus aims to assess the sustainability of these systems, but will also assess the role archaeology can play in such debates worldwide."
Summary
"The twin concepts of sustainability and conservation that are so pivotal within current debates regarding economic development and biodiversity protection both contain an inherent temporal dimension, since both refer to the need to balance short-term gains with long-term resource maintenance. Proponents of resilience theory and of development based on ‘indigenous knowledge’ have thus argued for the necessity of including archaeological, historical and palaeoenvironmental components within development project design. Indeed, some have argued that archaeology should lead these interdisciplinary projects on the grounds that it provides the necessary time depth and bridges the social and natural sciences. The project proposed here accepts this logic and endorses this renewed contemporary relevance of archaeological research. However, it also needs to be admitted that moving beyond critiques of the misuse of historical data presents significant hurdles. When presenting results outside the discipline, for example, archaeological projects tend to downplay the poor archaeological visibility of certain agricultural practices, and computer models designed to test sustainability struggle to adequately account for local cultural preferences. This field will therefore not progress unless there is a frank appraisal of archaeology’s strengths and weaknesses. This project will provide this assessment by employing a range of established and groundbreaking archaeological and modelling techniques to examine the development of two east Africa agricultural systems: one at the abandoned site of Engaruka in Tanzania, commonly seen as an example of resource mismanagement and ecological collapse; and another at the current agricultural landscape in Konso, Ethiopia, described by the UN FAO as one of a select few African “lessons from the past”. The project thus aims to assess the sustainability of these systems, but will also assess the role archaeology can play in such debates worldwide."
Max ERC Funding
1 196 701 €
Duration
Start date: 2014-02-01, End date: 2018-01-31
Project acronym ACMO
Project Systematic dissection of molecular machines and neural circuits coordinating C. elegans aggregation behaviour
Researcher (PI) Mario De Bono
Host Institution (HI) MEDICAL RESEARCH COUNCIL
Country United Kingdom
Call Details Advanced Grant (AdG), LS5, ERC-2010-AdG_20100317
Summary Elucidating how neural circuits coordinate behaviour, and how molecules underpin the properties of individual neurons are major goals of neuroscience. Optogenetics and neural imaging combined with the powerful genetics and well-described nervous system of C. elegans offer special opportunities to address these questions. Previously, we identified a series of sensory neurons that modulate aggregation of C. elegans. These include neurons that respond to O2, CO2, noxious cues, satiety state, and pheromones. We propose to take our analysis to the next level by dissecting how, in mechanistic molecular terms, these distributed inputs modify the activity of populations of interneurons and motoneurons to coordinate group formation. Our strategy is to develop new, highly parallel approaches to replace the traditional piecemeal analysis.
We propose to:
1) Harness next generation sequencing (NGS) to forward genetics, rapidly to identify a molecular ¿parts list¿ for aggregation. Much of the genetics has been done: we have identified almost 200 mutations that inhibit or enhance aggregation but otherwise show no overt phenotype. A pilot study of 50 of these mutations suggests they identify dozens of genes not previously implicated in aggregation. NGS will allow us to molecularly identify these genes in a few months, providing multiple entry points to study molecular and circuitry mechanisms for behaviour.
2) Develop new methods to image the activity of populations of neurons in immobilized and freely moving animals, using genetically encoded indicators such as the calcium sensor cameleon and the voltage indicator mermaid.
This will be the first time a complex behaviour has been dissected in this way. We expect to identify novel conserved molecular and circuitry mechanisms.
Summary
Elucidating how neural circuits coordinate behaviour, and how molecules underpin the properties of individual neurons are major goals of neuroscience. Optogenetics and neural imaging combined with the powerful genetics and well-described nervous system of C. elegans offer special opportunities to address these questions. Previously, we identified a series of sensory neurons that modulate aggregation of C. elegans. These include neurons that respond to O2, CO2, noxious cues, satiety state, and pheromones. We propose to take our analysis to the next level by dissecting how, in mechanistic molecular terms, these distributed inputs modify the activity of populations of interneurons and motoneurons to coordinate group formation. Our strategy is to develop new, highly parallel approaches to replace the traditional piecemeal analysis.
We propose to:
1) Harness next generation sequencing (NGS) to forward genetics, rapidly to identify a molecular ¿parts list¿ for aggregation. Much of the genetics has been done: we have identified almost 200 mutations that inhibit or enhance aggregation but otherwise show no overt phenotype. A pilot study of 50 of these mutations suggests they identify dozens of genes not previously implicated in aggregation. NGS will allow us to molecularly identify these genes in a few months, providing multiple entry points to study molecular and circuitry mechanisms for behaviour.
2) Develop new methods to image the activity of populations of neurons in immobilized and freely moving animals, using genetically encoded indicators such as the calcium sensor cameleon and the voltage indicator mermaid.
This will be the first time a complex behaviour has been dissected in this way. We expect to identify novel conserved molecular and circuitry mechanisms.
Max ERC Funding
2 439 996 €
Duration
Start date: 2011-04-01, End date: 2017-03-31
Project acronym ACROSS
Project Australasian Colonization Research: Origins of Seafaring to Sahul
Researcher (PI) Rosemary Helen FARR
Host Institution (HI) UNIVERSITY OF SOUTHAMPTON
Country United Kingdom
Call Details Starting Grant (StG), SH6, ERC-2017-STG
Summary One of the most exciting research questions within archaeology is that of the peopling of Australasia by at least c.50,000 years ago. This represents some of the earliest evidence of modern human colonization outside Africa, yet, even at the greatest sea-level lowstand, this migration would have involved seafaring. It is the maritime nature of this dispersal which makes it so important to questions of technological, cognitive and social human development. These issues have traditionally been the preserve of archaeologists, but with a multidisciplinary approach that embraces cutting-edge marine geophysical, hydrodynamic and archaeogenetic analyses, we now have the opportunity to examine the When, Where, Who and How of the earliest seafaring in world history.
The voyage from Sunda (South East Asia) to Sahul (Australasia) provides evidence for the earliest ‘open water’ crossing in the world. A combination of the sparse number of early archaeological finds and the significant changes in the palaeolandscape and submergence of the broad north western Australian continental shelf, mean that little is known about the routes taken and what these crossings may have entailed.
This project will combine research of the submerged palaeolandscape of the continental shelf to refine our knowledge of the onshore/offshore environment, identify potential submerged prehistoric sites and enhance our understanding of the palaeoshoreline and tidal regime. This will be combined with archaeogenetic research targeting mtDNA and Y-chromosome data to resolve questions of demography and dating.
For the first time this project takes a truly multidisciplinary approach to address the colonization of Sahul, providing an unique opportunity to tackle some of the most important questions about human origins, the relationship between humans and the changing environment, population dynamics and migration, seafaring technology, social organisation and cognition.
Summary
One of the most exciting research questions within archaeology is that of the peopling of Australasia by at least c.50,000 years ago. This represents some of the earliest evidence of modern human colonization outside Africa, yet, even at the greatest sea-level lowstand, this migration would have involved seafaring. It is the maritime nature of this dispersal which makes it so important to questions of technological, cognitive and social human development. These issues have traditionally been the preserve of archaeologists, but with a multidisciplinary approach that embraces cutting-edge marine geophysical, hydrodynamic and archaeogenetic analyses, we now have the opportunity to examine the When, Where, Who and How of the earliest seafaring in world history.
The voyage from Sunda (South East Asia) to Sahul (Australasia) provides evidence for the earliest ‘open water’ crossing in the world. A combination of the sparse number of early archaeological finds and the significant changes in the palaeolandscape and submergence of the broad north western Australian continental shelf, mean that little is known about the routes taken and what these crossings may have entailed.
This project will combine research of the submerged palaeolandscape of the continental shelf to refine our knowledge of the onshore/offshore environment, identify potential submerged prehistoric sites and enhance our understanding of the palaeoshoreline and tidal regime. This will be combined with archaeogenetic research targeting mtDNA and Y-chromosome data to resolve questions of demography and dating.
For the first time this project takes a truly multidisciplinary approach to address the colonization of Sahul, providing an unique opportunity to tackle some of the most important questions about human origins, the relationship between humans and the changing environment, population dynamics and migration, seafaring technology, social organisation and cognition.
Max ERC Funding
1 134 928 €
Duration
Start date: 2018-02-01, End date: 2023-01-31
Project acronym ACTINONSRF
Project MAL: an actin-regulated SRF transcriptional coactivator
Researcher (PI) Richard Treisman
Host Institution (HI) THE FRANCIS CRICK INSTITUTE LIMITED
Country United Kingdom
Call Details Advanced Grant (AdG), LS1, ERC-2010-AdG_20100317
Summary MAL: an actin-regulated SRF transcriptional coactivator
Recent years have seen a revitalised interest in the role of actin in nuclear processes, but the molecular mechanisms involved remain largely unexplored. We will elucidate the molecular basis for the actin-based control of the SRF transcriptional coactivator, MAL. SRF controls transcription through two families of coactivators, the actin-binding MRTFs (MAL, Mkl2), which couple its activity to cytoskeletal dynamics, and the ERK-regulated TCFs (Elk-1, SAP-1, Net). MAL subcellular localisation and transcriptional activity responds to signal-induced changes in G-actin concentration, which are sensed by its actin-binding N-terminal RPEL domain. Members of a second family of RPEL proteins, the Phactrs, also exhibit actin-regulated nucleocytoplasmic shuttling. The proposal addresses the following novel features of actin biology:
¿ Actin as a transcriptional regulator
¿ Actin as a signalling molecule
¿ Actin-binding proteins as targets for regulation by actin, rather than regulators of actin function
We will analyse the sequences and proteins involved in actin-regulated nucleocytoplasmic shuttling, using structural biology and biochemistry to analyse its control by changes in actin-RPEL domain interactions. We will characterise the dynamics of shuttling, and develop reporters for changes in actin-MAL interaction for analysis of pathway activation in vivo. We will identify genes controlling MAL itself, and the balance between the nuclear and cytoplasmic actin pools. The mechanism by which actin represses transcriptional activation by MAL in the nucleus, and its relation to MAL phosphorylation, will be elucidated. Finally, we will map MRTF and TCF cofactor recruitment to SRF targets on a genome-wide scale, and identify the steps in transcription controlled by actin-MAL interaction.
Summary
MAL: an actin-regulated SRF transcriptional coactivator
Recent years have seen a revitalised interest in the role of actin in nuclear processes, but the molecular mechanisms involved remain largely unexplored. We will elucidate the molecular basis for the actin-based control of the SRF transcriptional coactivator, MAL. SRF controls transcription through two families of coactivators, the actin-binding MRTFs (MAL, Mkl2), which couple its activity to cytoskeletal dynamics, and the ERK-regulated TCFs (Elk-1, SAP-1, Net). MAL subcellular localisation and transcriptional activity responds to signal-induced changes in G-actin concentration, which are sensed by its actin-binding N-terminal RPEL domain. Members of a second family of RPEL proteins, the Phactrs, also exhibit actin-regulated nucleocytoplasmic shuttling. The proposal addresses the following novel features of actin biology:
¿ Actin as a transcriptional regulator
¿ Actin as a signalling molecule
¿ Actin-binding proteins as targets for regulation by actin, rather than regulators of actin function
We will analyse the sequences and proteins involved in actin-regulated nucleocytoplasmic shuttling, using structural biology and biochemistry to analyse its control by changes in actin-RPEL domain interactions. We will characterise the dynamics of shuttling, and develop reporters for changes in actin-MAL interaction for analysis of pathway activation in vivo. We will identify genes controlling MAL itself, and the balance between the nuclear and cytoplasmic actin pools. The mechanism by which actin represses transcriptional activation by MAL in the nucleus, and its relation to MAL phosphorylation, will be elucidated. Finally, we will map MRTF and TCF cofactor recruitment to SRF targets on a genome-wide scale, and identify the steps in transcription controlled by actin-MAL interaction.
Max ERC Funding
1 889 995 €
Duration
Start date: 2011-10-01, End date: 2017-09-30
Project acronym ACTIVE_NEUROGENESIS
Project Activity-dependent signaling in radial glial cells and their neuronal progeny
Researcher (PI) Colin Akerman
Host Institution (HI) THE CHANCELLOR, MASTERS AND SCHOLARS OF THE UNIVERSITY OF OXFORD
Country United Kingdom
Call Details Starting Grant (StG), LS5, ERC-2009-StG
Summary A significant advance in the field of development has been the appreciation that radial glial cells are progenitors and give birth to neurons in the brain. In order to advance this exciting area of biology, we need approaches that combine structural and functional studies of these cells. This is reflected by the emerging realisation that dynamic interactions involving radial glia may be critical for the regulation of their proliferative behaviour. It has been observed that radial glia experience transient elevations in intracellular Ca2+ but the nature of these signals, and the information that they convey, is not known. The inability to observe these cells in vivo and over the course of their development has also meant that basic questions remain unexplored. For instance, how does the behaviour of a radial glial cell at one point in development, influence the final identity of its progeny? I propose to build a research team that will capitalise upon methods we have developed for observing individual radial glia and their progeny in an intact vertebrate nervous system. The visual system of Xenopus Laevis tadpoles offers non-invasive optical access to the brain, making time-lapse imaging of single cells feasible over minutes and weeks. The system s anatomy lends itself to techniques that measure the activity of the cells in a functional sensory network. We will use this to examine signalling mechanisms in radial glia and how a radial glial cell s experience influences its proliferative behaviour and the types of neuron it generates. We will also examine the interactions that continue between a radial glial cell and its daughter neurons. Finally, we will explore the relationships that exist within neuronal progeny derived from a single radial glial cell.
Summary
A significant advance in the field of development has been the appreciation that radial glial cells are progenitors and give birth to neurons in the brain. In order to advance this exciting area of biology, we need approaches that combine structural and functional studies of these cells. This is reflected by the emerging realisation that dynamic interactions involving radial glia may be critical for the regulation of their proliferative behaviour. It has been observed that radial glia experience transient elevations in intracellular Ca2+ but the nature of these signals, and the information that they convey, is not known. The inability to observe these cells in vivo and over the course of their development has also meant that basic questions remain unexplored. For instance, how does the behaviour of a radial glial cell at one point in development, influence the final identity of its progeny? I propose to build a research team that will capitalise upon methods we have developed for observing individual radial glia and their progeny in an intact vertebrate nervous system. The visual system of Xenopus Laevis tadpoles offers non-invasive optical access to the brain, making time-lapse imaging of single cells feasible over minutes and weeks. The system s anatomy lends itself to techniques that measure the activity of the cells in a functional sensory network. We will use this to examine signalling mechanisms in radial glia and how a radial glial cell s experience influences its proliferative behaviour and the types of neuron it generates. We will also examine the interactions that continue between a radial glial cell and its daughter neurons. Finally, we will explore the relationships that exist within neuronal progeny derived from a single radial glial cell.
Max ERC Funding
1 284 808 €
Duration
Start date: 2010-02-01, End date: 2015-01-31
Project acronym ACTSELECTCONTEXT
Project Action Selection under Contextual Uncertainty: the Role of Learning and Effective Connectivity in the Human Brain
Researcher (PI) Sven Bestmann
Host Institution (HI) University College London
Country United Kingdom
Call Details Starting Grant (StG), LS5, ERC-2010-StG_20091118
Summary In a changing world, one hallmark feature of human behaviour is the ability to learn about the statistics of the environment and use this prior information for action selection. Knowing about a forthcoming event allows for adjusting our actions pre-emptively, which can optimize survival.
This proposal studies how the human brain learns about the uncertainty in the environment, and how this leads to flexible and efficient action selection.
I hypothesise that the accumulation of evidence for future movements through learning reflects a fundamental organisational principle for action control. This explains widely distributed perceptual-, learning-, decision-, and movement-related signals in the human brain. However, little is known about the concerted interplay between brain regions in terms of effective connectivity which is required for flexible behaviour.
My proposal seeks to shed light on this unresolved issue. To this end, I will use i) a multi-disciplinary neuroimaging approach, together with model-based analyses and Bayesian model comparison, adapted to human reaching behaviour as occurring in daily life; and ii) two novel approaches for testing effective connectivity: dynamic causal modelling (DCM) and concurrent transcranial magnetic stimulation-functional magnetic resonance imaging.
My prediction is that action selection relies on effective connectivity changes, which are a function of the prior information that the brain has to learn about.
If true, this will provide novel insight into the human ability to select actions, based on learning about the uncertainty which is inherent in contextual information. This is relevant for understanding action selection during development and ageing, and for pathologies of action such as Parkinson s disease or stroke.
Summary
In a changing world, one hallmark feature of human behaviour is the ability to learn about the statistics of the environment and use this prior information for action selection. Knowing about a forthcoming event allows for adjusting our actions pre-emptively, which can optimize survival.
This proposal studies how the human brain learns about the uncertainty in the environment, and how this leads to flexible and efficient action selection.
I hypothesise that the accumulation of evidence for future movements through learning reflects a fundamental organisational principle for action control. This explains widely distributed perceptual-, learning-, decision-, and movement-related signals in the human brain. However, little is known about the concerted interplay between brain regions in terms of effective connectivity which is required for flexible behaviour.
My proposal seeks to shed light on this unresolved issue. To this end, I will use i) a multi-disciplinary neuroimaging approach, together with model-based analyses and Bayesian model comparison, adapted to human reaching behaviour as occurring in daily life; and ii) two novel approaches for testing effective connectivity: dynamic causal modelling (DCM) and concurrent transcranial magnetic stimulation-functional magnetic resonance imaging.
My prediction is that action selection relies on effective connectivity changes, which are a function of the prior information that the brain has to learn about.
If true, this will provide novel insight into the human ability to select actions, based on learning about the uncertainty which is inherent in contextual information. This is relevant for understanding action selection during development and ageing, and for pathologies of action such as Parkinson s disease or stroke.
Max ERC Funding
1 341 805 €
Duration
Start date: 2011-06-01, End date: 2016-05-31
